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this issue

Medicographia
Vol 34, No. 4, 2012
113
A
Ser vier
publication
Heart rate modulation
and exercise capacity
E DITORIAL
379
Heart rate in the management of cardiovascular patients: it’s time to act
La fréquence cardiaque dans la prise en charge des patients atteints
d’affections cardio-vasculaires : il est temps d’agir
R. Ferrari, Italy
T HEMED
387
ARTICLES
Heart rate as a treatable risk factor in cardiovascular disease
M. R. Cowie, United Kingdom
395
Heart rate response to exercise: impact on myocardial ischemia
and left ventricular function
M. Böhm, C. Ukena, Germany
400
Chronotropic incompetence and functional capacity in
cardiovascular disease
D. W. Kitzman, USA
407
Prognostic value of heart rate response to exercise
F. Carré, France
414
Heart rate in the assessment of cardiovascular prognosis
L. Riva, G. V. Coutsoumbas, A. P. Maggioni, Italy
421
Why should we consider heart rate in patients with cardiovascular disease?
B. D. Westenbrink, W. H. van Gilst, The Netherlands
Contents continued on next page
Medicographia
Vol 34, No. 4, 2012
113
A
C ONTROVERSIAL
Ser vier
publication
QUESTION
427 When should cardiac rehabilitation be started after a cardiovascular event?
C. Aguiar, Portugal - D. M. Aronov, Russia - F. Bacal, M. M. Fernandes
da Silva, Brazil - K. Daly, Ireland - D. R. Dimulescu, Romania N. M. Farag, Egypt - K. Naidoo, D. P. Naidoo, South Africa H. Ong-Garcia, Philippines - A. A. A. Rahim, Malaysia - H. Rasmusen,
Denmark - G. Sinagra, P. L. Temporelli, Italy - M. Zoghi, Turkey
P ROCORALAN
440 Clinical advantage of heart rate lowering with Procoralan in the
management of cardiovascular patients
I. Elyubaeva, France
I NTERVIEW
449 Heart rate reduction in coronary artery disease management: what can
we expect from the SIGNIFY trial?
K. Fox, United Kingdom
F OCUS
454 Heart rate in registries: an important, yet still neglected opportunity
P. G. Steg, France
U PDATE
460 Heart rate reduction and coronary flow reserve: mechanisms and treatment
P. E. Vardas, Greece
A
TOUCH OF
F RANCE
468 “Call back yesterday, bid time return”—Rochefort, the town where the
past comes alive
I. Spaak, France
477 Sickness and health on the high seas in the 18th century—The Former
Rochefort School of Naval Medicine and the birth of the French Navy
Health Service
C. Régnier, France
EDITORIAL
‘‘
Heart rate is an indirect marker of the body’s metabolic rate,
and hence controls how much energy the body consumes. This is
of paramount importance because
living creatures in this world compete for a fixed share of the vital
energy available to them. If they
consume or, more exactly, exhaust
it too quickly, their lives will have
to be shorter. One could then consider heart rate to be the timepiece or pacemaker, not only of
the heart, but also, viewed more
widely, of life itself.”
Heart rate in
the management of
cardiovascular patients:
it’s time to act
b y R . Fe r ra r i , I t a l y
ife starts and ends with a heartbeat. This has been well-known since the
times of Aristotle. Ironically, in many cases, we know how and why the heart
stops beating, but we know very little about its very first beat, ie, the origin
of life itself! Of course, the first heartbeat is generated by ion movements
across the sarcolemma of the sinus node cells. But how it happens, which is the
first ion to move, and what causes the first action potential is still a mystery.1 What
is extraordinary is that all of these ion movements across the heart membranes
occur at the rate of at least 60 times per minute throughout our lifetime—night
and day—and generate the heart rate. Although ancient civilizations, in one way or
another, have always linked the heart and heart rate to life, the importance of heart
rate has not been fully appreciated in recent years and actually, in some cases, was
even neglected. This is perhaps because of its familiarity and ease of measurement,
on the one hand, and the complex nature of its effect, on the other.
L
Roberto FERRARI, MD, PhD
University Hospital and LTTA
Centre of Ferrara and Salvatore
Maugeri Foundation IRCCS
Lumezzane, ITALY
Interest in the impact of heart rate in cardiovascular disease was given new impetus with the discovery of new currents responsible for its regulation and with the
introduction into clinical practice of the specific heart rate–lowering agent ivabradine in 2005.2 One of these newly discovered currents, the inward current If (with “I”
standing for “inward” and “f” for “funny”), seems to be the primary mechanism for initiating the slope of phase-4 depolarization. It was termed “funny” because Di Francesco and colleagues noted that it was unexpected that an inward current would
be activated on hyperpolarization of the cell membrane. In general, this occurs on
depolarization. Thus, this novel observation struck the investigators as “funny.”3
Address for correspondence:
Professor Roberto Ferrari, Chair
of Cardiology, University Hospital
of Ferrara, Via Aldo Moro 8,
44121 Cona (Ferrara), Italy
(e-mail: [email protected])
Medicographia. 2012;34:379-386
www.medicographia.com
This single finding generated several interesting discoveries. The first is almost philosophical, and is the recognition that heart rate could be considered as the language
of the body as well as a metabolic marker.4 This is an old concept. The Ebers papyrus, circa 1500 BC, identified the heart as the center of the cardiovascular system and found a close correlation between the heart and the pulsations of blood
vessels. The heart is in contact with virtually every cell in the body through the circulatory system and, more specifically, through the shear stress of the endothelium.
Local shear stress is sensed by endothelial mechanoreceptors and induces endothelial gene expression. Shear stress, for example, promotes dilatation (flow-mediated dilatation) by upregulating and stimulating constitutive nitric oxide synthase
(cNOS), which produces nitric oxide.5 This mechanism is highly sophisticated: night
and day (throughout our lifetime), not only does the heart contract to drive the circulation essential for life, it also sends out signals to keep the arteries open and relaxed, contributing to the maintenance of vascular tone.
Heart rate in the management of cardiovascular patients: time to act – Ferrari
MEDICOGRAPHIA, Vol 34, No. 4, 2012
379
EDITORIAL
An increase in heart rate favors bidirectional changes in flow,
reduces the average shear stress, and thus the production
of nitric oxide. This in turn produces vasodilatation, allowing
more blood to reach the peripheral tissues, increasing metabolism, and producing a relative increase in energy consumption and heat loss. Heart rate is an indirect marker of
the body’s metabolic rate, and hence controls how much energy the body consumes. This is of paramount importance
because living creatures in this world compete for a fixed
share of the vital energy available to them. If they consume
or, more exactly, exhaust it too quickly, their lives will have to
be shorter. One could then consider heart rate to be the timepiece or pacemaker, not only of the heart, but also, viewed
more widely, of life itself.4
A partial confirmation of this theory can be found in the relationships in the animal kingdom described by Levine,6 and
by the discovery that animals have approximately the same
number of heartbeats during their lifetime. These intriguing
observations have led to speculation on whether life could be
extended in man by slowing down the heart rate. Indeed,
Levine estimated that a decrease in heart rate from 70 to 60
bpm would increase life expectancy from 80 to 93.3 years
in humans.6
As a consequence, the scientific community has become
interested in retrospectively evaluating whether heart rate is
a prognostic indicator both in the general population and in
cardiac patients. A considerable body of evidence indicates
that elevated resting heart rate is an independent modifiable
risk factor for cardiovascular events and mortality in the
general population as well as in patients with coronary artery disease and heart failure.
More than 100 000 healthy males and females of various nationalities and ages (between 18 and 80 years of age) were
monitored for 36 years. Overall, there was a correlation between basal heart rate and all-cause mortality, irrespective of
demographic differences.7 Today, the scientific community no
longer contests the concept that heart rate is a prognostic
indicator in the general population, even though there are no
trials investigating the effects of deliberate heart rate reduction on healthy individuals. As a consequence, the importance
of heart rate as a risk factor has been recognized by the European Guidelines on Cardiovascular Prevention.8
A large number of epidemiological studies have also shown
that elevated heart rate is associated with mortality and cardiac events in patients with cardiovascular disease. Among
them, three particularly large studies are at the forefront.2 The
CASS study (Coronary Artery Surgery Study), the INVEST
study (INternational VErapamil-trandolapril STudy) and, more
recently, the ONTARGET/TRANSCEND trials (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial and Telmisartan Randomised AssessmeNt Study
380
in angiotension Converting Enzyme inhibitor iNtolerant subjects with cardiovascular Disease).9-11 All of these trials have
shown a relationship between elevated heart rate and cardiovascular mortality with a threshold of 70-75 bpm. These
data are, however, retrospective as prospective data on the
effects of heart rate on cardiovascular mortality have been difficult to obtain. This is because several drugs, notably β-blockers and non–dihydropyridine calcium channel blockers, which
reduce heart rate, have a wide range of other actions on the
vascular system and elsewhere in the body.2 By contrast, ivabradine has essentially no direct effects on the vascular system other than reducing the heart rate.
Thus, ivabradine has allowed to prospectively test whether
heart rate is a risk factor in cardiovascular disease. This was
investigated in the BEAUTIFUL trial (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary
disease and left ventricULar dysfunction study). In the placebo arm of the study, the relationship between baseline heart
rate and outcome was analyzed.12 Patients with baseline
heart rates of ⱖ70 bpm had a markedly increased risk of cardiovascular death, admission to hospital for heart failure, myocardial infarction, and need for coronary revascularization.
The benefits of heart rate reduction with ivabradine were also
evident in the subgroup of patients with heart rate ⱖ70 bpm,
where there were risk reductions of 36% in myocardial infarction and 30% in coronary revascularization.13 Furthermore,
in those patients with angina at entry,14 there was a significant
decrease in the primary composite end point and the rate of
myocardial infarction in the ivabradine group. These ivabradine-related benefits were clearly independent from baseline
heart rate, although they were more evident in those patients
with heart rate ⱖ70 bpm. These data therefore indicate that
heart rate ⱖ70 bpm is a risk factor for coronary artery disease.
There are several reasons why reducing heart rate is beneficial in coronary artery disease:
N Heart rate is a determinant of myocardial oxygen consumption. In humans, the heart beats on average 100 800 times
per day. This figure corresponds to 36.8×106 heartbeats in a
year and 29×108 in a lifetime (80 years on average). The heart
produces and immediately consumes approximately 30 kg
ATP every day—such is its turnover—corresponding to nearly 11 000 kg per year and approximately 880 000 kg in a
lifetime. It follows that each heartbeat has its own cost—approximately 300 mg ATP. This means that slowing down the
heart rate by 10 bpm per day would result in a saving of about
5 kg ATP in a day. To produce ATP the myocardium needs
oxygen, which is used by the mitochondria for oxidative phosphorylation. So, a reduction in heart rate would lead to a significant reduction in oxygen demand at the cellular level, and
in coronary artery disease, lack of oxygen is the critical pathogenetic factor.15
EDITORIAL
N Coronary flow is primarily diastolic. A high heart rate short-
ens diastole and hence reduces coronary flow, even in the absence of coronary lesions. This is why severe tachycardia can
induce ischemia, especially in hypertensive patients and the
elderly. A decrease in heart rate results in an increase in coronary flow.7
N Elevated heart rate increases arterial stiffness. Mechanical
damage due to aging or elevated heart rate causes changes
in elastin fibers. Epidemiological evidence indicates that a
chronically elevated heart rate is associated with an accelerated progression of arterial stiffness in normotensive and
hypertensive subjects.16
N Elevated heart rate favors coronary atherosclerosis. An association between elevated heart rate and atherosclerotic
plaque development was first reported in cynomolgus monkeys.17 Further evidence of a link between heart rate and atherosclerosis has come from the measurement of changes in
endothelial function and markers of inflammation. In rats, increasing the heart rate by 10% by electrical pacing significantly increased cardiac oxidative stress and triggered mitogen-activated protein kinase pathways, without any increase
in blood pressure. On the contrary, heart rate reduction with
ivabradine reduced oxidative stress, improved endothelial
function, and prevented atherosclerosis in apolipoprotein E-deficient mice. In men, microinflammatory markers were found
to increase progressively across quintiles of heart rate.18
N Increased heart rate favors acute coronary syndromes.
The mechanical stress exerted on the rim of the atherosclerotic plaque is related to heart rate. Hemodynamic wall stress
damages intracellular junctions and increases endothelial cell
permeability, thereby favoring the entry of atherogenic particles. These mechanisms explain why high heart rates are associated with plaque rupture and acute coronary syndromes.19
Elevated heart rate is also detrimental in heart failure. One
crucial feature of the failing heart is the reduction of the forcefrequency relationship,20 which is one of the basic mechanisms for regulating inotropy, as first characterized in 1871.21
In heart failure patients with pacemakers, an increase in paced
or exercise-induced heart rate is not accompanied by an increase in oxygen uptake or by an increase in exercise performance, indicating that in heart failure patients, elevated
heart rate increases myocardial load and oxygen consumption,22 thus being potentially proischemic. Furthermore, all cardiovascular interventions that reduce heart rate, such as βblocker treatment, have been shown to improve outcomes
in patients suffering from heart failure, while treatment with
β-adrenoceptor agonists adversely affect survival and morbidity.23 However, the beneficial effect of β-blockers in heart
failure may also be due to reasons other than heart rate reduction such as blood pressure lowering, negative inotropism,
arrhythmic action, and attenuation of catecholamine toxicity.
Recently, however, the role of heart rate in heart failure has
been elucidated thanks to the availability of ivabradine, which
causes a selective reduction in heart rate without any other
hemodynamic effects.
In a model of cardiac remodeling in rats, ivabradine was able
to prevent the global phenotype (hemodynamic, cardiac metabolism, neuroendocrine, and structure alterations, etc) of
ventricular remodeling.24 Similar findings were obtained in a
substudy of the BEAUTIFUL trial assessing left ventricular remodeling by echocardiography in patients with coronary artery disease and left ventricular dysfunction.25 Ivabradine treatment reduced the development of left ventricular remodeling
and improved ejection fraction. The recent SHIFT trial (Systolic Heart failure treatment with If inhibitor ivabradine Trial)
in 6558 patients with systolic heart failure included observational elements in which the relationship between baseline
heart rate and outcome was analyzed in the placebo group.26
The hazard ratio for all-cause mortality was 1.86 for patients
in the highest quintile of heart rate (>87 bpm) and was linearly reduced until the lowest quintile (70 to 72 bpm). These
data clearly suggest that in heart failure there is a direct link
between baseline heart rate and a worse outcome. Regarding
treatment, it should be mentioned that in SHIFT, a baseline
heart rate of ⱖ70 bpm was an entry requirement, and ivabradine treatment resulted in an 18% reduction (P<0.0001) in the
primary end point (the composite of cardiovascular death
and hospitalization for heart failure).27 The effects of ivabradine
were linearly more evident as heart rate was reduced from
87 to <60 bpm. The observational and interventional elements of this trial therefore indicate that heart rate is a modifiable risk factor in heart failure—rather than merely a risk
marker—and have confirmed the benefit of “pure” heart rate
reduction in patients with heart failure and elevated heart rate.
Conclusions
Although never neglected, the concept of heart rate is undoubtedly having a revival with the discovery of the If current in
the sinus node of the right atria, and of ivabradine, a drug capable of reducing this current, and hence of reducing heart rate.
There is now a mass of epidemiological, pathophysiological,
and clinical trial evidence indicating the importance of heart
rate control. However, recent surveys have revealed low rates
of heart rate control among patients with coronary artery disease in clinical practice. In the European Heart Survey of patients with stable angina attending cardiology services throughout Europe,28 the mean resting heart rate was 73 bpm, and
more than half of the patients (52.3%) had heart rates >70
bpm. Interestingly, approximately 40% of patients receiving
β-blockers had heart rates >70 bpm. The European Heart
Survey authors concluded that there was evidence that physicians and cardiologists gave inadequate attention to heart
rate and that a therapeutic opportunity was being missed as
a result. It’s time to act. This is what this issue of Medicographia is about. I
381
EDITORIAL
References
1. Ferrari R. The story of the heartbeat, I: part I—heart rate: the rhythm of life. Eur
Heart J. 2012;33(1):4-5.
2. Fox K, Ferrari R. Heart rate: A forgotten link in coronary artery disease? Nat Rev
Cardiol. 2011;8(7):369-379.
3. Di Francesco D. A new interpretation of the pacemaker current in calf purkinje
fibres. J Physiol. 1981;314:359-376.
4. Ferrari R. The story of the heartbeat, continued. Eur Heart J. 2012;33(3):288289.
5. Fleming I. Molecular mechanisms underlying the activation of eNOS. Pflugers
Arch. 2010;459(6):793-806.
6. Levine HJ. Rest heart rate and life expectancy. J Am Coll Cardiol. 1997;30(4):
1104-1106.
7. Ceconi C, Guardigli G, Rizzo P, Francolini G, Ferrari R. Heart rate lowering in
coronary artery disease management introduction: the heart rate story. Eur
Heart J. 2011;13(suppl C):C4-C13.
8. Graham I, Atar D, Borch-Johnsen K, et al; European Society of Cardiology (ESC)
Committee for Practice Guidelines (CPG). European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Eur Heart J.
2007;28(19):2375-2414.
9. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of
resting heart rate in patients with suspected or proven coronary artery disease.
Eur Heart J. 2005;26:967-974.
10. Kolloch R, Legler UF, Champion A, et al. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the
INternational VErapamil-SR/trandolapril STudy (INVEST). Eur Heart J. 2008;29:
1327-1334.
11. Rambiha S, Gao P, Teo K, Bohm M, Yusuf S, Lonn EM. Heart rate is associated with increased risk of major cardiovascular events, cardiovascular and allcause death in patients with stable chronic cardiovascular disease. An analysis
of ONTARGET/TRANSCEND. Circulation. 2011;122(suppl):A12667.
12. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL Investigators. Heart rate as a prognostic risk factor in patients with coronary artery
disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 2008;372(9641):817-821.
13. Fox, K, Ford, I, Steg PG, Tendera, M, Ferrari, R; BEAUTIFUL Investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic
dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial.
Lancet. 2008;372:807-816.
14. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL investigators. Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized,
controlled BEAUTIFUL trial. Eur Heart J. 2009;30(19):2337-2345.
15. Ferrari R. The rhythm of life: heart and heart rate in art, culture and science.
Wolters Kluwer Publisher; 2009:32-53.
16. Tomiyama H, Hashimoto H, Tanaka H, et al; baPWV/cfPWV Collaboration
Group. Synergistic relationship between changes in the pulse wave velocity
and changes in the heart rate in middle-aged Japanese adults: a prospective
study. J Hypertens. 2010;28:687-694.
17. Kaplan, JR, Manuck, SB, Clarkson, TB. The influence of heart rate on coronary
artery atherosclerosis. J Cardiovasc Pharmacol. 1987;10(suppl 2):S100-S102.
18. Rogowski O, Shapira I, Shirom A, Melamed S, Toker S, Berliner S. Heart rate
and microinflammation in men: a relevant atherosclerotic link. Heart. 2007;93:
940-944.
19. Heidland, UE, Strauer, BE. Left ventricular muscle mass and elevated heart rate
are associated with coronary plaque disruption. Circulation. 2001;104:14771482.
20. Böhm M, La Rosee K, Schmidt U, Schulz C, Schwinger RHG, Erdmann E.
Force-frequency relationship and inotropic stimulation in the non-failing and
failing human myocardium: implications for the medical treatment of heart failure. Clin Investig. 1992;70:421-425.
21. Bowditch HP. Über die Eigentümlichkeit der Reizbarkeit, welche die Muskelfasern des Herzens zeigen. Ber Sächs Ges (Akad) Wiss. 1871;23:652-689.
22. Kindermann M, Schwaab B, Finkler N, Schaller S, Böhm M, Fröhlig G. Defining
the optimum upper heart rate limit during exercise—a study in pacemaker patients with heart failure. Eur Heart J. 2002;23:1301-1308.
23. Kjekshus J, Gullestad L. Heart rate as a therapeutic target in heart failure. Eur
Heart J. 1999;1(suppl H):H64-H69.
24. Ceconi C, Comini L, Suffredini S, Stillitano F, Bouly M, Cerbai E, Mugelli A, Ferrari R. Heart rate reduction with ivabradine prevents the global phenotype of
left ventricular remodeling. Am J Physiol Heart Circ Physiol. 2011;300(1): H366H373.
25. Ceconi C, Freedman SB, Tardif JC, et al; BEAUTIFUL Echo-BNP investigators.
Effect of heart rate reduction by ivabradine on left ventricular remodeling in the
echocardiographic substudy of BEAUTIFUL. Int J Cardiol. 2011;146(3):408-414.
26. Böhm M, Swedberg K, Komajda M, et al; SHIFT Investigators. Heart rate as a
risk factor in chronic heart failure (SHIFT): the association between heart rate and
outcomes in a randomised placebo-controlled trial. Lancet. 2010;376:886-894.
27. Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and
outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled
study. Lancet. 2010;376:875-885.
28. Daly CA, Clemens F, Sendon JL, et al; Euro Heart Survey Investigators. Inadequate control of heart rate in patients with stable angina: results from the
European Heart Survey. Postgrad Med J. 2010;86:212-217.
Keywords: coronary artery disease; heart failure; heart rate; ivabradine; prognostic indicator
382
ÉDITORIAL
‘‘
La fréquence cardiaque est
un marqueur indirect du taux
métabolique de l’organisme qui
contrôle la quantité d’énergie
consommée. Elle est très importante, car les êtres vivants sont
en compétition pour une part fixe
d’énergie vitale. S’ils la consomment ou, plus exactement, l’épuisent trop rapidement, leur vie sera
raccourcie. La fréquence cardiaque est ainsi une horloge qui
impose son rythme non seulement
au cœur, mais également de façon
plus large, à la vie elle-même.”
La fréquence cardiaque dans
la prise en charge des patients
atteints d’affections cardiovasculaires : il est temps d’agir
p a r R . Fe r ra r i , I t a l i e
L
a vie commence et se termine par un battement de cœur. Cette vérité est
connue depuis l’époque d’Aristote. Il est ironique de constater que, dans la
plupart des cas, nous savons comment et pourquoi le cœur s’arrête de battre,
mais que nous connaissons très peu de choses sur le tout premier battement, c’est-à-dire l’origine de la vie elle-même ! Bien sûr, le premier battement de
cœur est généré par des mouvements ioniques à travers le sarcolemme des cellules
du nœud sinusal de Keith et Flack. Mais la manière dont cela survient, quel est le
premier ion à se déplacer et qu’est-ce qui provoque le premier potentiel d’action
reste un mystère.1 Il est extraordinaire de constater que l’ensemble de ces mouvements ioniques à travers les membranes cardiaques se produisent à un rythme
d’au moins 60 par minute pendant toute notre vie – nuit et jour – et génèrent la fréquence cardiaque.
Bien que les civilisations anciennes aient toujours lié d’une manière ou d’une autre
le cœur et la fréquence cardiaque à la vie, l’importance de la fréquence cardiaque
n’a pas été pleinement appréciée au cours de ces dernières années, et même, dans
certains cas, elle a été négligée. Cela est probablement dû à sa familiarité et à sa
facilité de mesure d’une part et à la nature complexe de ses effets d’autre part.
Un intérêt nouveau pour l’impact de la fréquence cardiaque sur les maladies cardio-vasculaires a été suscité par la découverte de nouveaux courants responsables de sa régulation, et avec l’introduction en 2005 dans notre pratique clinique de
l’ivabradine, un médicament réduisant spécifiquement la fréquence cardiaque.2 L’un
de ces deux courants récemment découverts, le courant entrant pacemaker If (la
lettre « I » correspondant à « inward » et la lettre « f » à « funny » ce qui signifie bizarre), semble être le mécanisme principal de l’initiation de la pente de dépolarisation de phase 4. Il a été dénommé « funny », car Di Francesco et coll. ont observé
qu’il était inattendu qu’un courant entrant soit activé par hyperpolarisation de la membrane cellulaire. En général, cela se produit au cours d’une dépolarisation. Par conséquent, cette nouvelle observation a été considérée par les investigateurs comme
« bizarre ».3 Ce résultat a en lui-même conduit à plusieurs découvertes intéressantes.
La première est avant tout philosophique : c’est la reconnaissance du fait que la fréquence cardiaque peut être considérée comme le langage du corps au même titre
qu’un marqueur métabolique.4 Il s’agit là d’un concept ancien. Le papyrus Ebers,
qui date d’environ 1500 avant Jésus-Christ, identifiait déjà le cœur comme le centre
du système cardio-vasculaire et établissait une étroite corrélation entre le cœur et
les pulsations des vaisseaux sanguins. Le cœur est en contact avec pratiquement
toutes les cellules de l’organisme par l’intermédiaire du système circulatoire et, plus
La fréquence cardiaque chez les patients atteints d’affections cardio-vasculaires – Ferrari
383
ÉDITORIAL
spécifiquement, par le stress de cisaillement de l’endothélium.
Le stress de cisaillement local est capté par des mécanorécepteurs endothéliaux et induit l’expression des gènes endothéliaux. Le stress de cisaillement, par exemple, favorise la dilatation (dilatation débit-dépendante) en stimulant la monoxyde
d’azote synthase constitutive (constitutive nitric oxide synthase, cNOS), qui produit le monoxyde d’azote.5 Ce mécanisme est extrêmement élaboré : nuit et jour (pendant toute
notre vie), non seulement le cœur se contracte pour assurer
la circulation essentielle à la vie, mais il envoie également des
signaux qui gardent les artères ouvertes et relaxées, ce qui
contribue au maintien du tonus vasculaire.
Une augmentation de la fréquence cardiaque favorise des
changements bidirectionnels de débit, réduit le stress de cisaillement moyen et par conséquent la production de monoxyde
d’azote. Ce phénomène entraîne en retour une vasodilatation,
permettant à une plus grande quantité de sang d’atteindre
les tissus périphériques, augmentant ainsi le métabolisme et
produisant une augmentation relative de la consommation
d’énergie et de la perte calorique. La fréquence cardiaque est
un marqueur indirect du taux métabolique de l’organisme qui
contrôle la quantité d’énergie consommée. Elle est très importante, car les êtres vivants sont en compétition pour une
part fixe d’énergie vitale. S’ils la consomment ou, plus exactement, l’épuisent trop rapidement, leur vie sera raccourcie.
La fréquence cardiaque est ainsi une horloge qui impose son
rythme non seulement au cœur, mais également de façon plus
large, à la vie elle-même.4
Une confirmation partielle de cette théorie se trouve dans les
relations au sein du royaume animal décrites par Levine,6 et
par la découverte que les animaux ont approximativement
le même nombre de battements cardiaques au cours de leur
vie. Ces observations étonnantes ont conduit à supposer que
la vie humaine pourrait être étendue en ralentissant la fréquence cardiaque. En effet, Levine a estimé qu’une diminution de la fréquence cardiaque de 70 à 60 bpm augmenterait l’espérance de vie de 80 à 93,3 ans chez l’homme.6
Par conséquent, la communauté scientifique a cherché à déterminer de manière rétrospective si la fréquence cardiaque
pouvait être un indicateur pronostique à la fois dans la population générale et chez les patients cardiaques. Un nombre de preuves très important ont indiqué qu’une augmentation de la fréquence cardiaque au repos était un facteur de
risque modifiable indépendant pour les événements cardiovasculaires et la mortalité dans la population générale, ainsi
que chez les patients atteints de coronaropathies et d’insuffisance cardiaque.
Plus de 100 000 hommes et femmes sains de différentes nationalités et d’âges variables (entre 18 et 80 ans) ont été suivis pendant 36 ans. D’une manière générale, il a été établi une
corrélation entre la fréquence cardiaque basale et la mortalité
384
de toute cause, indépendamment des différences démographiques.7 Aujourd’hui, la communauté scientifique ne conteste
plus le concept selon lequel la fréquence cardiaque est un indicateur pronostique dans la population générale, même en
l’absence d’études portant sur les effets d’une réduction délibérée de la fréquence cardiaque chez des individus sains. Par
conséquent, l’importance de la fréquence cardiaque comme
facteur de risque a été reconnue par les Directives européennes sur la prévention cardio-vasculaire (European Guidelines on Cardiovascular Prevention).8
Un grand nombre d’études épidémiologiques ont également
montré qu’une augmentation de la fréquence cardiaque était
associée à la mortalité et à des événements cardiaques chez
des patients atteints de maladies cardio-vasculaires. Parmi
elles, il faut souligner en particulier trois études importantes.2
L’étude CASS (Coronary Artery Surgery Study, Étude sur la
chirurgie des artères coronaires), l’étude INVEST (INternational VErapamil-trandolapril STudy, Étude internationale sur
le vérapamil et le trandolapril) et plus récemment les études
ONTARGET/TRANSCEND (ONgoing Telmisartan Alone and
in combination with Ramipril Global Endpoint Trial [Étude sur
le telmisartan seul et en association avec le ramipril] et Telmisartan Randomised AssessmeNt Study in angiotension
Converting Enzyme inhibitor iNtolerant subjects with cardiovascular Disease [Évaluation randomisée du telmisartan chez
les sujets intolérants aux inhibiteurs de l’enzyme de conversion
de l’angiotensine atteints de maladies cardio-vasculaires]).9-11
Toutes ces études ont montré une relation entre une augmentation de la fréquence cardiaque et la mortalité cardio-vasculaire avec un seuil de 70 à 75 bpm. Cependant, ces données
sont rétrospectives, dans la mesure où des données prospectives relatives aux effets de la fréquence cardiaque sur la
mortalité cardio-vasculaire ont été difficiles à obtenir. Cela est
dû au fait que différents médicaments, notamment les bêtabloquants et les inhibiteurs calciques non dihydropyridine, qui
réduisent la fréquence cardiaque, ont un grand nombre d’autres actions sur le système vasculaire et les autres systèmes
de l’organisme.2 En revanche, l’ivabradine n’a pratiquement
aucun effet direct sur le système vasculaire, autre que la réduction de la fréquence cardiaque.
Par conséquent, l’ivabradine a permis d’étudier de manière
prospective si la fréquence cardiaque constituait un facteur
de risque pour les maladies cardio-vasculaires. Cette exploration a été effectuée dans l’étude BEAUTIFUL (morBiditymortality EvAlUaTion of the If inhibitor ivabradine in patients
with coronary disease and left ventricULar dysfunction study,
Évaluation de la morbidité et de la mortalité de l’ivabradine,
un inhibiteur du courant If chez des patients atteints de coronaropathies et de dysfonctionnement ventriculaire gauche).
Dans le bras placebo de l’étude, la relation entre la fréquence
cardiaque initiale et les résultats a été analysée.12 Les patients
présentant une fréquence cardiaque initiale ⱖ 70 bpm ont
montré une nette augmentation du risque de mortalité cardio-
ÉDITORIAL
vasculaire, d’admission à l’hôpital pour insuffisance cardiaque,
infarctus du myocarde et revascularisation coronaire. Les bénéfices d’une réduction de la fréquence cardiaque avec l’ivabradine sont également évidents dans le sous-groupe de patients présentant une fréquence cardiaque ⱖ 70 bpm, dans
lequel il a été observé des réductions de risque de 36 %
pour l’infarctus du myocarde et de 30 % pour la revascularisation coronaire.13 En outre, chez les patients atteints d’angor
à l’entrée dans l’étude,14 une diminution significative du paramètre composite principal et du taux d’infarctus du myocarde
a été observée dans le groupe de l’ivabradine. Ces bénéfices
liés à l’ivabradine sont clairement indépendants de la fréquence
cardiaque initiale, bien qu’ils aient été plus manifestes chez les
patients présentant une fréquence cardiaque ⱖ 70 bpm. Ces
données indiquent par conséquent qu’une fréquence cardiaque ⱖ 70 bpm est un facteur de risque de coronaropathie.
Plusieurs raisons expliquent pourquoi la réduction de la fréquence cardiaque est bénéfique dans les coronaropathies :
N La fréquence cardiaque est un déterminant de la consom-
mation en oxygène du myocarde. Chez l’homme, le cœur bat
en moyenne 100 800 fois par jour. Ce chiffre correspond à
36,8 × 10 6 battements cardiaques par an et 29 × 10 8 au cours
d’une vie (de 80 ans en moyenne), ce qui fait que le cœur
produit et consomme immédiatement environ 30 kg d’ATP
chaque jour, soit près de 11 000 kg par an et de 880 000 kg
au cours de la vie. C’est-à-dire que chaque battement cardiaque a son prix – environ 300 mg d’ATP. Cela signifie que
le ralentissement de la fréquence cardiaque de 10 bpm par
jour entraînerait une économie d’environ 5 kg d’ATP par jour.
Pour produire de l’ATP, le myocarde a besoin d’oxygène, qui
est utilisé par les mitochondries pour la phosphorylation oxydative. Ainsi, une réduction de la fréquence cardiaque entraînerait une réduction significative de la demande d’oxygène
au niveau cellulaire, et dans les coronaropathies, le manque
d’oxygène est le facteur pathogène essentiel.15
N Le débit coronaire est principalement diastolique. Une fré-
quence cardiaque élevée raccourcit la diastole et par conséquent réduit le débit coronaire, même en l’absence de lésions
coronaires. C’est la raison pour laquelle une tachycardie
sévère peut induire une ischémie, en particulier chez les patients hypertendus et les sujets âgés. Une diminution de la
fréquence cardiaque conduit à une augmentation du débit
coronaire.7
N L’augmentation de la fréquence cardiaque augmente la rigidité artérielle. Des lésions mécaniques dues au vieillissement
ou une augmentation de la fréquence cardiaque provoquent
des changements au niveau des fibres d’élastine. Des preuves
épidémiologiques indiquent qu’une augmentation chronique
de la fréquence cardiaque est associée à une accélération
de la progression de la rigidité artérielle chez des sujets normotendus et hypertendus.16
N Une augmentation de la fréquence cardiaque favorise l’athérosclérose coronaire. Une association entre une augmentation
de la fréquence cardiaque et le développement de plaques
d’athérosclérose a été observée pour la première fois chez
des macaques cynomolgus.17 D’autres preuves d’un lien entre
la fréquence cardiaque et l’athérosclérose ont été obtenues
par la mesure des changements de la fonction endothéliale
et des marqueurs de l’inflammation. Chez le rat, une élévation
de la fréquence cardiaque de 10 % par stimulation électrique
a augmenté de manière significative le stress oxydatif cardiaque et a activé les voies des MAP kinases, sans augmentation de la pression artérielle. En revanche, une réduction de
la fréquence cardiaque par l’ivabradine a réduit le stress oxydatif, amélioré la fonction endothéliale et empêché l’athérosclérose chez des souris déficientes en apolipoprotéine E.
Chez l’homme, une augmentation progressive des marqueurs
micro-inflammatoires a été observée suivant les quintiles de
fréquence cardiaque.18
N L’augmentation de la fréquence cardiaque favorise les syndromes coronariens aigus. Le stress mécanique exercé sur
le bord de la plaque athéroscléreuse est lié à la fréquence
cardiaque. Le stress hémodynamique sur la paroi entraîne
des lésions au niveau des jonctions intracellulaires et augmente la perméabilité des cellules endothéliales, favorisant la
pénétration des particules athérogènes. Ces mécanismes expliquent pourquoi les fréquences cardiaques élevées sont
associées à une rupture des plaques et à des syndromes coronariens aigus.19
L’augmentation de la fréquence cardiaque est également nocive dans l’insuffisance cardiaque. L’une des caractéristiques
essentielles d’un cœur défaillant est la réduction de la relation
force-fréquence,20 qui est l’un des mécanismes de base de
la régulation de l’inotropie, caractérisée pour la première fois
en 1871.21 Chez les patients atteints d’insuffisance cardiaque
porteurs d’un stimulateur cardiaque, une élévation de la fréquence cardiaque imposée ou induite par l’exercice physique n’est pas accompagnée par une augmentation de la
capture d’oxygène ou des performances physiques, ce qui indique que, dans le cœur des patients insuffisants cardiaques,
une élévation de la fréquence cardiaque augmente la charge
myocardique et la consommation d’oxygène,22 deux phénomènes potentiellement pro-ischémiques. En outre, il a été
montré que toutes les interventions cardio-vasculaires qui réduisent la fréquence cardiaque, notamment un traitement par
les bêtabloquants, induisent une amélioration des critères
d’évolution chez les patients souffrant d’insuffisance cardiaque,
tandis qu’un traitement par des bêtamimétiques entraîne des
effets négatifs sur la survie et la morbidité.23 Cependant, l’effet bénéfique des bêtabloquants sur la fréquence cardiaque
n’est pas forcément dû à une réduction de la fréquence cardiaque, mais peut avoir d’autres causes comme par exemple
un abaissement de la pression artérielle, un effet inotrope négatif, une action anti-arythmique et l’atténuation de la toxicité
385
ÉDITORIAL
des catécholamines. Cependant, le rôle de la fréquence cardiaque dans l’insuffisance cardiaque a récemment été élucidé grâce à l’ivabradine, qui entraîne une réduction sélective
de la fréquence cardiaque sans autre effet hémodynamique.
Dans un modèle de remodelage cardiaque chez le rat, il a
été montré que l’ivabradine peut prévenir le phénotype global (altérations hémodynamiques, du métabolisme cardiaque,
neuroendocrines et structurelles, etc.) du remodelage ventriculaire.24 Des résultats similaires ont été obtenus dans une
sous-étude de l’essai BEAUTIFUL évaluant le remodelage
ventriculaire gauche par échocardiographie chez des patients
atteints de coronaropathie et de dysfonctionnement ventriculaire gauche.25 Un traitement par l’ivabradine a permis de réduire le développement du remodelage ventriculaire gauche
et d’améliorer la fraction d’éjection. La récente étude SHIFT
(Systolic Heart failure treatment with If inhibitor ivabradine Trial,
Traitement de l’insuffisance cardiaque systolique par l’ivabradine, un inhibiteur du courant If ) menée chez 6 558 patients
atteints d’insuffisance cardiaque systolique, a inclus des éléments observationnels grâce auxquels la relation entre la fréquence cardiaque initiale et les paramètres d’évolution a pu
être analysée dans le groupe placebo.26 Le risque relatif de
mortalité de toute cause a été déterminé à 1,86 pour les patients du quintile supérieur de fréquence cardiaque (> 87 bpm)
et a été réduit de manière linéaire jusqu’au quintile inférieur (70
à 72 bpm). Ces données suggèrent clairement que, dans l’insuffisance cardiaque, il existe un lien direct entre la fréquence
cardiaque initiale et une issue défavorable. En ce qui concerne
le traitement, il doit être mentionné que, dans l’étude SHIFT,
une fréquence cardiaque initiale ⱖ 70 bpm était l’un des critères d’inclusion, et que le traitement par l’ivabradine a entraîné une réduction de 18 % (p < 0,0001) du critère principal
(composite regroupant la mortalité cardio-vasculaire et l’hospitalisation pour insuffisance cardiaque).27 Les effets de l’ivabradine se sont montrés linéairement plus manifestes lorsque
la fréquence cardiaque a été réduite de 87 à moins de 60 bpm.
386
Les éléments observationnels et interventionnels de cette
étude indiquent par conséquent que la fréquence cardiaque
est un facteur de risque modifiable dans l’insuffisance cardiaque – plutôt qu’un simple marqueur du risque – et ont
confirmé le bénéfice d’une réduction exclusive de la fréquence
cardiaque chez des patients insuffisants cardiaques et présentant une augmentation de la fréquence cardiaque.
Conclusions
Bien qu’il n’ait jamais été négligé, le concept de fréquence
cardiaque connaît indubitablement un renouveau avec la découverte du courant pacemaker If dans le nœud sino-auriculaire de l’oreillette droite, et de l’ivabradine, un médicament
capable de réduire ce courant, et par conséquent de réduire
la fréquence cardiaque.
Nous disposons désormais d’un grand nombre de preuves
épidémiologiques, physiopathologiques et issues d’études
cliniques indiquant l’importance du contrôle de la fréquence
cardiaque. Malgré cela, de récentes enquêtes ont révélé le
faible taux de contrôle de la fréquence cardiaque chez les patients atteints de coronaropathie en pratique clinique. Dans
l’Enquête européenne de cardiologie (European Heart Survey) menée chez des patients atteints d’angor stable suivis
dans des services de cardiologie européens,28 la fréquence
cardiaque moyenne au repos était de 73 bpm, et plus de la
moitié des patients (52,3 %) présentaient une fréquence cardiaque > 70 bpm. Il est intéressant de souligner qu’environ
40 % des patients traités par les bêtabloquants présentaient
une fréquence cardiaque > 70 bpm. Les auteurs de l’European Heart Survey ont conclu à l’existence de preuves montrant que les médecins et les cardiologues n’accordaient pas
l’attention nécessaire à la fréquence cardiaque, et qu’une
opportunité thérapeutique était par conséquent manquée. Il
est temps d’agir. C’est précisément l’objet de ce numéro de
Medicographia. I
HEART
‘‘
The Bradford Hill criteria are
intended as guidelines to help determine whether an observed association reflects cause and effect. The more criteria that are met,
the more likely it is that the association is causal. There is increasing evidence for heart rate as a
true risk factor rather than simply
a marker of risk in cardiovascular
disease: it meets the criteria of
plausibility…, strength of association, dose response, consistency, and temporality.”
R AT E
M O D U L AT I O N
AND
EXERCISE
C A PA C I T Y
Heart rate as
a treatable risk factor in
by M. R. Cowie, United Kingdom
T
Martin R. COWIE, MD
FRCP, FRCP (Edin), FESC
National Heart and Lung Institute
Imperial College London and
Royal Brompton Hospital
London, UNITED KINGDOM
here is increasing evidence that elevated resting heart rate is associated with increased cardiovascular morbidity and mortality, both in the
general population and in patients with cardiovascular disease. Furthermore, data now suggest that heart rate is a treatable risk factor in patients with
cardiovascular disease, and not simply a prognostic marker. Heart rate meets
the key criteria for risk factor status. Until recently, despite considerable epidemiological evidence on the association between heart rate and cardiovascular outcomes, and the apparent benefit of reducing raised heart rate, there
has been uncertainty whether the relationship between heart rate and cardiovascular disease is causal. This is because conventional drugs that reduce
heart rate—such as 웁-blockers—have multiple effects on the cardiovascular
system and so it has been difficult to separate their effect on heart rate from
their other properties. Recent studies with ivabradine, a drug that lowers heart
rate but has no other direct cardiovascular effects, have allowed the effect of
heart rate lowering per se to be evaluated. The new data provide persuasive
evidence that lowering raised heart rate is clinically beneficial in heart failure and coronary artery disease. In hypertension, heart rate is of prognostic
importance, but has not yet been proven to be a modifiable risk factor.
Medicographia. 2012;34:387-394 (see French abstract on page 394)
here is increasing epidemiological and clinical trial evidence that raised resting heart rate is independently associated with increased cardiovascular
morbidity and mortality, both in the general population and in patients with
cardiovascular disease.
T
In the literature, heart rate has to date tended to be described as a risk or prognostic marker, rather than as a risk factor, indicating that the observed association between heart rate and cardiovascular outcomes is not necessarily causal.
Professor Martin R. Cowie,
Clinical Cardiology, National
Heart and Lung Institute,
Imperial College, Dovehouse Street,
London SW3 6LY, UK
A risk factor needs to fulfill certain criteria of causation, as first put forward by epidemiologist and statistician Sir Austin Bradford Hill in 1965 (Figure 1, page 388).1
This article reviews current evidence on the importance of heart rate in cardiovascular disease (coronary artery disease, acute coronary syndromes, heart failure, and
hypertension) and considers to what extent heart rate fulfills relevant Bradford-Hill
criteria. With the increasing body of evidence, can heart rate now be described as
a true modifiable risk factor and a target for treatment?
Heart rate as a treatable risk factor in cardiovascular disease – Cowie
387
HEART
R AT E
M O D U L AT I O N
AND
EXERCISE
C A PA C I T Y
BRADFORD HILL’S
SUGGESTIONS FOR
ASSESSING CAUSALITY
Strength of association
Consistency
Specificity
Temporality
Biological gradient
Plausibility
Coherence
Experiment
Analogy
Figure 1. The Bradford Hill criteria (left).
Sir Austin Bradford Hill, CBE, FRS, PhD, DSC (1897-1991).
After reference 1: Hill. Proc Roy Soc Med. 1965;58:295-300.
Photograph reproduced from Sir Austin Bradford Hill Archive. ©, London
School of Hygiene and Tropical Medicine. http://www.cardiff.ac.uk/insrv/libraries/
scolar/archives/bradfordhill/index.html
Plausibility
One of the risk factor criteria is plausibility, ie, is there a pathophysiological rationale for the suggestion that raised heart
rate is associated with increased cardiovascular disease?
In animal studies, accelerated heart rate is associated with
cellular signaling events leading to vascular oxidative stress,
endothelial dysfunction, and acceleration of atherogenesis.2
The precise mechanisms that link heart rate and cardiovascular outcomes have not been defined.2-4 However, elevated
heart rate is thought to play a central role in the pathophysiology of coronary artery disease, leading to acute ischemia in
patients with stable angina,5 and also directly affecting the progression of coronary atherosclerosis4,6 and plaque rupture.7
SELECTED
ABBREVIATIONS AND ACRONYMS
BEAUTIFUL morBidity-mortality EvAlUaTion of the If inhibitor
ivabradine in patients with coronary disease
and left ventricULar dysfunction
bpm
beat per minute
CASS
Coronary Artery Surgery Study
CHARM
Candesartan in Heart failure: Assessment of
Reduction in Mortality and morbidity
CIBIS II
Cardiac Insufficiency BIsoprolol Study II
COMET
Carvedilol Or Metoprolol European Trial
FINRISK
FINland cardiovascular RISK study
GISSI
Gruppo Italiano per lo Studio della Streptochinasi
nell’Infarto miocardico
HARVEST
Hypertension and Ambulatory Recording VEnetia
STudy
INVEST
INternational VErapamil-SR/trandolapril STudy
SHIFT
Systolic Heart failure treatment with the If inhibitor
ivabradine Trial
Syst-Eur
Systolic Hypertension in Europe
TNT
Treating to New Targets
388
Increased risk in patients with coronary artery disease may reflect autonomic imbalance, but experimental and clinical observations indicate that elevated heart rate per se may also
have direct detrimental effects on cardiovascular function by
increasing the ischemic burden or via local hemodynamic
forces on the endothelium and arterial wall, which can promote
progression of atherosclerosis and plaque rupture (Figure 2).2,3
Elevated heart rate was shown to be a predictor of the progression of coronary atherosclerosis in young men after myocardial infarction, and this appeared to be independent of
other well-established risk factors.6 Another study, which
retrospectively analyzed angiographic data in 106 patients
with coronary artery disease, showed a positive association
between mean heart rate >80 beats per minute (bpm) and
plaque disruption.7 In a recent population-based study of people without clinical cardiovascular disease at baseline, elevated resting heart rate was associated with increased incidence
and progression of atherosclerosis, as demonstrated by increased coronary artery calcium.4 There is therefore considerable evidence for the biological plausibility of heart rate as
a risk factor in coronary artery disease.
There is also a pathophysiological rationale for adverse outcomes from elevated heart rate in patients with heart failure,
since increased heart rate is associated with increased oxygen demand, reduced ventricular efficiency, and reduced
ventricular relaxation.8 Heart rate reduction decreases energy expenditure, increases blood supply by prolonging diastole, improves force-frequency associations, and reduces
ventricular loading.9
Strength and consistency of association and
graded response
Other important considerations in determining causality are
the strength and consistency of the association and whether
there is a biological gradient (or “dose response”). Heart rate
fares well on these criteria. Many studies have shown that elevated resting heart rate is associated with worse cardiovascular outcomes, both in the general population and in patients
with cardiovascular disease.
N General population
In the Framingham study, the 30-year follow-up showed increased heart rate to be associated with an increase in allcause mortality and cardiovascular mortality at all ages in both
men and women.10
The Paris Prospective Study involved 5139 men aged 42 to
53 years, initially free of cardiovascular disease, in whom resting heart rate was measured every year for 5 years, with follow-up for a mean of 23 years. Heart rate at rest and heart
rate change over 5 years were both predictors of mortality,
independent from standard cardiovascular risk factors. After
adjustment for confounding factors, and compared with sub-
HEART
Autonomic
imbalance
R AT E
M O D U L AT I O N
Inflammation
Total
ischemic burden
EXERCISE
C A PA C I T Y
low-up of 12 years. Hazard ratios for cardiovascular disease mortality for each 15-bpm
increase in resting heart rate were 1.24 in
men and 1.32 in women, after adjustment
for standard risk factors. A resting heart rate
of >90 bpm compared with one of <60
bpm was associated with an almost 2-fold
greater risk of cardiovascular mortality in
men and a 3-fold increased risk in women
(Figure 3).
Abnormal HRV
Elevated
heart rate
AND
Atherosclerosis
CV events
Local hemodynamic forces
N Coronary artery disease
The prognostic value of resting heart rate
was shown in an analysis of the CASS registry (Coronary Artery Surgery Study).14 A
total of 24 913 subjects with suspected or
proven stable coronary artery disease were
Figure 2. Suggested mechanisms whereby an elevated heart rate leads to adverse
followed for a median of 14.7 years. High
outcomes in patients with coronary artery disease.
resting heart rate was a predictor for total
Abbreviations: CV, cardiovascular; HRV, heart rate variability.
and cardiovascular mortality, independent
After reference 3: Lang et al. Atherosclerosis. 2010;212:1-8. © 2010, Elsevier Ireland Ltd.
of other risk factors. The association was
jects with unchanged heart rates (from –4 to +3 bpm) during found in all subgroups analyzed. Patients with resting heart
the 5 years, subjects with decreased heart rates (>4 bpm) had rates ⱖ83 bpm at baseline had a significantly higher risk of
a 14% decreased mortality risk (P=0.05), whereas subjects cardiovascular mortality (hazard ratio [HR], 1.31; CI, 1.15-1.48;
with increased heart rates (>3 bpm) had a 19% increased mor- P<0.0001) compared with those with baseline resting heart
tality risk (P<0.012).11 The study also showed that the heart rates ⱕ62 bpm.
rate profile during exercise and recovery was a predictor of
sudden death from myocardial infarction, and that sudden More recently, investigators from the TNT trial (Treating to New
death increased in people with a resting heart rate >75 bpm Targets) reported increased resting heart rate to be a strong
(relative risk [RR], 3.92; confidence interval [CI], 1.91-8.00).12 independent risk factor in a cohort of well-treated patients
with stable coronary artery disease, followed for a median of
The FINRISK study (FINland cardiovascular RISK study) con- 4.9 years. There was a linear relationship between resting heart
firmed a strong, graded, independent relationship between rate and cardiovascular outcomes: the rate of major cardioresting heart rate and incident cardiovascular disease in both vascular events was 11.9% in those with a baseline heart rate
men and women.13 This study involved over 20 000 people of ⱖ70 bpm versus 8.8% in those with a baseline heart rate
with no preexisting cardiovascular disease, with a median fol- of <70 bpm (Figure 4, page 390).15
Risk of plaque rupture
Tensile stress
Arterial stiffness
Involvement of low and oscillatory
endothelial sheer stress
After reference 13:
Cooney et al.
Am Heart J. 2010;
159:612-619.
© 2010, Mosby, Inc.
8
CVD Mortality rates in
each quintile of heart rate in men
CVD mortality rate (per 1000 person years)
Figure 3.
Cardiovascular
disease mortality
according to
resting heart rate
in healthy men
and women in
the FINRISK
study (FINland
cardiovascular
RISK study).
CVD mortality rate (per 1000 person years)
CVD Mortality rates in
each quintile of heart rate in women
6
4
2
0
<60
66-68
70-74
78-80
Heart rate quintile
>82
8
6
4
2
0
<60
62-66
68-72
74-80
>82
Heart rate quintile
389
HEART
R AT E
M O D U L AT I O N
AND
EXERCISE
C A PA C I T Y
Figure 4. Kaplan-Meier estimates of the cumulative incidence of a first major cardiovascular
event during follow-up by baseline heart rate
(ⱖ70 vs <70 bpm) in patients with stable coronary artery disease in the TNT trial (Treating to
New Targets). HR=hazard ratio; P value determined using log-rank test.
0.15
Major cardiovascular event (%)
HR=1.38 (95% CI 1.19-1.59)
P<0.0001
Heart rate M70 bpm
0.10
After reference 15: Ho et al. Am J Cardiol. 2010;105:905911. © 2010, Elsevier Inc.
Heart rate <70 bpm
0.05
0.00
0
1
2
3
4
5
1842
7110
1778
6916
966
3533
Years
Number at risk by baseline rate group
M70 bpm
<70 bpm
2007
7573
1969
7450
1901
7294
Analysis of data from the placebo group of the BEAUTIFUL
randomized controlled trial (morBidity-mortality EvAlUaTion
of the If inhibitor ivabradine in patients with coronary disease
and left ventricULar dysfunction) demonstrated a gradient between heart rate and cardiovascular outcome and confirmed
the prognostic importance of heart rate in patients with stable coronary artery disease and left ventricular dysfunction
receiving appropriate background therapy.16 A subgroup analysis compared outcomes in patients with a baseline heart rate
of ⱖ70 bpm with those with a heart rate of <70 bpm. Patients
with the higher heart rates had increased risk of cardiovascular death (34%; P=0.0041), admission to hospital for heart
failure (53%; P<0.0001), admission to hospital for myocardial
infarction (46%; P=0.0066), and coronary revascularization
(38%; P=0.037), after adjustment for other predictors of outcomes. For every increase of 5 bpm, there were increases in
cardiovascular death (8%; P=0.0005), admission to hospital
for heart failure (16%; P<0.0001), admission to hospital for
myocardial infarction (7%; P=0.052), and coronary revascularization (8%; P=0.034).
The prognostic effect of heart rate has also been shown in
acute coronary syndromes. A US study of 1807 patients with
acute myocardial infarction found that both in-hospital and
1-year mortality increased with increasing admission heart
rate. Mortality from hospital discharge to 1 year was also related to heart rate at discharge.17 In this study, heart rate was
a more powerful predictor of later mortality than assessment
of left ventricular function after arrival in hospital, suggesting
that elevated heart rate does not only reflect depressed cardiac function. Similarly, the GISSI studies of acute myocardial
infarction (Gruppo Italiano per lo Studio della Streptochinasi
390
nell’Infarto miocardico) showed a progressive increase in in-hospital mortality with increasing heart rate, and multivariate analysis
showed that heart rate was an independent prognostic factor. Increasing heart rate
at discharge was also associated with increased 6-month mortality.18
N Hypertension
There is considerable evidence that raised
heart rate is associated with increased risk
in patients with hypertension. For example,
the Framingham study identified resting heart
rate as a potential independent risk factor
in hypertensive patients. Among 4530 men and women with
raised blood pressure who were not taking antihypertensive
medication, each heart rate increase of 40 bpm was associated with odds ratios for all-cause mortality of 2.18 for men
and 2.14 for women and odds ratios for cardiovascular mortality of 1.68 for men and 1.70 for women.19
In the HARVEST study of individuals with stage 1 (untreated)
hypertension (Hypertension and Ambulatory Recording VEnetia Study), a persistently high heart rate was an independent
predictor of future sustained hypertension.20 Heart rate measurement at baseline and during the first few months of follow-up gave prognostic information over and above that provided by baseline office and ambulatory blood pressure. In
the placebo arm of the Syst-Eur trial (Systolic Hypertension
in Europe), which involved patients aged 60 years or older,
a clinic heart rate >79 bpm was a significant predictor of allcause, cardiovascular, and noncardiovascular mortality.21
The association between resting heart rate and adverse outcomes in elderly hypertensive patients with coronary artery disease was assessed in the INVEST population (INternational
VErapamil-SR/trandolapril Study),22 which showed that both
higher baseline and, particularly, follow-up resting heart rates
were associated with adverse outcome, with increased risk
starting at a resting heart rate of 75 bpm.
In 2010, the Glasgow Blood Pressure Clinic study investigated the relationship between resting heart rate and outcomes
in a cohort of 4065 patients with mild-to-severe hypertension.
Heart rate was measured at baseline and at final follow-up
(mean follow-up, 897 days; range, 7 to 7087 days). Heart rate
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was an independent predictor of all-cause, cardiovascular,
and ischemic heart disease mortality. In this study, change in
heart rate during follow-up was a better predictor of risk than
baseline or final heart rate, the highest risk being in patients
whose heart rate increased by ⱖ5 bpm.23 After correction for
rate-limiting therapy (β-blockers and calcium channel blockers), heart rate remained a significant independent risk factor,
suggesting that the relationship between heart rate and mortality cannot just be explained by the use of heart rate–lowering
interventions.
investigate whether raised heart rate was an independent risk
factor or merely a marker of subclinical disease, data were reanalyzed excluding all fatal events that occurred in the first
2 years of follow-up. There was no change in hazard ratios,
demonstrating a temporal sequence consistent with causality.
A further study measured resting heart rate annually during
treatment in 9190 patients with hypertension and left ventricular hypertrophy. After a mean follow-up of 4.8 years, higher
in-treatment heart rates were shown to be strongly associated with increased risk of cardiovascular and
all-cause mortality, independent of blood
pressure lowering or other risk factors.24
50
Experimental data in animals show that lowering heart rate
reduces atherosclerosis.28,29 There is also considerable evidence of the impact of heart rate reduction in patients with
cardiovascular disease: the beneficial effects of β-blockers
Experimental evidence is a key criterion for risk factor status,
providing the strongest support for causation: do disease rates
fall when the proposed causal agent has been eliminated?
P<0.0001
Patients with
primary composite end point (%)
N Heart failure
Raised heart rate has also been shown to
be associated with increased risk of mortality and morbidity in patients with heart failure. Analysis of data from the CHARM trials
(Candesartan in Heart failure: Assessment
of Reduction in Mortality and morbidity) in
patients with chronic heart failure showed
an 8% increase in the risk of cardiovascular death or heart failure hospitalization for
every 10-bpm increase in heart rate.25 The
placebo groups of two major trials assessing the effect of β-blockers in heart failure
have also provided data on the prognostic
importance of heart rate, with evidence of
increased mortality with increasing baseline heart rate.26, 27
Experimental evidence
40
30
20
$87 bpm
80 to <87 bpm
75 to <80 bpm
72 to <75 bpm
70 to <72 bpm
10
0
0
6
12
18
24
30
Months
Figure 5. Kaplan-Meier cumulative event curves for the primary composite end point
(cardiovascular death or first hospital admission for worsening heart failure) in the
placebo group (n=3264) of the SHIFT study (Systolic Heart failure treatment with the
If inhibitor ivabradine Trial), according to groups defined by quintiles of heart rate at
baseline. The log-rank P value is shown for the difference between the Kaplan-Meier
curves.
More recent data come from the placebo
arm of the SHIFT study (Systolic Heart fail- After reference 9: Böhm et al. Lancet. 2010;376:886-894. © 2010, Elsevier Ltd.
ure treatment with the If inhibitor ivabradine
Trial) in patients with chronic heart failure, which showed a in acute myocardial infarction and heart failure have been
continuous direct association between baseline heart rate and shown to be related, at least in part, to heart rate reduction.
outcomes.9 Patients with the highest heart rates (ⱖ87 bpm) However, the specific effect of heart rate lowering has been
had a more than 2-fold higher risk for the primary composite uncertain as the drugs that lower heart rate (primarily β-blockend point (cardiovascular death or first hospital admission for ers) have multiple pharmacological effects and it has not been
worsening heart failure) than patients with the lowest heart possible to separate their effect on heart rate from other porates (70 to <72 bpm; HR, 2.34; 95% CI, 1.84-2.98; P<0.0001). tential protective mechanisms—such as antiarrhythmic efThe risk of these end-point events increased by 3% with every fects—and hence to determine whether the benefit is related
bpm increase from baseline heart rate and by 16% for every to the drug class or to heart rate reduction per se.
5-bpm increase (Figure 5).
The development of the pure heart rate–lowering drug ivabraTemporal relationship
dine provided an opportunity to further evaluate the effect of
A temporal relationship is another risk factor criterion. This is- heart rate lowering in randomized controlled trials. Ivabradine
sue was specifically addressed in the FINRISK study of men acts only on sinoatrial node If channels. It lowers heart rate
and women without preexisting cardiovascular disease.13 To and has no other known cardiovascular effects.
391
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N Coronary artery disease
Ivabradine was evaluated in the BEAUTIFUL trial in patients
with stable coronary artery disease and left ventricular dysfunction. Ivabradine treatment did not significantly affect the
primary composite end point (cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new-onset or worsening heart failure) in the
overall trial population. However, in a subgroup of patients with
baseline heart rates above 70 bpm, ivabradine treatment reduced the risk of fatal and nonfatal myocardial infarction (a
secondary end point) by 36% (P=0.001). This benefit was observed despite the fact that 87% of patients were receiving
background β-blocker treatment.30 The study therefore strongly suggests clinical benefit from lowering raised heart rate.
There are as yet no data proving that heart rate reduction in
acute coronary syndromes improves survival, but analysis of
postmyocardial infarction β-blocker trials indicates that a reduction in resting heart rate is an important determinant of
clinical benefit.31,32 A meta-regression of these trials investigated the relationship between reduction in resting heart rate
and magnitude of clinical benefits. The results suggest that
the beneficial effect of β-blockers and calcium channel blockers on mortality and nonfatal reinfarction in postmyocardial infarction patients is proportional to the extent of reduction in
resting heart rate, with the benefit related to heart rate lowering rather than specific drug class.31 Each 10-bpm reduction
in resting heart rate was estimated to reduce the relative risk
of cardiac death by about 30%.
N Heart failure
Analysis of the major heart failure trials showed that treatments
that reduced heart rate were associated with reduced mortality while those that increased heart rate tended to increase
mortality (Figure 6).33
As with the postmyocardial infarction trials, data suggest that
heart rate reduction contributes, certainly in part, to the clinical benefits of β-blockers in heart failure. For example, multivariate analysis of the CIBIS II trial of bisoprolol in chronic
heart failure (Cardiac Insufficiency BIsoprolol Study II)26 showed
that the best outcome (in terms of survival and reduction in
hospital admissions) was in patients with the lowest baseline heart rate and the greatest heart rate change. The study
also showed that the beneficial effect of bisoprolol on survival was similar at any level of baseline heart rate and heart
rate change, indicating that heart rate reduction is not the
only mechanism for β-blocker benefit in heart failure. In the
COMET trial (Carvedilol Or Metoprolol European Trial),34 heart
rate achieved with β-blocker therapy had prognostic value for
mortality in heart failure patients.
A recent meta-regression analysis of β-blocker trials in heart
failure showed a statistically significant association between
the magnitude of heart rate reduction and survival benefit.35
392
For every heart rate reduction of 5 bpm the relative risk of
death decreased by 18% (CI, 6%-29%). Another analysis of
these trials36 found a close relationship between all-cause annualized mortality rate and heart rate and a strong correlation
between change in heart rate and change in ejection fraction.
More definitive evidence of the benefit of heart rate lowering
came from the SHIFT randomized placebo-controlled trial,
which assessed the pure heart rate–lowering drug ivabradine
in 6558 patients with symptomatic heart failure and an ejection fraction of ⱕ35%, sinus rhythm, and resting heart rates
of ⱖ70 bpm.37 Patients were on stable background therapy,
including a β-blocker if tolerated. Over a median follow-up of
22.9 months, there was an 18% relative risk reduction for the
primary composite end point of cardiovascular death or hospital admission for worsening heart failure (P<0.0001). The
effect was mainly driven by hospital admissions for worsening heart failure, which were reduced by 26% (P<0.0001),
60
PROFILE
40
Change in mortality (%)
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XAMOTEROL
PROMISE
20
VHeFT
(prezosin)
0
–20
–40
BHAT
GESICA ANZ
NOR
TIMOLOL
–60
–80
VHeFT
(HDZ/ISON)
CIBIS
SOLVD
CONSENSUS
US
CARVEDILOL
MOCHA
–100
–18 –16 –14 –12 –10 –8 –6 –4 –2
Change in heart rate
0
2
4
6
8 10
(beat • min–1)
Figure 6. Relationship between change in heart rate and mortality in chronic heart failure trials.
After reference 33: Kjekshus and Gullestad. Eur Heart J. 1999;1(suppl H):H64H69. © 1999, The European Society of Cardiology.
and deaths due to heart failure (relative risk reduction, 26%;
P=0.014). Treatment benefit was shown to be related to heart
rate reduction, with a direct association between heart rate
achieved at 28 days and subsequent cardiac outcomes.9
SHIFT thus demonstrated for the first time the beneficial effects of heart rate reduction alone in patients with systolic
heart failure.
N Hypertension
Resting heart rate has been shown to be a prognostic marker in patients with hypertension, but there is as yet no specific
evidence that reducing heart rate is linked to improved outcome in patients with hypertension.
HEART
Conclusion: strength of evidence for heart rate
as a cardiovascular risk factor
The Bradford Hill criteria1 are intended as guidelines to help
determine whether an observed association reflects cause
and effect. The more criteria that are met, the more likely it is
that the association is causal. There is increasing evidence
for heart rate as a true risk factor rather than simply a marker
of risk in cardiovascular disease: it meets the criteria of plau-
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sibility (although the exact mechanisms remain to be determined), strength of association, dose response, consistency,
and temporality. There is also now increasing evidence of improved outcomes following the reduction of raised heart rate,
thus meeting the important “experimental evidence” criterion. The recent studies with ivabradine provide persuasive
evidence that heart rate is a true modifiable risk factor in heart
failure and in coronary artery disease. I
References
1. Hill AB. The environment and disease: association or causation? Proc R Soc
Med. 1965;58: 295-300.
2. Custodis F, Schirmer SH, Baumhakel M, Heusch G, Bohm M, Laufs U. Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol. 2010;
56:1973-1983.
3. Lang CC, Gupta S, Kalra P, et al. Elevated heart rate and cardiovascular outcomes in patients with coronary artery disease: Clinical evidence and pathophysiological mechanisms. Atherosclerosis. 2010;212:1-8.
4. Rubin J, Blaha MJ, Budoff MJ, et al. The relationship between resting heart rate
and incidence and progression of coronary artery calcification: The multi-ethnic
study of atherosclerosis (MESA). Atherosclerosis. 2012;220:194-200.
5. Kop WJ, Verdino RJ, Gottdiener JS, O’Leary ST, Merz CNB, Krantz DS. Changes
in heart rate and heart rate variability before ambulatory ischemic events. J Am
Coll Cardiol. 2001;38:742-749.
6. Perski A, Olsson G, Landou C, de Faire U, Theorell T, Hamsten A. Minimum heart
rate and coronary atherosclerosis: independent relations to global severity and
rate of progression of angiographic lesions in men with myocardial infarction at
a young age. Am Heart J. 1992;123:609-616.
7. Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate
are associated with coronary plaque disruption. Circulation. 2001;104:1477-1482.
8. Reil JC, Custodis F, Swedberg K, et al. Heart rate reduction in cardiovascular
disease and therapy. Clin Res Cardiol. 2011;100:11-19.
9. Böhm M, Swedberg K, Komadja M, et al. Heart rate as a risk factor in chronic
heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376:886-894.
10. Kannel WB, Kannel C, Paffenbarger RS, Cupples LA. Heart rate and cardiovascular mortality: the Framingham study. Am Heart J. 1987;113:1489-1494.
11. Jouven X, Empana JP, Escolano S, et al. Relation of heart rate at rest and longterm (>20 years) death rate in initially healthy middle aged men. Am J Cardiol.
2009;103:279-283.
12. Jouven X, Empana JP, Schwartz PJ, Desnos M, Courbon D, Ducimetiere P.
Heart-rate profile during exercise as a predictor of sudden death. N Engl J Med.
2005;352:1951-1958.
13. Cooney MT, Vartiainen E, Laakitainen T, Juolevi A, Dudina A, Graham IM. Elevated resting heart rate is an independent risk factor for cardiovascular disease
in healthy men and women. Am Heart J. 2010;159:612-619.
14. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur
Heart J. 2005;26:967-974.
15. Ho JE, Bittner V, DeMicco DA, Breazna A, Deedwania PC, Waters DD. Usefulness of heart rate at rest as a predictor of mortality, hospitalization for heart
failure, myocardial infarction, and stroke in patients with stable coronary heart
disease (data from the Treating to New targets [TNT] trial). Am J Cardiol. 2010;
105:905-911.
16. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL investigators. Heart rate as a prognostic risk factor in patients with coronary artery
disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup
analysis of a randomised controlled trial. Lancet. 2008;372:817-821.
17. Hjalmarson A, Gilpin EA, Kjekshus J, et al. Influence of heart rate on mortality
after acute myocardial infarction. Am J Cardiol. 1990;65:547-553.
18. Zuanetti G, Hernandez-Bernal F, Rossi A, Comerio G, Paoluccin G, Maggioni
AP. Relevance of heart rate as a prognostic factor in myocardial infarction: the
GISSI experience. Eur Heart J. 1999;1(suppl H):H52-H57.
19. Gillman MW, Kannel WB, Belanger A, D’Agostino RB. Influence of heart rate on
mortality among persons with hypertension: The Framingham study. Am Heart J.
1993;125:1148-1154.
20. Palatini P, Dorigatti F, Zaetta V, et al. Heart rate as a predictor of development
of sustained hypertension in subjects screened for stage 1 hypertension: the
HARVEST study. J Hypertension. 2006;24:1873-1880.
21. Palatini P, Thijs L, Staessen JA, et al; Systolic Hypertension in Europe (Syst-Eur)
trial investigators. Predictive value of clinic and ambulatory heart rate for mortality in elderly subjects with systolic hypertension. Arch Intern Med. 2002;162:
2313-2321.
22. Koloch R, Legler UF, Champion A, et al. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the
international verapamil-SR/trandolapril study (INVEST). Eur Heart J. 2008;29:
1327-1334.
23. Paul L, Hastie CE, Li WS, et al. Resting heart rate pattern during follow-up and
mortality in hypertensive patients. Hypertension. 2010;55:567-574.
24. Okin PM, Kjeldsen SE, Julius S, et al. All-cause and cardiovascular mortality in
relation to changing heart rate during treatment of hypertensive patients with electrocardiographic left ventricular hypertrophy. Eur Heart J. 2010;31:2271-2279.
25. Pocock SJ, Wang D, Pfeffer MA, et al. Predictors of mortality and morbidity in
patients with chronic heart failure. Eur Heart J. 2006;27:65-75.
26. Lechat P, Hulot J-S, Escolano S, et al; CIBIS II investigators. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II
trial. Circulation. 2001;103:1428-1433.
27. Gullestad L, Wikstrand J, Deedwania P, et al; MERIT-HF study group. What
resting heart rate should one aim for when treating patients with heart failure
with a beta-blocker? Experiences from the Metoprolol Controlled Release/
Extended Release Randomized Intervention Trial in Chronic Heart Failure
(MERIT-HF). J Am Coll Cardiol. 2005;45:252-259.
28. Beere PA, Glagov S, Zarins CK. Retarding effect of lowered heart rate on coronary atherosclerosis. Science. 1984;226:180-182.
29. Kaplan JR, Manuck SB, Adams MR, Weingand KW, Clarkson TB. Inhibition of
coronary atherosclerosis by propranolol in behaviorally predisposed monkeys
fed an atherogenic diet. Circulation. 1987;76:1364-1372.
30. Fox K, Ford I, Steg PG, Tendera M, Ferrari R; BEAUTIFUL investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic
Lancet. 2008;372:807-816.
31. Cucherat M. Quantitative relationship between resting heart rate reduction and
magnitude of clinical benefits in post-myocardial infarction: a meta-regression
of randomized clinical trials. Eur Heart J. 2007;28:3012-3019.
32. Kjekshus JK. Importance of heart rate in determining beta-blocker efficacy in
acute and long-term acute myocardial infarction intervention trials. Am J Cardiol. 1986;57:43F-49F.
34. Metra M, Torp-Pedersen C, Swedberg K, et al; COMET investigators. Influence
of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with
chronic heart failure: results from the COMET trial. Eur Heart J. 2005;26:22592268.
35. McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med. 2009;150:784-794.
36. Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized controlled
trials on the effect of magnitude of heart rate reduction on clinical outcomes in
patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol.
2008;101:865-869.
37. Swedberg K, Komadja M, Bohm M, et al. Ivabradine and outcomes in chronic
heart failure (SHIFT): a randomised placebo controlled study. Lancet. 2010;376:
875-885.
Keywords: causality; heart rate; ivabradine; risk factor
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FRÉQUENCE CARDIAQUE , FACTEUR DE RISQUE SUSCEPTIBLE D ’ ÊTRE TRAITÉ
DANS LA MALADIE CARDIOVASCULAIRE
L’association d’une fréquence cardiaque élevée à une augmentation de morbidité et de mortalité cardiovasculaire,
à la fois dans la population générale et chez des patients atteints de maladie cardiovasculaire, est de mieux en mieux
démontrée. De plus, les données actuelles suggèrent que, chez les patients atteints de maladie cardiovasculaire,
la fréquence cardiaque n’est pas simplement un marqueur pronostique mais plutôt un facteur de risque susceptible
d’être traité. La fréquence cardiaque remplit les principales conditions de définition d’un facteur de risque. Jusqu’ à
récemment, la relation de causalité entre la fréquence cardiaque et la maladie cardiovasculaire n’était pas certaine
malgré des preuves épidémiologiques importantes de liens entre la fréquence cardiaque, l’évolution cardiovasculaire
et les avantages apparents du ralentissement de cette fréquence. Ceci en raison de la difficulté à séparer les effets
sur la fréquence cardiaque de médicaments comme les bêtabloquants, de leurs autres effets sur le système cardiovasculaire. Des études récentes sur l’ivabradine, un médicament qui ralentit la fréquence cardiaque sans autre effet
cardiovasculaire direct, ont permis d’évaluer uniquement l’effet de la réduction de la fréquence cardiaque. Ces nouvelles données montrent de façon convaincante que ralentir la fréquence cardiaque est cliniquement bénéfique dans
l’insuffisance cardiaque et la maladie coronaire. Dans l’hypertension, la fréquence cardiaque a une importance pronostique mais il n’est pas encore démontré qu’il s’agisse d’un facteur de risque modifiable.
394
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‘‘
In coronary artery disease,
increased heart rate is accompanied by overproportional shortening of diastole. Since myocardial
perfusion takes place predominantly in diastole, a high heart rate
is the primary denominator of myocardial ischemia in the presence
of significant coronary artery stenosis. Furthermore, relaxation and
contraction at high heart rates
consume extensive energy, predisposing to ATP deficiency during exercise.”
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Heart rate response
to exercise: impact on
myocardial ischemia and
left ventricular function
b y M . B ö h m a n d C . U ke n a , G e r m a n y
E
L
Michael BÖHM, MD
Christian UKENA, MD
Universitätsklinikum des
Saarlandes, Klinik für Innere
Medizin III, Kardiologie,
Angiologie und Internistische
Intensivmedizin
Homburg/Saar
GERMANY
levated heart rate is associated with cardiovascular outcome in the general population and in patients with hypertension, ischemic heart disease, and heart failure. During exercise the autonomic nervous system increases heart rate in response to increasing peripheral demand. In nondiseased
hearts, increased rate is associated with enhanced myocardial contractility
(Bowditch effect). In coronary artery disease, on the other hand, increased rate
shortens diastole, thereby decreasing myocardial perfusion, with the risk of severe ischemia and angina. In heart failure, in addition to these mechanisms,
the Bowditch effect is impaired. The combination of a negative force-frequency relationship and myocardial ischemia during exercise increases ventricular filling pressures and respiratory work, causing hypoxia, dyspnea, and impaired exercise tolerance. Thus, in heart failure, the hemodynamically optimal
upper heart rate may be below the maximum achieved heart rate. Since heart
rate determines oxygen consumption and delivery, its modulation, as by the
If channel inhibitor ivabradine, strongly influences exercise tolerance, in particular in coronary artery disease and heart failure.
eart rate is a major determinant at rest and during exercise of the response
to increased oxygen demand by working skeletal muscles and other vital organs.1 Adaptation to increased physical activity is accomplished by an increase in cardiac output, which requires an increase in heart rate in addition to adaptation of stroke volume in response to exercise. In special conditions, heart rate can
afford to be low at rest when stroke volume is high (as in athletes), or is obliged to
be high when cardiac function is compromised (as in heart failure). Stimulation of
the sympathetic nervous system and withdrawal of parasympathetic activity during exercise increases heart rate (positive chronotropy), shortens atrioventricular
conduction (positive dromotropy), increases intraventricular conductivity (positive
bathmotropy), and enhances the force of contraction (positive inotropy).2-4
H
Michael Böhm, Universitätsklinikum
des Saarlandes, Klinik für Innere
Medizin III, Kardiologie, Angiologie
und Internistische Intensivmedizin,
Kirrberger Str 1, D-66424,
Homburg/Saar, Germany
The direct effects of heart rate on contractility were described in 1871 by the American physiologist Henry Pickering Bowditch (1840-1911), writing in German in the
course of a 3-year stay in Europe.5 In nondiseased hearts, contractility increases
with increases in rate. This positive Bowditch (or Treppe) effect is an important addition to sympathetic activation in adapting contractility and cardiac output to increased peripheral demand. When the heart rate response to exercise is subnormal,
as in chronotropic incompetence,6-9 the increase in cardiac output remains inade-
Heart rate response to exercise: impact on MI and LV function – Böhm and Ukena
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quate, due directly to the inadequate increase in heart rate,
but also to the impaired adaptation of inotropy to exercise-related increases in heart rate, resulting in abnormally low exercise performance and aerobic capacity.6 The crucial role of
heart rate is highlighted by the fact that maximal heart rate
during exercise and heart rate recovery are the most commonly used parameters in cardiology for assessing the effects
of rehabilitation10,11 and exercise training.12-14 Rate-adaptive cardiac pacing was developed to optimize exercise tolerance in
patients with chronotropic incompetence.7,15 In summary, exercise tolerance can be impaired by chronotropic incompetence, structural heart disease, or by both acting in concert.
Myocardial ischemia
In coronary artery disease, increased heart rate is accompanied by overproportional shortening of diastole.16 Since myocardial perfusion takes place predominantly in diastole, a
high heart rate is the primary denominator of myocardial ischemia in the presence of significant coronary artery stenosis.16 Furthermore, relaxation and contraction at high heart
rates consume extensive energy, predisposing to ATP deficiency during exercise. In critical coronary artery disease, this
can result in severe ischemia with angina as its typical clinical manifestation.16
During ischemia, in particular in the presence of high heart
rate, ventricular muscle develops diastolic dysfunction.17 The
resulting rise in filling pressure impairs exercise tolerance and
increases pulmonary wedge pressure, causing shortness of
breath.17 Compounding factors are an increase in pulmonary
stiffness, responsible for an increase in ventilatory work,18,19
and an increase in diffusion distance, when interstitial pulmonary edema develops into alveolar fluid accumulation in
advanced pulmonary edema. The result is intrapulmonary
shunting, resulting in decreased oxygen saturation,20,21 aggravation of clinical congestion, and decreasing exercise tolerance.22 Heart rate reduction with β-blockers23 or the If channel
inhibitor ivabradine,24,25 has been shown to reduce symptoms
in myocardial ischemia by lengthening diastole, prolonging
coronary perfusion, and reducing oxygen consumption. The
example of ivabradine demonstrates that the effect of heart
rate reduction is crucially and uniquely mechanistic: ivabradine is a pure If channel inhibitor with no other known cardiovascular effects.26
Left ventricular dysfunction
In the failing heart, the Bowditch effect is impaired, resulting
in a negative force-frequency relationship in vitro27,28 and in
vivo.29,30 Initial evidence to this effect came from isolated cardiac preparations from patients undergoing heart transplantation.27,28 Failing heart preparations also develop a relaxation
deficit at higher heart rates.27 Although a high heart rate is a
key clinical finding in severe heart failure, one must assume
that adaptation of contractility in response to the elevated heart
rate is also blunted.30 The situation is aggravated by the fact
396
that the mechanisms described for coronary artery disease
and ischemia are replicated in the failing heart, since this is an
energy-depleted organ. Systolic dysfunction with left ventricular dilatation results in an increase in wall tension. This in turn
increases extracoronary/coronary resistance, resulting in reduced oxygen delivery to the myocardium. These findings
were obtained in patients with systolic dysfunction. The situation in patients with a preserved ejection fraction is largely
unknown.
The optimal heart rate in elderly individuals31 or in exercising
heart failure patients is still debated.30 Experimental data suggest that heart rate limits should differ from those in individuals with normal myocardial function because the inverse
force-frequency relationship limits the ability of cardiac output to increase exercise tolerance.27-30 In addition, the deleterious effects of oxygen deficiency at high heart rates persist
in coronary artery disease or impaired left ventricular function, prompting speculation that high heart rates compound
deterioration in myocardial function. In particular, cardiac pacemakers could be set to different parameters in patients with
heart failure and those with normal left ventricular function.30
Cardiac pacing at higher rates has been shown to produce
progressive remodeling, in particular in patients with impaired
left and/or right ventricular function.31,32
A study in patients requiring pacemaker therapy compared
those with impaired and normal left ventricular function.30 In
those with normal left ventricular function, pacing at rates from
70 to 160 bpm showed a close association with increases
in cardiac output as determined by maximum oxygen uptake
(VO2max). Up to maximal exercise tolerance, the increases
in heart rate ran parallel to those in VO2max. However, in individuals with heart failure, pacing only produced a parallel increase in VO2max from 70 to 120 bpm, after which VO2 leveled off while heart rate continued to increase and patients
continued to exercise. This finding indicates that in many patients with chronotropic incompetence the optimal upper rate
is below the maximal upper rate limit. In patients with pacemakers for chronotropic incompetence, optimal heart rate was
86% of age-predicted values at ejection fraction >55%, but
only 75% of age-predicted values at ejection fraction <45%.
Figure 1 summarizes the mechanisms of impaired exercise
tolerance at high heart rates.
When patients develop dyspnea, the adverse effects of elevated heart rate, such as shorter diastole and ischemia, may
be partly responsible for reduced exercise tolerance. A similar situation has been described in patients with critical low
output due to acute decompensated heart failure. The positive inotropic effect of the β-adrenoceptor agonist dobutamine is often used to increase cardiac output and lower left
ventricular filling pressure in acute heart failure.33 However, as
a β-adrenergic agonist, it also increases heart rate to a variable extent,33 which can have adverse effects on outcome in
HEART
acute heart failure.34 Ivabradine, on the other hand—administered in an attempt to restore chronotropic-inotropic balance—lowered heart rate while leaving inotropy unaffected in
a patient with severe heart failure on dobutamine: doses of 5
to 7.5 mg twice daily lowered heart rate from 110 to 72 bpm
while increasing cardiac output, stroke volume, and oxygen
saturation, and decreasing systemic vascular resistance.34 This
case report provides proof of concept that heart rate reduction in severe heart failure is not necessarily associated with
a reduction in cardiac output, but can actually increase cardiac output and myocardial efficiency, resulting in improved
hemodynamics.
Elevated resting heart rate is a general marker of morbidity.
It is associated with cardiovascular mortality in normal individuals,35,36 and in those with hypertension,37 coronary artery
disease,38 and in particular heart failure, where an additional 5 bpm is associated with a 16% increase per year in the
composite outcome of cardiovascular death and hospitaliza-
Sympathetic
activation
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heart rate recovery after exercise, while leaving the absolute
increase in heart rate intact.43 Denervation reduces excessive
sympathetic drive without inducing chronotropic incompetence and appears to restore sympathetic-parasympathetic
balance during rest.45 More studies are required to determine
whether improved heart rate recovery after exercise is associated with better outcome in conditions such as severe hypertension, ischemic heart disease and, in particular, heart
failure, where such data are completely lacking. We need to
know whether outcome in such common and serious conditions can be enhanced by modulating the exercise heart rate,
whether pharmacologically with β-blockers and ivabradine,
chronic endurance training, or sympathetic denervation.
Conclusion
Heart rate patterns at rest and during exercise predict cardiovascular outcomes. Since heart rate determines oxygen
consumption and delivery, its modulation by ivabradine strongly influences exercise tolerance, in particular during ischemia.
This property makes the drug a valuable
component in the armamentarium of coronary therapy. Chronic heart rate reduction
reduces cardiovascular hospitalizations in
Dyspnea
heart failure patients in sinus rhythm at heart
rates ⱖ70 bpm,46 and cardiovascular death
and all cardiovascular hospitalizations at
heart rates ⱖ75 bpm.47
Heart rate regulates cardiovascular function
and, in particular, cardiac output during exIncreased respiratory work
ercise and other output conditions. ReguHypoxia
lation
by the autonomic nervous system,
Hypercapnia
along with activation of sympathetic outflow and reduction of parasympathetic activity, increases heart rate and cardiac output, but also determines training condition
and cardiovascular comorbidities. Heart rate
elevation is a determinant of cardiovascular
outcome
in the general population, and in
Figure 1. Mechanisms of dyspnea in heart failure.
patients with hypertension, ischemic heart
Activation of the sympathetic nervous system during exercise increases phase 4 depolarization and increases heart rate. During exercise in heart failure, the increased heart rate shortens diastole, leading
disease, and heart failure. Delayed return of
to an increase in right ventricular filling pressures, which in turn increases respiratory work, hypoxia, and
heart rate to resting levels after exercise is
hypercapnia. These changes signal to the brain stem that diuresis is taking place thereby triggering
a risk factor for cardiovascular death, and in
dyspnea. In chronic heart failure altered chemoreceptor sensing leads to dyspnea at lower hypoxia
thresholds. Thus, there are vicious cycles in the interaction between sympathetic activation, heart rate,
particular, sudden death. In heart failure the
heart, lung, and central nervous system.
force-frequency relationship reverses from
tion for heart failure.39 Use of the exercise heart rate in risk positive to negative. As a result, increases in heart rate reduce
prediction is more complicated. While the absolute increase in contractility, increase myocardial stiffness, impair exercise tolheart rate appears associated with a good prognosis,40,41 im- erance, and precipitate dyspnea and cardiac congestion.
paired recovery of heart rate after exercise has proved an important denominator of cardiovascular outcomes.42 Delayed Clinical studies have provided pathophysiological proof of
decrease in heart rate after exercise is associated with an in- the benefits of heart rate reduction in conditions such as imcrease in cardiovascular death and sudden cardiac death in paired left ventricular function and heart failure. We need furparticular.42 Interestingly, a novel technique to treat resistant ther studies using novel techniques such as sympathetic denhypertension by renal sympathetic denervation produces not ervation if we want to fully elucidate the role of heart rate not
only a marked reduction in blood pressure,43,44 but also faster only at rest, but during and after exercise. I
Heart rate
397
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References
1. Reil JC, Custodis F, Swedberg K, et al. Heart rate reduction in cardiovascular
disease and therapy. Clin Res Cardiol. 2011;100:11-19.
2. Goldsmith RL, Bloomfield DM, Rosenwinkel ET. Exercise and autonomic function. Coron Artery Dis. 2000;11:129-135.
3. Arai Y, Saul JP, Albrecht P, et al. Modulation of cardiac autonomic activity during
and immediately after exercise. Am J Physiol. 1989;256:H132-H141.
4. Fletcher GP, Balady G, Froelicher VF, Hartley LH, Haskell WL, Pollock ML. Exercise standards: a statement for healthcare professionals from the American
Heart Association. Circulation. 1995;91:580-615.
5. Bowditch HP. [On the peculiarities of excitability which the fibres of cardiac
muscle show. (German)]. Ber Sächs Ges (Akad) Wiss. 1871;23:652-689. English version: http://www.iiftc.de/publications/bowditch_1.pdf (accessed June
25, 2012).
6. McGregor M, Klassen GA. Observations on the effect of heart rate on cardiac
output in patients with complete heart block at rest and during exercise. Circ
Res. 1964;15(suppl 2):215-224.
7. McElroy P, Janicki J, Weber K. Physiologic correlates of the heart rate response
to upright isotonic exercise: relevance to rate-responsive pacemakers. J Am
Coll Cardiol. 1988;11:94-99.
8. Ikkos D, Hanson JS. Response to exercise in congenital complete atrioventricular block. Circulation. 1960;22:583-590.
9. Edhag O, Zettenquist S. Peripheral circulatory adaptation to exercise in restricted cardiac output. A hemodynamic and metabolic study in patients with complete heart block and artificial pacemaker. Scand J Clin Lab Invest. 1968;21:
123-135.
10. Taylor RS, Brown A, Ebrahim S, et al. Exercise-based rehabilitation for patients
with coronary heart disease: systematic review and meta-analysis of randomized controlled trials. Am J Med. 2004;116:682-692.
11. Jolly M, Brennan D, Cho L. Impact of exercise on heart rate recovery. Circulation. 2011;124:1520-1526.
12. Convertine VA, Adams WC. Enhanced vagal baroreflex response during 24 h
after acute exercise. Am J Physiol. 1991;260:R570-R575.
13. Kingwell BA, Dart AM, Jennings GL, Korner PL. Exercise training reduces the
sympathetic component of the blood pressure-heart rate baroreflex in man.
Clin Sci (Lond). 1992;82:357-362.
14. Shetler K, Marcus R, Froelicher VF, et al. Heart rate recovery: validation and
methodologic issues. J Am Coll Cardiol. 2001;38:1980-1987.
15. Alt E, Schleg M, Matula M. Intrinsic heart rate response as a predictor of rateadaptive pacing benefit. Chest. 1995;107:925-930.
16. Heusch G. Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents. Br J Pharmacol. 2008;153:1589-1601.
17. Johnson BD, Beck KC, Olson LJ, et al. Ventilatory constraints during exercise
in patients with chronic heart failure. Chest. 2000;117:321-332.
18. Mancini DM, Henson D, La Manca J, Donchez L, Levine S. Benefit of selective
respiratory muscle training on exercise capacity in patients with chronic congestive heart failure. Circulation. 1995;91:320-329.
19. Mancini DM, Henson D, La Manca J, Levine S. Evidence of reduced respiratory muscle endurance in patients with heart failure. J Am Coll Cardiol. 1994;
24:972-981.
20. Johnson RL. Gas exchange efficiency in congestive heart failure. Circulation.
2000;101:2774-2776.
21. Johnson RL. Gas exchange efficiency in congestive heart failure II. Circulation.
2001;103:916-918.
22. Agostoni PG, Bussotti M, Palermo P, Guazzi M. Does lung diffusion impairment
affect exercise capacity in patients with heart failure? Heart. 2002;88:453-459.
23. Daly CA, Clemens F, Sendon JL, et al; Euro Heart Survey Investigators. The
initial management of stable angina in Europe. From the Euro Survey: a description of pharmacological management and revascularisation strategies initiated within the first month of presentation to a cardiologist in the Euro Heart
Survey of stable angina. Eur Heart J. 2005;26:1011-1022.
24. Tardif JC, Ford I, Tendera, Bourassa MG, Fox K; INITIATIVE Investigators. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients
with chronic stable angina. Eur Heart J. 2005;26:2529-2536.
25. Tardif JC, Ponikowski P, Kahan T; ASSOCIATE study investigators. Efficacy of
the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month randomised, placebo-controlled trial. Eur
Heart J. 2009;30:540-548.
26. DiFrancesco D, Camm AJ. Heart rate lowering by specific and selective If current inhibition with ivabradine. A new therapeutic perspective in cardiovascular disease. Drugs. 2004;64:1757-1765.
27. Böhm M, La Rosee K, Schmidt U, Schulz C, Schwinger RHG, Erdmann E.
Force-frequency relationship and inotropic stimulation in the nonfailing and failing human myocardium: implications for the medical treatment of heart failure.
Clin Investig. 1992;70:421-425.
28. Hasenfuss G, Reinecke H, Studer R, et al. Relation between myocardial function and expression of sarcoplasmatic reticulum Ca2+-ATPase in failing and nonfailing human myocardium. Circ Res. 1994;75:434-442.
29. Leclercq C, Walker S, Linde C, et al. Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic
atrial fibrillation. Eur Heart J. 2002;23:1780-1787.
30. Kindermann M, Schwaab B, Finkler N, Schaller S, Böhm M, Fröhlig G. Defining
the optimum upper heart rate limit during exercise. Eur Heart J. 2002;23:13011308.
31. Tanaka H, Monahan K, Seals D. Age-predicted maximal heart rate revisited.
J Am Coll Cardiol. 2001;37:153-156.
32. Kindermann M, Hennen B, Jung J, Geisel J, Böhm M, Fröhlig G; Homburg Biventricular Pacing Evaluation (HOBIPACE). Biventricular versus conventional
right ventricular stimulation for patients with standard pacing indication and left
ventricular dysfunction. J Am Coll Cardiol. 2006;10:1927-1937.
33. Eklayam U, Tasissa G, Binanay C, et al. Use and impact of inotropes and vasodilatatory therapy in hospitalized patients with severe heart failure. Am Heart J.
2007;153:98-104.
34. Link A, Reil JC, Selejan S, Böhm M. Effect of ivabradine in dobutamine induced
sinus tachycardia in a case of acute heart failure. Clin Res Cardiol. 2009;98:
513-515.
35. Levy RL, White PD, Stroud WD. Transient tachycardia: prognostic significance
alone and in association with transient hypertension. JAMA. 1945;129:585-588.
36. Kannel WB, Kannel C, Paffenbarger RS Jr, Cupples LA. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J. 1987;113:1489-1494.
37. Kolloch R, Legler UF, Champion A, et al. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the
INternational VErapamil-SR/trandolapril STudy (INVEST). Eur Heart J. 2008;
29:1327-1334.
38. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL investigators. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup
39. Böhm M, Swedberg K, Komajda M, et al; SHIFT investigators. Heart rate as a
risk factor in chronic heart failure (SHIFT): the association between heart rate
and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376:
886-894.
40. Ellestad MH, Wan MK. Predictive implications of stress testing: follow-up of 2700
subjects after maximum treadmill stress testing. Circulation. 1975;51:363-369.
41. Sandvik L, Erikssen J, Ellestad MH, et al. Heart rate increase and maximal heart
rate during exercise as predictors of cardiovascular mortality: a 16-year followup study of 1960 healthy men. Coron Artery Dis. 1995;6:667-679.
42. Lauer MS, Okin PM, Larson MG, Evans J, Levy D. Impaired heart rate response
to graded exercise: prognostic implications of chronotropic incompetence in
the Framingham Heart Study. Circulation. 1996;93:1520-1526.
43. Cole C, Blackstone E, Pashkow F, Snader C, Lauer M. Heart rate recovery immediately after exercise as a predictor of mortality. N Engl J Med. 1999;341:
1351-1357.
44. Ukena CM, Kindermann I, Barth C, et al. Cardiorespiratory response to exercise after renal sympathetic denervation in patients with resistant hypertension.
J Am Coll Cardiol. 2011;58:1176-1182.
45. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M. Renal sympathetic denervation in patients with treatment-resistant hypertension
(The Symplicity HTN-2-Trial): a randomised controlled trial. Lancet. 2010;376:
1903-1909.
46. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic
heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;
376:875-885.
47. Böhm M, Borer J, Ford I, et al. Heart rate at baseline influences the effect of
ivabradine on cardiovascular outcomes in chronic heart failure. Analysis from
the SHIFT study. Clin Res Cardiol. 2012 May 11. Epub ahead of print.
Keywords: exercise; heart rate; heart rate reduction; ivabradine; left ventricular dysfunction; myocardial ischemia
398
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RÉPONSE DE LA FRÉQUENCE CARDIAQUE À L’EFFORT :
EFFET SUR L’ ISCHÉMIE MYOCARDIQUE ET LA FONCTION VENTRICULAIRE GAUCHE
Dans la population générale et chez les patients hypertendus, coronariens et insuffisants cardiaques, l’élévation de
la fréquence cardiaque est associée à des évènements cardiovasculaires. Au cours de l’effort, le système nerveux
autonome augmente la fréquence cardiaque en réponse à l’augmentation de la demande périphérique. Chez les patients non cardiaques, l’augmentation de la fréquence est associée à une contractilité myocardique accrue (effet
Bowditch). À l’inverse, dans la maladie coronaire, l’augmentation de la fréquence raccourcit la diastole, diminuant
ainsi la perfusion myocardique, avec le risque d’une ischémie et d’un angor sévères. Dans l’insuffisance cardiaque,
en plus de ces mécanismes, l’effet Bowditch est diminué. L’association d’une relation force-fréquence négative et
d’une ischémie myocardique au cours de l’effort augmente les pressions de remplissage ventriculaires et le travail
respiratoire, provoquant une hypoxie, une dyspnée et une altération de la tolérance à l’effort. Ainsi, dans l’insuffisance
cardiaque, la fréquence cardiaque supérieure hémodynamiquement optimale peut être en dessous de la fréquence
cardiaque maximale réalisée. Puisque la fréquence cardiaque détermine la consommation et l’apport en oxygène,
sa modulation, comme par l’ivabradine, un inhibiteur du canal If , influe fortement sur la tolérance à l’effort, en particulier dans la maladie coronaire et l’insuffisance cardiaque.
399
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‘‘
Immediately after the termination of exertion, sympathetic withdrawal and increased parasympathetic tone to the sinoatrial node
combine to cause a rapid decline
in HR. A delayed recovery of HR
after exertion is independently associated with increased all-cause
mortality in a variety of asymptomatic and diseased populations.
In contrast, highly trained athletes
often display a rapid and profound
drop in HR of ⱖ30 to 50 beats during the first minute of recovery from
strenuous exertion.”
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Chronotropic incompetence
and functional capacity
in cardiovascular disease
b y D . W. K i t z m a n , U S A
T
Dalane W. KITZMAN, MD
Cardiology Section
Wake Forest University
School of Medicine
Winston-Salem
USA
he important role of heart rate (HR) in cardiovascular disease is well
established, but attention to HR has often been limited to discussion
of resting HR or HR at peak exercise. This paper highlights the importance of evaluating HR profiles during and after exercise. The ability of the
heart to increase HR to tightly match cardiac output to metabolic demand
during exercise is critical to physical performance. The increase in HR during exercise is the largest contributor to the ability to perform physical work
and therefore is an important determinant of quality of life. The high prevalence of impaired exercise HR response and its easy assessment in clinical
practice provides the rationale for screening for inadequate HR responses
during exercise testing and recovery after exercise. This condition is potentially treatable, and its management can lead to significant improvements in
exercise tolerance and quality of life.
Contribution of heart rate to exercise performance
he ability to perform physical work is an important determinant of quality of
life1 and is enabled by an increase in oxygen uptake (VO2).2 During maximal
aerobic exercise in healthy persons, VO2 increases approximately 4-fold.2 This
is achieved by a 2.2-fold increase in heart rate (HR), a 0.3-fold increase in stroke
volume, and a 1.5-fold increase in arteriovenous oxygen difference.2 The increase
in HR is thus the largest contributor to the ability to perform sustained aerobic exercise.3 Therefore, an abnormal HR response to exercise can be the primary cause
of, or a significant contributor to, severe, symptomatic exercise intolerance.
T
Heart rate control and recovery
Dr Dalane W. Kitzman, Cardiology
Section, Wake Forest University
School of Medicine, Medical Center
Boulevard, Winston-Salem, NC
27157-1045
400
Instantaneous HR reflects the dynamic balance between the sympathetic and parasympathetic divisions of the autonomic nervous system. An intact HR response
is critical to tightly match a subject’s cardiac output to metabolic demands during
exertion.4 Failure to achieve maximal HR, inadequate submaximal HR, or HR instability during exertion are all examples of impaired chronotropic response. These conditions are relatively common in patients with sick sinus syndrome, atrioventricular
block, coronary artery disease, and heart failure (HF).4 Immediately after the termination of exertion, sympathetic withdrawal and increased parasympathetic tone to
the sinoatrial node combine to cause a rapid decline in HR. A delayed recovery of
HR after exertion is independently associated with increased all-cause mortality in
a variety of asymptomatic and diseased populations.5,6 In contrast, highly trained
Chronotropic incompetence and functional capacity – Kitzman
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Men
Women
220
y=208.7-0.73x
y=208.1-0.77x
r=–0.90
r=–0.90
Maximal heart rate (bpm)
180
160
140
120
20
30
40
50
60
70
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declines by 5 to 6 bpm for each decade of age such that the
resting HR of an 80-year-old is not much slower than the intrinsic HR.10 This indicates that there is reduced and minimal parasympathetic tone at rest. This is supported by the
fact that the increase in HR after atropine in an older person
is less than half that in the young.12
200
10
R AT E
80
90
Age (year)
Figure 1. Relationship between age and maximal heart rate
(group mean values) obtained from a meta-analysis including
18 712 subjects.
From these data, a new prediction equation was proposed: peak heart rate =
206 – (0.88 × age).
Adapted from reference 17: Tanaka et al. JACC. 2001;37:153-156. © 2001,
American College of Cardiology.
athletes often display a rapid and profound drop in HR of ⱖ30
to 50 beats during the first minute of recovery from strenuous
exertion.7 The Framingham Offspring study and the MRFIT
study (Multiple Risk Factor Intervention Trial) demonstrated
that a delayed HR recovery is an independent predictor of
all-cause death in asymptomatic persons.8 In an important recent study, Jolly et al showed that exercise training improved
HR recovery in a group of over 1000 patients with cardiovascular disease undergoing phase 2 cardiac rehabilitation.9 Patients with abnormal HR recovery at baseline and whose HR
recovery was normalized with exercise training had a mortality similar to that of individuals with normal baseline HR
recovery.
Effect of age and gender on the maximal HR
response to exercise
There is no change in resting HR with adult aging. However,
in healthy men and women, there is a marked age-related
decrease in maximum HR in response to exercise that is inexorable and predictable and occurs in other mammalian
species as well as humans.3,10,11 The age-related decline in
maximal HR is the most substantial biological age–related
change in cardiac function, both in magnitude and consequence.3,12,13 It is primarily responsible for the age-related decline in peak aerobic exercise capacity.3,13 Starting from early
adulthood, maximal HR declines with age at a rate of approximately 0.7 beats per minute (bpm) per year in healthy sedentary, recreationally active, and endurance exercise–trained
adults.14 Though the mechanism(s) of this decline are not fully understood, dual-blockade studies show that intrinsic HR
There are also significant alterations in the sympathetic influence on HR response to exercise with aging, with increased
circulating catecholamines and reduced responsiveness.12
Doses of isoproterenol that increase HR by 25 bpm in young
healthy men produce an increase of only 10 bpm in older persons.12 The normal, age-related decline in maximal HR during
exercise is not significantly modified by vigorous exercise training, suggesting that it is not due to the age-related decline in
physical activity level.10 It also does not appear to be due to
inadequate sympathetic stimulation, since both serum norepinephrine and epinephrine are increased rather than decreased at rest in healthy elderly individuals. Furthermore, with
exertion or stress, catecholamines increase even more than in
young persons under the same stress conditions.
The traditional equation to predict normal maximal HR (220 –
age), was developed based on studies primarily conducted
in middle-aged men, some of whom had known coronary artery disease and were taking β-blockers.15,16 This equation has
large intersubject variability with a standard deviation of 11
bpm17 that increases to 40 bpm in patients with coronary heart
disease receiving β-blockers.18 An alternative formula from
Tanaka et al (208 – 0.7 × age) is becoming more accepted
for determining age-predicted maximal HR (APMHR) even
though it may still underpredict APMHR in older adults (Figure 1).17
Several earlier studies suggested that gender affects the HR
trajectory during exercise and recovery, and that the traditional equation (220 – age) overestimates maximal HR in younger
women, but underestimates it in older women.15,17 A metaSELECTED
APHRR
APMHR
bpm
CI
HF
HFpEF
HFrEF
HR
MCR
MRFIT
RER
VE/VCO2
VO2
age-predicted heart rate reserve
age-predicted maximal heart rate
beat per minute
chronotropic incompetence
heart failure
heart failure and preserved ejection fraction
heart failure and severely reduced ejection fraction
heart rate
metabolic-chronotropic relationship
Multiple Risk Factor Intervention Trial
respiratory exchange ratio
ventilatory efficiency
oxygen uptake
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Not β-blocked group
β-Blocked group
n: 90 patients
35
30
Peak VO2 (ml/kg)
30
Peak VO2 (ml/kg)
n: 549 patients
35
25
20
15
10
r=0.630
P<0.0001
25
20
15
10
0
r=0.572
P<0.0001
0
20
60
100
140
20
60
∆HR (bpm)
100
140
∆HR (bpm)
Figure 2. Relationship between exercise-induced change in heart rate (∆HR) and peak oxygen consumption (peak VO2) in 웁-blocked
and not 웁-blocked patients.
There is a significant relationship between ∆HR during exercise and peak VO2 in patients with heart failure and severely reduced ejection fraction (HFrEF), but there is
no significant difference in this relationship between patients taking 웁-blockers (right panel) and those not taking them (left panel). “r” values are for Spearman analysis.
Adapted from reference 24: Magri et al. Cardiovasc Ther. 2012;30:100-108. © 2010, Blackwell Publishing Ltd.
analysis indicated that maximal HR is unaffected by gender.17
A large prospective study in over 5000 asymptomatic women
showed that the traditional equation significantly overestimates
maximal HR and thus proposed a new equation where maximal HR = 206 – (0.88 × age).15
Brawner et al18 demonstrated that the 220 – age equation is
not valid in patients with coronary heart disease taking βadrenergic blockade therapy and subsequently developed the
equation [164 – (0.7 × age)] for this population.
ue exercising until true symptom-limited (exhaustive) maximal
levels are achieved. Symptoms and subjective ratings of perceived exertion (RPE) can provide an estimate of exertion levels. However, the respiratory exchange ratio (RER, ie, volume
of carbon dioxide produced/volume of oxygen consumed)
obtained from expired respiratory gas analysis at peak exertion during the exercise test, is the most definitive, objective,
reliable, clinically available measure of the physiological level
of effort during exercise. RER is a continuous variable, ranging from <0.85 at quiet rest to >1.20 during intense, exhaustive exercise. Higher RER values increase confidence that
Definition, criteria, and measurement of
chronotropic incompetence
However, before concluding that a patient has CI, it is important to consider their level of effort and reasons for terminating
the exercise test. Patients should be encouraged to contin-
402
CI BB
CI No BB
No CI BB
No CI No BB
170
150
130
Heart rate
Chronotropic incompetence (CI) is most commonly diagnosed
when HR fails to reach an arbitrary percentage (either 85%,
80%, or less commonly, 70%) of the APMHR (usually based
on the 220 – age equation described earlier) obtained during an incremental dynamic exercise test.14,19,20 CI can also
be determined by the HR reserve, which is the change in HR
from rest to peak exercise during an exercise test. Since the
proportion of HR achieved during exercise depends in part
on the resting HR, the chronotropic response to exercise can
also be assessed as the fraction of the HR achieved at maximal effort. Thus, adjusted HR reserve, determined from the
change in HR from rest to peak exercise divided by the difference between resting HR and APMHR has been commonly used.21 The majority of studies have used failure to obtain
ⱖ80% of the HR reserve obtained during a graded exercise
test as the primary criterion for CI.
110
90
70
50
0
5
10
15
Exercise time (minutes)
Figure 3. Heart rate slopes for subjects with heart failure with and
without chronotropic incompetence stratified by 웁-blocker use.
In patients with heart failure, 웁-blockers (BB) do not significantly impact the
relationship between heart rate and exercise time, regardless of whether
chronotropic incompetence (CI) is present.
Adapted from reference 25: Jorde et al. Eur J Heart Fail. 2008;10:96-101.
© 2007, European Society of Cardiology.
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maximal effort was achieved while RER <1.05 at peak exercise suggests submaximal effort and should lead to caution in diagnosing CI.
sertion for CI by reprogramming or suspending the device with
a magnet, taking care to ensure the patient is not completely
pacemaker-dependent beforehand.
Wilkoff et al utilized the expired gas analysis technique to more
objectively evaluate CI using the relationship between HR and
VO2 during exercise.22 With this approach, the metabolicchronotropic relationship (MCR) is calculated from the ratio of
the HR reserve to the metabolic reserve during submaximal
exercise. The advantage of using the MCR is that it adjusts
for age, physical fitness, and functional capacity and it appears
to be unaffected by the exercise testing mode or protocol. In
normal adults, the percentage of HR reserve achieved during
exercise equals the percentage of metabolic reserve achieved.
This physiological concept allows determination of whether
a single HR achieved at any point during an exercise study is
consistent with normal chronotropic function. A specific CI exercise testing protocol that evaluates the MCR relationship
from 2 stages of a treadmill protocol has been employed in
some laboratories.22
Contribution of impaired HR response to exercise intolerance in HF
24
Without CI
With CI
22
20
VO2 peak (mL kg–1 min–1)
Effect of medications and other confounding
influences on chronotropic incompetence
A hallmark of chronic HF is a markedly reduced capacity for
physical exertion, with a subsequent 15% to 40% reduction
in peak VO2 compared with healthy matched controls.29 We
have shown that patients with HF and preserved ejection fraction (HFpEF) have similar reductions in peak VO2, exercise
time, ventilatory anaerobic threshold, and 6-minute walk distance as patients with HF and severely reduced ejection fraction (HFrEF).30
18
16
14
Many commonly used cardiovascular medications including
β-blockers, digitalis, calcium channel blockers, amiodarone,
and others can confound the determination of CI. β-Blockers
may result in pharmacologically induced CI and obscure identification of an underlying intrinsic abnormality in neural balance.
In one study,23 a suitable threshold for CI in HF patients using
β-blockers was found to be ⱕ62% of APHRR. Using this lower HR threshold, CI could be reliably identified and was found
to be an independent predictor of death.23 Care should be taken before applying these criteria to ensure that the patient
is on a nontrivial dose and is compliant with the medication.
The use of separate CI criteria for patients taking β-blocker
medications has been challenged by other studies that failed
to demonstrate any effect of β-blockers, including at high
dose, on the occurrence of CI.24 Figure 2 shows the similar
relationship between HR reserve and VO2 at peak exercise
(peak VO2) in HF patients who were either taking or not taking
β-blockers. Similarly, Jorde and colleagues examined the relationship between exercise time and HR during treadmill exercise testing in HF patients.25 As seen in Figure 3, the HR
slope is abnormal in HF patients with CI, yet β-blockers have
no impact on this relationship in these patients.26 Chronic treatment of HF patients with β-blockers may paradoxically improve chronotropic response by decreasing sympathetic tone
and/or by increasing β-receptor activity.27 Furthermore, there
appears to be potentially important differences between βblockers in the relationship between HR reduction and exercise capacity.28
Reduced peak VO2 in HFrEF as well as HFpEF patients is due
to a combination of reduced peak cardiac output and arterialvenous oxygen content difference.31 The latter is related to
abnormalities of skeletal muscle and vascular function that
limit the exercise intolerance associated with HF. The reduced
cardiac output response in HF patients can be due to reduced
stroke volume and reduced HR during peak exercise. In
HFpEF patients, reduced peak HR appears to be a stronger
contributor to reduced peak VO2 than stroke volume.31 Whereas maximal HR during exercise may be only mildly reduced,
HR reserve is often blunted more substantially in HF patients
owing to the sympathetically driven increase in resting HR.32
Criteria for the diagnosis of CI in the presence of atrial fibrillation have not been established. Exercise testing can be used
to assess the adequacy of response following pacemaker in-
We recently demonstrated that HR reserve was significantly
correlated (r=0.40) with peak VO2 in elderly HF patients with
either HFrEF or HFpEF (Figure 4).33 Furthermore, the increase
12
10
8
6
4
0
20
40
60
80
100
HRR (bpm)
Figure 4. Relationship of heart rate reserve (HRR) to peak exercise oxygen consumption (peak VO2) in older patients with heart
failure and either severely reduced (HFrEF) or preserved ejection
fraction (HFpEF), with and without chronotropic incompetence (CI).
There is a significant correlation between HRR and peak VO2 in those with CI
(R=0.39; P=0.04) and those without CI (R=0.41; P=0.01).
Adapted from reference 33: Brubaker et al. J Cardiopulm Rehabil. 2006;26:
86-89. © 2006, Lippincott Williams & Wilkins Inc.
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in HR during exercise accounted for an appreciable portion
(ie, 15%) of the observed differences in peak VO2. This was
unchanged even after accounting for medications, including
β-blockers. These findings were confirmed and expanded by
Borlaug et al, who reported that HFpEF patients also had a
slower HR rise and impaired HR recovery, indicating abnormal autonomic function (Figure 5).34
Mechanisms of chronotropic incompetence in
heart failure
160
CI in HF is associated with a 50% reduction in β-adrenergic
receptor density in the left ventricular myocardium, downregulation of β-receptors, and desensitization assessed by
decreased responsiveness to norepinephrine infusion and exercise.36 HF patients also have significant sinus node remodeling.37 The relationship between change in HR and change
in plasma norepinephrine is significantly correlated with anaerobic threshold, peak VO2, and ventilatory efficiency (ventilatory
equivalent to carbon dioxide output slope [VE/VCO2]).38
Heart rate (bpm)
140
Control
120
HFpEF
100
80
Effect of exercise training on chrotropic
incompetence in heart failure
60
0
200
400
600
Exercise duration (s)
Figure 5. Heart rate profiles during and after cycle ergometry in
patients with heart failure and preserved ejection fraction (HFpEF)
compared with age- and gender-matched subjects with similar
comorbidities including left ventricular hypertrophy (control).
These data demonstrate the delayed and attenuated heart rate response often
seen in chronotropically impaired heart failure patients.
Adapted from reference 34: Borlaug et al. Circulation. 2006;114:2138-2147.
© 2006, American Heart Association, Inc.
Prevalence of chronotropic incompetence in
heart failure
The reported prevalence of CI within the HF population has
varied considerably, with a range of 25% to 70%. This substantial variability is likely to be influenced by the criteria employed to determine CI as well as differing patient characteristics. In older HFrEF patients, Witte et al found that 103 of
237 (43%) HF patients met the criterion of <80% of APMHR,
whereas 170 of 237 (72%) met the criterion of <80% of
APHRR.35 Patients taking β-blockers were more likely to have
CI than those not taking β-blockers when <80% APMHR was
used (49% vs 32%, respectively) or <80% APHRR was used
(75% vs 64%, respectively). When the criterion of ⱕ62%
APHRR was used for HF patients on β-blocker therapy, a significantly smaller percentage (22%) of patients were diagnosed
with CI.23
We evaluated the prevalence of CI in older (ⱖ60 years) HFrEF
and HFpEF patients as well as in age-matched healthy subjects using ⱕ80% of APMHR and the Wilkoff approach.33
While CI was uncommon in healthy older adults (just 2 out of
404
28 subjects, or 7%), the prevalence of CI was relatively similar between older HFrEF (12 of 46, or 26%) and HFpEF (11
of 56, or 19%) patients. Phan et al reported that the prevalence of CI increased to 63% of HFpEF patients when the criterion of 80% of HR reserve was used as the definition of CI.26
Thus, a significant portion (one-third or more depending on
the criteria employed) of both HFrEF and HFpEF patients have
significant CI, which contributes to their exercise intolerance.
In addition to many other health benefits, endurance exercise
training in healthy individuals results in favorable changes in
chronotropic function such as decreased resting and submaximal exercise HR, as well as a more rapid decline in postexercise HR. Most of these HR adaptations appear to be related to an alteration in the balance of the sympathetic and
parasympathetic influence of the autonomic nervous system.
Endurance exercise training generally improves exercise tolerance in HF patients through a variety of potential central and
peripheral mechanisms. A meta-analysis of 35 randomized
studies of exercise training in HFrEF patients indicated that
peak HR increased by an average of 4 bpm, or 2.5% of the
pretraining level.39 Keteyian et al demonstrated that after 24
weeks of endurance exercise training, peak exercise HR increased by 7% (approximately 9 bpm) yet remained unchanged
in a nonexercise control group.40 Furthermore, the traininginduced increase in peak HR accounted for 50% of the increase in peak VO2 in the exercise training group.
While alterations in β-adrenergic receptor sensitivity may explain these findings, the mechanisms responsible for the improved chronotropic response with exercise training in HFrEF
are not known. We recently reported that exercise training
in HFpEF patients improved peak HR, but this was counterbalanced by a reduced stroke volume response, such that
cardiac output did not change with training.41 Thus, in HFpEF,
improved CI may not contribute to improved exercise capacity, which appears to be primarily due to improved peripheral mechanisms. More information is needed regarding the
impact of exercise training on the chronotropic response of
HFrEF and HFpEF patients.
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Effect of rate-adaptive pacing on chronotropic
incompetence and exercise performance in
heart failure
There is a linear relationship between HR and VO2 during exercise in a variety of patient populations, including patients
with HF.42 Not surprisingly, rate-adaptive pacing has been
shown to enhance functional capacity in a variety of patients
with CI.22,43 However, despite the prominent role of abnormal
HR responses in HF, there has been relatively little attention
to rate-adaptive pacing in this specific population.44,45
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jectively measured exercise intolerance.26,33,34 One trial was
designed to help determine if rate-responsive pacing can potentially improve exercise function in HFpEF.patients with
overt CI.47
A recent report noted that CI is common in clinical HF patients
who already have implanted pacemakers and is associated
with worse exercise capacity.48 Further, the authors recommended periodic optimization of pacemaker settings and reevaluation of β-blocker dosages.
Summary
Tse et al examined the potential benefit of rate-adaptive pacing, in conjunction with cardiac resynchronization therapy, on
exercise performance in HFrEF patients.46 A total of 20 HFrEF
patients with CI with an implanted cardiac resynchronization
device underwent exercise testing with measurement of VO2.
In the overall group, rate-adaptive pacing during cardiac resynchronization therapy increased peak exercise HR and
exercise time, but did not increase peak exercise VO2. However, in the 11 (55%) HF patients with more severe CI (those
achieving <70% APMHR), rate-adaptation significantly increased peak HR, exercise time, and peak VO2. Further, in the
majority (82%) of these patients, the improvement in chronotropic response was associated with an approximately 20%
increase in peak VO2. But in patients with less severe CI there
was little or no benefit, and one-third of the patients experienced a reduction in exercise capacity with rate-adaptive
pacing.46 Thus, while it appears that rate-adaptive pacing may
have potential benefits in carefully selected patients with HFrEF,
advances in this area are hindered by the lack of standardized, accepted definitions and selection criteria. Furthermore,
at this time it is unclear if CI is causal or simply a marker of
advanced disease and if treating it with a pacemaker would
improve functional status in HFrEF patients. Clearly, this issue will require further investigation in the future.
CI is a common, easily diagnosed, and potentially treatable
cause of exercise intolerance and merits more attention by
clinicians when they encounter patients with symptoms of
effort intolerance. I
Even less is known regarding pacing in patients with HFpEF,
despite the significant prevalence of CI in this population and
the contribution of impaired chronotropic response to their ob-
Acknowledgments. Supported in part by National Institutes of Health
grant R37AG18915. The sponsor had no role in the design and conduct
of the study; the collection, management, analysis, and interpretation
of the data; or the preparation, review, or approval of the manuscript.
CI is a common and important cause of exercise intolerance,
and an independent predictor of major adverse cardiovascular events and mortality. The diagnosis of CI should take into
account the confounding effects of aging, physical condition, and medications, but can be achieved objectively with
widely available exercise testing methods and standardized
definitions. If CI is found to be present, a search for potentially reversible causes is warranted.
In HF, β-adrenergic blockade may have a less detrimental effect on exercise capacity than previously thought, and may
even paradoxically improve exercise performance. The potential of more novel β-blockers to reduce the prevalence of
CI in HF patients is unclear. While exercise training and rateadaptive pacing have been shown to improve chronotropic
responses and exercise capacity in HF, more research is needed to fully evaluate the impact of these therapies on key clinical outcomes.
References
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11. Haidet GC. Dynamic exercise in senescent beagles: oxygen consumption and
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13. Ogawa T, Spina RJ, Martin WH, Kohrt WM, Schechtman KB. Effect of aging,
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14. Dresing TJ, Blackstone EH, Pashkow FJ. Usefulness of impaired chronotropic
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coronary artery disease. Am J Cardiol. 2000;86:602-609.
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response to exercise stress testing in asymptomatic women. The St. James
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729-733.
17. Tanaka H, Monahan KD, Seals DR. Age-predicted maximal heart rate revisited. J Am Coll Cardiol. 2001;37:153-156.
18. Brawner CA, Ehrman JK, Schairer JR, Cao JJ, Keteyian SJ. Predicting maximum heart rate among patients with coronary heart disease receiving betaadrenergic blockade therapy. Am Heart J. 2004;148:910-914.
19. Lauer MS, Francis GS, Okin PM, Pashkow FJ, Snader CE, Marwick TH. Impaired chronotropic response to exercise stress testing as a predictor of mortality [see comments]. JAMA. 1999;281:524-529.
20. Elhendy A, van Domburg RT, Bax JJ, et al. The functional significance of
chronotropic incompetence during dobutamine stress test. Heart. 1999;81:
398-403.
21. Okin PM, Lauer MS, Kligfield P. Chronotropic response to exercise. Improved
performance of ST-depression criteria after adjustment for heart rate reserve.
Circulation. 1996;94:3226-3231.
22. Wilkoff BL, Miller RE. Exercise testing for chronotropic assessment. Cardiol
Clin. 1992;10:705-717.
23. Khan ME, Pothier CE, Lauer MS. Chronotropic incompetence as a predictor
of death among patients with normal electrocardiograms taking beta blockers.
Am J Cardiol. 2005;96:1328-1333.
24. Magri D, Palermo P, Cauti FM, et al. Chronotropic incompetence and functional capacity in chronic heart failure: no role of β-blockers and β-blocker dose.
Cardiovasc Ther. 2012;30:100-108.
25. Jorde UP, Vittorio T, Kasper ME, et al. Chronotropic incompetence, beta-blockers, and functional capacity in advanced congestive heart failure: time to
pace? Eur J Heart Fail. 2008;10:96-101.
26. Phan T, Shivu G, Weaver R, Ahmed I, Frenneaux M. Impaired heart rate recovery and chronotropic incompetence in patients with heart failure with preserved ejection fraction. Circ Heart Fail. 2010;3:29-34.
27. Vittorio T, Lanier G, Zolty R, et al. Association between endothelial function
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28. Volterrani M, Cice G, Caminiti G, Vitale C, D'Isa S, Perrone Filardi P, Acquistapace
F, Marazzi G, Fini M, Rosano GM. Effect of carvedilol, ivabradine or their combination on exercise capacity in patients with heart failure (the CARVIVA HF
trial). Int J Cardiol. 2011;151:218-224.
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failure. Prog Cardiovasc Dis. 1995;28:1-22.
30. Kitzman DW, Little WC, Brubaker PH, et al. Pathophysiological characterization
of isolated diastolic heart failure in comparison to systolic heart failure. JAMA.
2002;288:2144-2150.
31. Haykowsky MJ, Brubaker PH, John JM, Stewart KP, Morgan TM, Kitzman DW.
Determinants of exercise intolerance in elderly heart failure patients with preserved ejection fraction. J Am Coll Cardiol. 2011;58:265-274.
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33. Brubaker PH, Joo KC, Stewart KP, Fray B, Moore B, Kitzman DW. Chronotropic incompetence and its contribution to exercise intolerance in older heart failure patients. J Cardiopulm Rehabil. 2006;26:86-89.
34. Borlaug BA, Melenovsky V, Russell SD, et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation. 2006;114:2138-2147.
35. Witte KK, Cleland J, Clark AL. Chronic heart failure, chronotropic incompetence,
and the effects of beta blockade. Heart. 2006;92:481-486.
36. Bristow MR, Hershberger RE, Port JD, et al. Beta-adrenergic pathways in nonfailing and failing human ventricular myocardium. Circulation. 1990;82:12-25.
37. Sanders P, Kistler PM, Morton JB, Spence SJ, Kalman JM. Remodeling of sinus node function in patients with congestive heart failure: reduction in sinus
node reserve. Circulation. 2004;110:897-903.
38. Samejima H, Omiya K, Uno M, et al. Relationship between impaired chronotropic response, cardiac output during exercise, and exercise tolerance in patients
with chronic heart failure. Jpn Heart J. 2003;44:515-525.
39. van Tol BA, Huijsmans RJ, Kroon DW, Schothorst M, Kwakkel G. Effects of exercise training on cardiac performance, exercise capacity and quality of life in
patients with heart failure: a meta-analysis. Eur J Heart Fail. 2006;8:841-850.
40. Kavanaugh T, Myers MG, Baigrie R, et al. Quality of life and cardiorespiratory
function in chronic heart failure: effects of 12 months of aerobic training. Heart.
1996;76:42-49.
41. Haykowsky MJ, Brubaker PH, Stewart KP, Morgan TM, Eggebeen J, Kitzman
DW. Effect of endurance training on the determinants of peak exercise oxygen consumption in elderly patients with stable compensated heart failure and
preserved ejection fraction. J Am Coll Cardiol. 2012;60:120-128.
42. Keteyian SJ, Brawner CA, Schairer JR, et al. Effects of exercise training on
chronotropic incompetence in patients with heart failure. Am Heart J. 1999;
138:233-240.
43. Kappenberger L, Herpers L. Rate responsive dual chamber pacing. Pacing Clin
Electrophysiol. 1986;9:987-991.
44. Buckingham TA. Effects of ventricular function on exercise hemodynamics of
variable rate pacing. J Am Coll Cardiol. 1998;11:1269-1277.
45. Freedman RA. Assessment of pacemaker chronotropic response: implementation of the Wilkoff mathematical model. Pacing Clin Electrophysiol. 2001;24:
1748-1754.
46. Tse HF, Siu CW, Lee KLF, Fan K, Chan HW, Tang MO, Tsang V, Lee SWL, Lau
CP. The incremental benefit of rate-adaptive pacing on exercise performance
during cardiac resynchronization therapy. J Am Coll Cardiol. 2005;46:22922297.
47. Kass DA, Kitzman DW, Alvarez GE. The restoration of chronotropic competence in heart failure patients with normal ejection fraction (RESET) study: rationale and design. J Card Fail. 2010;16:17-24.
48. Ujeyl A, Stevenson LW, West EK, Kato M, Liszkowski M, Campbell P, Forman
DE. Impaired heart rate responses and exercise capacity in heart failure patients
with paced baseline rhythms. J Card Fail. 2011;17:188-195.
Keywords: aging; chronotropic incompetence; ejection fraction; exercise; heart failure; heart rate
INCOMPÉTENCE
CHRONOTROPE ET CAPACITÉ FONCTIONNELLE
DANS LA MALADIE CARDIOVASCULAIRE
L’importance du rôle de la fréquence cardiaque (FC) dans la maladie cardiovasculaire est bien établie mais l’attention qui lui est portée se limite souvent à une analyse au repos ou à l’acmé de l’effort. Cet article souligne l’importance de l’évaluation de la FC pendant et après l’effort. L’aptitude du cœur à augmenter la FC pour ajuster au plus
près le débit cardiaque à la demande métabolique lors de l’effort est indispensable à la performance physique. C’est
l’augmentation de la FC au cours de l’effort qui participe le plus à la réalisation du travail physique et c’est donc un
déterminant important de la qualité de vie. La forte prévalence des anomalies de la réponse de la FC à l’effort et la
facilité de leur évaluation en pratique clinique sont deux arguments en faveur d’un dépistage des réponses inadaptées de la FC durant l’effort et lors de la récupération après l’effort. Cette pathologie peut se traiter et sa prise en
charge peut améliorer significativement la capacité à l’effort ainsi que la qualité de vie.
406
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‘‘
Heart rate is the easiest component of the cardiovascular system to study continuously, noninvasively, and repeatedly during
exercise testing. Kinetic analysis
of heart rate provides an opportunity to study cardiovascular regulation by the autonomic nervous
system at various phases of rest,
exercise, and recovery. It therefore
seems interesting and appropriate
to investigate the ability of the autonomic nervous system to appropriately regulate heart rate during
exercise.”
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Prognostic value
of heart rate response
to exercise
b y F. C a r ré , Fra n c e
E
François CARRÉ, MD, PhD
Université Rennes 1
Hôpital Pontchaillou
INSERM U1099
Rennes, FRANCE
xercise testing is commonly undertaken in cardiology for both diagnostic and prognostic purposes. Aside from the diagnostic criteria, new
parameters have been proposed for improving the prognostic value of
exercise testing, including kinetic analysis of heart rate changes during and
after exercise. Three main parameters are currently proposed: chronotropic
incompetence, heart rate recovery after exercise, and heart rate increase at
the beginning of exercise. All of these are regulated by the autonomic nervous
system, and abnormal values are linked to a decrease in parasympathetic effect and an increase in sympathetic effect. Chronotropic incompetence and
heart rate recovery are currently the two easiest parameters to determine and
are the most predictive. Both a low maximal heart rate and a decreased heart
rate recovery are predictors of all-cause and cardiovascular mortality, both
in healthy adults with or without risk factors, and in patients with coronary artery disease or heart failure. Their prognostic value is independent of the classical cardiovascular risk factors. Although chronotropic incompetence seems
a stronger predictor of cardiovascular mortality than heart rate recovery, the
risk seems most powerfully stratified when the two parameters are used together.
xercise testing is a very common test in cardiology, both for diagnostic and
prognostic evaluation. Over the last decade, the classic exercise test used to
predict adverse cardiovascular outcomes has evolved. The main parameters to
initially be validated and used during exercise testing were electrocardiogram (ECG)
alterations (mainly ischemic ST-segment depression) and hemodynamic changes.
E
Prof François Carré, Unité Biologie
et Médecin du Sport, Hôpital
Pontchaillou, 35033 Rennes, France
(e-mail:
[email protected])
Today, interpretation of the exercise test is no longer limited to these changes.1
Indeed, several other parameters have been validated and their value recognized.
Fitness capacity is now well described as the best marker for life expectancy.2-4
The role of the autonomic nervous system in cardiac arrhythmia and survival after a
cardiovascular event is also now well accepted.5 Frequent ventricular ectopy (mainly during recovery) appears to be associated with an increased death rate.6 Last,
several studies have underlined the prognostic value of analyzing the kinetics of
heart rate (HR) changes during and after an exercise test (reviewed in references
7-9).7-9 The aim of this short review is to clarify validated data in this area to enable
proper use of these new parameters in the context of risk stratification and management of patients with cardiovascular diseases.
Prognostic value of heart rate response to exercise – Carré
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Heart rate adaptations to dynamic exercise in
healthy people
The cardiovascular system plays a major role in the body’s
adaptations to the acute hemodynamic and metabolic constraints imposed by physical exercise. These cardiovascular
adaptations also play a major role in fitness capacity.
It is usual to describe two types of exercise; dynamic (or isotonic), and static (or isometric). Static exercise will not be discussed here, because the involvement of the cardiovascular
system is quite minor. Dynamic exercise is characterized by
alternating phases of contraction-relaxation of large skeletal
muscle masses. It is performed with free ventilation, and its
intensity gradually increases to a peak of effort, which corresponds to the individual maximum oxygen consumption (VO2
max).
Here, we shall focus on cardiac—in particular HR—adaptations observed during exercise and in the recovery phases
of maximal dynamic exercise.9 During exercise, cardiac output
gradually increases in line with exercise intensity (from 5 L/min
to 20-25 L/min in healthy, sedentary people). Its main role is
to increase the supply of oxygen to the skeletal muscles involved so that they can provide the energy requested. Cardiac output depends on two factors, HR and stroke volume.
Stroke volume increases from the beginning of exercise, and
it levels out at between 50% to 60% of VO2 max, which corresponds to a HR of 110-130 beats per minute (bpm) in healthy,
sedentary people. Normally, HR increases throughout the exercise duration, producing two broadly different slopes before and after the leveling of the stroke volume.
Individual resting HR depends on intrinsic HR (HR observed
after a double autonomic pharmacological blockade) and the
effects of the autonomic nervous system. Intrinsic HR is determined by the phase IV depolarization of the action potential of pacemaker cells in the sinus node. Intrinsic HR is 100
to 110 bpm in young healthy people, and it gradually decreases with age (5 to 6 bpm per decade). This intrinsic HR is continuously regulated by the two arms of the autonomic nervous
system (parasympathetic and sympathetic), which play the
main role in HR regulation both at rest and during exercise.
At rest, parasympathetic input slows the automatic discharge
rate and acts as a brake, while sympathetic input, and blood
catecholamines, act as an accelerator.9 Control of the autonomic nervous system is both centralized and reflexive. This
double regulation allows rapid HR adaptation in cases of sudden stress, for example at the onset of physical exercise. It explains the fine regulation of the HR level to exercise intensity.
From the beginning of exercise, and sometimes before it (the
anticipatory phase), the central autonomic control lifts the
parasympathetic brake. This central effect is reinforced by the
skeletal muscle reflexes, known as the exercise pressor reflex. These peripheral reflexes originate in contracting skeletal
408
muscles. Mechano- and metabo-ergoreceptors activate these
reflexes and thus continuously inform the cardiovascular control centers about the effort level.10 Thus, the initial HR increase is mainly due to the vagal “brake” release.7,11 Beyond
50% to 60% of VO2 max, HR increases linearly due to the
combined effects of the sympathetic nervous system and circulating catecholamines. During the recovery phase, the HR
decrease is exponential. Its initial fall (in 1 minute or less) is
marked. It is mainly due to the fast slowdown vagal effect and
is independent of the level of exercise intensity. The second
phase of HR decrease is slower. It is mainly caused by the
cessation of sympathetic nervous system activity and the delayed effects of circulating catecholamines.12,13
To summarize, during progressive and maximal dynamic exercise HR is regulated by the levels of parasympathetic and
sympathetic activities and blood catecholamine levels. HR
response to these factors also depends on the relative sensitivity of the sinoatrial node to catecholamines.
Heart rate regulation in chronic heart failure
patients
It is interesting to note that this physiological relationship can
be altered in cardiac patients.14 In patients with chronic heart
failure, for example, several alterations of both the sinus node
and its regulation by the autonomic nervous system have been
reported. Indeed, chronic heart failure causes dysfunction of
the sinoatrial and atrioventricular nodes. Intrinsic HR is thus
decreased in heart failure. In experimental models, changes
have been reported in the sensitivity of the sinoatrial node to
acetylcholine and vagal nerve stimulation. These alterations
are linked to extensive remodeling of ion channels, gap junction channels, ionic handling proteins, and receptors in the
sinoatrial node.15 Impaired exercise-induced norepinephrine
release associated with marked postsynaptic β-receptor desensitization influences HR regulation during exercise in these
patients.15 The disturbances in autonomic balance can also
create an electrically unstable substrate, which can play a role
in the occurrence of arrhythmias.5,15
Thus, HR is the easiest component of the cardiovascular system to study continuously, noninvasively, and repeatedly during exercise testing. Kinetic analysis of HR provides an opportunity to study cardiovascular regulation by the autonomic
nervous system at various phases of rest, exercise, and recovery. It therefore seems interesting and appropriate to investigate the ability of the autonomic nervous system to appropriately regulate HR during exercise.
SELECTED
bpm
ECG
HR
MET
beat per minute
electrocardiogram
heart rate
metabolic equivalent task
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Chronotropic incompetence as a prognostic
factor for mortality and cardiac events
In 1972, the first data were reported showing that a low peak
HR response during exercise was associated with an increased risk of cardiac death.7 It is now well accepted that
chronotropic incompetence is associated with a worse prognosis for all-cause mortality and for both cardiac mortality and
cardiac events (for example, myocardial infarction).16-26 This relationship is independent of the traditional cardiovascular risk
factors and individual exercise capacity.7 The association
has been reported in large populations of men and women of
Study
Population (n)
Follow-up
Exercise test
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different ages (but mainly over 40 years of age), in otherwise
healthy individuals, in those with or without known risk factors,
and in those with coronary artery disease, post–myocardial
infarction, and/or heart failure (see Table). The predictive value is observed in coronary patients and cardiac heart failure
patients even when they are taking β-blockers.19-21,29 Moreover, in coronary patients, this predictive value is independent
of the severity of coronary artery disease, and in patients with
coronary artery bypass grafting, impaired chronotropic response to exercise identifies subjects at risk for worse clinical outcomes such as myocardial infarction, stroke, or graft
Chronotropic
incompetence
HRR-3 min
Conclusion
Adabag
200822
12 555 males, 35-57 years
old, asymptomatic, CV
risk >average Framingham;
follow-up 7 years
Treadmill;
Bruce protocol
Gulati
201025
5437 women, >35 years old
(52±11), asymptomatic;
follow-up 15.9±2 years
Treadmill; Bruce
protocol
Savonen
201127
1102 males, 42-61 years old,
asymptomatic; follow-up
18 years
Ergocycle
HRR-2 min
<12 bpm
Relationship with all-cause
mortality
Nishime
200012
9454 (78% male), >30 years
old (average 53), no HF,
valve disease, pacemaker;
follow-up 5.2 years
Treadmill; Bruce
protocol (DTS)
HRR-1 min
<12 bpm
DTS and HRR independent predictors of
mortality
Lauer
199616
1575 males, 43 years old,
Framingham Offspring
Study; follow-up 7.7 years
Treadmill; Bruce
protocol;
submaximal
Witte
200620
237 HF patients
Ergocycle
% Max-PPHR <80%;
% HR reserve <80%
Myers
200721
1910 male veterans;
follow-up 5.1±2.1 years
Treadmill;
individualized
ramp protocol
% HR reserve <80%;
population specific
Kahn
200519
3736 (68% male), 58±11
years old, with BB, without
HF; follow-up 4.5 years
Treadmill
% HR reserve <62%
mortality
Kiviniemi
201129
494, recent myocardial
infarction; follow-up 8 years
Low % HR reserve
Predictor of cardiac
mortality
Gayda
201228
4907, stable CAD;
follow-up 14.7 years
Treadmill; passive
recovery
Yes
Heart rate
recovery
<1 standard deviation
predicted HR (2060.88 age); CI <0.8
All-cause mortality with
both altered HRR and
CI; CI predicts CAD
and SD
mortality
% Max-PPHR <85%;
actual increase in
HR from rest to peak
exercise; CI at stage 2
Independent relationship
with all-cause mortality and CAD incidence
No relationship with
mortality; more frequent
with BB; correlated with
lower pVO2
HRR-2 min
<22 bpm
HRR-3 min
<46 bpm
CI and HRR-2 min
predict CV mortality;
CI + HRR-2 min >one
parameter; CI >HRR-2
min; low impact of BB
treatment
Predictor of all-cause
and CV mortality
Table. Results of some of the main studies to have investigated the prognostic value of chonotropic incompetence (CI) and heart rate
recovery (HRR).
The percentages for maximum age-predicted peak heart rate (% Max-PPHR) and heart rate reserve (% HR reserve) were calculated with a cut-off of <80%. Duke
Treadmill Score (DTS) index is defined as: (exercise time) - (5 x maximum ST-segment deviation) - (4 x treadmill angina index).
Abbreviations: BB, 웁-blocker; CAD, coronary heart disease; CV, cardiovascular; HF, heart failure; pVO2 , mixed venous oxygen tension; SD, sudden death.
409
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occlusion.30,31 Maximal HR has also been proposed to calculate the ST segment/heart rate index (abnormal index >1.6
µV/bpm) to improve prediction of death from coronary artery
disease in asymptomatic men.32 Chronotropic incompetence
positively correlates with functional capacity in patients with
mild and moderate cardiac heart failure and with diastolic
dysfunction in healthy people.33,34 In subjects without apparent structural heart disease, chronotropic incompetence appears to be mainly induced by altered sympathetic activation
that affects HR increase.35
Chronotropic incompetence produces a physiologically inappropriate HR response to metabolic demand. Several chronotropic incompetence indexes have been described, but the
best method for clinical practice has not been established.8
Currently, there are three main widely used criteria.
The first, failure to achieve 80% to 85% of the maximum agepredicted HR, and the second, failure to achieve 80% of the
HR reserve (maximal HR minus resting HR; or 100% agepredicted maximal HR minus resting HR) are usually closely
associated. The reported prevalence of chronotropic incompetence in study populations is higher with the second criteria than the first.8 It must be noted that these two criteria
are based on the assessment of maximal HR. The maximal
HR of an individual must be determined during maximal effort with a symptom-limited exercise test. Several formulas
have been proposed for the predicted value of maximal HR.
Maximal HR depends mainly on age, but also on the ergometer used, and to a lesser extent on gender and fitness level.
Briefly, maximal HR—which always decreases with age—is
lower in women than in men, and is higher with treadmill exercise than with an ergocycle.25 Thus, an adapted equation for
predicted maximal HR must be used for the two chronotropic incompetence indexes described above.
The third index is the chronotropic index, which takes into
account age, physical fitness (exercise capacity), and resting HR. It quantifies the relationship between HR increment
and oxygen consumption during exercise testing.8,25 The
chronotropic index is the ratio of HR reserve to metabolic reserve. Age-predicted maximal HR is usually determined with
the traditional formula of 220 – age (note that this formula was
established with the ergocycle), although because of the aforementioned limits, a specifically adapted formula would seem
more suitable. Ideally, individual metabolic reserve is calculated during a maximal cardiopulmonary exercise test with
direct gas exchange analysis.8 Exercise capacity is estimated
in metabolic equivalent tasks (METs; 1 MET = 3.5 ml/min/kg
O2), and metabolic reserve is calculated as follows: (MET peak
– 1)/(100% predicted MET peak – 1). The use of the chronotropic index enables evaluation of the chronotropic response
at any stage of the exercise protocol. In healthy subjects, there
is a direct and linear association between HR response and
the metabolic work during exercise, and the chronotropic
410
index is around 1.0. A lower chronotropic index is a sign of
chronotropic incompetence. In healthy adults, a chronotropic index of <0.8 has been reported to be associated with a
higher mortality risk.25
It is thus now well acknowledged that determination of the
presence of chronotropic incompetence has important diagnostic, therapeutic, and prognostic implications, although the
exact mechanism underlying chronotropic incompetence is
at present unclear. Autonomic dysfunction involving an attenuated sympathetic drive during exercise occurring in subclinical cardiovascular disease, with or without early manifestation
of cardiac ischemia, has been proposed as a potential explanation. These disturbances could favor lethal arrhythmias with
an increased mortality risk in predisposed individuals.8,14
Heart rate recovery as a prognostic factor for
mortality and cardiac events
There is increasing evidence that the recovery phase after
exercise is a vulnerable period for cardiovascular events such
as myocardial infarction, sudden cardiac death, and atrial fibrillation. Coactivation of both arms of the autonomic nervous
system, which can occur during the recovery phase, may partly explain the clustering of various cardiovascular events in
the recovery phase of exercise.13
Measurement of autonomic function via the study of HR during the early phase of recovery can provide prognostic information on cardiovascular events in both the general population and various patient groups, independent of classical
cardiovascular risk factors (see Table).27,36-39 In coronary patients, for example, mortality was predicted by abnormal HR
recovery (hazard ratio, 2.5; 95% confidence interval, [CI] 2.03.1; P<0.0001) and by disease severity (hazard ratio, 2.0; 95%
CI, 1.6-2.6; P<0.0001). Both variables gave additive and independent prognostic information.40 There is a significant correlation between abnormal postexercise HR recovery during
the first minute (ⱕ18 bpm) and both coronary artery calcium
score (quantified with electron-beam computed tomography
scanning) and the extent of major epicardial coronary involvement.41 Heart failure is also associated with blunted HR recovery after exercise, often in association with chronotropic
incompetence, and it is more marked in severely affected patients with distinct echocardiographic, neurohormonal, and
hemodynamic signs of the disease.42 Treatment with β-blockade has minimal impact on the prognostic power of HR recovery.21 In male veterans (n=5974), HR recovery at 2 minutes
after treadmill exercise and low fitness were found to be associated with higher mortality risk both together and independently. However, mortality risk was overestimated when exercise capacity was not considered. When both low fitness (ⱕ6
METs) and low HR recovery (ⱕ14 bpm) were present, mortality risk was approximately sevenfold higher than in highly
fit and high–HR recovery subjects.43 Last, it is known that
regular physical activity decreases sympathetic tone, and to
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a lesser extent increases parasympathetic tone, in healthy
subjects and in patients. It was found that in patients undergoing exercise training in a phase II cardiac rehabilitation program, the increase in HR recovery after training was associated with an improvement in the prognosis for all-cause mortality.
Conversely, persistence of abnormal HR recovery despite
physical training is a marker of worse prognosis.44
Abnormal HR recovery is associated with several other altered
functions. When used together, there seems to be an improvement in the power of risk prediction for all-cause and cardiovascular death in low-risk populations. Moreover, addition of both HR recovery and chronotropic incompetence to
the Duke Treadmill Score improved (c-statistic from 0.61 to
0.68) the outcome prediction for all-cause mortality and
nonfatal myocardial infarction in high-risk patients.45 Abnormal HR recovery and HR variability are both reduced in a
parallel manner in coronary artery disease patients.41 Abnormal HR recovery is independently associated with diastolic dysfunction in subjects with normal systolic function at
rest and during exercise. This relationship can be explained
by the fact that diastolic dysfunction is partly due to an autonomic abnormality.34 The value of abnormal HR recovery
as a predictor of mortality is improved when exercise capacity is also considered.43
Again, protocol methodology plays a major role in determining the prognostic value of HR recovery.46 First, the choice of
the ergometer used for exercise testing is important, because
individual values for maximal HR (maximal workload achievement) are higher when exercise is performed with a treadmill than with an ergocycle. Moreover, during the early phase
of recovery, the drop in HR is slower after treadmill exercise.47
Indeed, in healthy subjects and heart failure patients, during
active recovery after maximal exercise, recovery HR at 1 minute
after exercise is lower after cycle exercise than treadmill exercise.48 By contrast, HR recovery 2 and 3 minutes after the
end of exercise does not differ as a function of the ergometer used.48 During stress echocardiography, because of the
supine position of the exercise, HR decrease during the recovery phase is blunted compared with exercise in the standing or sitting position. Thus, to avoid false individual prognostic predictions, the absolute values proposed for chronotropic
incompetence and abnormal HR recovery must be adapted
to the ergometer used.47,49 Second, variations in the exercise
termination protocol may play a role in the magnitude of HR
recovery. The mode of recovery, passive or active, must be
specified. It may be easier to use a passive mode of recovery,
because an active mode can have many specifics (workload,
speed, rate of pedaling).22 Third, both HR recovery at 1 and 2
minutes after exercise seem higher in men than in women.49
Fourth, although HR recovery at 1, 2, 3, 4, or 5 minutes after
exercise have all been found to be inversely associated with
death,37 the recovery duration investigated does play a role.
Indeed, as previously described, HR recovery during the first
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minute of recovery is mediated primarily by vagal reactivation.
It is almost independent of both sympathetic activity and exercise intensity. HR recovery in the second minute is affected
by sympathetic nerve activity and exercise workload,47 and
it appears that HR recovery during the second minute does
provide the best prognostic value.43,49 Last, there is no true
agreement in the literature about the “gold” cutoff value;
whether ⱕ12 bpm or ⱕ18bpm for abnormal HR recovery
during the first minute after exercise, or ⱕ22 bpm for abnormal
passive HR recovery in the second minute after exercise.27,41,43,49
The precise mechanisms underlying the relationship between
abnormalities in HR recovery and risk of mortality are not yet
well understood. However, it is well known that impaired flowmediated vasodilation in peripheral arteries is closely correlated with endothelial dysfunction in coronary artery disease.
There is an involvement between the sympathetic nervous
system and endothelial function.41 It has been shown that
HR recovery is significantly correlated with large artery stiffness, and in coronary artery disease patients, those with attenuated HR recovery show lower endothelium-dependent
flow-mediated vasodilation.41,50 Thus, HR recovery seems to
be a predictor of endothelial dysfunction that is independent
of classical cardiovascular risk factors.
Initial heart rate response to exercise as a
prognostic factor for mortality and cardiac events
Recently, some investigators have focused on the early HR
response to exercise.51,52 Initially, a fast HR increase at the onset of exercise was linked to an increased risk of adverse cardiovascular events including cardiac death, especially in patients with coronary disease.51
In animals with previous myocardial infarction, a large HR increase at the onset of exercise was associated with a risk of
developing ventricular fibrillation. This relationship was thought
to be due to enhanced cardiac sympathetic activation.5 The
results of a more recent study, however, performed in a large
population tested with symptom-limited exercise testing on a
treadmill for routine clinical indications showed the opposite;
ie, that a large early rise in HR during exercise is associated
with increased survival.52 This last result is in accordance with
data suggesting that the early HR profile during exercise is
mainly dominated by parasympathetic nervous tone.53 The
higher the parasympathetic tone, the greater the HR rise early
during exercise. The discrepancy observed between current
studies may be due to the exercise protocols used. It seems
that an individualized ramp protocol is best for studying individual HR profiles during exercise.52 Thus, the exact relationship between early HR changes in response to exercise
and prognosis still remains to be determined in humans.
Many studies have demonstrated the prognostic value of dynamic exercise HR response parameters. Although further
studies are needed to truly determine the most useful param-
411
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eter and to explain its pathophysiological relationship with
mortality, use of HR response parameters must be recommended when exercise testing is performed. Chronotropic
incompetence and HR recovery are currently the two easiest parameters to determine and are the most predictive.
Chronotropic incompetence appears to be a stronger predictor of cardiovascular mortality than HR recovery in patients referred for exercise testing for clinical reasons. However, when both parameters are used, the risk seems to be
most powerfully stratified. I
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23. Girotra S, Keelan M, Weinstein AR, Mittleman MA, Mukamal KJ. Relation of
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27. Savonen KP, Kiviniemi V, Laaksonen DE, et al. Two-minute heart rate recovery
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28. Gayda M, Bourassa MG, Tardif JC, Fortier A, Juneau M, Nigam A. Heart rate
recovery after exercise and long-term prognosis in patients with coronary artery disease. Can J Cardiol. 2012;28:201-207.
29. Jorde UP, Vittorio TJ, Kasper ME, et al. Chronotropic incompetence, betablockers, and functional capacity in advanced congestive heart failure: time
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45. Maddox TM, Ross C, Ho PM, et al. The prognostic importance of abnormal
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46. Shetler K, Marcus R, Froelicher VF, et al. Heart rate recovery: validation and
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plications of exercise test modality on modern prognostic markers in patients
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50. Fei DY, Arena R, Arrowood JA, Kraft KA. Relationship between arterial stiff-
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ness and heart rate recovery in apparently healthy adults. Vasc Health Risk
Manag. 2005;1:85-89.
51. Falcone C, Buzzi MP, Klersy C, Schwartz PJ. Rapid heart rate increase at onset of exercise predicts adverse cardiac events in subjects with coronary artery
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52. Leeper NJ, Dewey FE, Ashley EA, et al. Prognostic value of heart rate increase
at onset of exercise testing. Circulation. 2007;115:468-474.
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Keywords: autonomic nervous system; cardiovascular prognostic factor; chronotropic incompetence; coronary artery
disease; exercise; heart failure; heart rate response; mortality risk factor
VALEUR
PRONOSTIQUE DE LA RÉPONSE DE LA FRÉQUENCE CARDIAQUE À L’ EFFORT
L’épreuve d’effort est couramment utilisée en cardiologie dans un but à la fois diagnostique et pronostique. Parallèlement aux critères diagnostiques, de nouveaux paramètres ont été proposés pour améliorer la valeur pronostique
de l’épreuve d’effort, comme l’analyse cinétique des variations de la fréquence cardiaque pendant et après l’effort.
Trois paramètres principaux sont actuellement proposés : l’incompétence chronotrope, la récupération de la fréquence cardiaque après l’effort et l’élévation de la fréquence cardiaque au début de l’effort. Tous ces paramètres sont
régulés par le système nerveux autonome, des valeurs anormales étant liées à une diminution de l’effet parasympathique et à une augmentation de l’effet sympathique. L’incompétence chronotrope et la récupération de la fréquence
cardiaque sont actuellement les paramètres les plus faciles à déterminer et les plus prédictifs. Une fréquence cardiaque maximale basse à l’effort et une récupération de la fréquence cardiaque plus basse que la normale après l’effort sont prédicteurs de mortalité toutes causes et cardiovasculaire, à la fois chez des adultes sains avec ou sans
facteurs de risque, et chez des patients coronariens ou insuffisants cardiaques. Leur valeur pronostique est indépendante des facteurs de risque cardiovasculaire classiques. L’incompétence chronotrope semble être un prédicteur
plus fort de la mortalité cardiovasculaire que la récupération de la fréquence cardiaque, mais le risque paraît mieux
stratifié lorsque les deux paramètres sont utilisés ensemble.
413
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‘‘
Epidemiological studies have
reported a strong association between heart rate and cardiovascular risk…This relationship has been
consistent and was observed in
healthy populations among men
and women, various races, hypertensive subjects, patients with coronary artery disease, and in those
with heart failure. This increasing
evidence suggests that heart rate
does not merely predict outcome,
but that elevated heart rate may be
a true cardiovascular risk factor.”
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Heart rate in the assessment
of cardiovascular prognosis
b y L . R i va , G . V. C o u t s o u m b a s ,
a n d A . P. M a g g i o n i , I t a l y
O
L
Aldo Pietro MAGGIONI,
MD, FESC
ANMCO Research Center
Firenze, ITALY
Letizia RIVA, MD, PhD
Gloria Vassilikì
COUTSOUMBAS, MD
Cardiology Department
Maggiore Hospital
Bologna, ITALY
Aldo P. Maggioni, ANMCO Research
Center, Via La Marmora 34,
50121 Firenze, Italy
414
bservational studies have shown that resting heart rate (HR) is an independent predictor of cardiovascular and all-cause mortality. In patients with heart failure, there are benefits to pharmacologically reducing HR. It seems desirable to maintain HR in the “normal” range, below
the traditionally defined tachycardia threshold of 90 or 100 beats per minute
(bpm). In coronary patients, including those treated with percutaneous coronary intervention, a HR greater than or equal to 70 bpm increases cardiovascular risk; and in patients affected by heart failure, a HR lower than 60 bpm
is associated with fewer cardiovascular events than are higher HRs. Resting
HR would be a particularly useful measure to include in risk models because
it is extremely easy to apply and has no associated costs. For this reason, and
its strong correlation with both in-hospital mortality and mortality in the subsequent follow-up period, HR is already included in a number of risk assessment models for acute coronary syndrome.
eart rate (HR) is a major determinant of myocardial oxygen demand, coronary blood flow, and myocardial performance, and affects nearly all stages
of cardiovascular disease.
H
It has been postulated that reducing HR might prolong life, but, until now, this effect has not been demonstrated.1 However, in the past two decades, there has been
growing evidence that resting HR might be a marker of risk or even a risk factor for
cardiovascular morbidity and mortality. The importance of resting HR as a prognostic factor or as potential therapeutic target is not yet generally accepted. Recent
large epidemiological studies have confirmed earlier studies that showed resting
HR to be an independent predictor of cardiovascular and all-cause mortality, with
a global estimation of 30% to 50% mortality excess for every 20 beats per minute
(bpm) increase at rest. Studies have found a continuous increase in risk with HR
above 60 bpm. A considerable number of epidemiological studies have reported
a strong association between HR and cardiovascular risk, and this association appears to be independent of other major risk factors for atherosclerosis.2 This relationship has been consistent and was observed in healthy populations among men
and women, various races, hypertensive subjects, patients with coronary artery disease (CAD), and in those with heart failure. This increasing evidence suggests that
HR does not merely predict outcome, but that elevated HR may be a true cardiovascular risk factor.
Heart rate in the assessment of cardiovascular prognosis – Maggioni and others
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Increased heart rate
Pulsatile shear
stress
Endothelial
dysfunction
Cardiac
noradrenaline
synthesis
Apoptosis
Adverse ventricular
remodeling
Development of
atherosclerosis
Arterial elasticity
Diastolic duration
Coronary perfusion time
Pulsatile load
Myocardial O2
requirement
Progression of
heart failure
HR, when adjusted for age, is higher in women than in men
(approximately 2-7 bpm)3 and has been reported to decrease
with age (around 1 beat/min over 8 years).4 It has a clear circadian rhythm and is substantially higher during waking hours,
varying relatively little between 10 AM and 6 PM.5 HR is affected by posture, and is approximately 3 bpm higher in the
ACS
bpm
CAD
COPD
GRACE
GUSTO
Collateral perfusion pressure
Collateral flow
Obstruction
to coronary
flow
Imbalance of oxygen
supply and demand
In clinical practice, risk models may be useful for patient risk
stratification and treatment decisions. Resting HR would be
a particularly useful measure to include in risk models because
it is extremely easy to apply and has no associated costs.
SELECTED
Plaque
rupture
acute coronary syndrome
beat per minute
coronary artery disease
chronic obstructive pulmonary disease
Global Registry of Acute Coronary Events
Global Utilization of Streptokinase and t-PA for
Occluded coronary arteries
GWTG-HF Get With the Guidelines–Heart Failure
HR
heart rate
InTIME-II Intravenous nPA for Treatment of Infarcting
Myocardium Early
NRMI
National Registry of Myocardial Infarction
OR
odds ratio
PAMI
Primary Angioplasty in Myocardial Infarction
PCI
percutaneous coronary intervention
SHIFT
ivabradine Trial
STEMI
ST-segment–elevation myocardial infarction
TIMI
Thrombolysis In Myocardial Infarction
Myocardial ischemia / infarction
Figure 1.
Pathophysiological
mechanisms
promoted
by increased
heart rate.
After reference
10: Malcolm et al.
Can J Cardiol.
2008;24(suppl A):
3A-8A. © 2008,
Pulsus Group Inc.
sitting position than in the supine position.6 Resting HR varies
widely, but there does seem to be a pattern of distribution
within the population, albeit not a normal distribution: Palatini et al have shown a mixture of two subpopulations, the
first with a “normal” mean resting HR and the second with a
“high” mean resting HR.7 The segregation value between the
subgroups varied between 75 and 85 bpm. The previous
epidemiological data suggest that it is desirable to keep HR
within the “normal” rather than the “high” range, and more
specifically, to maintain resting HR substantially below the
tachycardia threshold of 90 or 100 bpm.
Pathophysiological mechanisms linking elevated
HR and cardiovascular disease
Increased HR, due to imbalances of the autonomic nervous
system with increased sympathetic activity or reduced vagal tone, has an impact on perfusion-contraction matching,
which is the dynamic that regulates myocardial blood supply and function. An increase in HR results not only in an increase in myocardial oxygen demands, but also in a potential impairment of oxygen supply resulting from a reduction in
collateral perfusion pressure.8 The imbalance may promote
ischemia, arrhythmias, and ventricular dysfunction, as well as
acute coronary syndromes (ACS), heart failure, and sudden
death. With increased HR, the diastolic perfusion time lessens
while myocardial oxygen demand increases. Peak coronary
flow increases markedly during diastole, subjecting the coronary arteries to enhanced endothelial shear stress and pulsatile wall stress. The stressed endothelium releases growth
hormones and vasoconstrictor peptides, while rapid pulsatile
changes are associated with increased mechanical damage
on the already stressed endothelium. All these factors encourage the development of atherosclerotic lesions (Figure 1).9,10
415
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Odds of death by 30 days
Figure 2. Independent predictors of 30-day
mortality after
STEMI in TIMI
risk score.
Abbreviations:
BP, blood pressure;
CI, confidence interval; LBBB, left bundle branch block;
MI, myocardial
infarction; OR, odds
ratio; STEMI, STsegment– elevation
myocardial infarction; TIMI, Thrombolysis In Myocardial
Infarction.
After reference 13:
Morrow et al. Circulation. 2000;102:
2031-2037. © 2000,
American Heart
Association, Inc.
97%
3%
Multivariate
OR (95% CI)
Age M75
11.0
2.7 (2.2-3.2)
Killip II-IV
9.3
2.3 (1.9-2.7)
Heart rate >100 beats/min
7.7
2.3 (1.9-2.8)
Anterior MI or LBBB
6.1
1.6 (1.4-1.9)
Systolic BP <100 mm Hg
5.5
2.7 (1.9-3.8)
Time to thrombolytic >4 hours
4.0
1.4 (1.2-1.6)
Weight <67 kg
3.7
1.4 (1.2-1.7)
Prior angina
3.4
1.4 (1.1-1.6)
Diabetes
3.3
1.4 (1.2-1.7)
History of hypertension
3.2
1.3 (1.1-1.5)
Never smoked
2.9
1.3 (1.1-1.5)
Prior myocardial infarction
2.8
1.3 (1.1-1.6)
Peripheral vascular disease
2.6
1.5 (1.1-1.9)
Antiarrhythmic medication
2.4
1.8 (1.1-2.8)
Lipid-lowering medication
2.2
0.7 (0.5-0.97)
Female
2.0
1.2 (1.0-1.5)
0.1
Lower risk
Epidemiological association between HR and
cardiovascular morbidity/mortality
Observational studies have shown an elevated resting HR to
be associated with future development of cardiovascular disease, but all data on the possible importance of HR are retrospective and a demonstration of the benefits of reducing
HR pharmacologically is limited to patients with myocardial
infarction or heart failure. HR is already included in many models of risk assessment in patients affected by CAD—including
those treated with percutaneous coronary intervention (PCI)—
or heart failure.
N Increased HR and CAD
N HR and angina pectoris
HR reduction is helpful in preventing angina, and there is some
evidence that it may improve coronary endothelial function
and atherosclerosis. To assess whether a lower HR is also associated with a more favorable prognosis in patients with CAD,
an analysis was performed in 24 913 patients with suspected
or proven CAD from the Coronary Artery Surgery Study (CASS)
registry followed for a median time period of 14.7 years.11 In
this study, patients with resting HR between 77 and 82 bpm
had a significantly higher risk of total mortality (hazard ratio
1.16), and this association was even stronger in patients with
a resting HR ⱖ83 bpm (hazard ratio 1.32). The association between HR and total mortality held true in all analyzed subgroups. A high resting HR was also an independent predictor
of time to first rehospitalization due to angina and congestive
416
Z score
1
Higher risk
10
heart failure. Interestingly, the multivariable models were adjusted for the use of β-blockers and this confirmed resting
HR as an independent predictor of overall and cardiovascular
mortality.
N HR and acute risk stratification in ACS
Considerable variability in mortality risk exists among patients
with acute coronary syndromes (ACS). Individual patients reflect a combination of clinical features that influence prognosis, and these factors must be appropriately weighted to produce an accurate assessment of risk.
In the thrombolytic era, a number of studies were performed
to define prognosis in ST-segment–elevation myocardial infarction (STEMI), initially developing sophisticated multivariable
models not readily applied in routine clinical practice, and later proposing more convenient bedside clinical risk scores.
A multivariable analysis from GUSTO-I (Global Utilization of
Streptokinase and t-PA for Occluded coronary arteries; a randomized trial of four thrombolytic strategies in 41 021 patients
with STEMI) identified a large number of independent clinical
predictors correlated with prognosis (30-day mortality), five
of which contain most of the prognostic information: age, lower systolic blood pressure, higher Killip class, elevated HR, and
anterior infarction.12 Similarly, a subsequent study derived from
logistic regression analysis of the InTIME-II database (Intravenous nPA for Treatment of Infarcting Myocardium Early II
trial, in which 15 078 patients with STEMI were randomized to
HEART
two different thrombolytic strategies within 6 hours of symptom onset) identified 10 baseline variables that were independent predictors of 30-day all-cause mortality, accounting
for 97% of the predictive capacity of the multivariate model
(Figure 2).13 Based on these data, the Thrombolysis In Myocardial Infarction (TIMI) risk score was assessed, calculated
from the simple arithmetic sum of point values assigned to
each risk factor based on the multivariate-adjusted risk relationship (1 point for odds ratios [ORs] from 1.0 to <2.0; 2
points for ORs >2.0 to 2.5; 3 points for ORs >2.5). This score
system was validated for the prediction of 30-day all-cause
mortality in an external population of patients treated with fibrinolytics for STEMI, derived from the TIMI 9 A/B trial. In this
model, HRs >100 bpm (OR 2.3 [1.9-2.8] at the multivariate
analysis) received 2 points, as did Killip classes II-IV and ages
65-74 years.
In order to further simplify the prognostic risk stratification in
the acute phase of STEMI, a simple risk index—the TIMI risk
index—based only on age and vital signs, was derived from
the InTIME-II trial.14 The TIMI risk index was calculated using
the equation: (HR x [age/10]2 / systolic blood pressure) and
when tested in the real world (153 486 patients with STEMI
from the National Registry of Myocardial Infarction [NRMI] 3
and 4) revealed a significant graded relationship with all-cause
mortality at 24 hours, hospital discharge, and 30 days. Also,
the evaluation of the individual components of the TIMI risk
index, using a logistic regression model, showed similar associations with mortality in the InTIME-II trial and in NRMI-2
and -3, further supporting the assertion that these variables
are useful alone or in combination for risk stratification in a
general population with STEMI. In this analysis, each HR increase of 10 bpm significantly raised the mortality risk, with
an OR of 1.3 in In-TIME-II and 1.2 in NRMI (Table I).
InTIME-II
OR
C statistic
Age (10 y)
2.3
BP (10 mm Hg)
0.89
HR (10 beats/min)
Index (10 U)
NRMI
OR
C statistic
0.75
1.8
0.75
0.56
0.82
0.66
1.3
0.63
1.2
0.62
2.2
0.79
2.3
0.79
Table I. Odds ratios for mortality and discriminative capacity (C
statistic) for individual components of the TIMI risk index.
Abbreviations: BP, blood pressure; HR, heart rate; NRMI, National Registry of
Myocardial Infarction; OR, odds ratio; InTIME-II, Intravenous nPA for Treatment
of Infarcting Myocardium Early II (trial); TIMI, Thrombolysis In Myocardial Infarction; U, units.
After reference 14: Wiviott et al. J Am Coll Cardiol. 2004;44:783-789. © 2004,
American College of Cardiology Foundation.
With the increasing adoption of primary PCI as the preferable method for achieving reperfusion, risk scores based on
primary PCI trials were developed and validated. The Primary
Angioplasty in Myocardial Infarction (PAMI) score, developed
from 3252 PCI-treated patients enrolled in the various PAMI
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trials, is based on only 5 clinical and electrocardiographic
characteristics—similarly to the TIMI risk score (age, Killip >1,
HR >100 bpm, diabetes mellitus, and anterior STEMI or new
left branch bundle block)—which are strictly associated with
30-day and 1-year all-cause mortality.15 With the exception of
age, all components of this score had the same statistical
weight (2 points) (Table II).
PAMI (0-15)
Age >75 y
7
Age 65-75 y
3
Killip’s classification >1
2
Heart rate >100 beats/min
2
Diabetes mellitus
2
Anterior STEMI or left branch bundle rock
2
Table II. Components of PAMI risk score.
Abbreviations: PAMI, Primary Angioplasty in Myocardial Infarction; STEMI,
ST-segment–elevation myocardial infarction.
After reference 15: Addala et al. Am J Cardiol. 2004;93:629-632. © 2004,
Excerpta Medica, Inc.
A new model to determine the risk of 90-day mortality in patients undergoing primary PCI was derived from the analysis of APEX AMI (Assessment of Pexelizumab in Acute Myocardial Infarction trial), which enrolled 5745 patients with
STEMI undergoing primary PCI within 6 hours of symptom onset.16 Of the variables assessed at the time of presentation
that were independently predictive of 90-day mortality, the 7
most significantly associated with prognosis were incorporated in the final model: older age (hazard ratio 2.03 per increments of 10 years), lower systolic blood pressure (hazard
ratio 0.86 per increments of 10 mm Hg), higher Killip class
(hazard ratio 4.28 per Killip 3-4), higher HR (hazard ratio 1.45;
HR >70 to <110 bpm per increments of 10 bpm), baseline
total ST deviations (hazard ratio 1.25 per increments of 10
mm), serum creatinine higher than 90 mol/L (hazard ratio 1.23
per increments of 10 mol/L), and anterior location of myocardial infarction (hazard ratio 1.47). It is remarkable that even
though the reperfusion method is different and more effective, many of the most important predictors in STEMI remained
the same, and, in particular, elevated HR was confirmed to
have an independent inverse correlation with prognosis.
A general score applicable to all ACS (ST-elevated or not) was
determined by the analysis of the large multinational, observational, Global Registry of Acute Coronary Events (GRACE)
(43 810 patients presenting with ACS with or without ST-segment elevation) with two primary end points: all-cause death
and the composite outcome measure of death or nonfatal
myocardial infarction during admission to hospital or within 6
months from discharge.17 The GRACE risk score includes 8
variables (age, HR, systolic blood pressure, Killip class, initial
serum creatinine concentration, elevated initial cardiac markers, cardiac arrest on admission, and ST-segment deviation)
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containing most (>90%) of the predictive information. This
model was externally validated using the GUSTO IIb dataset
including 12 142 patients with ACS, confirming its excellent
discrimination power. In GRACE, the hazard ratio for death in
association with HR was 1.2 (1.16-1.31) per incremental increase of 30 bpm during the period from hospital admission
to the 6-month follow-up assessment.
In conclusion, HR measured at presentation has confirmed
prognostic value in the ACS setting and is predictive of inhospital mortality and mortality during follow-up.
N HR and subsequent risk stratification in ACS
HR retains its prognostic value even when measured after the
acute phase of ACS. An analysis of the GISSI-Prevenzione
study (Gruppo Italiano per lo Studio della Streptochinasi nell’
Infarto miocardico – Prevenzione; including 11 324 patients
recruited within 3 months of myocardial infarction and followed
up for 4 years) identified major determinants of prognosis.18
Among other determinants, a HR >75 bpm was significantly
associated with worse prognosis when compared with lower
HRs (relative risk for HR >75 bpm in males, 1.32; in females,
1.52). Lower HR (64 bpm in males and 69 bpm in females)
was associated with lower risk.
This study proved the existence of a strong correlation between HR and prognosis in ACS acute phase or in the short
term, and showed that this correlation remains strong in the
longer term—after years—as well.
N Increased HR and heart failure
Elevated resting HR is one of the key findings in acute and
chronic heart failure. The association of HR with mortality was
retrospectively addressed in the subanalyses of CIBIS-II (Cardiac Insufficiency BIsoprolol Study II),19 MERIT-HF (MEtoprolol CR/XL Randomised Intervention Trial in-congestive Heart
Failure),20 and the COMET trial (Carvedilol Or Metoprolol European Trial).21 The general trend of these three trials clearly
demonstrated that high resting HR contributed to poor survival in patients with advanced systolic heart failure. However,
it was unknown whether, or to what extent, the benefit from
β-blockers in patients with heart failure is attributable to HR
reduction per se or to other beneficial effects, such as protection of the myocardium from the effects of prolonged exposure to high levels of circulating catecholamines or improved
β-receptor function.
In the SHIFT trial (Systolic Heart failure treatment with the If
inhibitor ivabradine Trial), the effect of pure HR reduction by
ivabradine was evaluated in addition to guideline-based treatment on cardiovascular outcomes, symptoms, and quality of
life in patients with systolic heart failure (left ventricular ejection fraction ⱕ35%). Similarly to the β-blocker trials, treatment
with ivabradine was associated with an average reduction in
HR of nearly 15 bpm from a baseline value of 80 bpm, which
418
was associated with an 18% risk reduction for the primary
composite end point: cardiovascular death or hospital admission for worsening heart failure.22 Therefore, SHIFT demonstrated for the first time the beneficial effects of HR reduction alone in patients with systolic heart failure. Previously, in
the BEAUTIFUL study (morBidity-mortality EvAlUaTion of the
If inhibitor ivabradine in patients with coronary disease and
left ventricULar dysfunction), no overall benefit of ivabradine
vs placebo was demonstrated in patients with stable coronary heart disease and left ventricular systolic dysfunction;23
however, in the prespecified subgroup with a baseline HR
ⱖ70 bpm, there was a significant reduction in the secondary end point of hospital admission for acute myocardial infarction or unstable angina and coronary revascularization.24
Several existing predictive models for long-term mortality in
heart failure include more than 20 variables, some of which
are not frequently assessed in clinical practice for heart failure.25,26 The American Heart Association Get With the Guidelines–Heart Failure (GWTG-HF) risk score reliably predicts inhospital mortality of patients with preserved or impaired left
ventricular systolic function using 7 clinical factors routinely
collected at the time of admission.27 Older age, low systolic
blood pressure, elevated HR, low serum sodium, elevated
blood urea nitrogen, presence of chronic obstructive pulmonary
disease (COPD), and nonblack race predicted an increased
risk of death. This model is widely applicable because it includes a relatively small number of variables routinely assessed
at the time of patient hospital admission. The application of
this risk score could influence the type and quality of care provided to patients hospitalized with heart failure by guiding clinical decision-making. Nevertheless, in the GWTG-HF risk score,
age, systolic blood pressure, and blood urea nitrogen contributed most substantially to the overall point score, whereas HR, presence of COPD, serum sodium, and nonblack race
contributed relatively few points to the overall score.
N Increased HR and hypertension
Several studies have demonstrated that individuals with high
HR have increased blood pressure readings28 and that this
association is stronger in subjects with elevated sympathetic
activity.29 This phenomenon may be due to hypertension and
tachycardia having a common denominator: increased sympathetic tone. Thus, it is crucial to know whether HR also has
independent predictive power for cardiovascular mortality in
hypertensive individuals. Much less is known about the association of HR and mortality in hypertensive patients as
only three studies have examined this relationship in such a
population30,31,32 and only one study in elderly subjects with
isolated systolic hypertension.33 In the Framingham Study, it
was found that for an increment of 40 bpm there was a
118% and 114% increased age- and systolic BP–adjusted
OR in men and women, respectively, for total mortality, and a
68% and 70% increased risk, respectively, for cardiovascular
mortality.30 In the Syst-Eur study (Systolic Hypertension in Eu-
HEART
rope), performed in elderly patients with systolic hypertension,
patients with a HR higher than 79 bpm had an 89% greater
risk of mortality than those with a HR ⱕ79 bpm.33
On the other hand, data derived from HARVEST (Hypertension and Ambulatory Recording VEnetia STudy) demonstrated that baseline resting HR and changes in HR in the first few
months of follow-up were able to predict the development of
sustained hypertension in white, younger subjects evaluated
for stage 1 hypertension.34
Even if all data on the possible relevance of HR lowering in
hypertensive patients are retrospective, it is reasonable that
patient outcome may be improved with drugs that reduce
both blood pressure and HR. On the basis of the epidemiological data, for a 10%-12% reduction in HR, a 20%-40% decrease in cardiovascular morbidity–mortality should be expected.35
N Increased HR and diabetes mellitus
There are few data specifically exploring the relationship between resting HR and cardiovascular outcome in patients with
diabetes mellitus. However, the association between HR, glucose, and insulin levels is strong. In addition, diabetes is commonly associated with abnormal function of the autonomic
nervous system, the main regulator of resting HR. In the Swiss
cohort of the World Health Organization Multinational Study
of Vascular Disease in Diabetes, a relationship between resting HR and both all-cause and cardiovascular mortality was
reported in patients affected by type 2 diabetes mellitus. Interestingly, a similar relationship was not observed in patients
with type 1 diabetes mellitus.36 Recently, the Euro Heart Survey investigators reported that, in diabetic patients, a higher
resting HR was associated with an increased risk in all-cause
mortality.37 In the ADVANCE study (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), a higher resting HR was associated with a significant-
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ly increased risk in all-cause mortality, cardiovascular death,
and major cardiovascular outcomes. The increased risk associated with a higher baseline resting HR was more obvious in
patients with previous macrovascular complications. Moreover, the relationship between HR and metabolic derangement has been reinforced by data derived from the Chicago
Heart Association Detection Project: in middle-aged patients,
the adjusted risk of developing diabetes increased by 10%
for each 12-bpm increment in baseline HR in patients older
than 65 years.38 It remains unclear whether a higher HR directly mediates increased risk or whether it is a marker for
other factors that determine a poor outcome.39
Conclusion
There is consistent evidence that resting HR is able to predict
life expectancy and is an independent predictor of morbidity
and mortality in healthy subjects. Furthermore, resting HR is
a predictor of death in both stable CAD and ACS. Elevated
resting HR is also able to independently predict clinical outcomes in patients with heart failure. In spite of the large body
of evidence on the evaluation of cardiovascular risk, little attention has been paid to the role of HR in cardiovascular risk
assessment in daily practice, even if this is a simple and easily measurable clinical parameter that can be utilized with no
additional cost.40
Recent evidence supports the concept that increased resting HR is an independent cardiovascular risk factor. A HR
ⱖ70 bpm increases cardiovascular risk and this measurement
should be used to guide therapy in coronary patients. HR is
also an important target for the treatment of heart failure.
Specifically, patients affected by heart failure with HRs lower than 60 bpm have fewer cardiovascular events than patients with higher HRs. For all these reasons and the strong
correlation with both in-hospital and long-term mortality, HR
has already been included in many models of ACS risk assessment. I
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24. Fox K, Ford I, Steg PG, et al; BEAUTIFUL Investigators. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular
systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 2008;372:817-821.
25. Pocock SJ, Wang D, Pfeffer MA, et al. Predictors of mortality and morbidity
in patients with chronic heart failure. Eur Heart J. 2006;27:65-75.
26. Levy WC, Mozaffarian D, Linker DT, et al. The Seattle Heart Failure Model: pre-
diction of survival in heart failure. Circulation. 2006;113:1424-1433.
27. Peterson PN, Rumsfeld JS, Liang L, et al; American Heart Association Get With
the Guidelines-Heart Failure Program. A validated risk score for in-hospital mortality in patients with heart failure from the American Heart Association Get
With the Guidelines Program. Circ Cardiovasc Qual Outcomes. 2010;3:25-32.
28. Palatini P, Julius S. Review article: heart rate and the cardiovascular risk. J Hypertens. 1997;15:3-17.
29. Narkiewicz K, Somers VK. Interactive effect of heart rate and muscle sympathetic nerve activity on blood pressure. Circulation. 1999;100:2514-2518.
30. Gillmann MW, Kannel WB, Belanger A, et al. Influence of heart rate on mortality
among persons with hypertension: The Framingham Study. Am Heart J. 1993;
125:1148-1154.
31. Thomas F, Bean K, Provost JC, et al. Combined effects of heart rate and pulse
pressure on cardiovascular mortality according to age. J Hypertens. 2001;19:
863-869.
32. Thomas F, Rudnichi A, Bacri AM, et al. Cardiovascular mortality in hypertensive
men according to presence of associated risk factors. Hypertension. 2001;37:
1256-1261.
33. Palatini P, Thijs L, Staessen JA, et al. Predictive value of clinic and ambulatory
heart rate for mortality in elderly subjects with systolic hypertension. Arch Intern
Med. 2002;162:2313-2321.
34. Palatini P, Dorigatti F, Zaetta V, et al. Heart rate as a predictor of development
of sustained hypertension in subjects screened for stage 1 hypertension: the
HARVEST study. J Hypertension. 2006;24:1873-1880.
35. Palatini P, Benetos A, Grassi G, et al; European Society of Hypertension. Identification and management of the hypertensive patient with elevated heart rate:
statement of a European Society of Hypertension Consensus Meeting. J Hypertens. 2006;24:603-610.
36. Stettler C, Bearth A, Allemann S, et al. QTc interval and resting heart rate as
long-term predictors of mortality in type 1 and type 2 diabetes mellitus: a 23year follow-up. Diabetologia. 2007;50:186-194.
37. Anselmino M, Ohrvik J, Ryden L. Resting heart rate in patients with stable coronary artery disease and diabetes: a report from the Euro Heart Survey on diabetes and the heart. Eur Heart J. 2010;31:3040-3045.
38. Carnethon MR, Yan L, Greenland P, et al. Resting heart rate in middle age and
diabetes development in older age. Diabetes Care. 2008;31:335-339.
39. Hillis GS, Woodward M, Rodgers A, et al. Resting heart rate and the risk of death
and cardiovascular complications in patients with type 2 diabetes mellitus.
Diabetologia. 2012;55(5):1283-1290.
40. Tardif JC. Heart rate as a treatable cardiovascular risk factor. Br Med Bull. 2009;
90:71-84.
Keywords: cardiovascular disease; cardiovascular prognosis; heart rate; risk factor
LA
FRÉQUENCE CARDIAQUE DANS L’ ÉVALUATION DU PRONOSTIC CARDIOVASCULAIRE
Des études observationnelles ont montré que la fréquence cardiaque de repos (FC) est un facteur prédictif indépendant de mortalité toutes causes et cardiovasculaire. Il est bénéfique, chez les patients insuffisants cardiaques, de
réduire la FC de façon pharmacologique. Il semble souhaitable de maintenir la FC dans des fourchettes normales,
en dessous du seuil de tachycardie défini traditionnellement à 90 ou 100 battements par minute (bpm). Chez les patients coronariens, y compris ceux traités par angioplastie coronaire percutanée, une FC supérieure ou égale à 70 bpm
augmente le risque cardiovasculaire ; et chez les insuffisants cardiaques, une FC inférieure à 60 bpm est associée à
un nombre inférieur d’événements cardiovasculaires. La FC de repos est une mesure particulièrement utile à inclure
dans des modèles de risque parce qu’elle est très facile à mesurer et n’induit pas de coûts supplémentaires. C’est
pourquoi la FC est déjà comprise dans un certain nombre de modèles d’évaluation du risque de syndrome coronaire
aigu en raison de son association forte, à la fois avec à la mortalité hospitalière et avec la mortalité de la période de
suivi ultérieure.
420
HEART
‘‘
Sustained elevation in heart
rate may lead to critical pathophysiological changes in the cardiovascular system. These include
endothelial dysfunction and atherosclerotic plaque development, reduction in coronary blood flow, impaired systolic and diastolic left
ventricular function, and a susceptibility to arrhythmia. Higher heart
rates predict cardiovascular events
and mortality in patients with or
without prior cardiovascular disease.”
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EXERCISE
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Why should we consider
heart rate in patients with
cardiovascular disease?
b y B . D . We s t e n b r i n k a n d
W. H . va n G i l s t , T h e N e t h e r l a n d s
H
L
Wiek H. VAN GILST, PhD
eart rate has a fundamental role in cardiovascular performance and
is one of the most readily accessible and informative vital signs. An elevated heart rate is an independent risk factor for mortality and morbidity in people with and without cardiovascular disease. Accordingly, pharmacological agents that reduce heart rate can alleviate symptoms and improve
clinical outcomes in several cardiac diseases. Unfortunately, perhaps because
of our familiarity with heart rate, or the lack of clear data to support a specific
heart rate range, heart rate is often overlooked. In this review we will discuss
the value of elevated heart rate and its reduction in cardiovascular disease
and attempt to provide practical, evidence-based recommendations for its
management.
B. Daan WESTENBRINK,
MD, PhD
Department of Cardiology
University Medical Center
Groningen, Groningen
THE NETHERLANDS
How to measure heart rate
eart rate is one of the most readily accessible vital signs. It can be determined
in virtually any setting, by any health care provider, and by many patients
themselves. In hospitalized patients, heart rate is documented at least daily,
with every electrocardiogram, during most medical procedures, and/or continuously. Exercise equipment and commercial blood pressure monitors report heart rate
values at home, familiarizing patients with their basic cardiovascular dynamics. Expanding indications for implantable medical devices allow us to remotely monitor
heart rates, without even involving the patient. Cardiovascular clinicians are thus continuously informed about their patients’ heart rate. While electrocardiographic detection is the most accurate, palpation of the peripheral pulse may suffice in most
instances and most patients. There are, of course, several other aspects of heart
rate measurement that should be taken into account, including posture, physical activity, duration of measurement, temperature, and emotional factors, none of which
we shall discuss in detail in this paper.
H
Why should we consider heart rate?
B. Daan Westenbrink, Department
of Cardiology, University Medical
Center Groningen, Hanzeplein 1,
P. O. Box 30001, 9700 RB
Groningen, Netherlands
Heart rate has an intimate and complex involvement in several parameters of cardiovascular function and pathophysiology. Cardiac output, for instance, is determined by heart rate and stroke volume. Since it is vastly easier to modulate heart rate
than stroke volume, variations in heart rate are our principal mechanism for adjusting cardiac output to metabolic demand. Heart rate is also, however, a major determinant of myocardial oxygen consumption. Sustained elevation in heart rate may
lead to critical pathophysiological changes in the cardiovascular system. These in-
Why should we consider heart rate in patients with CVD? – Westenbrink and van Gilst
421
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clude endothelial dysfunction and atherosclerotic plaque development, reduction in coronary blood flow, impaired systolic
and diastolic left ventricular function, and a susceptibility to
arrhythmia. Higher heart rates predict cardiovascular events
and mortality in patients with or without prior cardiovascular
disease.1,2
lodipine on central and peripheral blood pressure.14 Atenolol
was associated with a paradoxical increase in central blood
pressure, while the converse was true for amlodipine.14 In addition, an atenolol-based antihypertensive regimen conferred
less cardiovascular risk reduction than an amlodipine-based
regimen.15 Heart rate reduction is therefore not a specific treatment target in patients with hypertension.12
While this association has been known for decades,3 it is still
very timely. A subgroup analysis of the placebo arm of the
BEAUTIFUL trial (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left
ventricULar dysfunction), for instance, demonstrated that a
resting heart rate of 70 bpm or higher was a strong and independent predictor of long-term outcome in patients with coronary artery disease.4 In a similar analysis of the SHIFT trial (Systolic Heart failure treatment with the If inhibitor ivabradine Trial)
in heart failure patients with a heart rate above 70 bpm despite optimal β-blocker therapy, risk of death in the highest
heart rate quintile (>87 bpm) was more than that in the lowest quintile (70-72 bpm).5
N Stable coronary artery disease
Heart rate reduction is an important method of reducing myocardial oxygen consumption in patients with stable coronary
artery disease. Heart rate reduction with β-blockers or calcium channel blockers reduces the manifestations of ischemia.
Indeed, anti-ischemic drugs that reduce heart rate are often
more effective than regimens with no effect on heart rate.9
There is, however, no evidence that heart rate reduction with
these conventional agents improves prognosis or reduces the
incidence of acute coronary syndromes.9 The benefits of ivabradine on angina are also fairly well established and seem
at least proportional to those of β-blockers and calcium channel blockers.16,17 Ivabradine added to an atenolol-based regimen further reduces angina and improves exercise capacity.18 The BEAUTIFUL trial tested whether specific heart rate
reduction with ivabradine improves clinical outcomes in patients with stable coronary artery disease and left ventricular
systolic dysfunction. Surprisingly, ivabradine did not reduce
the incidence of the primary composite end point of mortality,
myocardial infarction, or heart failure hospitalization.19 Clear
survival benefit was, however, apparent in a prespecified subgroup analysis of patients with a resting heart rate above 70
bpm and in patients with limiting angina. These findings suggest that the lack of benefit in BEAUTIFUL could be explained
by a relatively heterogeneous population with a large proportion of patients in whom heart rate was already well controlled.
Thus, although three classes of heart rate–modifying drugs alleviate symptoms, unequivocal evidence of mortality benefit is lacking and recommendations for a specific heart rate
range cannot be made. It would, however, be prudent to target heart rates to values between 50-70 bpm (see below), although treatment should always focus on symptom alleviation
rather than on heart rate values themselves.
Prognostic value is not confined to resting rates. The chronotropic response to exercise and subsequent efficiency of heart
rate recovery have also been associated with cardiovascular events and mortality in presence or absence of prior cardiovascular disease.6 The value of the exercise heart rate is
extensively discussed in another review in this issue of Medicographia.
Heart rate is not only of prognostic importance, but is also an
established therapeutic target. Pharmacological therapies that
reduce heart rate are associated with improved coronary perfusion, reduced myocardial oxygen consumption, enhanced
left ventricular function, and beneficial left ventricular remodeling.2,7-9 These functional changes translate into improvements in exercise capacity, cardiac function, angina, and quality of life.2,7-9 The beneficial effects of β-blockers on survival
are also proportional to the degree of heart rate reduction
achieved, suggesting that it is the most important therapeutic target.10 More direct and unequivocal evidence for heart
rate reduction is currently emerging from studies with the specific heart rate–reducing agent ivabradine.11 In summary, there
is thus ample pathophysiological, epidemiological, and clinical evidence that elevated heart rate has deleterious effects
for cardiovascular patients. The evidence that supports heart
rate reduction in clinical practice is discussed below.
Which cardiovascular patients might benefit from
heart rate reduction?
N Hypertension
The inverse relation between heart rate and prognosis can be
extended to patients with hypertension.12 However, the value
of heart rate reduction with β-blockers in patients with hypertension is disputed.13 The CAFE study (Conduit Artery Function Evaluation) compared the effects of atenolol and am-
422
SELECTED
BEAUTIFUL
morBidity-mortality EvAlUaTion of the If inhibitor
CAFE
Conduit Artery Function Evaluation
COPERNICUS CarvedilOl ProspEctive RaNdomIzed
CUmulative Survival
DIG
Digitalis Investigation Group
SHIFT
Systolic Heart failure treatment with the
If inhibitor ivabradine Trial
HEART
N Acute coronary syndromes
The effect of heart rate on myocardial oxygen consumption
is especially critical in acute coronary syndromes. Indeed,
an elevated admission heart rate is one of the most important predictors of early mortality.20 Heart rate–lowering antiischemic drugs can reduce symptoms in patients with acute
coronary syndromes.21 Furthermore, several trials and metaanalyses have demonstrated that β-blockers reduce mortality and prevent reinfarctions when initiated in the subacute
phase after acute myocardial infarction.22 It is, however, unknown whether early heart rate reduction is beneficial in acute
coronary syndromes. Indeed, early intravenous β-blockers followed by oral doses during acute ST-segment elevation myocardial infarction (STEMI) was not associated with net clinical
benefit, due in part to an increased incidence of cardiogenic
shock.23-26 These studies used very high doses of β-blockers
and were conducted in the pre-reperfusion era, suggesting
that results may have differed if performed with current drugs
or titration schemes. The efficacy of early heart rate reduction
with ivabradine is currently under investigation in patients with
acute coronary syndromes.27 Oral β-blockers are recommended in all patients with acute coronary syndromes and calcium
channel blockers in patients who remain symptomatic despite
β-blockers and nitrates.8,21 There is no evidence to support
specific heart rate targets during acute coronary syndromes.
Considering the efficacy of β-blockers after myocardial infarction and the results of the SHIFT study (see below), targeting
a heart rate range between 50 to 70 bpm appears sensible.
N Heart failure
Myocardial workload and oxygen consumption are directly
proportional to heart rate, while diastolic filling time and oxygen delivery are inversely related to heart rate. Elevated heart
rates are especially detrimental to the failing heart, which relies heavily on diastolic filling and is relatively deprived of oxygen and nutrients. Accordingly, heart rate reduction in failing
hearts is associated with decreased energy expenditure, improved perfusion, improved contractility, decreased afterload,
and restoration of ventricular synchrony.1,2,5,28 The first evidence
that heart rate reduction could enhance clinical outcome was
presented in the DIG trial (Digitalis Investigation Group).29 Heart
rate reduction with digoxin reduced hospital admission for
worsening heart failure, although it did not reduce mortality.
More robust evidence for heart rate reduction came from multiple randomized controlled trials that firmly established the
efficacy of β-blockers in heart failure.7 Importantly, the mortality benefits of β-blockers are strongly related to the degree
of heart rate reduction achieved.10 β-Blockers and digoxin have
several cardiovascular and extracardiovascular (side) effects
that may partially explain their efficacy, but also affect their
tolerability. Indeed, only 56% of patients tolerated the target
dose of carvedilol in the COPERNICUS trial (CarvedilOl ProspEctive RaNdomIzed CUmulative Survival),30 and even fewer
patients tolerate the target dose of β-blockers outside the
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clinical trial setting.31 While individual dose-response characteristics vary and careful titration may allow patients to tolerate higher doses,32 side effects significantly limit the degree of
heart rate reduction that can be achieved. The SHIFT study
specifically targeted those patients with heart rate control that
remained suboptimal on conventional medication.11 In SHIFT,
6505 chronic systolic heart failure patients in sinus rhythm
with a resting heart rate ⱖ70 bpm despite a maximally tolerated β-blocker dose were randomized to ivabradine or placebo. Ivabradine was titrated to a target dose rather than a heart
rate target, but the dose was reduced when heart rate dropped
below 50 bpm. It achieved an average heart rate reduction
of 11 bpm and reduced the occurrence of the primary composite end point of cardiovascular death or heart failure hospitalizations by 18%. This effect was mainly driven by a 26%
reduction in hospitalizations for worsening heart failure or heart
failure-related deaths. Prespecified post-hoc analysis also
showed that heart rate reduction reversed left ventricular remodeling and improved both cardiac function and quality of
life.33,34 This study not only shows ivabradine to be effective,
but also unequivocally proves that heart rate is a nodal point
for intervention in the cardiovascular system.
Which rate is best for the heart?
Extensive epidemiological studies and the evidence provided by the BEAUTIFUL and SHIFT trials indicate that heart rates
above 70 bpm are unfavorable. More importantly, they show
that reducing heart rate in these patients can improve clinical
outcome. Although the SHIFT and the BEAUTIFUL studies did
not target a specific heart rate range, the dose was adjusted
when the heart rate fell below 50 bpm. We therefore propose
that the optimal resting heart rate range is between 50 and
70 bpm, at least in patients with heart failure, stable coronary
artery disease, and left ventricular systolic dysfunction. However, the inclusion criteria for these studies were broadly defined and not mutually exclusive. The primary etiology for left
ventricular dysfunction and heart failure, for instance, is a previous acute coronary syndrome. It is therefore likely that the
findings of both trials can be extrapolated to other populations
as well. The optimal heart rate range for patients with heart
disease is probably between 50 to 70 bpm. Future studies
with ivabradine will hopefully help us to further define the optimal heart rate targets. Moreover, new avenues for heart rate
reduction will likely emerge.35
Conclusions
Extensive data from pathophysiological and epidemiological
studies and clinical trials have established heart rate reduction as an effective and feasible tool to alleviate symptoms
and improve prognosis in patients with coronary artery disease
and heart failure. Trials with the specific heart rate–reducing
agent ivabradine have unequivocally proven this concept and
provided us with a novel and specific tool to control heart
rate. I
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References
1. Custodis F, Schirmer SH, Baumhakel M, Heusch G, Böhm M, Laufs U. Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol. 2010;56:1973-1983.
2. Fox KM, Ferrari R. Heart rate: A forgotten link in coronary artery disease? Nat
Rev Cardiol. 2011;8:369-379.
3. Kannel WB, Kannel C, Paffenbarger RS Jr, Cupples LA. Heart rate and cardiovascular mortality: The Framingham study. Am Heart J. 1987;113:1489-1494.
4. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R. Heart rate as a
prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): A subgroup analysis of a randomised
controlled trial. Lancet. 2008;372:817-821.
heart failure (SHIFT): The association between heart rate and outcomes in a
randomised placebo-controlled trial. Lancet. 2010;376:886-894.
6. Palatini P, Grassi G. Assessment of exercise blood pressure and heart rate in
patients with coronary artery disease: Is it worth it? J Hypertens. 2010;28:21842187.
7. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: The Task Force for
the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the
European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of
Intensive Care Medicine (ESICM). Eur Heart J. 2008;29:2388-2442.
8. Hamm CW, Bassand JP, Agewall S, et al. ESC guidelines for the management
of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the Management of Acute Coronary Syndromes (ACS) in Patients presenting Without Persistent ST-Segment Elevation
of the European Society of Cardiology (ESC). Eur Heart J. 2011;32:2999-3054.
9. Skalidis EI, Vardas PE. Guidelines on the management of stable angina pectoris. Eur Heart J. 2006;27:2606; author reply 2606-2607.
10. Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers.
Am J Cardiol. 2008;101:865-869.
11. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic
heart failure (SHIFT): A randomised placebo-controlled study. Lancet. 2010;
376:875-885.
12. Palatini P, Benetos A, Grassi G, et al. Identification and management of the hypertensive patient with elevated heart rate: Statement of a European Society of
Hypertension Consensus Meeting. J Hypertens. 2006;24:603-610.
13. Palatini P. Elevated heart rate in hypertension: A target for treatment? J Am Coll
Cardiol. 2010;55:931; author reply 931-932.
14. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressurelowering drugs on central aortic pressure and clinical outcomes: Principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;
113:1213-1225.
15. Poulter NR, Wedel H, Dahlof B, et al. Role of blood pressure and other variables
in the differential cardiovascular event rates noted in the Anglo-Scandinavian
Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet.
2005;366:907-913.
16. Ruzyllo W, Tendera M, Ford I, Fox KM. Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris:
A 3-month randomised, double-blind, multicentre, noninferiority trial. Drugs.
2007;67:393-405.
17. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of ivabradine, a new
selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529-2536.
18. Tardif JC, Ponikowski P, Kahan T. Efficacy of the I(f) current inhibitor ivabradine
in patients with chronic stable angina receiving beta-blocker therapy: A 4month, randomized, placebo-controlled trial. Eur Heart J. 2009;30:540-548.
19. Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Ivabradine for patients with stable
coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL):
A randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807816.
20. Lee KL, Woodlief LH, Topol EJ, et al. Predictors of 30-day mortality in the era
of reperfusion for acute myocardial infarction. Results from an international trial
of 41,021 patients. GUSTO-I investigators. Circulation. 1995;91:1659-1668.
21. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force
on the Management of ST-Segment Elevation Acute Myocardial Infarction of
the European Society of Cardiology. Eur Heart J. 2008;29:2909-2945.
22. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta blockade after
myocardial infarction: Systematic review and meta regression analysis. BMJ.
1999;318:1730-1737.
23. Chen ZM, Pan HC, Chen YP, et al. Early intravenous then oral metoprolol in
45,852 patients with acute myocardial infarction: Randomised placebo-controlled trial. Lancet. 2005;366:1622-1632.
24. Hjalmarson A, Herlitz J, Holmberg S, et al. The Göteborg metoprolol trial. Effects on mortality and morbidity in acute myocardial infarction. Circulation. 1983;
67:I26-I32.
25. Metoprolol in Acute Myocardial Infarction (MIAMI). A randomised placebo-controlled international trial. The MIAMI trial research group. Eur Heart J. 1985;6:
199-226.
26. Randomised trial of intravenous atenolol among 16 027 cases of suspected
acute myocardial infarction: ISIS-1. First International Study of Infarct Survival
Collaborative Group. Lancet. 1986;2:57-66.
27. Fasullo S, Cannizzaro S, Maringhini G, et al. Comparison of ivabradine versus
metoprolol in early phases of reperfused anterior myocardial infarction with impaired left ventricular function: preliminary findings. J Card Fail. 2009;15:856863.
28. Reil JC, Reil GH, Böhm M. Heart rate reduction by I(f)-channel inhibition and
its potential role in heart failure with reduced and preserved ejection fraction.
Trends Cardiovasc Med. 2009;19:152-157.
29. Ahmed A, Rich MW, Love TE, et al. Digoxin and reduction in mortality and hospitalization in heart failure: A comprehensive post hoc analysis of the DIG trial.
Eur Heart J. 2006;27:178-186.
30. Maggioni AP, Dahlstrom U, Filippatos G, et al. EURObservational research
programme: The Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail. 2010;
12:1076-1084.
31. Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity
of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;
106:2194-2199.
32. Cullington D, Goode KM, Cleland JG, Clark AL. Limited role for ivabradine in
the treatment of chronic heart failure. Heart. 2011;97:1961-1966.
33. Ekman I, Chassany O, Komajda M, et al. Heart rate reduction with ivabradine
and health related quality of life in patients with chronic heart failure: Results
from the SHIFT study. Eur Heart J. 2011;32:2395-2404.
34. Tardif JC, O'Meara E, Komajda M, et al. Effects of selective heart rate reduction
with ivabradine on left ventricular remodelling and function: Results from the
SHIFT echocardiography substudy. Eur Heart J. 2011;32:2507-2515.
35. Nuding S, Ebelt H, Hoke RS, et al. Reducing elevated heart rate in patients
with multiple organ dysfunction syndrome by the I(f) (funny channel current) inhibitor ivabradine: Modi(f)y trial. Clin Res Cardiol. 2011;100:915-923.
Keywords: coronary artery disease; heart failure; heart rate; heart rate reduction; hypertension; ivabradine
424
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FAUT- IL SURVEILLER LA FRÉQUENCE CARDIAQUE DES PATIENTS
AYANT UNE MALADIE CARDIOVASCULAIRE ?
La fréquence cardiaque joue un rôle essentiel dans la fonction cardiovasculaire et c’est un des signes vitaux les plus
facilement accessibles et instructifs. Une fréquence cardiaque élevée est un facteur de risque indépendant de mortalité et de morbidité chez les personnes ayant ou non une maladie cardiovasculaire. C’est pourquoi les traitements
qui réduisent la fréquence cardiaque peuvent soulager les symptômes et améliorer les résultats cliniques dans de
nombreuses maladies cardiaques. Malheureusement, peut-être parce que la fréquence cardiaque nous est familière,
ou parce que nous manquons de données claires pour la définir de façon spécifique, elle est souvent négligée.
Dans cet article, nous allons analyser l’importance d’une fréquence cardiaque élevée et de sa réduction dans la maladie cardiovasculaire et essayer de donner des recommandations pratiques, fondées sur des preuves, pour sa prise
en charge.
425
THE QUESTION
CONTROVERSIAL
ardiac rehabilitation is an
important component of the
multidisciplinary approach
to the management of cardiovascular patients. Cardiac rehabilitation has traditionally been provided to lower-risk patients, however,
the demographics of patients who
can be candidates for rehabilitation training has changed. Should
we now consider cardiac rehabilitation as an essential component
of the treatment of patients with
multiple presentations of coronary
heart disease and heart failure? If
so, when should it be started?
QUESTION
C
When should cardiac
rehabilitation be started
after a cardiovascular event?
1.
C. Aguiar, Portugal
2.
D. M. Aronov, Russia
3.
F. Bacal, M. M. Fernandes da Silva, Brazil
4.
K. Daly, Ireland
5.
D. R. Dimulescu, Romania
6.
N. M. Farag, Egypt
7.
K. Naidoo, D. P. Naidoo, South Africa
8.
H. Ong-Garcia, Philippines
9.
A. A. A. Rahim, Malaysia
10 .
H. Rasmusen, Denmark
11.
G. Sinagra, P. L. Temporelli, Italy
12 .
M. Zoghi, Turkey
When should cardiac rehabilitation be started after a cardiovascular event?
427
CONTROVERSIAL
QUESTION
1. C. Aguiar, Portugal
A recent systematic review showed that exercise training has
a beneficial effect on LV remodeling in clinically stable post-MI
patients.3 The greatest benefit occurs when training starts early after MI (from 1 week) and lasts longer than 3 months. For
each week that exercise was delayed, an additional month of
training was required to achieve the same level of benefit on
LV remodeling.
Carlos AGUIAR, MD
Cardiologist
Hospital de Santa Cruz
Carnaxide
PORTUGAL
H
alting the progression of atherosclerosis is possible,
and it is an important objective in the treatment of
coronary heart disease. It is achieved by correction of
risk factors through lifestyle intervention and evidence-based
pharmacotherapy.
Cardiac rehabilitation programs provide counseling on risk factor modification and exercise training for secondary prevention of coronary heart disease. For most patients with coronary
heart disease (including the elderly), the benefits of cardiac rehabilitation are well documented; this includes patients with
recent myocardial infarction (MI), those who have undergone
myocardial revascularization, and patients with chronic stable
angina. The benefits are cost effective and involve improvement in adherence to preventive medications, improved risk
factor profiles, enhanced functional, psychosocial, and vocational status, better quality of life, less recurrent hospitalizations,
reduced risk of reinfarction, and increased survival. Furthermore, exercise training per se lowers resting heart rate and enhances heart rate recovery in post-MI patients, suggesting that
it improves autonomic function.
In the post-MI setting, the European Society of Cardiology
(ESC) recommends enrolment in a secondary prevention or
cardiac rehabilitation program, particularly for patients with
multiple modifiable risk factors and moderate- to high-risk patients in whom supervised guidance is warranted. The ESC
has recently stated that they consider such enrolment to be
a performance measure for monitoring and improving the
standards of post-MI care.1,2 The process should start as soon
as possible after hospital admission, and be continued in the
succeeding weeks and months.
For exercise training prescription, symptom-limited exercise
testing can safely be performed between 1 and 2 weeks after
primary percutaneous coronary intervention (PCI). Several factors should be considered when deciding on the appropriate timing for submaximal exercise testing (during the first
month after an acute coronary syndrome); namely, clinical,
hemodynamic, and electrophysiological stability, functional
completeness of revascularization, degree of left ventricular
(LV) dysfunction, prior physical condition, and orthopedic limitations.
428
Cardiac rehabilitation and secondary prevention are also recommended for all revascularized patients, and should be initiated during hospitalization.4 Counseling regarding physical
activity can start as early as the next day after uncomplicated PCI or coronary surgery.
Over the past decades, mortality from acute cardiovascular
diseases such as MI has dramatically declined, but the increasing number of patients subsequently affected by chronic conditions such as heart failure has driven up the costs and
needs of health systems. Exercise training in compensated
heart failure is safe and has several benefits, including enhanced peak oxygen uptake, improved muscle energetics,
restoration of autonomic function, reduced neurohormonal
activation, and reverse LV remodeling; it thus leads to better
functional capacity, an important objective of heart failure management. These benefits are apparent as early as 3 weeks
after commencement of training. Evidence from randomized
controlled trials further indicates that physical rehabilitation
may ultimately reduce heart failure–related hospitalization and
improve health-related quality of life in patients with mild to
moderate systolic heart failure.
The ESC recommends exercise training for all stable chronic heart failure patients.5 For hospitalized patients, inpatient
counseling and education should begin as soon as possible after hospital admission. I
References
1. Piepoli MF, Corrà U, Benzer W, et al. Secondary prevention through cardiac rehabilitation: from knowledge to implementation. A position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation. Eur J Cardiovasc Prev Rehabil. 2010;17:1-17.
2. Hamm CW, Bassand JP, Agewall S, et al. ESC guidelines for the management
of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the Task Force for the Management of Acute Coronary Syndromes
(ACS) in Patients Presenting Without Persistent ST-Segment Elevation of the
European Society of Cardiology (ESC). Eur Heart J. 2011;32:2999-3054.
3. Haykowsky M, Scott J, Esch B, et al. A meta-analysis of the effects of exercise
training on left ventricular remodeling following myocardial infarction: start early
and go longer for greatest exercise benefits on remodeling. Trials. 2011;12:92.
4. Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur
Heart J. 2010;31:2501-2555.
5. McMurray JJ, Adamopoulos S, Anker SD, et al; ESC Committee for Practice
Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and
Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in
collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J.
2012;33:1787-1848.
CONTROVERSIAL
QUESTION
2. D. M. Aronov, Russia
David M. ARONOV, MD, PhD
Professor & Honored Worker
of Science of the RF
State Research Center for
Preventive Medicine
Moscow, RUSSIA
T
his question was resolved definitively in as early as 1968
in a document prepared by a working group of the World
Health Organization Regional Office for Europe entitled,
“A programme for the physical rehabilitation of patients with
acute myocardial infarction” (Copenhagen, 1968). In the document, the recommendation after hospital admission of a patient with acute myocardial infarction was “…to start physical rehabilitation as soon as possible.” Today, with significantly
reduced lengths of stay in the cardiology department, the first
rehabilitation measures can be started as soon as relief of pain
and serious cardiovascular complications have been successfully addressed.
The objectives of in-hospital rehabilitation are as follows: (i)
to prevent the development of hypokinesia caused by the
patient’s limited physical activity; and (ii) to provide early educational and psychological support to the patient to allow
him/her to understand the need for further complex stepwise
rehabilitation, including special exercise training that transforms into a lifetime secondary prevention measure.
The first objective is achieved by permitting the patient to be
active early, and by allowing patients with a complicated disease course to perform therapeutic exercises. These exercises are started from the first or second day of the patient’s stay
in hospital. At the earliest stage, rehabilitation of the patient
with acute coronary syndrome begins through discussion of
the concepts of myocardial infarction (or acute coronary syndrome), the importance of drug treatment, application of rehabilitation methods, and further long-term secondary prevention.
unit is a good first step that will increase motivation for the
upcoming treatment and rehabilitation and improve adherence to them.
Discussion with the patient and, if possible, with his or her relatives, has a favorable psychological effect. The doctor informs
the patient about the purpose of rehabilitation, the methods,
and the achievable results at different stages. The patients
must understand that a combination of medical and nonmedical interventions (physical rehabilitation, adherence to an
antiatherosclerotic diet, a training program, psychotherapy,
and modification of risk factors) will allow them to quickly recover and return to an active life and their professional activities. Patient awareness of these interventions has been found
to increase motivation and improve compliance with implementation of the treatment, rehabilitation, and secondary prevention measures.1
There is also a physical aspect to rehabilitation. Depending
on the severity of the patient’s state, the doctor will determine
the tentative discharge date from hospital. In cases of uncomplicated myocardial infarction, patients can be discharged in
about 1 week. They are not threatened by hypokinesia. However, if the prognosis is poor, the length of stay in hospital becomes longer. In such cases, the patient is prescribed a sparing regimen of physical activity and calisthenics in order to
prevent hypodynamia and secure an early expansion of physical activity. So-called breathing exercises and exercises for
small muscle groups are used, and are performed under the
supervision of a physiotherapist or trained nurse.
Rehabilitation is carried out not only after myocardial infarction, but also after coronary artery bypass graft (CABG) and
percutaneous coronary intervention. The 2011 recommendations of the American College of Cardiology Foundation/
American Heart Association state: “Cardiac rehabilitation is
recommended for all eligible patients after CABG. Class I,
Level of Evidence: A.” 2 I
References
The patient must understand what, why, and in what time
frame he or she should undertake activities, which are for lifesaving purposes, improvement of the disease course, fastest
possible recovery of physical performance, and a return to
work activities. Ensuring the patient’s awareness of the need
for strict compliance with the medical and nonmedical recommendations of doctors during the stay in the coronary care
1. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice
Guidelines (Committee to Revise the 1999 Guidelines for the Management of
Patients with Acute Myocardial Infarction). Circulation. 2004;110:e82-e292.
2. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA guideline for coronary
artery bypass graft surgery: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124:2610-2642.
429
CONTROVERSIAL
QUESTION
L
3. F. Bacal, M. M. Fernandes da Silva, Brazil
Fernando BACAL, MD, PhD
Professor of Cardiology, University of São
Paulo Medical School, Heart Institute (InCor)
Heart Failure and Heart Transplant Unit
BRAZIL
was a single-center study, and also allowing time for healing
of the access site, it seems appropriate to perform exercise
testing and initiate CR 5 to 7 days after an elective percutaneous coronary intervention.
Miguel Morita FERNANDES DA SILVA, MD
Cardiologist, Rehabilitation Department
Hospital Cardiológico Costantini
University of São Paulo, BRAZIL
A
lmost 7 decades ago, healing of a myocardial infarction
was described as taking 3 to 4 weeks, and a theoretical 6 to 8 weeks of bed rest was considered necessary after an acute myocardial infarction (AMI).1 With technological advances and improvements in the management of
cardiac disease, recovery has become faster and long periods of inactivity are generally no longer needed. On the other hand, as more people survive after a cardiovascular event,
there are more patients in a poor health condition and with
comorbidities, and these patients are considered for cardiac
rehabilitation (CR).
Although there is some controversy regarding the effects of
CR on heart failure mortality, CR leads to a 26% reduction in
cardiovascular mortality in coronary heart disease.2 The core
component of CR is exercise training, which has known benefits including positive effects on quality of life, anti-inflammatory effects, improvement in autonomic and endothelial function, an increase in fibrinolysis, and a decrease in coagulability.
Although recommended by the American Heart Association,
American College of Cardiology, and European Society of Cardiology in the treatment of patients with coronary artery disease and heart failure,3 CR is still underused.
Before starting exercise training after a cardiovascular event,
exercise testing is recommended to guide prescription. Safety
concerns regarding when to perform testing—and thus when
to initiate the exercise program—stem from the risk of triggering a fatal arrhythmia, prolonged ischemia during exercise
sessions leading to myocardial necrosis, or worsening of ventricular function with an unfavorable outcome in the long term.
In addition, acute exercise may lead to a transitory prothrombotic state and elevated wall stress, which can raise concerns
in patients with a coronary stent, especially in areas that are
not covered by endothelium.4 This issue was investigated in a
study in which patients with no recent myocardial infarction
(within 1 week) were randomized to symptom-limited treadmill exercise testing or not the day after uncomplicated percutaneous revascularization with stent placement. There was no
difference in AMI or access site complications between the
groups,5 indicating that this approach is safe. Given that this
430
After an acute coronary syndrome, including AMI or unstable
angina, symptom-limited exercise testing can be performed
14 days after an uncomplicated event, when an exercise training program can also be initiated. After a large and/or complicated myocardial infarction including heart failure, arrhythmias,
pericarditis, or mechanical complications, physical activity
should start only after clinical stabilization. With regard to possible deleterious effects on ventricular function, aerobic exercise for 3 months initiated within 2 weeks after AMI does
not appear to cause unfavorable left ventricular remodeling
and still reduces myocardial ischemia after 6 months.6
Although low-intensity exercise can be started in hospital after cardiac surgery, the aim of this management phase is to
prevent respiratory complications and profound venous thrombosis, and no study has specifically investigated when symptom-limited exercise testing can safely be performed. Upper
body training can be started when the wound is stable. For
patients submitted for cardiac transplantation, exercise training can start 2 to 3 weeks after the procedure, but should be
discontinued during corticosteroid bolus therapy for rejection.3
Clinical trials have generally included heart failure patients receiving optimal treatment at stable doses in the previous 6 to
12 weeks. After an episode of decompensation, it would seem
appropriate to initiate CR when the patient is clinically compensated with maximal tolerated doses, also allowing for the use
of exercise testing for appropriate prognosis evaluation. I
References
1. [No authors listed] I National Consensus of Cardiovascular Rehabilitation. Arq
Bras Cardiol. 1997;69:267-291.
2. Heran BS, Chen JM, Ebrahim S, et al. Exercise-based cardiac rehabilitation for
coronary heart disease. Cochrane Database Syst Rev. 2012;1:CD001800.
3. Corra U, Piepoli MF, Carre F, et al. Secondary prevention through cardiac rehabilitation: physical activity counselling and exercise training: key components of
the position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation. Eur Heart J. 2010;31:
1967-1976.
4. Thompson PD, Franklin BA, Balady GJ, et al. Exercise and acute cardiovascular events placing the risks into perspective: a scientific statement from the
American Heart Association Council on Nutrition, Physical Activity, and Metabolism and the Council on Clinical Cardiology. Circulation. 2007;115:2358-2368.
5. Roffi M, Wenaweser P, Windecker S, et al. Early exercise after coronary stenting
is safe. J Am Coll Cardiol. 2003;42:1569-1573.
6. Giallauria F, Acampa W, Ricci F, et al. Effects of exercise training started within
2 weeks after acute myocardial infarction on myocardial perfusion and left ventricular function: a gated SPECT imaging study. Eur J Cardiovasc Prev Rehabil.
2011 Sep 30. Epub ahead of print.
CONTROVERSIAL
QUESTION
4. K. Daly, Ireland
patients will have attempted to return to normal work and activity, and while remaining concerned as to the appropriate
lifestyle and exercise level, they find themselves unable to engage in a delayed program.
Kieran DALY, MB Dch, FRCPI, FESC, FACC
Consultant Cardiologist, Cardiology
Department, University College Hospital
Galway, IRELAND
C
ardiac rehabilitation (CR) has been shown to accelerate physical and psychological recovery and reduce
mortality after acute cardiac events. The programs
help modify risk factors and increase the likelihood of a return to work. It is a cost-effective intervention that improves
prognosis and reduces recurrent hospitalization and health
care expenditure. When originally introduced, CR was primarily aimed at patients after cardiac surgery and myocardial
infarction without intervention. Traditionally, Phase II CR commenced 4 to 6 weeks after the event when wound healing
had occurred.
Over the past decade, the profile of patients that would benefit from CR has changed greatly. The duration of hospitalization following percutaneous coronary intervention (PCI) and
even primary angioplasty has greatly reduced. Patients undergoing these procedures are fully mobile on discharge and
mostly keen to return to work and normal activity. Yet recent
surveys have indicated that less than 35% of heart attack
and other cardiac event patients attend CR programs. The
cause is likely multifactorial, and includes a lack of services,
patient anxiety and lack of motivation, lack of social support,
travel time, and needing to take time off from work. A major
factor is undoubtedly the length of time between discharge
and commencement of outpatient CR, during which many
Concern has existed regarding possible adverse effects of
early CR after discharge from hospital. However, there is now
extensive evidence that early CR does not have any adverse
effect on left ventricular size or myocardial function, and that
rates of completion of CR are greater if started within 14 days
post discharge. Equally, CR exercise programs can be safely
started—even in the elderly—2 weeks after discharge following cardiac surgery, and they lead to better exercise tolerance.
Ensuring higher levels of participation in CR will require significant multidisciplinary organization. Intensive in-hospital
Phase I CR, enthusiastic physician endorsement, more accessible early programs, and tailoring of programs to patients’
needs, sex, and age are necessary. Community- rather than
hospital-based programs should be more acceptable to patients, and initiatives such as home-based telemonitored exercise programs could support traditional CR. Issues such
as the relatively poor take-up of CR by women will need to
be addressed.
In summary, the value of CR is beyond doubt. The current low
level of participation by patients following cardiac events will
only be addressed by an enthusiastic multidisciplinary Phase I
approach, followed by early (2 weeks ideally) enrolment in
Phase II programs with a strong community element. Barriers to CR participation need to be identified. Databases on
cardiac intervention, acute coronary syndromes, and cardiac
surgery need to be linked to CR programs with regular local
and national audit. I
431
CONTROVERSIAL
QUESTION
5. D. R. Dimulescu, Romani
mal symptom-limited cardiopulmonary exercise testing, and
physical training should resume gradually at 50% of maximal exercise capacity in hospital to verify clinical tolerability
and stability. Daily moderate-intensity exercise after hospitalization is recommended (Class I).5
Doina R. DIMULESCU, MD, PhD, FESC
Professor, University of Medicine
and Pharmacy “C. Davila”
Head of Cardiology Clinic
Elias University Hospital
17, Bd. Marasti, Sector 1
Bucharest, ROMANIA
P
rolonged bed rest and hospitalization was the standard
care for patients after acute myocardial infarction (AMI)
some decades ago; exercise helped to reduce the hospitalization period and physical deconditioning, and to delay
the onset of angina after AMI before the era of myocardial
revascularization. With the advent of modern effective therapeutic interventions in AMI, physical training is now also aimed
at improving psychological wellbeing, controlling depression
and anxiety, improving adherence to medication, and controlling risk factors.
Exercise training after AMI has beneficial hemodynamic effects, producing an average 20% improvement in aerobic capacity. Improved functional capacity allows patients to return
to work and helps elderly patients maintain independent living.1 A reduction in recurrent myocardial infarction and mortality in coronary artery disease patients included in physical
training programs has been documented in a meta-analysis,
and the results do not differ from those of trials conducted in
the era of cardiac revascularization.2 A recent large observational study in more than 600 000 patients aged >65 years discharged after hospitalization for coronary disease showed a
21% to 34% decrease in all-cause mortality at 5 years in those
patients included in physical training programs compared with
controls.3
When should physical training start after an acute coronary
syndrome? The European Society for Cardiology (ESC) guidelines for the management of ST-segment elevation myocardial
infarction recommend risk stratification and exercise testing.4
A position paper from the ESC on cardiac rehabilitation in secondary prevention makes recommendations as to the timing
and intensity of physical training after AMI and in heart failure patients.5 In uncomplicated AMI, ambulation should begin
after 12 to 24 hours (Class I); predischarge physical training
may start in hospital after an electrocardiogram stress test. Patients with preserved exercise capacity may resume physical activity for 30 to 60 minutes daily at 75% to 80% of peak
heart rate (Class I). After large or complicated infarcts with
heart failure, shock, or arrhythmias, patients should maintain
bed rest for longer and physical activity should begin only
after stabilization. Patients with left ventricular systolic dysfunction should be tested for peak exercise capacity with maxi-
432
Each stage of increased physical work capacity is associated
with an 8% to 14% reduction in all-cause mortality risk.5 Physical training is safe, and data reported in clinical trials show
one event (AMI, cardiac arrest) in 50 000 to 100 000 supervised patient-hours of physical training.1
In patients with heart failure, which frequently has an ischemic
etiology, the benefits of physical training are less clear. HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes
of Exercise Training) randomized 2331 patients with left ventricular ejection fraction ⱕ35% to exercise training or control.
There was an 11% decrease in total mortality or hospitalization ( P=0.03) and a 15% decrease in cardiovascular mortality and cardiovascular hospitalization ( P=0.03) with exercise
training, suggesting that this has some beneficial effects in
patients with heart failure—findings consistent with the results
of 33 previous clinical trials and a meta-analysis.
Questions about the role of exercise training remain unanswered: the optimal amount, intensity, and combination of exercise training modalities in patients with systolic heart failure,
as well as its utility in patients with cardiac resynchronization
therapy.6 Although recognized as a core component of multifactorial cardiac rehabilitation, physical training is still underused (less than 50% in observational studies). Lack of knowledge, skills, and motivation on the part of health care providers,
as well as patients’ lack of adherence in changing their lifestyle
and insufficient insurance funding, are all possible causes and
must be addressed. I
References
1. Wenger KN. Current status of cardiac rehabilitation. JACC. 2008;51:1619-1631.
with coronary heart disease: systematic review and meta-analysis of randomized controlled trials. Am J Med. 2004;116:682-692.
3. Suaya JA, Stason WB, Ades PhA, et al. Cardiac rehabilitation and survival in
older coronary patients. JACC. 2009;54:25-33.
4. Management of acute myocardial infarction in patients with persistent ST-segment elevation. The Task Force on the Management of ST-Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2008;29:
2909-2945.
5. Corra U, Piepoli MF, Carre F, et al. Secondary prevention through cardiac rehabilitation: physical activity counselling and exercise training: key components of
the position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation. Eur Heart J. 2010;31:
1967-1976.
6. Kraus WE. Exercise in heart failure. In: Mann DL, ed. Heart Failure. A Companion
to Braunwald′s Heart Disease. 2nd ed. St. Louis, MO: Elsevier Saunders; 2011:
834-844.
CONTROVERSIAL
QUESTION
6. N. M. Farag, Egypt
Nabil M. FARAG, MD, FSCAI
Professor of Cardiology, Ain Shams University
Chairman of Cardiology Department
Dar Alfouad Hospital
71 Elhegaz Street, Elmahkama Square
Heliopolis, Cairo, EGYPT
I
n recent years, there has been impressive progress in pharmacological therapies and sophisticated technology-based
diagnostic and therapeutic procedures in cardiovascular
diseases. As a consequence, a greater number of men and
women now survive acute events, but with a heavier subsequent burden of chronic conditions and clinical need. Cardiac
rehabilitation includes patient assessment, counseling on physical activity, exercise training, diet/nutritional counseling, weight
control management, lipid management, blood pressure monitoring, smoking cessation, and management of psychosocial
well-being.
Inpatient and outpatient cardiac rehabilitation for eligible cardiovascular patients is an essential component of care that
should be incorporated into treatment plans. Increasing the
number of people who participate in cardiac rehabilitation
can also reduce health care costs associated with recurrent
events and reduce the burden for families and caregivers of
patients with serious sequelae.1
Exercise training should be recommended to all patients after
acute coronary syndrome or primary percutaneous coronary
intervention (PCI) (supervised or monitored in moderate- to
high-risk patients). The training program should include at
least 30 minutes of aerobic exercise, 5 days per week. After
uncomplicated procedures, physical activity can start the next
day. After substantial and/or complicated myocardial damage,
physical activity should start after clinical stabilization and be
increased slowly according to the patient’s symptoms.2-5 Inpatient rehabilitation is focused on early mobilization, and starts
as soon as patients are hemodynamically stable and free of
symptoms of ischemia, arrhythmia, or heart failure. As the patient progresses to ECG telemetry, progressive ambulation
becomes appropriate, initially with assistance and hemodynamic assessment before, during, and after exercise. Patients
should first try to sit up, stand, and walk in their room. Subsequently, they should start to walk in the hallway at least twice
daily, for certain specific distances or as tolerated, and should
not be unduly pushed or held back.
Early outpatient rehabilitation includes surveillance of symptoms, hemodynamics, glycemic response to exercise (in diabetics), weight, tobacco use, emotional status, and adherence
with medications, diet, and home exercise. It also includes review of each individual’s pharmacological and device therapy to ensure adherence with consensus guidelines. This monitoring phase is an intensive, multidisciplinary intervention
focused on educating the individual about the disease, its
manifestations, and all aspects of its treatment. This provides
participants with the tools needed to slow disease progression, maintain optimal functional status, and become an informed and active participant in managing their condition.
Most cardiac rehabilitation participants progress to independent exercise without a transitional “Phase III.” The main goal
of maintenance lifetime rehabilitation is to promote habits that
lead to a healthy satisfying lifestyle. In patients with stable
coronary artery disease and post–elective PCI, symptom-limited exercise testing can safely be performed the day after the
intervention, but it scarcely is. In patients with multiple risk factors and moderate-to-high risk (ie, recent heart failure episode),
medically supervised exercise training programs are recommended at initiation, and ensure the patient’s motivation for
long-term adherence.2,5
Exercise training in heart failure can improve both cardiac
and noncardiac indices.6 Experience has shown that exercise
is safe and well tolerated if appropriately prescribed. During
the initial stage (first 1 to 2 weeks), intensity should be kept
at a low level in patients with NYHA functional Class III (50%
of peak VO2 ), and the duration should be increased from 20
to 30 minutes according to the perceived symptoms and
clinical status. During the improvement stage, a gradual increase in intensity (60% of peak VO2 , then 70% to 80%, if tolerated) is the primary aim. Prolongation of exercise is a secondary goal. I
References
1. Ades PA, Pashkow FJ, Nestor JR. Cost-effectiveness of cardiac rehabilitation
after myocardial infarction. J Cardiopulm Rehabil. 1997;17:222-231.
2. Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation. Eur
Heart J. 2008;29:2909-2945.
3. Bassand JP, Hamm CW, Ardissino D, et al; Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European
Society of Cardiology. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J. 2007;28:1598-1660.
4. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA
2004 Guidelines for the Management of Patients With ST-Elevation Myocardial
Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2008;51:210-247.
5. Thompson PD, Buchner D, Pina IL, et al. Exercise and physical activity in the
prevention and treatment of atherosclerotic cardiovascular disease. A statement
from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity). Circulation. 2003;107:3109-3116.
6. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC guidelines for the diagnosis
and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European
Society of Cardiology. Eur Heart J. 2008;29:2388-2442.
433
CONTROVERSIAL
QUESTION
7. K. Naidoo, D. P. Naidoo, South Africa
L
Kumari NAIDOO, MD, ChB
University of KwaZulu-Natal
Durban, SOUTH AFRICA
Datshana P. NAIDOO, MD
Professor of Cardiology
Head of the Cardiology Department
Nelson R. Mandela School of Medicine
University of KwaZulu-Natal
Durban, SOUTH AFRICA
C
ardiac rehabilitation (CR) is aimed at improving physical and psychosocial functioning after a cardiovascular event, and targets the underlying disease process to prevent further events. CR is today relevant to a more
diverse patient population than previously. The epidemic of
chronic disease has resulted in younger patients of all ethnicities being affected by coronary events. Advances in cardiology have also led to more patients surviving major cardiac
events and living with disabilities.
Today, CR extends beyond post-infarct to revascularized patients post–coronary artery bypass graft or percutaneous coronary intervention. It also includes patients with chronic stable
angina and those who have sustained repeated events resulting in myocardial dysfunction and heart failure (HF). The
stepwise process of rehabilitation begins immediately after
the cardiac event and continues throughout life, with different
interventions introduced at appropriate stages.
Standard drug therapy for post-infarct and HF patients is usually instituted while the patient is still in hospital. Target blood
pressure is 140/90 mm Hg (lower in diabetes and chronic kidney disease). HbA1C should be maintained at <7% in diabetics.
Latest guidelines recommend lower lipid targets, with statins
as baseline therapy.
Provided the patient is clinically stable, physical activity should
begin in hospital. This prevents complications of prolonged
immobilization and acts as a psychological booster. After being able to sit up, patients may walk in the corridors for 2 to
5 minutes, 4 times daily. Heart rate (HR) should not exceed
120 beats per minute, while patients with resting tachycardia
should not exceed a 20-beat increase from resting HR.
A graded exercise program is implemented at Phase III, and
begins with a risk assessment based on history, physical examination, and resting electrocardiogram (ECG). Exercise
stress testing and ECG is required in high-risk patients for assessment of ventricular function and residual ischemia and
434
those who wish to participate in high-intensity exercise. Highrisk patients (with residual ischemia or significant left ventricular dysfunction) require constant monitoring and the presence
of health care professionals trained in advanced life support.
HR should not be allowed to exceed 10 beats below the rate
at which ischemia was provoked on stress testing. Impaired
chronotropic response (failure to reach 80% of maximum HR)
is associated with increased mortality post–myocardial infarction, especially with HF, and may be improved by 웁-blockade
and ivabradine.
The following factors preclude participation in an exercise
program: (i) myocardial infarction complicated by persistent
HF, cardiogenic shock, or complex ventricular arrhythmias; (ii)
angina or breathlessness at low levels of exercise; (iii) ST-segment depression >1 mm on resting ECG; and (iv) marked STsegment depression (>2 mm) or symptoms experienced at
<5 metabolic equivalent tasks during exercise stress testing.
Patients should be encouraged to stop smoking at every opportunity and be educated on other risk factor targets. The
basic principles of a cardioprotective diet should be adhered
to. Target body mass index is 21 to 25 kg/m2. Overweight patients should aim for 10% initial weight loss through exercise
and diet.
Low mood, anxiety, irritability, and tearfulness are natural after a cardiac event; however, persisting symptoms may suggest clinical depression or anxiety. A truly comprehensive rehabilitation program strives to assist in reintegrating the patient
into the home, family, and work environments. Patients may
return to work as soon as they are physically capable. Patients
may return to sexual activity 2 to 3 weeks after an uncomplicated myocardial infarction.
There is strong evidence that exercise-based rehabilitation
yields a 20% reduction in total mortality and a 26% reduction
in cardiac mortality, compared with usual medical care. It is an
essential component of the management of all patients with
cardiovascular disease and should start immediately after
an event and be maintained long term. I
Further reading
– Smith SC, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006
update. Circulation. 2006;113:2363-2372.
– Contractor AS. Cardiac rehabilitation after myocardial infarction. J Assoc Physicians India. 2011;59(suppl):51-55.
CONTROVERSIAL
QUESTION
8. H. Ong-Garcia, Philippines
Helen ONG-GARCIA, MD, FPCP, FPCC
President, Cardiac Rehabilitation
Society of the Philippines
Room 1115, South Tower
Cathedral Heights Building
St. Luke’s Medical Center
Quezon City, PHILIPPINES
B
eing a cardiac patient with multiple issues is never easy.
An acute cardiac event is always devastating and persistently debilitating, so that complete management can
never be truly accomplished. Assuming that all algorithms for
recognized standards of care have been implemented, improvement of the condition does not necessarily indicate better overall functionality and disposition. Thus, the evolution of
cardiac rehabilitation as a discipline has come about. The benefits of cardiac rehabilitation are multifaceted; exercise rehabilitation has a positive impact on a number of factors, including improvement in a patient’s lipid profile, blood pressure
reduction, and prevention or treatment of type 2 diabetes.
Other potentially contributory factors to the benefits of cardiac
rehabilitation and exercise training include a reduction in inflammation, as indicated by a decrease in serum C-reactive
protein, possible ischemic preconditioning, improved endothelial function, and a more favorable fibrinolytic balance.1 Such
neurochemical improvements would thus anticipate the positive clinical outcomes seen in several studies involving patients who underwent cardiac rehabilitation.
Studies involving cardiac patients, particularly those investigating changes in clinical functional parameters and quality of life
measures, have indicated that cardiac rehabilitation, whether
exercise-based or focused on a comprehensive risk factor
prevention program (which remains a contentious issue), has
significant benefits. Exercise rehabilitation, with or without risk
factor education and counseling, produced greater reductions in total cholesterol, triglycerides, systolic blood pressure,
and self-reported smoking than control conditions, without
significant differences in low-density lipoprotein or high-density lipoprotein cholesterol levels.2 Quality of life improved to a
similar degree with both cardiac rehabilitation and usual care,
although some studies found a trend toward a superior improvement with cardiac rehabilitation.
In a study of over 500 consecutive coronary patients enrolled
in a cardiac rehabilitation program, depressive symptoms were
assessed by questionnaire and mortality was evaluated at a
mean follow-up of 40 months. Depressed patients had a fourfold higher mortality than nondepressed patients, and depressed patients who completed rehabilitation had a 73%
lower mortality rate than control patients not completing rehabilitation. Only a mild improvement in fitness level was needed to produce the benefit on depressive symptoms and the
associated decrease in mortality.3
As of March 2006, the US Centers for Medicare and Medicaid Services concluded that cardiac rehabilitation is reasonable and necessary after acute myocardial infarction (within
the prior 12 months), coronary artery bypass graft surgery,
stable angina pectoris, percutaneous coronary intervention
with or without stenting, heart valve repair or replacement, and
heart or heart-lung transplantation. Despite this, enrolment
remains low and the discipline is underutilized. It has also
been documented that earlier enrolment stands to produce
a greater reduction in symptoms and better cardiovascular
outcomes. As it is, with an underrated and underappreciated modality that has confirmed benefits, the dictums of “the
earlier the better” and “the more the merrier” are a must. I
References
1. Milani RV, Lavie CJ, Mehra MR. Reduction in C-reactive protein through cardiac
rehabilitation and exercise training. J Am Coll Cardiol. 2004;43:1056-1061.
with coronary heart disease: systematic review and meta-analysis of randomized
controlled trials. Am J Med. 2004;116:682-692.
3. Milani RV, Lavie CJ. Impact of cardiac rehabilitation on depression and its associated mortality. Am J Med. 2007;120:799-806.
435
CONTROVERSIAL
QUESTION
9. A. A. A. Rahim, Malaysia
increases participation in secondary preventive programs. Observational studies report that CR initiation after 1 week leads
to a 90% increase in participation compared with initiation at
4 weeks, with an earlier return to work.
Aizai Azan Abdul RAHIM, MD, MMed
Consultant Cardiologist
National Heart Institute
Kuala Lumpur
MALAYSIA
T
he role of cardiac rehabilitation (CR) in the continuum
of care in cardiovascular disease is undisputed. It is a
Class I recommendation in most evidence-based guidelines, but remains underutilized. Historically, in the early 1930s,
patients with acute myocardial infarction (AMI) were recommended bed rest for 6 weeks. Chair therapy was introduced
in the 1940s, but by the 1950s, clinicians realized that early
ambulation was not harmful and could help avoid many of
the complications associated with prolonged rest, and daily
walking exercises beginning 4 weeks post-AMI were advocated. Comprehensive CR programs have since come a long
way, but questions remain regarding the optimum initiation
time.
Previously, CR patients were post–coronary artery bypass graft
(CABG) surgery, post–valvular repair/replacement surgery, or
post–acute coronary syndrome (ACS), and they attended an
outpatient CR program typically 4 to 6 weeks after discharge.
Recently, eligibility for CR has evolved to include patients after
percutaneous coronary intervention (PCI) and heart transplantation, those with pacemakers, implantable cardiac defibrillators, and ventricular assist devices, and those with peripheral arterial disease, pulmonary arterial hypertension, heart
failure (HF) with preserved ejection fraction, stable angina, and
compensated chronic HF with impaired ejection fraction. Patients are increasingly older with multiple comorbidities. These
complexities make the decision regarding how soon to implement CR more challenging.
There is no evidence as to when exercise training (ET) should
commence after ACS or PCI to derive maximal benefits.1,2
Nevertheless, many national associations have formulated their
own guidelines on a consensus basis. Most CR programs
delay ET until ⱖ4 to 6 weeks after AMI and 3 weeks postPCI.3 There are suggestions that clinically stable patients after
uncomplicated AMI may begin 1 week after discharge, continuing for up to 6 months to achieve maximal antiremodeling
benefits. There is no evidence that this causes any harm.4 Trials have shown no increase in the risk of complications with
earlier physical activity. No additional adverse events occurred
during 6-month ET sessions initiated approximately 1 week
post AMI in patients with mild to moderate left ventricular (LV)
systolic dysfunction.5 Earlier commencement of ET markedly
436
Drug-eluting stents may require 9 to 12 months before complete vessel healing occurs, but should we delay ET in these
patients? There is no evidence of an increased risk from moderate exercise, and in a recent retrospective analysis, participation in CR following PCI was associated with a decrease
in all-cause mortality.6
Following CABG and surgical valvular procedures, 6 weeks are
usually needed for adequate healing. Light weights, breathing exercises, and walking are possible before this time. Consensus papers recommend that CR commence 2 to 4 weeks
post-CABG and valvular procedures in patients with normal/
slightly reduced LV function, 4 to 6 weeks following cardiac
transplantation, and 1 to 2 weeks following minimally invasive
heart surgery.
Patients with stable compensated HF were shown to benefit from ET in HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of exercise traiNing) but there was no
indication as to how early or late the training started after discharge. The ongoing EJECTION-HF (Exercise Joins Education: Combined Therapy to Improve Outcomes in Newly-discharged Heart Failure) may shed light on this matter.
Many issues regarding optimal ET wait times in CR programs
remain unanswered, and there is no internationally accepted
policy. Many factors need to be considered, including the resources and facilities available in each country. These in turn
must then be guided by emerging science and results of future studies. I
References
1. Dafoe W, Arthur H, Stokes H, et al. Universal access but when? Treating the right
patient at the right time: access to cardiac rehabilitation. Can J Cardiol. 2006;22:
905-911.
2. Piepoli M, Corra U, Benzer W, et al. Secondary prevention through cardiac rehabilitation: physical activity counseling and exercise training: key components
of the position paper from the Cardiac Rehabilitation Section of the European
Association of Cardiovascular Prevention and Rehabilitation. Eur Heart J. 2010;
31:1967-1976.
3. Clark AM, Hartling L, Vandermeer B, et al. Meta-analysis: secondary prevention
programs for patients with coronary artery disease. Ann Intern Med. 2005;143:
659-672.
4. Kovoor P, Lee AK, Carrozzi F, et al. Return to full normal activities including work
at two weeks after acute myocardial infarction. Am J Cardiol. 2006;97:952-958.
5. Giallauria F, Cirillo P, Lucci R, et al. Left ventricular remodeling in patients with
moderate systolic dysfunction after myocardial infarction: favourable effects of
exercise training and predictive role of N-terminal pro-brain natriuretic peptide.
Eur J Cardiovasc Prev Rehabil. 2008;15:113-118.
6. Goel K, Lennon RJ, Tilbury RT, et al. Impact of cardiac rehabilitation on mortality and cardiovascular events after percutaneous coronary intervention in the
community. Circulation. 2011;123:2344-2352.
CONTROVERSIAL
QUESTION
10. H. Rasmusen, Denmark
chemic heart disease is a chronic disease that is not only treated with acute invasive treatment. CR is considered—and recommended to be—part of the overall treatment.
Hanne RASMUSEN, PhD, MD
Consultant Cardiologist
Bispebjerg University Hospital
Copenhagen, DENMARK
A
lthough the incidence and mortality rates of coronary
heart disease (CHD) have been decreasing in most
countries, CHD still accounts for one third of deaths
globally, and in Europe, it is the most common cause of death.1
Nearly half of the decrease in CHD mortality has been attributed to treatment (including 11% attributed to secondary prevention, 13% to heart failure treatment, 8% to initial treatment
of acute myocardial infarction, and 3% to hypertension treatment), and about 50% of the decline has been attributed to
population-wide risk factor reduction.2
Cardiac rehabilitation (CR) aids recovery from a cardiac event
and reduces the likelihood of further illness.3 CR has been
defined as the “coordinated sum of interventions required to
ensure the best physical, psychological and social conditions so that patients with chronic or post-acute cardiovascular disease may, by their own efforts, preserve or resume
optimal functioning in society and, through improved health
behaviours, slow or reverse progression of disease.”4
Core components of CR in patients post–acute coronary syndrome, used in individually tailored programs, include systematic risk factor management and clinical assessment, patient
education, counseling on physical activity and exercise training, diet/nutritional counseling and weight control management, lipid management, blood pressure monitoring, smoking cessation, and management of psychosocial wellbeing.5
In recent years, attention has increasingly focused on the fact
that patients are especially vulnerable during the transitions
between phases due to a lack of coordination between the
different phases and the efforts of all those involved, with the
risk of a loss of the health benefits achieved. This emphasizes
the importance of systematic assessment of all patients to
determine their CR needs. Not all patients need CR, but all
patients should be offered risk stratification, optimal medication, and counseling regarding their needs and the resources
available.
Almost all clinical trials of CR have exclusively enrolled lowrisk, middle-aged men after myocardial infarction. The exclusion or underrepresentation of women, elderly people, and
other cardiac groups (post–revascularization and angina pectoris) not only limits the applicability of the evidence to contemporary cardiovascular practice, but also fails to consider
those who may benefit most from rehabilitation.
In conclusion, CR is cost effective, reduces mortality and morbidity, and should be offered to all patients following a cardiovascular event. Optimally, CR starts during hospital admission to ensure that all patients know how to manage their
disease after discharge and the importance of reducing risk
factors and receiving optimal medical treatment. Phase II CR
focuses on risk factor intervention, exercise training, psychosocial management, and patient education. Unfortunately, very
few studies have focused on Phase III, the maintenance of
CR. While it is important that CR begins during Phase I, it is
equally important that interventions carried out during Phase II
are maintained during Phase III, in order to maintain the effects of the interventions in Phase II. I
References
Despite the high number of patients suffering from a cardiovascular event and the proven beneficial effects of CR, no
study has addressed the question of when exactly the optimal time to start CR is. A CR program usually has three phases: Phase I, during hospital admission; Phase II, hospitalbased outpatient cardiac rehabilitation; and Phase III, the late
maintenance and follow-up phase. Most studies have focused on the effect of CR in Phase II; nevertheless, Phase I
is of equal importance in improving patient uptake and increasing patient adherence to CR after discharge. Starting
CR during hospital admission helps to emphasize that is-
1. World Health Organization, World Heart Federation, World Stroke Organization. Global Atlas on Cardiovascular Disease Prevention and Control. Available
at: http://whqlibdoc.who.int/publications/2011/9789241564373_eng.pdf. Accessed June 26th, 2012.
2. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in US deaths from
coronary disease, 1980-2000. N Engl J Med. 2007;356:2388-2398.
3. Heran BS, Chen JM, Ebrahim S, et al. Exercise-based cardiac rehabilitation for
coronary heart disease. Cochrane Database Syst Rev. 2011;(7):CD001800.
4. Fletcher GF, Balady GJ, Amsterdam EA, et al. Exercise standards for testing and
training: a statement for healthcare professionals from the American Heart Association. Circulation. 2001;104:1694-1740.
5. Piepoli MF, Corra U, Benzer W, et al. Secondary prevention through cardiac rehabilitation: from knowledge to implementation. A position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation. Eur J Cardiovasc Prev Rehabil. 2010;17:1-17.
437
CONTROVERSIAL
QUESTION
L
11. G. Sinagra, P. L. Temporelli, Italy
Gianfranco SINAGRA, MD, FESC
Chief, Cardiovascular Department
Ospedali Riuniti, University of Trieste
ITALY
for more complicated, disabled patients; and (ii) outpatient
CR for more independent, low-risk and clinically stable patients requiring less supervision.4
Pier Luigi TEMPORELLI, MD
Director, Laboratorio Per Lo Studio
Del Rimodellamento Ventricolare
Ed Emodinamica Non-Invasiva
IRCCS Fondazione Salvatore Maugeri
Pavia, ITALY
C
ardiovascular disorders are the leading cause of mortality and morbidity worldwide. The survivors represent an additional reservoir of cardiovascular disease
morbidity. Cardiac rehabilitation (CR) programs, first developed
in the 1960s, are associated with significant reduction in mortality rates in individuals with coronary artery disease.1 At the
beginning, exercise was the primary component of these programs, and they were predominantly offered to survivors of
uncomplicated myocardial infarction and initiated at a time
remote from the acute event.2 In recent years, there has been
growing evidence to support a benefit of CR for patients with
chronic heart failure,3 peripheral artery disease, and those
who have undergone cardiac surgical procedures such as
valvular or coronary artery bypass surgery.4
Today, CR is a multifaceted and multidisciplinary intervention
that improves functional capacity, recovery, and psychological well-being.4 The rehabilitation team includes a physician,
one or more nurses with coronary care experience, and at
least one exercise physical therapist. Other complementary
staff such as a dietician and psychologist may be included,
whether accessed onsite or through associated private practices. Core components of CR or secondary prevention programs are baseline patient assessment, physical activity counseling and exercise training, nutritional counseling, risk factor
management (lipids, hypertension, weight, diabetes, and smoking), psychosocial management, vocational counseling, and
optimized medical therapy.4
CR should be started soon after discharge from the acute
care setting. In disabled and unstable patients, the more immediate objectives of CR services are to achieve clinical stability, limit the physiological and psychological effects of cardiac illness, improve the overall functional status, and help
the patient maintain their independence with an emphasis on
quality of life. In the longer term, the objectives are to reduce
the risk of future cardiovascular events, delay progression
of the underlying atherosclerotic process and clinical deterioration, and ultimately, reduce morbidity and mortality.
CR programs vary in length, content, and the place of delivery. Different patterns of rehabilitative care are currently delivered by specialized hospital-based teams: (i) residential CR
438
Residential CR programs should be followed up with a longterm outpatient risk reduction and secondary prevention program, with appropriate clinical and functional monitoring. Some
patients may benefit from a home-based comprehensive CR
program validated for patients after myocardial infarction that
incorporates education, exercise, and stress management
components, with follow-up sessions with a trained facilitator.5
This should be offered to patients as part of a menu-based
approach, but should not be used to replace a multidisciplinary hospital-based program, particularly for patients with complex conditions that need specialist assessment. A homebased program produces similar gains to hospital programs,
and has been shown to be preferred by many patients.
On the basis of the body of evidence in favor of the positive
effects of CR, clinical guidelines identify CR as an essential
component (Class I level recommendation) in the care of patients following myocardial infarction or acute coronary syndrome, chronic stable angina, heart failure, coronary artery
bypass surgery or percutaneous coronary intervention, valve
surgery, or cardiac transplantation.6
In conclusion, CR is a structured program of care that helps
patients through lifestyle modification and appropriate use of
medication. There is a large body of evidence addressing the
efficacy of short- and long-term CR programs for the secondary prevention of cardiovascular events. Consequently, effort
should be made to include CR in every patient’s hospital discharge prescription. I
References
1. Goel K, Lennon RJ, Tilbury RT, Squires RW, Thomas RJ. Impact of cardiac rehabilitation on mortality and cardiovascular events after percutaneous coronary
intervention in the community. Circulation. 2011;123:2344-2352.
2. Giannuzzi P, Saner H, Bjornstad H, et al. Secondary prevention through cardiac
rehabilitation: position paper of the Working Group on Cardiac Rehabilitation and
Exercise Physiology of the European Society of Cardiology. Eur Heart J. 2003;
24:1273-1278.
3. Davies EJ, Moxham T, Rees K, et al. Exercise training for systolic heart failure: Cochrane systematic review and meta-analysis. Eur J Heart Fail. 2010;12:706-715.
4. Balady GJ, Ades PA, Bittner VA, et al; American Heart Association Science Advisory and Coordinating Committee. Referral, enrollment, and delivery of cardiac
rehabilitation/secondary prevention programs at clinical centers and beyond: a
presidential advisory from the American Heart Association. Circulation. 2011;124:
2951-2960.
5. Taylor R, Dalal H, Jolly K, Moxham T, Zawada A. Home-based versus centre-based
cardiac rehabilitation. Cochrane Database Syst Rev. 2010;(1):CD007130.
6. Thomas RJ, King M, Lui K, Oldridge N, Pina IL, Spertus J. AACVPR/ACCF/AHA
2010 update: performance measures on cardiac rehabilitation for referral to cardiac rehabilitation/secondary prevention services: a report of the American Association of Cardiovascular and Pulmonary Rehabilitation and the American College
of Cardiology Foundation/American Heart Association Task Force on Performance Measures (Writing Committee to Develop Clinical Performance Measures
for Cardiac Rehabilitation). Circulation. 2010;122:1342-1350.
CONTROVERSIAL
QUESTION
12. M. Zoghi, Turkey
Mehdi ZOGHI, MD, FESC
Professor and Board Member,
Heart Failure Working Group of
Turkish Society of Cardiology
Ege University Department of Cardiology
Bornova, 35100, Izmir
TURKEY
‘‘S
tart in hospital, continue at home.” There are several
pieces of evidence supporting the benefits of cardiac
rehabilitation and secondary prevention programs following a cardiovascular event such as myocardial infarction or
heart failure, coronary artery bypass graft surgery, or heart
transplantation.1
The exercise training component of cardiac rehabilitation programs produces enhanced peak VO2 , oxygen utilization, and
endothelial function, improvement in cardiac symptoms and
mortality, and reduced sympathetic tonus and neurohumoral
activity comparable to that of younger patients with heart failure.2 Despite the effectiveness of cardiac rehabilitation, only
one in four patients is referred for cardiac rehabilitation. In
Turkey, the proportion of eligible patients who attend any cardiac rehabilitation program is very low compared with other
European countries; 7.3% of patients after an index event.3
Clinical status, as well as demographics, the presence of comorbidities, logistics, and socioeconomic status are all barriers to enrolment in cardiac rehabilitation and secondary prevention programs after hospitalization. Cardiovascular event
rates and hospitalization are higher in elderly patients. However, it is notable that patients over 75 years of age, as well
as female patients and patients with comorbidities, are less
likely attend to these programs. Dobson et al demonstrated
that the mortality benefits for these patient populations are
greater than those in a young male cohort.4
Heart failure is the most common discharge diagnosis, particularly in elderly hospitalized patients. Although cardiac rehabilitation is recommended for all eligible patients with stable coronary artery disease and New York Heart Association
Class I–III heart failure (no serious arrhythmias or limitations to
exercise), the start of cardiac rehabilitation is often delayed
while waiting for the initiation of an exercise program. Exercise is the cornerstone of cardiac rehabilitation, but cardiac
rehabilitation is a multidisciplinary approach and exercise prescriptions should be combined with psychological and medical educational components. Starting exercise programs immediately after hospitalization is not possible for most patients,
and rehabilitation programs should not be delayed for the
exercise prescription. Although most programs are outpatient
based, cardiac rehabilitation should be started as soon as
possible in hospital, and exercise programs should be added
within 1 to 3 months after discharge. The duration and frequency of the exercise prescription are important elements in
the cardiac rehabilitation program. Exercise should be practiced for 30 minutes 3 days a week, taking into consideration the results of HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of exercise traiNing).5
The regular continuation of a cardiac rehabilitation program is
as fundamentally important as starting the program immediately. Long-term rehabilitation programs reduce cardiovascular
mortality by approximately 1.5-fold compared with short-term
interventions. A clinical nurse specialist and/or physiotherapist is the most likely person to coordinate the rehabilitation
program.6 Home-based strategies can overcome the problems related to hospital-based programs. Home-based exercise programs are as effective as hospital-based programs in
improving functional capacity, left ventricular ejection fraction,
quality of life, and significantly reducing depression symptoms.6
A home-based cardiac rehabilitation program is more effective at ensuring patients remain in their rehabilitation program,
and should absolutely be considered in countries that have
a limited number of outpatient heart failure clinics.
Aside from patient characteristics, certain barriers to cardiac
rehabilitation may be unique to each country and be related
to the level and number of cardiac rehabilitation services, public health care, and insurance policies. With the current economic problems, home-based rehabilitation is increasingly
coming to the fore. Cardiac rehabilitation is an essential component of the management of patients of all ages with heart
failure and/or coronary artery disease. Ideally, it should be
started in hospital, combined with exercise training programs
within 1 to 3 months after discharge, and must be continued
for the patient’s lifetime. I
References
1. Forman DE, Rich MW, Alexander KP, et al. Cardiac care for older adults. Time
for a new paradigm. J Am Coll Cardiol. 2011:57:1801-1810.
2. Thomas RJ, King M, Lui K, Oldridge N, Piña IL, Spertus J; American Association of Cardiovascular and Pulmonary Rehabilitation/American College of Cardiology/American Heart Association Cardiac Rehabilitation/Secondary Prevention
Performance Measures Writing Committee. AACVPR/ACC/AHA 2007 performance measures on cardiac rehabilitation for referral to and delivery of cardiac rehabilitation/secondary prevention services. Circulation. 2007;116:1611-1642.
3. Tokgözoğlu L, Kaya EB, Erol C, Ergene O; EUROASPIRE III Turkey Study Group.
EUROASPIRE III: a comparison between Turkey and Europe. Turk Kardiyol Dern
Ars. 2012;38:164-172.
4. Dobson LE, Lewin RJ, Doherty P, Batin PD, Megarry S, Gale CP. Is cardiac rehabilitation still relevant in the new millennium? J Cardiovasc Med (Hagerstown).
2012 Jan;13(1):32-37.
5. O’Connor CM, Whellan DJ, Lee KL, et al. Efficacy and safety of exercise training
in patients with chronic heart failure: HF-ACTION randomized controlled trial.
JAMA. 2009;301:1439-1450.
6. Horgan J, Bethel H, Carson P, et al. Working party report of cardiac rehabilitation.
Br Heart J. 1992;67:412-418.
439
PROCORALAN
‘‘
By reducing heart rate, Procoralan decreases myocardial oxygen consumption and increases
myocardial perfusion, both of which
explain its ability to preserve cardiac energy metabolism, something that is profoundly impaired
during heart failure. Sustained
heart rate reduction with Procoralan has been shown to improve
cardiac function by significantly
decreasing left ventricular endsystolic diameter and increasing
stroke volume.”
Clinical advantage of
heart rate lowering with
Procoralan in the management
of cardiovascular patients
b y I . E l y u b ae va , Fra n c e
P
Irina ELYUBAEVA, MD, PhD
Servier International
Division of Medical Information
Suresnes, FRANCE
rocoralan (ivabradine) is the first selective and specific If inhibitor, and
provides pure heart rate (HR) reduction without alteration to myocardial contractility, the cardiac conduction system, or coronary vascular
resistance. Experimental data have demonstrated the specific nature of the
HR-lowering action of Procoralan, and suggest that the mechanism by which
slowing of HR is achieved may affect the extent of its benefit. Selective HR
slowing with Procoralan offers additional benefits not found with other HRslowing agents, and enables the full benefits of HR reduction to be realized for
improved coronary perfusion and pump efficiency. Dual cardiac and vascular
protection through prevention of endothelial dysfunction and development of
atherosclerosis may contribute to the reduction in cardiac events seen in the
clinical setting with Procoralan. The ability of Procoralan to positively affect
angina symptoms and myocardial ischemia and to improve clinical outcomes
makes it an important agent in the management of patients with CAD. Following the breakthrough results of SHIFT (Systolic Heart failure treatment with If
inhibitor ivabradine Trial), Procoralan was approved for use in heart failure (HF)
patients with left ventricular systolic dysfunction, representing a major step forward in the management of these patients. This approval brings the promise
of a better prognosis and improved quality of life for millions of patients with
chronic HF.
Pure heart rate reduction with Procoralan: anti-ischemic effect and
dual cardiac and vascular protection in CAD and HF
rocoralan (ivabradine) is a specific heart rate (HR)–lowering agent, and the
first agent of its type to be approved for therapeutic use.1 In contrast with
other HR-lowering agents such as β-blockers, Procoralan acts uniquely on
the pacemaker activity of the sinoatrial node of the heart, which results in important differences between Procoralan and other HR-reducing agents. Procoralan
inhibits If , an ionic current that modulates pacemaker activity, and it thus lowers
HR without directly affecting cardiac conduction or contractility.2 Myocardial perfusion, particularly in the subendocardium, takes place almost entirely during diastole. Normal physiological changes in HR mainly involve adjustments to the duration
of diastole, and a lower HR leads to prolonged diastole, both in absolute terms and
as a fraction of the cardiac cycle, facilitating myocardial perfusion.3 Procoralan, in
common with physiological HR reduction, lowers HR essentially by prolonging diastole.4 By contrast, β-blockers, because of their negative effect on myocardial con-
P
Dr Irina Elyubaeva, MD, PhD,
Servier International, 50 rue Carnot,
92284 Suresnes Cedex, France
(e-mail:
[email protected])
440
Clinical advantage of HR lowering with Procoralan in the management of CV patients – Elyubaeva
PROCORALAN
tractility, tend to also prolong systole, which reduces their beneficial effect on diastolic time fraction. β-Blockers also affect
vasomotion in the coronary circulation by unmasking α-adrenergic vasoconstriction, resulting in constriction of large and
small coronary arteries during exercise.3 By contrast, Procoralan maintains the vasodilation that occurs during exercise.
All of the experimental data suggest that pharmacological HR
reduction with Procoralan more closely resembles physiological changes in HR than does HR reduction with β-blockade,
so that physiological changes in diastolic time fraction, left ventricular (LV) relaxation and synchrony, and coronary vasomotion are not compromised.5 As a consequence, the full benefit of HR reduction in improving coronary perfusion and pump
efficiency can be realized.
By reducing HR, Procoralan decreases myocardial oxygen
consumption and increases myocardial perfusion, both of
which explain its ability to preserve cardiac energy metabolism, something that is profoundly impaired during heart failure (HF). Sustained HR reduction with Procoralan has been
shown to improve cardiac function by significantly decreasing LV end-systolic diameter and stroke volume.6 Procoralan
preserves cardiac output through its ability to increase stroke
volume, reduces LV collagen density, and increases LV capilSELECTED
ADDITIONS prActical Daily efficacy anD safety of Procoralan
In combinaTION with betablockerS (trial)
bpm
beat per minute
CAD
CARVIVA HF effect of CARVedilol, IVAbradine or their combination on exercise capacity in patients with
Heart Failure (trial)
CCS
Canadian Cardiovascular Society
CFR
coronary flow reserve
HF
heart failure
HR
heart rate
INITIATIVE INternatIonal TrIAl on the Treatment of angina
with IVabradinE versus atenolol
LV
left ventricular
MI
myocardial infarction
NYHA
New York Heart Association
QOL
quality of life
REDUCTION Reduction of ischemic Events by reDUCtion of
hearT rate In the treatment Of stable aNgina
with ivabradine
SHIFT
Systolic Heart failure treatment with If inhibitor
ivabradine Trial
SIGNIFY
Study assessInG the morbidity–mortality beNefits of the If inhibitor ivabradine in patients with
coronarY artery disease
lary density. Similar cardiac effects were observed in rats when
Procoralan was given either immediately before or after myocardial infarction (MI), highlighting both the preventive and
curative benefits of Procoralan in HF.7 These experimental
data show that long-term HR reduction with Procoralan optimizes energy consumption, reverses remodeling, and prevents disease progression in HF.
Endothelial dysfunction is a common feature of many cardiac
diseases, including coronary artery disease (CAD) and congestive HF. HR lowering with Procoralan may improve endothelial function and inhibit development of atherosclerotic
plaque. In dyslipidemic mice expressing human apolipoprotein B 100, 3 months of treatment with Procoralan completely
prevented deterioration of endothelium-dependent vasodilation in the renal and cerebral arteries.8 Despite similar HR
reduction, the protective effect of Procoralan was not fully
reproduced by metoprolol, possibly due to inhibition of βadrenoceptor–mediated activation of endothelial nitric oxide
synthase. In another model involving severe hypercholesterolemia in apolipoprotein E–deficient mice, Procoralan treatment
improved endothelial function and reduced the atherosclerotic plaque area in the aortic root (by over 40%) and ascending aorta (by over 70%).9
These experimental data emphasize the specific nature of
the HR–lowering action of Procoralan, and suggest not only
that HR slowing is associated with cardiovascular benefits,
but also that the mechanism by which HR slowing is achieved
may affect the extent of the benefit. Selective HR slowing with
Procoralan offers additional advantages that enable the full
benefit of HR reduction to be realized for improved coronary
perfusion and pump efficiency, and which may produce greater
improvements in exercise capacity than β-blockade for a given
reduction in HR. Dual cardiac and vascular protection through
prevention of endothelial dysfunction and development of atherosclerosis may contribute to the reduction in cardiac events
seen in the clinical setting.
Clinical benefits of pure heart rate reduction with
Procoralan
The results of clinical trials have underlined the importance
of HR in the pathophysiology of CAD and HF, and they support the value of pure HR reduction for the management of
patients with stable CAD and HF.
N Clinical benefits of heart rate reduction with Procoralan
in stable coronary artery disease
N Heart rate
Procoralan significantly reduces HR at rest and during exercise. In the large randomized, double-blind, controlled multicenter INITIATIVE trial (INternatIonal TrIAl on the Treatment of
angina with IVabradinE versus atenolol) involving 939 patients
with stable angina, Procoralan significantly reduced HR after
1 and 4 months of treatment, both at rest and at peak exer-
441
PROCORALAN
cise.10 At rest, HR was reduced by 14.3 beats per minute (bpm)
in the Procoralan 7.5 mg twice-daily group and by 15.6 bpm
in the atenolol 100 mg once-daily group.
A further characteristic of the HR–lowering action of Procoralan is that its effect is largest in those patients with the highest HR before treatment.11 This important property is related
to the use-dependence of the HR-lowering mechanism of Procoralan: the magnitude of If inhibition is directly related to the
frequency with which channels are open. Inverse linear correlations between pretreatment HR and changes in HR during
treatment have been observed for all dosages of Procoralan
(Figure 1). This property has important clinical implications, as
it results in greater efficacy in patients with higher HR at baseline and protects against excessive bradycardia.
stantially reduced the frequency of angina attacks compared with placebo from 4.14 attacks to 0.95 attacks per
week (P<0.001). Procoralan also reduced the consumption
of short-acting nitrates compared with placebo, which decreased from 2.28 units per week to 0.50 units per week
(P<0.001).13 The antianginal efficacy of Procoralan was also
confirmed in INITIATIVE: at 4 months, the number of angina
attacks decreased by 1.6 with Procoralan 7.5 mg twice daily and by 1.2 with atenolol 100 mg once daily.10
The aforementioned long-term study with Procoralan 5 mg
and 7.5 mg twice daily in patients with stable angina demonstrated the maintenance of substantial antianginal efficacy over 1 year of treatment. The mean number of angina attacks per week decreased significantly by more than 50%
with both dosages of Procoralan after 12 months of treatment (P<0.001).12
Baseline heart rate (bpm)
Change in heart rate (bpm)
0
60-64
65-74
75-84
>85
–5
– 10
– 15
– 20
Procoralan 7.5 mg bid
–25
Figure 1. Change in heart rate with Procoralan treatment according to heart rate at baseline. Data are from a pooled analysis of
patients treated with Procoralan 7.5 mg twice daily (bid; n=940).
Abbreviations: bid, twice daily; bpm, beat per minute.
After reference 11: Borer JS, Le Heuzey JY. Am J Ther. 2008;15:461-473.
© 2008, Lippincott Williams & Wilkins, Inc.
A randomized double-blind trial involving 386 patients with
stable angina treated with Procoralan twice daily for 1 year
(either 5 mg or 7.5 mg) showed that HR reduction with Procoralan in patients with stable angina is maintained during
long-term treatment.12 Both doses of Procoralan were associated with a substantial reduction in resting HR: 10 bpm with
Procoralan 5 mg twice daily (from 71 to 62 bpm) and 12 bpm
with Procoralan 7.5 mg twice daily (71 to 59 bpm). This reduction is consistent in magnitude with that found in earlier
studies, and confirms that patients can be optimally treated
with Procoralan over the long term.
N Antianginal efficacy
HR reduction with Procoralan is associated with a substantial decrease in angina symptoms and short-acting nitrate
consumption, both with short-term and long-term treatment. In a randomized double-blind study, Procoralan sub-
442
In a study comparing the efficacy of the combination of Procoralan 7.5 mg twice daily plus bisoprolol 5 mg once daily
versus full-dose bisoprolol (10 mg once daily) in patients with
stable angina and LV systolic dysfunction, 2 months of treatment with Procoralan substantially reduced the mean weekly number of angina attacks compared with bisoprolol alone
(from 3.3 to 1.7 compared with 3.2 to 2.5; P=0.041).14 As a
result, there were more patients with Canadian Cardiovascular Society (CCS) Class I stable angina in the Procoralan group
than in the group receiving bisoprolol alone (82% versus 67%,
respectively; P=0.037).
REDUCTION (Reduction of ischemic Events by reDUCtion of
hearT rate In the treatment Of stable aNgina with ivabradine)
confirmed the antianginal efficacy of Procoralan in routine clinical practice in 4954 patients with stable angina.15,16 After 4
months of treatment with Procoralan, angina attacks were reduced from 2.4 to 0.4 per week (P<0.0001). Consumption of
short-acting nitrates was reduced from 3.3 to 0.6 units per
week (P<0.0001). In the recent non-interventional, multicenter, prospective trial ADDITIONS (prActical Daily efficacy anD
safety of Procoralan In combinaTION with betablockerS), which
involved the treatment of 2330 patients with stable angina in
routine clinical practice with Procoralan added to β-blockers,
the addition of Procoralan resulted in a significant reduction in
angina attacks and short-acting nitrate consumption (from 1.7
to 0.3 and from 2.3 to 0.4 units per week, respectively).17
N Anti-ischemic efficacy and improvement of exercise
capacity
HR is a major determinant of myocardial oxygen consumption and thus resting myocardial blood flow and coronary flow
reserve (CFR). Autoregulation of coronary vessels maintains a
marginal balance of oxygen supply and demand under physiological conditions. The coronary circulation is particularly sensitive to increased HR, particularly if endothelial dysfunction,
atherosclerosis, or hypertensive wall thickening impair auto-
PROCORALAN
The addition of Procoralan to bisoprolol in the treatment of
patients with stable angina and LV systolic dysfunction resulted in an improvement in exercise capacity: workload increased from 5.9 ±1.6 to 7.0 ±1.4 metabolic equivalents
(P=0.004) compared with bisoprolol alone (from 5.7 ±1.4 to
6.2 ±1.4 metabolic equivalents, P=0.141).14
N Improvement of quality of life
Poor quality of life (QOL) is a major issue for angina patients.
Improvement of QOL is therefore an important goal and measure of therapeutic success in the management of angina. Few
studies, however, have reported the effects of antianginal therapy on QOL, and those results that have been reported have
been inconsistent. In ADDITIONS, the effect of Procoralan on
QOL was assessed using the EQ-5D questionnaire.17 After 4
months of therapy with Procoralan, the proportion of patients
at CCS Class I had more than doubled, and Procoralan significantly improved QOL (EQ-5D index as well as Visual Analogue Scale score). This improvement in QOL was consistent
with the substantial reduction in the number of angina attacks
and consumption of short-acting nitrates. Procoralan is thus
an important treatment option for patients with stable angina
for improvement of both symptoms and QOL.
N Prevention of coronary events in patients with stable CAD
and LV systolic dysfunction with elevated heart rate
Reduction of elevated HR in patients with stable CAD could
be a potential approach to lowering the risk of cardiovascular events. Epidemiological studies and retrospective clinical
analysis have shown that a high HR is an independent predic-
tor of cardiovascular events in coronary patients.20 BEAUTIFUL
(morBidity-mortality EvAlUaTion of the If inhibitor Procoralan
in patients with coronary disease and left ventricULar dysfunction) was the first randomized controlled trial designed to assess the effect of pure HR reduction with Procoralan on cardiovascular events in patients with documented CAD and
associated LV dysfunction. BEAUTIFUL was also the first clin-
4
3
CFR
regulation. The effect of Procoralan on coronary blood flow
velocity and CFR was assessed in a study involving 21 patients with stable CAD, in whom coronary blood flow was assessed invasively using intracoronary Doppler measurements.18
After 2 weeks of treatment with Procoralan, HR was found to
be significantly lower (reduced by 13 bpm; P<0.001). Treatment with Procoralan significantly improves hyperemic coronary flow velocity and CFR in patients with stable CAD (Figure 2). These data have important clinical implications, not
only regarding the anti-ischemic effect of Procoralan, but also
regarding the impact of Procoralan on ischemic events, as CFR
predicts adverse cardiovascular long-term outcomes.19 Procoralan showed significant anti-ischemic efficacy compared
with placebo in a randomized double-blind study.13 The time
to 1-mm ST-segment depression improved by more than 1
minute compared with placebo (P<0.001). The anti-ischemic
effect of Procoralan was also demonstrated using the treadmill stress test in INITIATIVE, where it produced an increase
of approximately 1.5 minutes.10 The group receiving Procoralan 7.5 mg twice daily also showed an increase in total exercise duration of 86.8 seconds at trough of drug activity; this
was compared with 78.8 seconds in the atenolol 100 mg
once-daily group. Noninferiority with atenolol was demonstrated for all exercise tolerance test parameters (P<0.001).
2
1
Baseline
Procoralan
Figure 2. Box plots of coronary flow reserve (CFR) at baseline and
after 1 week of treatment with Procoralan 5 mg twice daily.
After reference 18: Skalidis et al. Atherosclerosis. 2011;215 (1):160-165. © 2010,
Elsevier Ireland Ltd.
ical trial to prospectively determine that patients with elevated
HR have a higher risk of cardiovascular events.21 In BEAUTIFUL, Procoralan significantly reduced all coronary end points
in patients with an elevated resting HR of ⱖ70 bpm (n=5392):
Procoralan significantly reduced admission to hospital for MI
(relative risk reduction [RRR], 36%; P=0.001) (Figure 3, page
444), admission to hospital for MI or unstable angina (RRR,
22%; P=0.023), and coronary revascularization (RRR, 30%;
P=0.016).22 These results were achieved in patients already
receiving optimal treatment for CAD (87% of patients were
taking β-blockers, 90% were taking renin-angiotensin-aldosterone system inhibitors, 94% were taking antithrombotics,
and 74% were on statins). In patients whose limiting symptom at baseline was angina (n=1507), Procoralan reduced the
composite end point of cardiovascular mortality or hospitalization for fatal and nonfatal MI or HF by 24% (P=0.05).23 Treatment with Procoralan resulted in a 42% reduction in the risk
of hospitalization for fatal and nonfatal MI in all patients with
limiting angina, and a 73% reduction in those with a resting
HR of 70 bpm or higher.23
Another major ongoing trial is evaluating the efficacy of Procoralan in patients with preserved LV function. SIGNIFY (Study
assessInG the morbidity–mortality beNefits of the If inhibitor
ivabradine in patients with coronarY artery disease) includes
stable CAD patients with an ejection fraction of above 40%,
a HR of 70 bpm or higher, and no clinical signs of HF.24 After
a run-in period of 2 to 4 weeks, patients are randomized to
placebo twice daily or Procoralan with a starting dose of 7.5
443
PROCORALAN
A
A
Hospitalization for
10
Primary composite end point (CV death or
hospital admission for worsening HF)
P=0.001
Placebo
5
Procoralan
Cumulative frequency (%)
Proportion admitted to
hospital with
myocardial infarction (%)
40
HR (95% CI), 0.82 (0.75-0.90)
P<0.0001
Number at risk
Placebo group 2693
Procoralan group 2699
0.5
2548
2573
1
Years
1.5
2347
2364
1493
1503
–18%
30
Procoralan
20
10
0
0
Placebo
0
2
0
6
12
18
617
632
B
Coronary revascularization
Proportion with
coronary
revascularization (%)
10
P=0.016
Placebo
5
Placebo
HR (95% CI), 0.74 (0.66-0.83)
P<0.0001
–26%
20
Procoralan
10
Procoralan
0
0
6
12
18
24
30
Months
0
Number at risk
Placebo group 2693
Procoralan group 2699
0.5
1
Years
1.5
2
2552
2571
2347
2356
1483
1495
624
629
C
Figure 3. Kaplan-Meier time-to-event plots by treatment group
(Procoralan or placebo) in the BEAUTIFUL trial in patients with
stable coronary artery disease and left ventricular systolic dysfunction with an elevated resting heart rate (ⱖ70 bpm).
After reference 22: Fox K et al. Lancet. 2008;372:807-816. © 2008, Elsevier.
mg twice daily, which is adjusted at every visit to a target HR
of 55 to 60 bpm. Over 19 000 patients have been enrolled in
the study, which is expected to end in 2014.
N Clinical benefits of heart rate reduction with Procoralan
in heart failure
N Improvement of major outcomes
Given the prognostic implications of HR in patients with HF,
the ability of Procoralan to decrease HR without impairing key
cardiovascular or hemodynamic parameters such as myocardial contractility and ventricular relaxation makes it a particularly pertinent treatment in HF.25 The ability of Procoralan to
improve prognosis in HF was successfully tested in the SHIFT
trial (Systolic Heart failure treatment with If inhibitor ivabradine
Trial). This randomized placebo-controlled clinical trial evaluated the effects of Procoralan on morbidity and mortality in
6558 patients with moderate to severe chronic HF and LV systolic dysfunction (LV ejection fraction of ⱕ35%) and a resting
Death from heart failure
10
0
444
30
Hospitalization for heart failure
30
B
24
Months
HR (95% CI), 0.74 (0.58-0.94)
P=0.014
Placebo
–26%
5
Procoralan
0
0
6
12
18
24
30
Months
Figure 4. Kaplan-Meier cumulative event curves for different end
points in the Systolic Heart failure treatment with If inhibitor ivabradine Trial (SHIFT) in the Procoralan and placebo arms.
Abbreviations: CI, confidence interval; CV, cardiovascular; HF, heart failure;
HR, hazard ratio.
After reference 26: Swedberg K et al. Lancet. 2010;376:875-885. © 2010,
Elsevier.
HR of ⱖ70 bpm. Procoralan was taken on top of guidelinerecommended therapies, and the median follow-up was 22.9
months.26 After 28 days, Procoralan reduced HR by 15.4 bpm
(10.9 bpm, placebo-corrected). The primary composite end
point (cardiovascular death or hospital admission for worsening HF) was significantly reduced by 18% (P<0.0001). Procoralan significantly reduced HF death (RRR, 26%; P=0.014)
and hospitalization for HF (RRR, 26%; P<0.0001) (Figure 4).
PROCORALAN
Results were consistent across all subgroups. On the strength
of the absolute risk reduction on the primary end point, 26
patients would need to be treated for 1 year to prevent one
cardiovascular death or HF-related hospital admission. Cardiovascular death and all-cause death diminished by 9% and
10%, respectively, and in patients with a HR of ⱖ75 bpm,
there was a statistically significant 17% reduction in all-cause
mortality (P=0.0109) and 17% reduction in cardiovascular
mortality (P=0.0166) (Figure 5).27 Procoralan reduced the total burden of HF hospitalizations reducing the total number
of hospitalizations by 25% (P=0.0002). During the almost 2
years of follow-up, Procoralan reduced the rates for both second and third hospitalizations for worsening heart failure by
34%; (P<0.001) and 29% (P=0.012), respectively.
These results are important for clinical practice as readmissions are not only distressing for patients and their families,
but they are also associated with poor prognosis and are the
major driver of the economic burden of heart failure (Figure 6).28
The results of SHIFT clearly demonstrate that Procoralan brings
major prognostic benefits to patients with HF when taken on
top of the best possible recommended therapy.
Patients with
cardiovascular death (%)
After reference 27: Böhm et al. Clin Res Cardiol. 2012 May 11.
Epub ahead of print. © 2012, Springer-Verlag.
A
Cardiovascular death
30
Hazard ratio=0.83
P=0.0166
Placebo
20
Procoralan
10
0
0
B
Patients with
all-cause death (%)
Figure 5. Kaplan-Meier cumulative event curves for Procoralan
or placebo for primary cardiovascular death (A) and total death (B)
in patients with baseline heart rates of 57 bpm and above.
6
12
18
Time (months)
24
30
Total death
30
Hazard ratio=0.83
P=0.0109
20
Placebo
Procoralan
10
0
0
6
12
18
Time (months)
24
30
N Improvement of symptoms
and quality of life
Procoralan
Placebo
Hazard ratio
P-value
In addition to improvement of out(n=3241)
(n=3264)
(95% CI)
comes, improvement of sympFirst
P<0.001
514 (16%) 672 (21%) 0.75 (0.65-0.87)
toms and well-being are also imhospitalization
portant targets for therapy in HF.
Second
P<0.001
189 (6%)
283 (9%)
0.66 (0.55-0.79)
In SHIFT, the New York Heart Ashospitalization
sociation (NYHA) class was signifThird
P<0.012
90 (3%)
128 (4%)
0.71 (0.54-0.93)
hospitalization
icantly improved in those patients
receiving Procoralan (29.0% ver0.6
1.0
1.2
0.4
0.8
sus 24.2% in the placebo group,
Favors
Favors
P<0.0156), as was the patient-reProcoralan
placebo
ported global assessment score
(65.9% versus 61.3% in the pla- Figure 6. Estimate of Procoralan treatment effect on recurrence of hospitalizations for worsening
cebo group, P<0.0345) in the heart failure.
overall SHIFT population.26 Fur- Abbreviation: CI, confidence interval.
reference 28: Borer JS et al. Eur Heart J. 2012 Sep 12. Epub ahead of print. © 2012, European Society of
thermore, a substudy of SHIFT in After
Cardiology.
1944 patients demonstrated that
in parallel to the improved outcomes in SHIFT, Procoralan im- (Figure 7, page 446). After 12 months, the clinical summary
proved health-related QOL in patients with HF, as assessed score, which includes physical limitations and the total sympby the specific Kansas City Cardiomyopathy Questionnaire tom domain scores, was improved by 5.0 points with Pro(KCCQ).29 Treatment with Procoralan significantly improved coralan compared with 3.3 points with placebo (P=0.018).
both the overall summary score and the clinical summary Qualitatively, similar benefits were found with Procoralan comscore on the KCCQ. At 12 months, the overall summary score, pared with placebo at 4 months, and these were maintained
which includes physical limitations, total symptoms, QOL, throughout the study follow-up period. These data demonand social limitation scores, was improved by 6.7 points with strate that the reduction in HF severity produced by ProcoProcoralan compared with 4.3 points with placebo (P<0.001) ralan, as reflected by reduced hospital admissions and im-
445
PROCORALAN
P<0.001
KCCQ - OSS mean (SD)
change at 12 months
7
6
6.7
(17.3)
5
4
4.3
(16.7)
3
2
1
0
Procoralan
(n=842)
Placebo
(n=839)
Figure 7. Change at 12 months in the Kansas City Cardiomyopathy Questionnaire overall summary score for the Procoralan and
placebo groups of the SHIFT trial.
Abbreviations: KCCQ, Kansas City Cardiomyopathy Questionnaire; OSS, overall summary score; SD, standard deviation; SHIFT, Systolic Heart failure treatment
with If inhibitor ivabradine Trial.
Based on data from reference 29: Ekman I et al. Eur Heart J. 2011;32:23952404. © 2011, Oxford University Press.
proved NYHA functional class, also translates into a favorable
impact on health-related QOL. This makes Procoralan a particularly pertinent treatment for achieving all of the therapeutic
targets in HF patients: improvement of symptoms and wellbeing, together with improvement of outcomes. Other treatments that improve prognosis in patients with HF, such as
β-blockers or angiotensin-converting enzyme inhibitors, have
not demonstrated improvement of QOL in these patients.
The recent randomized open blinded end point trial, CARVIVA HF (effect of CARVedilol, IVAbradine or their combination
on exercise capacity in patients with Heart Failure), assessed
the effect of HR reduction with carvedilol (25 mg twice daily),
Procoralan (7.5 mg twice daily), and their combination (12.5/
7.5 mg twice daily) on exercise capacity and QOL in 121 HF
patients receiving the maximal dose of angiotensin-converting enzyme inhibitor.30 After 3 months of therapy, the NYHA
class improved significantly more in patients receiving Procoralan or combination therapy than in those allocated to
carvedilol alone. Procoralan alone or in combination was also
more effective in improving exercise capacity and QOL compared with carvedilol alone.
tion fraction was improved by 2.4%, whereas there was no
change in the placebo group at all. Moreover, these results
occurred despite treatment with β-blockers and renin-angiotensin-aldosterone system antagonists, each of which was
used in more than 90% of patients. Reversal of LV remodeling has important clinical implications in itself, since cardiac
remodeling is a central feature of the progression of HF and is
an established prognostic factor in patients with HF. The beneficial impact of Procoralan on LV remodeling and function
may contribute to the reduction in cardiac morbidity and mortality found with Procoralan in patients with HF.
N Good tolerability profile and easy use in practice
Throughout its entire clinical development program, Procoralan has demonstrated a good safety profile consistent with
its highly specific and selective mode of action on the If current. Procoralan preserves the main electrophysiological parameters of the heart, including the refractory period of the
atrium, the atrioventricular conduction time, and the duration of repolarization.32 The absence of any changes in the corrected QT interval throughout the clinical trial follow-up periods provides strong evidence of a lack of any significant direct
effect of Procoralan on the duration of ventricular repolarization, indicating an absence of proarrhythmic action. In some
patients, Procoralan can induce visual symptoms, mainly phosphenes; this is related to inhibition of the Ih current in retinal
hyperpolarization-activated cyclic nucleotide-gated channels.32
These symptoms are generally mild and well tolerated, resolving spontaneously during or after treatment, and have led to
withdrawal in less than 1% of patients, without safety concerns.
Bradycardia was reported in 2.2% of angina patients treat-
P<0.001
80
70
60
LVESVI (mL/m2 )
8
∆ –7 (16.3)
65.2
∆ –0.9 (17.1)
63.6
62.8
Baseline
M8
58.2
50
40
30
20
10
N Reversal of ventricular remodeling
Aside from the clinical standpoint, the results of SHIFT have
important pathophysiological implications in that they demonstrate that Procoralan is able to reverse remodeling. An echocardiography substudy carried out in 611 patients from SHIFT
found that 8 months of therapy with Procoralan produced a
7 mL/m2 reduction in LV end-systolic volume index, as compared with 0.9 mL/m2 in the placebo group (Figure 8).31 LV
end-diastolic volume index was also reduced by 7.9 mL/m2
as compared with 1.8 mL/m2 in the placebo group; LV ejec-
446
0
Baseline
M8
Procoralan (n=208)
Placebo (n=203)
Evaluation of FASE = 411
Values in parentheses are standard deviations
Figure 8. Change from baseline to 8 months in left ventricular endsystolic volume index (LVESVI) in the echocardiography substudy
of SHIFT.
Based on data from reference 31: Tardif JC et al. Eur Heart J. 2011;32:25072515. © 2011, Oxford University Press.
PROCORALAN
ed with Procoralan 7.5 mg twice daily, compared with 4.4%
of angina patients treated with atenolol 100 mg once daily.10
In HF patients receiving Procoralan in SHIFT, bradycardia led
to permanent withdrawal from the study in only 1% of patients.26 This low percentage is explained by a clear plateau
in the dose-response curve of If current inhibition and by the
direct rate-related dynamics of the HR-lowering effect, limiting the risk of excessive bradycardia and ensuring the greatest HR reduction in patients with the highest pretreatment HR.11
Achievement of the target dose of Procoralan is simple, with
uptitration from 5 mg (starting dose) through to 7.5 mg twice
daily if HR remains above 60 bpm. This simplifies the management of angina or HF patients compared with other treatments.
Importantly, the abrupt discontinuation of Procoralan does not
result in a rebound phenomenon.11 The absence of rebound
tachycardia with Procoralan not only simplifies the manage-
ment of antianginal treatment, but also reduces the risk of adverse effects following missed doses or unscheduled gaps in
medication administration. These characteristics of the HR–
lowering action of Procoralan make it suitable and simple to
use in most symptomatic patients with CAD or HF.
Conclusion
The pharmacological and clinical properties of Procoralan
make it an important agent in the management of patients
with stable CAD due to its ability to positively affect angina
symptoms and myocardial ischemia and improve clinical outcomes. Following the breakthrough results of SHIFT, Procoralan was approved for use in HF patients, which represents
a major step forward in the management of these patients.
This approval brings promise of a better prognosis and improved QOL for millions of patients with chronic HF. I
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and safety. Drug Saf. 2008;31:95-107.
447
PROCORALAN
Keywords: coronary artery disease; heart failure, heart rate reduction; If current; ivabradine; Procoralan; sinus node; stable
angina
AVANTAGES
CLINIQUES DE L’ABAISSEMENT DE LA FRÉQUENCE CARDIAQUE AVEC P ROCORALAN
DANS LA PRISE EN CHARGE DES PATIENTS ATTEINTS DE MALADIE CARDIOVASCULAIRE
Procoralan (ivabradine) est le premier inhibiteur sélectif et spécifique du courant If , réduisant uniquement la fréquence
cardiaque (FC) sans altérer la contractilité myocardique, la conduction cardiaque ou la résistance vasculaire coronaire. Des données expérimentales ont démontré la nature spécifique du mode d’action de Procoralan, qui abaisse
la FC, et suggèrent que le mécanisme par lequel la FC est ralentie influe sur une grande partie de ses bénéfices. Le
ralentissement sélectif de la FC avec Procoralan présente des avantages supplémentaires, inexistants avec d’autres
médicaments abaissant la FC, ainsi que tous ceux permettant d’améliorer la perfusion coronaire et l’efficacité de la
pompe cardiaque. La double protection cardiaque et vasculaire, grâce à la prévention de la dysfonction endothéliale
et de l’athérosclérose, peut contribuer à la réduction des événements cardiaques observés en clinique avec Procoralan. Procoralan, en agissant positivement sur les symptômes angoreux et l’ischémie myocardique et en améliorant
l’évolution clinique, occupe une place importante dans la prise en charge des patients coronariens. Après les résultats décisifs de l’étude SHIFT (Systolic Heart failure treatment with If inhibitor ivabradine Trial), Procoralan a obtenu
l’indication chez les insuffisants cardiaques (IC) présentant une dysfonction systolique ventriculaire gauche, ce qui
représente une étape majeure dans la prise en charge de ces patients. Cette autorisation apporte aux millions de patients IC chroniques la promesse d’un meilleur pronostic et d’une meilleure qualité de vie.
448
INTERVIEW
‘‘
The recent results from the
SHIFT trial, which showed significant, substantial reductions in CV
death or HF hospitalization as well
as in HF deaths in patients with
chronic CHF, have significantly extended the range of the clinical
benefits of ivabradine to patients
with HF. Thus, by assessing the effect of ivabradine on cardiovascular outcomes in patients with stable
CAD without clinical HF, SIGNIFY
is a logical extension of the clinical
program of ivabradine in CAD.”
Heart rate reduction in
management: what can we
expect from the SIGNIFY trial?
I n t e r v i e w w i t h K . F ox , U n i t e d K i n g d o m
P
Kim FOX, MD, FRCP
Professor of Clinical Cardiology and
Head of the National Heart and
Lung Institute, Imperial College
Executive Chairman of the Institute
of Cardiovascular Medicine and
Science, Royal Brompton Hospital
London, UK
atients with stable coronary artery disease (CAD) have high event rates
despite modern treatments. Large studies with long-term follow-up have
shown that elevated heart rate (HR) is an independent predictor of allcause and cardiovascular mortality in patients with cardiovascular disease, including CAD patients. A high resting HR is a potentially modifiable cardiovascular risk factor. Thus, lowering HR could reduce mortality and cardiovascular
events in patients with cardiovascular disease. The data from the BEAUTIFUL
trial (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients
with coronary disease and left ventricULar dysfunction) indicated that ivabradine prevents coronary outcomes in patients with stable CAD and left ventricular dysfunction who have a HR of ⱖ70 beats per minute (bpm). The aim of the
ongoing SIGNIFY trial (Study assessInG the morbidity-mortality beNefits of
the If inhibitor ivabradine in patients with coronarY artery disease) is to test the
hypothesis that HR reduction with ivabradine could improve cardiovascular
outcomes in patients with CAD and preserved left ventricular systolic function. This trial is a randomized, double-blind, placebo-controlled, multicenter
study designed to assess the superiority of ivabradine vs placebo on cardiovascular mortality or nonfatal myocardial infarction (composite primary end
point) in patients with stable CAD without clinical heart failure who are receiving appropriate cardiovascular treatment for their disease. It includes patients
aged 55 years or older with stable CAD without clinical heart failure (ejection
fraction >41%), in sinus rhythm, and with a resting HR ⱖ70 bpm. If the results
of the SIGNIFY trial show that ivabradine treatment reduces cardiovascular
morbidity in this population, it will constitute a breakthrough in the treatment
of patients with stable CAD.
What is the prognosis of patients with stable coronary artery disease?
oronary artery disease (CAD) remains the leading cause of mortality and a
major source of morbidity in developed countries. In the European Union,
CAD is associated with 744 000 deaths annually, including 17% of all deaths
in men and 16% in women.1 CAD mortality has declined in many industrialized, socioeconomically well-established countries thanks to major advances in secondary
preventive strategies. However, these favorable trends are accompanied by a shift
of the main burden of clinically manifest CAD—particularly its milder manifestations—
toward older age groups, resulting in a constant number of deaths from atheroscle-
C
Professor K. Fox, NHLI Imperial
College and ICMS, Royal Brompton
Hospital, London, UK
Heart rate reduction in coronary artery disease management: what to expect from SIGNIFY – Fox
449
INTERVIEW
rosis-related events every year. The prognosis in patients with
chronic CAD is not uniform; it depends on several factors, including underlying coronary anatomy, left ventricular function,
and comorbidities. Coronary atherosclerosis most commonly manifests as angina pectoris, followed by acute coronary
syndromes (acute myocardial infarction [MI] and unstable
angina), and finally, as sudden cardiac death. The Heart and
Soul Study, which included 937 outpatients with stable CAD,
demonstrated that the presence of inducible ischemia is associated with a greater than 2-fold increased rate of recurrent
CAD events.2 During an average of 3.9 years of follow-up,
coronary events (MI or CAD death) occurred in 7% of participants without angina or inducible ischemia, in 10% of those
with angina alone, in 21% of those with inducible ischemia
alone, and in 23% of those with both angina and inducible ischemia. The data from outpatients with atherothrombosis from
the REACH registry (Reduction of Atherothrombosis for Continued Health)—a large, stable, contemporary outpatient cohort of patients with atherosclerotic arterial disease or with
multiple atherothrombotic risk factors—has confirmed that
among patients with cardiovascular disease, those with established stable CAD have the highest rates of nonfatal MI and
nonfatal stroke. The registry reported annual event rates of
15.2% for death, stroke, MI, or hospitalization for an atherothrombotic event, as well as 6.4% for unstable angina, 4.5%
for death, acute MI, and stroke, and 3.8% for revascularization by percutaneous coronary intervention.3 Thus, approximately 3 out of 20 patients with established CAD had a major event or were hospitalized within a year of follow-up. The
high event rates observed in the subgroup of patients with
established CAD in the REACH registry indicate that continued efforts are needed to improve secondary prevention and
clinical outcomes.
What is the importance of heart rate control in
the treatment of coronary artery disease?
R reduction is a well-recognized strategy for ischemia
prevention in patients with CAD. HR reduction decreases myocardial work and myocardial oxygen consumption, and increases diastolic filling time and myocardial oxygen
supply, thereby minimizing the pathophysiological substrate
of angina.4 It is the primary mechanism of the anti-ischemic
effects of agents that reduce HR nonselectively—like β-blockers—or selectively—like ivabradine.
H
Although HR slowing during exercise is important in the prevention of angina pectoris, even a reduction in resting HR may
have an impact on long-term outcomes. Experimental and
clinical findings suggest that an elevated resting HR predisposes to the development of atherosclerosis and plaque rupture, which can trigger the acute coronary events that are linked
to mortality in patients with CAD.4 Furthermore, a meta-regression of randomized clinical trials with β-blockers and calcium
channel blockers in post-MI patients strongly suggests that
450
resting HR reduction could be a major determinant of the clinical benefits seen in these trials.5 In addition, the investigators
of BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left
ventricULar dysfunction) have also made a substantial contribution to the understanding of the importance of HR reduction for the prevention of coronary events. BEAUTIFUL was
the first study to prospectively evaluate the impact of an elevated resting HR on outcomes in patients with stable CAD
and left ventricular systolic dysfunction (LVSD). The prospective analysis of the data from the placebo arm demonstrated that elevated resting HR (ⱖ70 beats per minute [bpm]) is
a strong independent predictor of clinical outcomes.6 The
BEAUTIFUL study also showed that in patients with HR ⱖ70
bpm, HR reduction with ivabradine significantly reduces coronary events.7 Given the important role of HR in the pathophysiology of CAD, it seems clear that HR reduction should be
considered as a key therapeutic goal in patients with CAD.
What heart rate should be targeted in this
population?
n keeping with the important role of elevated HR in the pathophysiology of myocardial ischemia, it is recommended to
reduce resting HR to 55-60 bpm in stable coronary patients as well as in acute coronary settings. Thus, the current
American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of chronic stable angina stipulate that β-blocker dosages should be ad-
I
SELECTED
ACTION
A Coronary disease Trial Investigating Outcome
with Nifedipine gastrointestinal therapeutic
system
ASSOCIATE evaluation of the Antianginal efficacy and Safety
of the aSsociation Of the If Current Inhibitor
ivAbradine with a beTa-blockEr
bpm
beat per minute
CAD
CAMELOT Comparison of AMlodipine vs Enalapril to Limit
Occurrences of Thrombosis
CLARIFY
prospeCtive observational LongitudinAl RegIstry
oF patients with stable coronary arterY disease
HR
heart rate
IONA
Impact Of Nicorandil in Angina
LVSD
left ventricular systolic dysfunction
MI
REACH
Reduction of Atherothrombosis for Continued
Health
SIGNIFY
Study assessInG the morbidity-mortality beNefits
of the If inhibitor ivabradine in patients with
coronarY artery disease
TNT
Treating to New Targets
INTERVIEW
justed to reduce resting HR to 55-60 bpm, or to <50 bpm in
patients with severe angina. In the management of unstable
angina and non–ST-segment-elevation MI, the ACC/AHA and
European Society of Cardiology (ESC) guidelines agree that
when β-blockers are used as an initial intervention, a target
resting HR of 50-60 bpm is appropriate. A new analysis of
the TNT trial (Treating to New Targets) in 9602 patients with
established CAD evaluated the optimal HR level in relation to
the risk of cardiovascular events. In patients with CAD, the
relationship between HR and outcomes follows a J-curve pattern.8 This analysis identified a nadir of 52.4 bpm, which was
associated with the lowest event rate for the primary end point
of death from CAD, nonfatal MI, resuscitated cardiac arrests,
and fatal or nonfatal stroke. There was no target-organ heterogeneity and the nadir was similar for all outcomes, indicating that a target range of 50-59 bpm is optimal for best prognosis in patients with CAD.
The existing evidence suggests that a HR of 55-60 bpm
may be considered as optimal for both ischemia prevention
and—perhaps—the prevention of cardiovascular events.
In daily practice, is heart rate controlled in
coronary patients?
espite a large body of evidence indicating the importance of HR control, survey data have revealed that in
a majority of patients, HR is not optimal. For example,
in the European Heart Survey of patients with stable angina,
the mean resting HR was 73 bpm, suggesting that a majority
of patients had a HR above the recommended level of 55-60
bpm.9 The baseline data from the CLARIFY registry (prospeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease), which includes 33 177 contemporary outpatients with stable CAD, confirms the previous
observations that HR is not well controlled among stable outpatients with CAD and that many coronary patients are still
symptomatic. The mean pulse HR was 68.3 bpm, and 22%
of coronary patients had angina symptoms.10 These findings
suggest that there is room for improving HR control in CAD.
D
What is the SIGNIFY trial?
IGNIFY (Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease) is an ongoing randomized, doubleblind, placebo-controlled, multicenter study assessing the
effect of ivabradine in patients with CAD without clinical heart
failure (HF).11
S
What is the goal of the SIGNIFY trial?
T
he SIGNIFY trial was designed to determine if lowering
resting HR with ivabradine would reduce cardiovascular mortality or nonfatal MI (composite end point) in pa-
tients with stable CAD without clinical HF who are receiving
appropriate cardiovascular treatment for their disease. The
secondary objectives of the trial include assessment of the
effect of ivabradine compared with placebo on all-cause mortality, cardiovascular mortality, nonfatal MI, coronary revascularization, and new-onset or worsening HF, as well as some
composite coronary end points. In addition, the effect of ivabradine on quality of life and angina symptoms will be assessed
in patients presenting with angina symptoms at baseline.
Why was ivabradine chosen for the treatment of
these patients?
vabradine is a HR-lowering agent that selectively reduces HR
by inhibiting the sinoatrial pacemaker If current and thereby decreases HR without having any effect on other cardiac
functions.12 Existing evidence on the prevention of myocardial ischemia and coronary- and HF-related events make it
an important agent in the management of patients with CAD
as well as HF. Ivabradine has been proven to prevent myocardial ischemia effectively and to reduce symptoms in patients
with chronic stable angina pectoris. In head-to-head comparisons, its effectiveness on exercise-induced ischemia is
comparable with established drugs such as β-blockers or calcium channel blockers. The ASSOCIATE trial (evaluation of
the Antianginal efficacy and Safety of the aSsociation Of the
If Current Inhibitor ivAbradine with a beTa-blockEr) showed
that, when added to chronic treatment with β-blockers, ivabradine further reduces HR and improves exercise capacity while
being well tolerated. The BEAUTIFUL trial shed new light on
the role of HR control in cardiovascular disease and showed
that ivabradine prevents coronary outcomes in patients with
stable CAD and LVSD with HR >70 bpm. Moreover, in 1500
BEAUTIFUL patients with angina as a limiting symptom at
baseline, ivabradine not only provided significant benefit in the
primary outcome as well as in secondary outcomes, but this
benefit was also evident throughout the whole HR spectrum.
The recent results from the SHIFT trial (Systolic Heart failure
treatment with the If inhibitor ivabradine Trial), which showed
significant, substantial reductions in CV death or HF hospitalization as well as in HF deaths in patients with chronic CHF,
have significantly extended the range of the clinical benefits
of ivabradine to patients with HF.13 Thus, by assessing the effect of ivabradine on cardiovascular outcomes in patients with
stable CAD without clinical HF, SIGNIFY is a logical extension
of the clinical program of ivabradine in CAD.
I
What is the design of the study?
IGNIFY is a randomized, double-blind, placebo-controlled,
multicenter trial in patients with stable CAD without clinical HF, with two parallel and balanced treatment arms.
It is designed to demonstrate the superiority of ivabradine over
placebo in the reduction of cardiovascular mortality or nonfatal MI (composite end point).
S
451
INTERVIEW
Following a run-in period of 14 to 30 days, patients will be randomized to the active double-blind treatment period (ivabradine versus placebo). The study has enrolled over 19 000 patients, with a minimal follow-up of at least 18 months. In keeping
with current recommendations, the target HR range is 5560 bpm. Since the patients included in this trial are clinically stable patients with elevated HR (ⱖ70 bpm), the starting
dose of ivabradine is 7.5 mg twice daily, with a possible increase to 10 mg twice daily after 1 month (according to HR
and the presence or absence of signs and symptoms indicative of bradycardia). Although a twice-daily dose of 7.5 mg is
the current recommended dose for ivabradine after uptitration, the range of ivabradine doses selected for this study has
been chosen based on the doses used in the patients with
CAD and stable angina who were involved in the development program of ivabradine.
post-MI and HF. Moreover, the post-MI trials with β-blockers
were performed without the extensive use of angiotensin-converting enzyme inhibitors and statins, which leaves uncertainty regarding their efficacy on top of modern management
strategies. Calcium channel blockade failed to reduce cardiovascular mortality and morbidity in the CAMELOT (Comparison of AMlodipine vs Enalapril to Limit Occurrences of Thrombosis) and ACTION (A Coronary disease Trial Investigating
Outcome with Nifedipine gastrointestinal therapeutic system)
trials.14,15 In the IONA trial (Impact Of Nicorandil in Angina),
treatment with nicorandil resulted in a lower event rate for the
composite end point, which included refractory angina. This
trial was not powered to show a benefit on major cardiovascular events, such as CAD mortality and nonfatal MI, or allcause mortality. Therefore, it is not possible to draw conclusions regarding these end points.16
What patient population is included in the study?
So, if the results of the SIGNIFY trial show that ivabradine
treatment reduces cardiovascular morbidity and mortality in
patients with stable CAD and preserved LV function, it will constitute a breakthrough in the treatment strategies for patients
with stable CAD, allowing us to reach the two main goals of
treatment in patients with stable CAD: to prevent cardiovascular events, and to reduce symptoms and improve quality
of life.
he inclusion and exclusion criteria were designed to select a group of patients aged ⱖ55 years, with stable
CAD and without clinical HF (ejection fraction ⱖ41%),
in sinus rhythm, with resting HR ⱖ70 bpm, and receiving appropriate medication to treat their cardiovascular conditions.
Patients should have additional risk factors, which may be
either at least one risk factor such as angina symptoms (Canadian Cardiovascular Society class II or higher), objective evidence of myocardial ischemia induced by stress testing within the previous 12 months, and recent hospitalization for major
coronary event (acute MI or unstable angina) within the previous 12 months; or at least two of the following risk factors:
low HDL cholesterol and/or high LDL cholesterol, treated diabetes mellitus, presence of peripheral artery disease, current
smoking, and age >70 years.
T
What is the importance of the expected results in
clinical practice?
atients with stable CAD have high event rates despite
modern treatments. Large studies with long-term followup have shown that elevated HR is an independent predictor of all-cause and cardiovascular mortality in patients with
cardiovascular disease including CAD patients. A high resting
HR is a potentially modifiable cardiovascular risk factor and
therefore HR lowering could reduce mortality and cardiovascular events in patients with cardiovascular disease. The aim
of the SIGNIFY study is to increase the evidence on the prognostic benefits of HR reduction with ivabradine in a population of patients with CAD and preserved LV systolic function.
The BEAUTIFUL trial demonstrated that ivabradine improves
coronary events in patients with stable CAD and LVSD with
HR ⱖ70 bpm.6 Other antianginal strategies have either never
been tested or failed to demonstrate benefits on cardiovascular events in stable CAD patients. The well-known benefits of
β-blockade in terms of reduction of mortality are limited to
P
452
What kind of patients will benefit from the new
approach?
he results of the SIGNIFY trial will be important for the
large spectrum of patients with stable CAD. In future
years, as the general population continues to age, the
number of patients with stable CAD is expected to increase.
According to global and regional projections of mortality and
disease burden, CAD will remain the leading cause of death
for the next 20 years. Moreover, a recently published estimation indicates a significant growth in the projected crude
prevalence of cardiovascular disease—including CAD—in the
next 2 decades.17 In the USA, these increases will translate
into an additional 8 million people with CAD in 2030, relative
to 2010. Despite all the advances in modern treatments, patients with stable CAD have high event rates. HR reduction
is a modifiable risk factor that provides an important therapeutic opportunity to improve prognosis in coronary patients.
T
However, despite the recommendation to reduce HR to 5560 bpm, resting HR remains uncontrolled in a significant proportion of patients in clinical practice. Many surveys conducted in coronary patients have revealed low rates of HR control.
As mentioned previously, the results of the European Heart
Survey of patients with stable angina suggest that a majority of patients have a HR >70 bpm. Therefore, the data from
SIGNIFY will provide a great therapeutic opportunity for the
large population of patients with stable CAD. I
INTERVIEW
References
1. Petersen S, Peto V, Rayner M, Leal J, Luengo-Fenrnadez R, Gray A. European
cardiovascular disease statistics. London, UK: British Heart Foundation; 2005.
2. Gehi AK, Ali S, Na B, Schiller NB, Whooley MA. Inducible ischemia and the
risk of recurrent cardiovascular events in outpatients with stable coronary heart
disease. The Heart and Soul Study. Arch Intern Med. 2008;168:1423-1428.
3. Steg PG, Bhatt DL, Wilson PW, et al. One-year cardiovascular event rates in
outpatients with atherothrombosis. JAMA. 2007;297:1197-1206.
4. Fox KM, Ferrari R. Heart rate: a forgotten link in coronary artery disease? Nat
Rev Cardiol. 2011;8:369-379.
5. Cucherat M. Quantitative relationship between resting heart rate reduction and
magnitude of clinical benefits in post-myocardial infarction: a meta-regression
of randomized clinical trials. Eur Heart J. 2007;28:3012-3097.
6. Fox K, Ford I, Steg PG? et al. Ivabradine for patients with stable coronary artery disease and left ventricular dysfunction (BEAUTIFUL): a randomized, double-blind, placebo controlled trial. Lancet. 2008;372:807-816.
7. Fox K, Ford I, Steg PG, et al. Heart rate as a prognostic risk factor in patients with
coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL):
a subgroup analysis of a randomised controlled trial. Lancet. 2008;372:817-821.
8. Bangalore S, Wun CC, DeMicco DA, Breazna A, Deedwania P, Messerli FH;
TNT steering committee and investigators. Heart rate in patients with coronary
artery disease – the lower the better? An analysis from the Treating to New Targets (TNT) trial. Eur Heart J. 2011;32(abstract suppl):339.
9. Daly CA, Clemens F, Lopez Sendon JL, et al; Euro Heart Survey Investigators.
Inadequate control of heart rate in patients with stable angina: results from the
European Heart Survey. Postgrad Med J. 2010;86:212-217.
10. Steg PG. Heart rate, anginal symptoms, and use of beta-blockers in stable
coronary artery disease outpatients. The CLARIFY registry. Eur Heart J. 2011;32
(abstract suppl):340.
11. Trial registration: ISRCTN61576291 – Effects of ivabradine in patients with
stable coronary artery disease without heart failure.
12. Ferrari R, Ceconi C. Selective and specific I(f) inhibition with ivabradine: new
perspectives for the treatment of cardiovascular disease. Expert Rev Cardiovasc Ther. 2011;9:959-973.
13. Swedberg K, Komajda M, Böhm M, et al; SHIFT investigators. Ivabradine and
study. Lancet. 2010;376:875-885.
14. Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA. 2004;292:
2217-2225.
15. Poole Wilson PA, Lubsen J, Kirwan BA, et al. Effect of long-acting nifedipine on
mortality and cardiovascular morbidity in patients with stable angina requiring
treatment (ACTION trial): randomised controlled trial. Lancet. 2004;364:849857.
16. Dargie HJ. Effect of nicorandil on coronary events in patients with stable angina:
the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet. 2002;359:
1269-1275.
17. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American
Heart Association. Circulation. 2011;123:933-944.
Keywords: cardiovascular outcome; coronary artery disease; heart rate lowering; ivabradine; SIGNIFY
LA
RÉDUCTION DE LA FRÉQUENCE CARDIAQUE DANS LA MALADIE CORONAIRE
QUE POUVONS - NOUS ATTENDRE DE L’ ÉTUDE SIGNIFY ?
:
Le taux d’événements (cardiaques) des patients coronariens stables est élevé malgré les traitements modernes.
De grandes études au suivi à long terme ont montré qu’une fréquence cardiaque (FC) élevée est un facteur prédictif indépendant de mortalité toutes causes et cardiovasculaire chez les patients atteints de maladie cardiovasculaire, y compris les patients coronariens. Une FC de repos élevée est un facteur de risque cardiovasculaire potentiellement modifiable. Abaisser la FC pourrait ainsi diminuer la mortalité et les événements cardiovasculaires chez les
patients ayant une maladie cardiovasculaire. Les données de l’étude BEAUTIFUL (morBidity-mortality EvAlUaTion
of the If inhibitor ivabradine in patients with coronary disease and left ventricular dysfunction) ont montré que l’ivabradine prévient les événements coronaires chez les patients coronariens stables ayant une dysfonction ventriculaire
gauche dont la FC est ⱖ 70 battements par minute (bpm). Le but de l’étude SIGNIFY en cours (Study assessInG the
morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease) est d’analyser l’hypothèse que la réduction de la FC due à l’ivabradine peut améliorer les événements cardiovasculaires des patients
coronariens dont la fonction systolique ventriculaire gauche est préservée. Cette étude est randomisée, en double
aveugle, contrôlée contre placebo, multicentrique, conçue pour évaluer la supériorité de l’ivabradine vs placebo sur
la mortalité cardiovasculaire ou sur l’infarctus du myocarde non fatal (critère primaire composite) chez des patients
coronariens stables sans insuffisance cardiaque clinique qui reçoivent un traitement cardiovasculaire adapté à leur
maladie. Des patients âgés de 55 ans ou plus, coronariens stables, sans insuffisance cardiaque clinique (fraction
d’éjection > 41 %), en rythme sinusal, et dont la FC au repos est ⱖ 70 bpm, ont été inclus. Si les résultats de l’étude
SIGNIFY montrent que le traitement par ivabradine diminue la morbidité cardiovasculaire dans cette population,
cela constituera un pas décisif dans le traitement des patients coronariens stables.
453
FOCUS
‘‘
Heart rate is probably the
most frequently measured physiological parameter. Despite its considerable variability, it is emerging
as a parameter of utmost physiological and prognostic importance
in cardiovascular disease. It is one
of the major determinants of myocardial oxygen consumption, and
therefore, increased heart rate is an
important precipitating factor for
myocardial ischemia and anginal
symptoms.”
Heart rate in registries:
an important, yet still
neglected opportunity
b y P. G . S t e g , Fra n c e
R
Philippe Gabriel STEG, MD
AP-HP, Hôpital Bichat
Université Paris Diderot
Sorbonne Paris Cité
INSERM U-698
Paris, FRANCE
egistries are the key to understanding the characteristics, management,
and outcomes of patients with coronary artery disease (CAD), particularly since information gathered from randomized clinical trials often has
limited external validity given the stringent selection criteria used to select trial participants. Resting heart rate is emerging as a key prognostic determinant of outcomes, particularly cardiovascular mortality in patients with stable
and unstable forms of CAD and heart failure. Yet, while heart rate is the most
commonly measured physiological parameter, surprisingly little information
has been gathered regarding actual heart rate in patients with CAD and its relation to the use of heart rate–lowering medications (particularly 웁-blockers)
and subsequent outcomes. In recent years, many registries from various countries in Europe and elsewhere have gathered information on the characteristics of patients with CAD. They have consistently found that although the majority of patients receive 웁-blockers, resting heart rate is very frequently above
70 bpm. In addition, they have showed that elevated resting heart rate is associated with a greater prevalence of anginal symptoms and, more importantly, with increased cardiovascular mortality. In patients with acute coronary syndromes, however, very low heart rates were also associated with increased
mortality, suggesting that the relationship between heart rate and survival in
CAD may follow a “J curve.” The large international CLARIFY registry (ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary
arterY disease), which has enrolled more than 33 000 patients worldwide,
will provide robust information about resting heart rate in relation to anginal
symptoms, the use of heart rate–lowering agents—particularly 웁-blockers—
and, most importantly, clinical outcomes up to 5 years.
The importance of registries in understanding the epidemiology of
ardiovascular medicine has made major strides in the past 30 years, with substantial progress in the diagnosis, evaluation, management, and prevention
of cardiovascular disease. In fact, progress in the field of cardiovascular disease accounts for most of the increase in life expectancy witnessed in the Western
world between 1970 and 2000.1 Advances have largely stemmed from evidence
accumulated via large randomized clinical trials (RCTs) testing new interventions,
devices, and drugs. While randomized clinical trials provide the highest level of evidence regarding the value of interventions, they have some important shortcomings.
C
Philippe Gabriel Steg, Cardiology,
Hôpital Bichat, 46 rue Henri Huchard,
75018 Paris, France.
454
Heart rate in registries: an important, yet still neglected opportunity – Steg
FOCUS
First, they tend to recruit highly selected patient populations
who are more compliant with medical care and therapies than
the average patient encountered in routine clinical practice.
Additionally, because of the often stringent inclusion and exclusion criteria, patients enrolled in RCTs tend to be healthier
and suffer from fewer comorbidities than patients encountered
in routine care. It is therefore important to complement the information gathered from randomized clinical trials with additional information, more representative of routine clinical practice and collected via observational registries. Registries have
important additional advantages over RCTs: they are much
cheaper and thus can be conducted on a very large scale.
They do not require the same level of training or infrastructures
as RCTs and can enroll patients from all types of hospitals (not
necessarily academic or tertiary institutions), from both hospital and outpatient settings, and can gather data from broad
geographic sources. They can collect comprehensive information regarding the clinical characteristics of patients, their
management, and their outcomes, and they tend to have
greater external validity than RCTs.2 External validity is critical
to the interpretation and application of evidence-based medicine: there is ample evidence that patients enrolled in clinical
trials tend to have better clinical outcomes than patients in
routine practice. Yet, we tend to extend the results of RCTs to
patients from routine clinical practice who have characteristics
similar to those of the participants in RCTs. There have been
demonstrations, for example in ST-segment elevation myocardial infarction (STEMI),3 that even “trial-eligible patients” from
registries actually experience much worse outcomes than actual trial participants.
SELECTED
Information on patients with coronary artery
disease is limited
Despite a steady decline in the Western world over the past
30 years, coronary artery disease (CAD) is still the first cause
of death worldwide4 and is expected to remain so due to an
epidemic of coronary heart disease in emerging countries. Yet,
our knowledge of the clinical epidemiology of CAD remains
limited. Much of the information available predates the emergence of percutaneous coronary intervention (PCI) as the dominant form of revascularization, and therefore, reflects patient
profiles that differ markedly from current clinical practice. Most
of the information stems from highly selective RCTs or from
registries enrolling patients hospitalized for an acute coronary
event or a procedure (PCI or coronary artery bypass grafting
[CABG]). This wealth of data regarding patients who are admitted to hospital for an acute event does not necessarily reflect the situation of stable outpatients. There are some large
registries, but they have focused mostly on patients with anginal symptoms, such as, for example, the Euro Heart Survey
on stable angina, which enrolled patients with angina.5 Finally,
most of the information comes from sources located in North
America or Europe, overlooking the important differences in
patient characteristics, management, and environment in other regions of the world. The fact is that our knowledge of the
global characteristics of patients with CAD is scant. Little is
known about their clinical characteristics, functional status,
quality of life, clinical management (including the use of functional testing and imaging) and the use of evidence-based
therapies and medications and their outcomes. Gathering such
information is critical to identifying gaps in evidence as well as
gaps between evidence and routine clinical practice, which
can then inform quality assurance initiatives.
CABG
coronary artery bypass grafting
CAD
CASS
Coronary Artery Surgery Study
CLARIFY
ProspeCtive observational LongitudinAl RegIstry
oF patients with stable coronary arterY disease
CRUSADE
Can Rapid risk stratification of Unstable angina
patients Suppress ADverse outcomes with
Early implementation of the American College
of Cardiology/American Heart Association
Guidelines?
GRACE
Global Registry of Acute Coronary Events
PCI
percutaneous coronary intervention
PURSUIT
Platelet glycoprotein IIb/IIIa in Unstable angina:
Receptor Suppression Using Integrilin Therapy
RCT
randomized clinical trial
SHIFT
ivabradine Trial
STEMI
ST-segment–elevation myocardial infarction
Heart rate is emerging as an important prognostic
and physiological parameter in coronary artery
disease and chronic heart failure
Heart rate is probably the most frequently measured physiological parameter. Despite its considerable variability, it is
emerging as a parameter of utmost physiological and prognostic importance in cardiovascular disease. It is one of the
major determinants of myocardial oxygen consumption, and
therefore, increased heart rate is an important precipitating
factor for myocardial ischemia and anginal symptoms. Indeed,
some of the most effective treatments to prevent or treat myocardial ischemia and angina, such as β-blockers or some
(but not all) calcium channel blockers, act by lowering the heart
rate. In fact, the American College of Cardiology/American
Heart Association (ACC/AHA) guidelines for the management
of patients with angina recommend targeting a heart rate of
less than 60 beats per min (bpm) for patients with stable
angina.6
In addition, despite the short-term variability in heart rate, large
epidemiological observational studies, such as the Chicago
epidemiological studies7 or other large studies in apparently
455
FOCUS
healthy individuals,8 have consistently linked resting heart rate
with long-term cardiovascular risk in subjects without established cardiovascular disease: the higher the heart rate, the
greater the risk of cardiovascular and even all-cause mortality.9 An analysis of the CASS registry (Coronary Artery Surgery Study)10 also showed the long-term prognostic value of
resting heart rate in patients with suspected or proven CAD:
24 913 patients from the CASS registry were followed for a
median duration of 14.7 years. All-cause mortality and cardiovascular mortality increased with increasing heart rate. This
persisted after adjustment for multiple baseline clinical variables (Figure 1). Likewise, Copie et al showed that resting
heart rate and heart rate variability were important predictors
of outcomes after myocardial infarction.11 More recently, prespecified analyses of the placebo arm of the BEAUTIFUL randomized trial (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left
Adjusted survival curves for
overall mortality
A
1.0
Cumulative survival
0.8
1.0
0.9
0.8
P<0.0001
P<0.0001
0.7
0.7
0.6
0.6
0.5
0.5
0
5
10
15
Years after enrollment
20
ventricULar dysfunction) in patients with CAD and left ventricular dysfunction examined the relationship between heart
rate at enrollment and subsequent outcomes.12 After adjustment for baseline characteristics, patients with heart rates
of 70 bpm or greater (n=2693) had an increased risk of cardiovascular death (34%; P=0.0041), admission to hospital for
heart failure (53%; P<0.0001), admission to hospital for myocardial infarction (46%; P=0.0066), and coronary revascularization (38%; P=0.037) than those with heart rates below
70 bpm (n=2745). For every increase of 5 bpm, there were increases in cardiovascular death (8%; P=0.0005), admission to
hospital for heart failure (16%; P<0.0001), admission to hospital for myocardial infarction (7%; P=0.052), and coronary
revascularization (8%, P=0.034). In patients with CAD and left
ventricular systolic dysfunction, elevated heart rate (70 bpm
or greater) identifies those at increased risk of cardiovascular
outcomes. Similar observations regarding the prognostic importance of heart rate in congestive heart failure were made
in the SHIFT randomized trial (Systolic Heart failure treatment
456
Figure 1. Survival
curves for overall
mortality (A) and
cardiovascular
mortality (B) in the
Coronary Artery
Surgery Study
(CASS) registry.
Adjusted survival curves for
cardiovascular mortality
B
m62 bpm
63-70 bpm
71-76 bpm
77-82 bpm
M83 bpm
0.9
with the If inhibitor ivabradine Trial).13 SHIFT was a double-blind
placebo-controlled trial comparing ivabradine—a specific If
inhibitor (which is a pure heart rate–reducing agent)—with
placebo, in addition to optimal medical therapy in patients with
chronic heart failure.14 In the placebo group, patients with the
highest heart rates (ⱖ87 bpm) had a more than 2-fold higher
risk of cardiovascular death or hospital admission for worsening heart failure than patients with the lowest heart rates (70 to
<72 bpm; hazard ratio, 2.34; 95% CI, 1.84-2.98; P<0.0001).
The risk increased by 3% with every bpm increase from baseline heart rate. Ivabradine improved outcomes with an 18%
relative reduction in cardiovascular deaths or hospital admissions for heart failure (P<0.0001). Interestingly, the effect of
ivabradine was accounted for by heart rate reduction, as
shown by the neutralization of the treatment effect after adjustment for change in heart rate after 4 weeks of treatment
(hazard ratio, 0.95; 95% CI, 0.85-1.06, P=0.352).
0
5
10
15
Years after enrollment
20
A high resting heart
rate is an independent
predictor of mortality
in coronary artery
disease patients.
Data from the CASS
registry in 24 913
patients, with 14.7
years of follow-up.
After reference 10:
Diaz et al. Eur Heart J.
2005;26:967-974.
© 2005, European
Society of Cardiology.
Heart rate in coronary artery disease registries
As surprising as it may seem, there is relatively little largescale data on the resting heart rate of patients with CAD. In
addition, interpretation of heart rate data requires access to
information regarding the use of β-blockers and other heart
rate–lowering agents as well as information on the doses and
types of β-blockers used as some β-blockers may exhibit
sympathomimetic activity and therefore not result in heart rate
lowering at rest.
Stable angina registries
In the European Heart Survey of stable angina the mean baseline heart rate in patients with stable CAD was 73 bpm and
approximately half of the patients had a baseline heart rate
above 70 bpm,15 despite the fact that some guidelines recommend a target heart rate of 55 to 60 bpm for patients with
stable angina on β-blockers.6 Interestingly, over half of the patients were not on any chronotropic medication (ie, no β-blockers or any other heart rate–lowering medication). Among pa-
FOCUS
Figure 2. Risk calculator for 6-month
postdischarge mortality after hospitalization for acute coronary syndrome.
Computation of the GRACE (Global Registry of
Acute Coronary Events) risk score, a validated risk
prediction model, to predict 6-month post discharge outcomes after acute coronary syndrome.
After reference 25: Eagle et al. JAMA.
2004;291:2727-2733. © 2004, American
Medical Association.
tients receiving β-blockers, the doses used were lower than those found
to be effective in clinical trials. Finally, a higher heart rate at baseline was
associated with higher rates of mortality and hospitalization for heart failure at follow-up.
Findings at initial
hospital presentation
Medical history
1 Age in years
m29
30-39
40-49
50-59
60-69
70-79
80-89
M90
2 History of
Points
0
0
18
36
55
73
91
100
24
Points
rate, bpm
m49.9
50-69.9
70-89.9
90-109.9
110-149.9
150-199.9
M200
0
3
9
14
23
35
43
5 Systolic blood pressure,
12
myocardial
infarction
m79.9
80-99.9
100-119.9
120-139.9
140-159.9
160-199.9
M200
7 Initial serum
Points
creatinin, mg/dL
mm Hg
congestive
heart failure
3 History of
4 Resting heart
Findings
during hospitalization
0-0.39
0.4-0.79
0.8-1.19
1.2-1.59
1.6-1.99
2-3.99
M4
8 Elevated cardiac
1
3
5
7
9
15
20
15
enzymes
24
22
18
14
10
4
0
9 No in-hospital
12
percutaneous
coronary intervention
Probability
In a British registry of 500 patients
with chronic stable angina,16 a large
proportion of patients did not achieve
6 ST-segment
11
depression
the target resting heart rate of <60
bpm; 27% had a resting heart rate
Predicted all-cause mortality from
>70 bpm and an additional 40% had
Points
hospital discharge to 6 months
0.50
a heart rate between 60 and 69 bpm,
1
despite the fact that 78% of patients
2
0.40
were receiving β-blockers. The rest3
ing heart rate was not related to the
4
0.30
dose of β-blocker. Similar or higher
5
0.20
proportions of patients with elevated
6
heart rate and similar rates of β-block7
0.10
er use were seen in other studies
8
from Portugal, Italy, France, Austria,
9
0
and Poland.17-21 Studies focusing on
Total risk record
Sum of points
70
90 110 130 150 170 190 210
older patients tend to find lower rates
Mortality risk
From plot
Total risk score
of β-blocker use.22 The Lhycorne registry enrolled 8922 hypertensive
patients with stable CAD.23 In this study, the mean resting heart in-hospital outcomes in ACS, but also postdischarge outrate was 70 ± 6 bpm, with 54% of the patients having a heart comes, indicating that it is a robust marker of long-term outrate ⱖ70 bpm and 62% of the population receiving β-block- comes (Figure 2).25 Likewise, heart rate is also a predictor of
ers. In the above-mentioned studies, patients with higher rest- outcomes in the PURSUIT risk score (Platelet glycoprotein
ing heart rates experienced more frequent anginal symptoms. IIb/IIIa in Unstable angina: Receptor Suppression Using InteOne study found that the link between a higher resting heart grilin Therapy).26 In the GRACE risk prediction model, the risk
rate and adverse clinical outcomes in patients with stable CAD of events increases by 30% for every 30-beat increase in heart
may be limited to patients with diabetes mellitus, possibly be- rate. An analysis of the large CRUSADE acute coronary syncause it reflects autonomic disturbances.24 This study was, dromes quality improvement initiative (Can Rapid risk strathowever, limited by a relatively short follow-up of only 1 year. ification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of
Acute coronary syndromes registries
Cardiology/American Heart Association Guidelines?) found
Heart rate is an independent predictor of outcomes in pa- that the relationship between resting heart rate at presentatients with acute coronary events. For example, the GRACE tion and cardiovascular outcomes follows a “J-shaped” curve,
risk score (Global Registry of Acute Coronary Events), the most with higher event rates at high heart rates, but also at very low
widely recommended risk score for acute coronary syndromes, heart rates (below 60 beats per minute), even after controlling
collects information regarding heart rate at presentation and for baseline variables.27 The lowest risk of adverse outcomes
correlates this with the in-hospital risk of death and myocar- was seen in patients with a resting heart rate between 60 and
dial infarction. Interestingly, heart rate does not solely predict 69 bpm. One issue requiring clarification is that of the extent
457
FOCUS
to which the detrimental prognostic impact of heart rate may
have been confounded by heart failure and whether more
modern studies of acute coronary syndromes in which PCI
is widely used may fail to show a link between resting heart
rate and survival. In a recent analysis of 1453 STEMI patients
treated with primary PCI, Antoni et al found that heart rate at
discharge after STEMI is a strong predictor of mortality following STEMI, with patients with a heart rate ⱖ70 bpm having
twice the mortality of patients with a lower heart rate, at 1 and
4 years. Every increase of 5 bpm in heart rate at discharge
was associated with a 29% and 24% increased risk of cardiovascular mortality at 1 and 4 years of follow-up, respectively.28
The CLARIFY registry
CLARIFY (ProspeCtive observational LongitudinAl RegIstry oF
patients with stable coronary arterY disease) is an ongoing
international, prospective, observational, longitudinal cohort
study in stable CAD outpatients, with a 5-year follow-up. The
study rationale and methods have been published previously.29 The enrolled population is representative of the broad
spectrum of CAD patients and detailed information on heart
rate was collected at baseline and will continue to be collected on a yearly basis for up to 5 years. CLARIFY will provide a
robust database to assess the determinants of outcomes in
CAD, prospectively explore the role of heart rate, and evaluate the degree of heart rate reduction achieved with the different types of heart rate–lowering medications used at various
doses. In particular, it will help build a robust model of outcomes in CAD and test the importance of heart rate.
Patients were enrolled in 45 countries in Africa, Asia, Australia,
Europe, the Middle East, and North, Central, and South America. These patients are being treated according to usual clinical practice at each participating institution, with no specific tests or therapies defined in the study protocol. Patients
eligible for enrollment were outpatients with stable CAD proven
by a history of at least one of the following: documented myocardial infarction (>3 months before enrollment); coronary
stenosis >50% on coronary angiography; chest pain with myocardial ischemia proven by stress electrocardiogram, stress
echocardiography, or myocardial imaging; and history of CABG
or PCI (performed >3 months before enrollment).
Patients hospitalized for cardiovascular disease within the previous 3 months (including for revascularization), patients for
whom revascularization was planned, and patients with con-
ditions expected to hamper participation in the 5-year followup (eg, limited cooperation or legal capacity, serious noncardiovascular disease, conditions limiting life expectancy, or severe cardiovascular disease [advanced heart failure, severe
valve disease, history of valve repair/replacement, etc]) were
excluded from the study.
In order to enroll a population of stable CAD outpatients that
mimicked the epidemiological patterns of each country, recruitment was based on a predefined selection of physician
specialties (cardiologists, internists, and primary care physicians) and aimed for consecutive enrollment of eligible patients. Physician selection was based on the best available
sources—either local or regional—of epidemiological and medical care data, including available market data and epidemiological surveys. A general target of 25 patients per million
inhabitants was used (range, 12.5-50) to ensure a balanced
representation of the participating countries. Each physician
recruited between 10 and 15 outpatients with stable CAD, as
defined by the inclusion criteria, over a brief period of time, in
order to avoid selection bias. Information collected at baseline
included: demographics, medical history, risk factors and lifestyle, results of physical examination, heart rate (determined
by both pulse palpation and the results of the most recent electrocardiogram performed within the previous 6 months), current
symptoms, laboratory values (eg, fasting blood glucose, hemoglobin A1c, cholesterol, triglycerides, serum creatinine, hemoglobin, if available), and current chronic medical treatments.
Data are collected centrally using an electronic, standardized,
international case report form (translated into local languages)
and sent electronically to the data management center, where
checks for completeness, internal consistency, and accuracy
are run. Data quality control is performed onsite in 5% of sites
chosen at random in each country with, at each site, monitoring of 100% of case report forms for source documentation and accuracy. All patients gave written informed consent
to participate, in accordance with national and local guidelines. The CLARIFY registry is registered in the ISRCTN registry of clinical trials with the number ISRCTN43070564. All
CLARIFY data are collected and analyzed at an independent
academic statistics center at the Robertson Centre for Biostatistics, University of Glasgow, UK. The baseline data and
1-year outcome data from CLARIFY were presented at the
2011 and 2012 European Society of Cardiology (ESC) congresses, respectively.30,31 I
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6. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update
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8. Gillum RF, Makuc DM, Feldman JJ. Pulse rate, coronary heart disease, and death:
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9. Fox K, Borer JS, Camm AJ, et al; Heart Rate Working Group. Resting heart rate
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10. Diaz A, Bourassa MG, Guertin MC, et al. Long-term prognostic value of resting
heart rate in patients with suspected or proven coronary artery disease. Eur
Heart J. 2005;26:967-974.
11. Copie X, Hnatkova K, Staunton A, Fei L, Camm AJ, Malik M. Predictive power
of increased heart rate versus depressed left ventricular ejection fraction and
heart rate variability for risk stratification after myocardial infarction. Results of a
two-year follow-up study. J Am Coll Cardiol. 1996;27:270-276.
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heart failure (SHIFT): the association between heart rate and outcomes in a
randomised placebo-controlled trial. Lancet. 2010;376:886-894.
14. Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo controlled study. Lancet. 2010;
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15. Daly CA, Clemens F, Sendon JL, et al. Inadequate control of heart rate in patients with stable angina: results from the European Heart Survey. Postgrad
Med J. 2010;86:212-217.
16. Elder DHJ, Pauriah M, Lang CC, et al. Is there a Failure to Optimize theRapy
in anGina pEcToris (FORGET) study. QJM. 2010;103:305-310.
17. Seabra Gomes R. Caracterização de uma população de doentes coronários
estáveis em ambulatório e importância da frequência cardíaca: Registo PULSAR Rev Port Cardiol. 2010;29:483-508.
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22. Vitale C, Spoletini I, Volterrani M, Iellamo F, Fini M; CARDIf-3 investigators.
Pattern of use of beta-blockers in older patients with stable coronary artery disease. an observational, cross-sectional, multicentre survey. Drugs Aging. 2011;
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23. Lorgis L, Zeller M, Jourdain P, et al. Heart rate distribution and predictors of increased heart rate among French hypertensive patients with stable coronary
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24. Anselmino M, Ohrvik J, Ryden L. Resting heart rate in patients with stable coronary artery disease and diabetes: a report from the Euro Heart Survey on diabetes and the heart. Eur Heart J. 2010 31:3040-3045.
25. Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms
of acute coronary syndrome: estimating the risk of 6-month postdischarge death
in an international registry. JAMA. 2004;291:2727-2733.
26. Boersma E, Pieper KS, Steyerberg EW, et al. Predictors of outcome in patients
with acute coronary syndromes without persistent ST segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators.
Circulation. 2000;101:2557-2567.
27. Bangalore S, Messerli FH, Tamis-Holland J, et al; CRUSADE investigators. The
association of admission heart rate and in-hospital cardiovascular events in patients with non-ST-segment elevation acute coronary syndromes: results from
135 164 patients in the CRUSADE quality improvement initiative. Eur Heart J.
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28. Antoni ML, Boden H, Delgado V, et al. Relationship between discharge heart
rate and mortality in patients after acute myocardial infarction treated with primary PCI. Eur Heart J. 2012:33:96-102.
29. Steg PG. Heart rate management in coronary artery disease: the CLARIFY registry. Eur Heart J. 2009;11(suppl D):D13-D18.
30. Steg PG, Ferrari R, Ford I, et al; CLARIFY Investigators. Heart rate and use of
beta-blockers in stable outpatients with coronary artery disease. PLoS One.
2012;7(5):e36284.
31. Steg PG, Greenlaw N, Tardif JC, et al; CLARIFY Registry Investigators. Women
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Aug 26. Epub ahead of print. doi:10.1093/eurheartj/ehs289.
Keywords: clinical outcome; coronary artery disease; heart failure; heart rate; mortality; registry
LA
FRÉQUENCE CARDIAQUE DANS LES REGISTRES
:
UNE CHANCE À SAISIR ENCORE NÉGLIGÉE
Les registres sont la clé de la compréhension des caractéristiques, de la prise en charge et de l’évolution des patients
coronariens. Ceci en particulier étant donné que la validité externe de l’information recueillie lors des études cliniques
randomisées est souvent limitée par les critères rigoureux de sélection des participants. La fréquence cardiaque de
repos apparaît comme un déterminant pronostique clé de l’évolution, en particulier de la mortalité cardiovasculaire
chez les patients aux formes stables et instables de maladie coronaire et d’insuffisance cardiaque. Cependant, bien
que la fréquence cardiaque soit le paramètre physiologique le plus couramment mesuré, il n’existe que très peu d’information sur la fréquence cardiaque véritable des patients coronariens et son lien avec l’utilisation des médicaments
abaissant la fréquence cardiaque (en particulier les 웁-bloquants) et l’évolution ultérieure. Ces dernières années, de
nombreux registres émanant de différents pays d’Europe et d’ailleurs ont recueilli des informations sur les caractéristiques des patients coronariens. Bien que la majorité des patients reçoivent des 웁-bloquants, ces registres ont enregistré une fréquence cardiaque de repos très souvent supérieure à 70 bpm. De plus, ces registres ont montré qu’une
fréquence cardiaque de repos élevée est associée à une prévalence plus importante des symptômes angoreux et à
une mortalité cardiovasculaire accrue. Cependant, chez les patients ayant un syndrome coronaire aigu, des fréquences
cardiaques très basses sont elles aussi associées à une augmentation de la mortalité, ce qui suggère que la relation
entre la fréquence cardiaque et la survie au cours de la maladie coronaire pourrait suivre une courbe en « J ». Le grand
registre international CLARIFY (prospeCtive observational LongitudinAl RegIstry oF patients with stable coronary
arterY disease), avec un effectif de plus de 33 000 patients dans le monde entier, va fournir des informations solides
sur les relations entre la fréquence cardiaque de repos et les symptômes angoreux, l’utilisation des médicaments
abaissant la fréquence cardiaque (en particulier les 웁-bloquants), et le plus important, l’évolution clinique à 5 ans.
459
U P DAT E
‘‘
Heart rate is one of the major
determinants of myocardial oxygen consumption and myocardial
blood flow… and heart rate reduction is an established and important therapeutic strategy in the prevention of ischemia. A strong association between elevated heart
rate and increased risk of total and
cardiovascular mortality has been
shown in the general population,
as well as in patients with hypertension, diabetes, and coronary
artery disease.”
Heart rate reduction
and coronary flow reserve:
mechanisms and treatment
b y P. E . Va rd a s , G re e c e
H
Panos E. VARDAS, MD, PhD
Hellenic Cardiovascular
Research Society
Chalandri, GREECE
eart rate is a major determinant of myocardial oxygen consumption
and therefore myocardial blood flow and coronary flow reserve. Consequently, heart rate reduction is an established important therapeutic strategy in the prevention of ischemia. Ivabradine reduces heart rate by
inhibition of the If -channels in the sinus node. Treatment with ivabradine not
only reduces resting myocardial blood flow, but also significantly improves
hyperemic coronary flow and coronary flow reserve in patients with stable
coronary artery disease. These effects remain even after heart rate correction,
indicating improved microvascular function. Although the pathophysiological
explanation of our findings remains to be elucidated, if the effect of ivabradine
on microvascular function is confirmed in similar studies then we have an additional therapeutic approach for patients with coronary artery disease, targeting microvascular function.
Coronary blood flow control
he heart, like all other organs, cannot function without blood flowing through
its vessels. Coronary vessels carrying 5% to 10% of the cardiac output run
over the surface of the heart, giving rise to branches which penetrate the
heart muscle and which in turn branch into smaller vessels (microcirculation) that
supply the heart’s capillary network (vessels only 5 µm in diameter) with blood.
T
Prof Panos E. Vardas, Department
of Cardiology, Heraklion University
Hospital, PO Box 1352 Stavrakia,
GR-711 10 Heraklion (Crete), Greece
460
This coronary blood flow is regulated by the heart, changing according to the heart’s
metabolic needs, and maintained near the minimum level required for the supply
of oxygen. Under normal conditions, the heart extracts roughly 70% of all the oxygen from the blood. Increases in myocardial oxygen consumption which occur during exercise must be accommodated by an increase in coronary blood flow through
changes in microvascular resistance.1 The microcirculation (vessels <200 µm in diameter) consists of a channel of passive networks, but it is also an active site for blood
flow control through a number of metabolic, myogenic, and other mechanisms. Capillary hydrostatic pressure is held constant within the myocardium at approximately
30 mm Hg, made possible by the strong and immediate myogenic response (autoregulation) of arteriolar smooth muscle.
At rest (baseline), the ability to regulate blood flow is high, since 60% of total myocardial vascular resistance is offered by arterioles.2,3 However, when hyperemia is induced, smooth muscle vasodilatation results in dilatation of the arterioles and venules
Heart rate reduction and coronary flow reserve: mechanisms and treatment – Vardas
U P DAT E
with no change in the capillaries. Total myocardial vascular resistance decreases and capillary resistance now accounts for
75% of the total myocardial vascular resistance. Thus, capillaries offer the most resistance to coronary blood flow during
hyperemia and provide a ceiling to hyperemic blood flow.2,3
It is clear that under normal circumstances, coronary blood
flow is much lower than maximum, which allows the coronary
control vessels to be able to adapt the flow to an increased
level of metabolism. The extent to which coronary blood flow
can increase above control is generally referred to as coronary
flow reserve (CFR).
Physiological and pathophysiological disturbances
of coronary blood flow
Coronary blood flow is subject to physiological disturbances
created by the contraction of the heart. When pressure is generated in the left ventricle, the vessels in the heart muscle are
compressed as well, impeding coronary blood flow (often referred to as extravascular resistance). Consequently, coronary
blood flow occurs predominantly during diastole, paralleling
the large changes in input impedance caused by ventricular
contraction and relaxation of intramyocardial vessels.
Heart rate is one of the major determinants of myocardial oxygen consumption and myocardial blood flow. An increase in
heart rate does more than increase metabolic demand for
blood flow, it also increases extravascular resistance by decreasing myocardial perfusion time. Thus, by increasing heart
rate, arteriolar dilatation must compensate for both increase in
demand and increase in extravascular resistance. Balance between demand and supply may also be disturbed by (patho)physiological factors such as perfusion pressure (defined as
the difference between central aortic pressure and left ventricular pressure).1
Atherosclerosis is a well-recognized pathophysiological mechanism negatively affecting the supply of blood. This disease
process can lead to local or more diffuse narrowing of the larger coronary arteries, adding to the resistance of the coronary
SELECTED
APV
time-averaged peak coronary flow velocity
CAD
CFR
coronary flow reserve
h-APV
hyperemia-APV
HCN
hyperpolarization-activated, cyclic nucleotidegating channel protein
MPV
maximum diastolic peak coronary flow velocity
r-APV
resting-APV
system. Such obstruction, interpreted by local flow control
processes as a reduction in pressure, would lead to a vasodilatory response. The added resistance to flow reduces the
range of oxygen demand that the coronary circulation is able
to accommodate, thus the need to compensate for the arterial narrowing would overwhelm the vasodilatory capability of
the coronary resistance vessels and bring the control system
to the limit of its working range.1
Heart rate reduction as an important therapeutic
strategy
Heart rate, as previously mentioned, is a main determinant of
myocardial oxygen consumption and heart rate reduction is
an established and important therapeutic strategy in the prevention of ischemia. A strong association between elevated
heart rate and increased risk of total and cardiovascular mortality has been shown in the general population, as well as in
patients with hypertension, diabetes, and coronary artery disease (CAD).4
BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor
ivabradine in patients with coronary disease and left ventricULar dysfunction) has provided significant data relating to the
prognostic importance of heart rate,5 and to the importance
of heart rate reduction with ivabradine6 for reduction of coronary events in CAD patients with left ventricular dysfunction.
The results showed that elevated resting heart rate (>70 bpm)
is a strong predictor of outcome in patients with stable CAD
and left ventricular dysfunction. Patients in the subgroup with
resting heart rate >70 bpm were 34% more likely to die from
cardiovascular causes and 53% more likely to be hospitalized
for new or worsening heart failure. Similarly, elevated heart rate
was associated with a 46% increased risk of fatal and nonfatal myocardial infarction and a 38% increase in the need for
coronary revascularization. Also, BEAUTIFUL investigated the
effect of ivabradine on outcomes in stable CAD patients.6 Although ivabradine did not affect the primary composite end
point, in patients with a heart rate of 70 bpm or greater, ivabradine had a significant impact on all end points linked to coronary events. There was a 36% reduction in the relative risk of
hospitalization for fatal and nonfatal myocardial infarction in
the patients treated with ivabradine and a 30% relative risk
reduction for coronary revascularization. Nevertheless, the underlying mechanism remains unknown.
Effects of ivabradine on coronary blood flow
and coronary flow reserve
Although CFR predicts long-term adverse cardiovascular outcome7,8 and decisions for coronary revascularization are based
on a physiological assessment of coronary artery lesions,9,10
there were previously no data in humans concerning the effect of ivabradine on coronary hemodynamics. In a recently
published study from my department,11 we examined the effects of ivabradine on coronary blood flow and flow reserve in
patients with stable CAD. In this study, we assessed 21 pa-
461
U P DAT E
r-APV: 49 cm/sec CFR=2.3
r-APV: 18 cm/sec
Baseline
r-APV: 21 cm/sec
Ivabradine-pace
Ivabradine
Figure 1. Resting (r)
and maximal hyperemia (h) time-averaged peak coronary
flow velocity (APV)
recordings at baseline
(Baseline) and after
one week’s ivabradine
treatment, both at the
intrinsic heart rate
(Ivabradine) and at a
paced rate similar to
that of baseline (Ivabradine-pace).
r-APV: 21 cm/sec
Abbreviation: CFR, coronary flow reserve.
From reference 11 supplementary data: Skalidis
et al. Atherosclerosis. 2011;
215(1):160-165. © 2010
Elsevier Ireland Ltd.
4
Abbreviation: CFR, coronary flow reserve.
After reference 11: Skalidis et al. Atherosclerosis. 2011;215(1):160-165.
© 2010 Elsevier Ireland Ltd.
3
tients with stable CAD of one or two vessels, amenable for
percutaneous coronary intervention. Immediately following
coronary angiography, the culprit vessel/s for coronary intervention were defined according to guidelines and a nonculprit vessel was selected for coronary flow measurements.
The nonculprit vessel was selectively engaged with a guide
catheter. Intracoronary nitroglycerin (200 µg) was given every
15 minutes of the procedure to prevent catheter-induced coronary artery spasm and to avoid changes in coronary artery
diameter. A 0.014-in, 15-MHz Doppler guide wire (FloWire, Volcano Therapeutics Inc) was advanced through the catheter
to the nonculprit vessel.
Once resting flow-velocity data had been collected, a 30-µg
bolus injection of intracoronary adenosine was given to obtain
data during hyperemia. To confirm that maximal hyperemia
had been achieved, doses increasing in 30-µg increments
were infused until a plateau in flow velocity was reached.
462
CFR
Figure 2. Mean values with 95% confidence intervals of coronary
flow reserve at baseline (Baseline) and after one week’s ivabradine
treatment, both at the intrinsic heart rate (Ivabradine) and at a
paced rate similar to that of baseline (Ivabradine-pace).
2
1
Baseline
Ivabradine
Ivabradine-pace
All measurements were made in the nonculprit vessel: i) during diagnostic coronary angiography (baseline); ii) during programmed coronary intervention in the culprit vessel/s (before the procedure), 1 week after treatment with ivabradine
(5 mg twice daily) at the same location at the intrinsic heart
rate (ivabradine); and iii) at a pacing heart rate similar to baseline (ivabradine-pace), accomplished by pacing the right atrial
appendage via a temporary pacing lead. Time-averaged peak
coronary flow velocity (APV cm/s) was measured and CFR was
determined as the ratio of APV at maximal hyperemia (h-APV)
to APV at rest (r-APV).
U P DAT E
Since at the beginning of the diastolic period extravascular
compressive forces are minimized and coronary perfusion
pressure is highest, maximum coronary blood flow occurs in
the early diastolic period.12 Consequently, changes in maximum diastolic peak coronary flow velocity (MPV cm/s) at maximal hyperemia were used as an index of early diastolic blood
flow alterations. As expected, heart rate was significantly lower after treatment with ivabradine (78±14 bpm vs 65±9 bpm,
P<0.001).
There was a significant effect of ivabradine treatment on both
r-APV and h-APV hyperemia APV. With ivabradine treatment
(nonpaced heart rate), r-APV was significantly lower than at
baseline. However, there was no significant difference in r-APV
with ivabradine treatment + pacing and baseline. In contrast,
h-APV with ivabradine treatment (nonpaced heart rate) was
significantly higher than at baseline. Similarly, h-APV with ivabradine + pacing was significantly higher than at baseline. Ivabradine treatment also had a significant effect on CFR. CFR after
ivabradine was significantly higher than at baseline. Similarly,
CFR with ivabradine + pacing was significantly higher than at
baseline (Figures 1 and 2).11
In summary, we found that ivabradine treatment significantly
reduces resting coronary blood flow and increases hyperemic
coronary flow, leading to CFR improvement in patients with
stable CAD. Also, although resting coronary blood flow returns
to the pretreatment values after heart rate correction, the enhancement of hyperemic coronary blood flow remains. Therefore, even after heart rate correction, CFR remains significantly
higher than the pretreatment values,
indicating improved microvascular
function with ivabradine treatment.
As heart rate is a major determinant
A
of myocardial oxygen consumption,
it thus influences myocardial blood
flow and CFR. However, hyperemic
coronary blood flow in the absence of
hemodynamically significant epicardial coronary artery stenosis is not
heart rate dependent and is associated with the integrity (either functional
or structural) of the microcirculation.13
However, changes in h-APV are more complicated. Hyperemic coronary blood flow increases after ivabradine treatment
because the diastolic period is prolonged (per cardiac beat
and per minute) as expected. The most possible explanation
behind h-APV enhancement after heart rate correction may be
the improvement of ventricular relaxation caused by ivabradine treatment which in turn enhances coronary blood flow
during hyperemia. As mentioned earlier, Ivabradine is an Ifchannel inhibitor. The gene for the If-channel was first discovered in the mouse brain, and four isoforms of this hyperpolarization-activated, cyclic nucleotide-gating channel protein
(HCN 1, 2, 3, and 4) have been identified in animal hearts.14,15
In the animal heart, HCN4 levels are higher than HCN1 in the
sinus node, while HCN2 levels are lower in ventricular myocardium. Despite that, HCN2 is considered to be the dominant
isoform because of the larger mass of ventricular myocytes
compared with sinus tissue.16 Nevertheless, HCN channels
expressed in other cardiac tissues seem to be nonfunctional
at these locations under normal conditions. The most positive activation is in the sinoatrial node and is associated with
the highest pacing rate, whereas the most negative activation (ventricular myocytes) normally exhibits no diastolic depolarization at all.16 Ivabradine, by blocking If-channels reduces
entry of Na+ into the myocytes, leading to reduced cytosolic
calcium. Moreover, ivabradine improves reuptake of calcium
by the sarcoplasmic reticulum. The cumulative effect of those
ivabradine actions is improvement of ventricular relaxation.17,18
Furthermore, Heusch et al19 and Fox et al20 have previously
reported a beneficial effect of ivabradine that was at least
B
C
How does ivabradine affect
r-APV and h-APV?
Ivabradine is a selective inhibitor of the
If-channel and reduces heart rate by
inhibiting these channels in the sinus
node. Consequently, changes in r-APV
are easily explained by corresponding
alterations in heart rate during ivabradine treatment both at the intrinsic
heart rate and at the pacing rate similar to that before treatment.
Figure 3. Comparison of maximal hyperemia time-averaged peak coronary flow velocity
recordings.
A) After one week’s ivabradine treatment at the intrinsic heart rate; B) The missing diastolic flow after heart rate
correction; C) At a paced rate similar to that of baseline.
After reference 11: Skalidis et al. Atherosclerosis. 2011; 215(1):160-165. © 2010 Elsevier Ireland Ltd.
463
U P DAT E
in part heart rate independent and supports the pleiotropic
actions of ivabradine.21,22 In addition, it is possible that enhanced diastolic relaxation may increase early diastolic coronary blood flow by a “suction effect.”23 In fact, the increase in
h-APV after ivabradine treatment is related not only to the increase in the diastolic period, but also to the overall improvement of flow, since h-MPV—which represents early diastolic
flow—is higher. Therefore, as can be seen in Figure 3 (page
463),11 despite the shortening of the diastolic period after
heart rate correction by pacing, the improvement of flow remains because the average flow (C) which will replace the
missing period per minute is not less than the average flow
during the missing period (B).
changes in rate pressure were detected after treatment, since
heart rate was not stable, and vasodilating actions were allowed because intracoronary nitroglycerin was not used—
at least in the second study. Consequently, the observed increase in CFR could be explained by differences in heart rate,
endothelial function, and/or coronary artery diameter, and not
as a result of an improvement in microvascular function. In
support of this is the control group of the latter study, but also
the control group from a study recently published from our
department.26 In both of these, no changes in hyperemic coronary flow were observed with β-blocker treatment.
Conclusion
Other studies showing improvement of coronary
flow reserve with pharmacological intervention
in stable CAD patients
Ivabradine treatment significantly improves hyperemic coronary flow and CFR in patients with stable CAD. These effects
remain even after heart rate correction, indicating improved
microvascular function.
To the best of our knowledge, there are only two invasive studies showing improvement of CFR with pharmacological intervention in patients with stable CAD. One involved metoprolol24 and the other nebivolol.25 These studies (from the same
research group) used different methodologies. Both were carried out in the stented artery of patients with CAD; significant
Although the pathophysiological explanation remains to be elucidated, if the effect of ivabradine on microvascular function is
confirmed in similar studies, then we have an additional therapeutic approach for patients with CAD, targeting the microvascular function, with profound clinical implications.7,8 I
References
1. Spaan JA. Coronary Blood Flow: Mechanics, Distribution, and Control. Dordrecht, The Netherlands: Kluwer Academic Publishers; 1991.
2. Jayaweera AR, Wei K, Coggins M, et al. Role of capillaries in determining coronary blood flow reserve: new insights using myocardial contrast echocardiography. Am J Physiol. 1999;277:H2363-H2372.
3. Kaul S, Ito H. Microvasculature in acute myocardial ischemia. Part I: Evolving
concepts in pathophysiology, diagnosis, and treatment. Circulation. 2004;109
(2):146-149.
4. Graham I, Atar D, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Fourth Joint Task
Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of
nine societies and by invited experts). Eur J Cardiovasc Prev Rehabil. 2007;14
(suppl 2):E1-E40.
5. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R. Heart rate as a
prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomized controlled trial. Lancet. 2008;372:817-821.
6. Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coronary artery
disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised,
double-blind, placebo-controlled trial. Lancet. 2008;372:807-816.
7. Britten MB, Zeiher AM, Schächinger V. Microvascular dysfunction in angiographically normal or mildly diseased coronary arteries predicts adverse cardiovascular long-term outcome. Coron Artery Dis. 2004;15:259-264.
8. Herzog BA, Husmann L, Valenta I, et al. Long-term prognostic value of 13Nammonia myocardial perfusion positron emission tomography added value of
coronary flow reserve. J Am Coll Cardiol. 2009;54:150-156.
9. Pijls NH, van Schaardenburgh P, Manoharan G, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER
Study. J Am Coll Cardiol. 2007;49:2105-2111.
10. Tonino PA, De Bruyne B, Pijls NH, et al; FAME Study Investigators. Fractional
flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360:213-224.
11. Skalidis EI, Hamilos MI, Chlouverakis G, Zacharis EA, Vardas PE. Ivabradine improves coronary flow reserve in patients with stable coronary artery disease.
Atherosclerosis. 2011;215(1):160-165.
12. Gould KL. Pressure-flow characteristics of coronary stenoses in unsedated
dogs at rest and during coronary vasodilation. Circ Res. 1978;43:242-253.
464
13. Rossen JD, Winniford MD. Effect of increases in heart rate and arterial pressure on coronary flow reserve in humans. J Am Coll Cardiol. 1993;21:343-348.
14. Accili EA, Proenza C, Baruscotti M, et al. From funny current to HCN channels:
20 years of excitation. News Physiol Sci. 2002;17:32-37.
15. Ludwig A, Zong X, Jeglitsch M, et al. A family of hyperpolarization-activated
mammalian cation channels. Nature. 1998;393:587-591.
16. Shi W, Wymore R, Yu H, et al. Distribution and prevalence of hyperpolarizationactivated cation channel (HCN) mRNA expression in cardiac tissues. Circ Res.
1999;85:e1-e6.
17. Ceconi C, Cargnoni A, Francolini G, et al. Heart rate reduction with ivabradine
improves energy metabolism and mechanical function of isolated ischaemic
rabbit heart. Cardiovasc Res. 2009;84:72-82.
18. Gewirtz H. ‘Funny’ current: if heart rate slowing is not the best answer, what
might be? Cardiovasc Res. 2009;84:9-10.
19. Heusch G, Skyschally A, Gres P, et al. Improvement of regional myocardial blood
flow and function and reduction of infarct size with ivabradine: protection beyond heart rate reduction. Eur Heart J. 2008;29:2265-2275.
20. Fox K, Ford I, Steg PG, et al; BEAUTIFUL Investigators. Relationship between
ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina:
a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur Heart J.
2009;30:2337-2345.
21. Heusch G. A BEAUTIFUL lesson—ivabradine protects from ischaemia, but not
from heart failure: through heart rate reduction or more? Eur Heart J. 2009;30:
2300-2301.
22. Heusch G. Pleiotropic action(s) of the bradycardic agent ivabradine: cardiovascular protection beyond heart rate reduction. Br J Pharmacol. 2008;155:
970-971.
23. Davies JE, Whinnett ZI, Francis DP, et al. Evidence of a dominant backwardpropagating “suction” wave responsible for diastolic coronary filling in humans,
attenuated in left ventricular hypertrophy. Circulation. 2006;113:1768-1778.
24. Billinger M, Seiler C, Fleisch M, et al. Do beta-adrenergic blocking agents increase coronary flow reserve? J Am Coll Cardiol. 2001;38:1866-1871.
25. Togni M, Vigorito F, Windecker S, et al. Does the β-blocker nebivolol increase
coronary flow reserve? Cardiovasc Drugs Ther. 2007;21:99-108.
26. Skalidis EI, Hamilos MI, Chlouverakis G, et al. Acute effect of esmolol intravenously on coronary microcirculation in patients with idiopathic dilated cardiomyopathy. Am J Cardiol. 2007;100:1299-1302.
U P DAT E
Keywords: coronary artery disease; coronary blood flow; coronary flow reserve; heart rate; ivabradine
RÉDUCTION
DE LA FRÉQUENCE CARDIAQUE ET RÉSERVE CORONAIRE
MÉCANISMES ET TRAITEMENT
:
La fréquence cardiaque est un facteur déterminant majeur de la consommation d’oxygène myocardique et donc du
débit sanguin myocardique et de la réserve coronaire. La réduction de la fréquence cardiaque est par conséquent
une stratégie thérapeutique importante, éprouvée dans la prévention de l’ischémie. L’ivabradine diminue la fréquence
cardiaque en inhibant les canaux If dans le nœud sinusal. Le traitement par ivabradine non seulement réduit le débit sanguin myocardique de repos mais aussi améliore significativement le débit coronaire hyperémique et la réserve
coronaire chez les patients coronariens stables. Ces effets persistent même après correction de la fréquence cardiaque, ce qui témoigne d’une fonction microvasculaire améliorée. Nos résultats ne sont pas clairs sur le plan physiopathologique mais si l’effet de l’ivabradine sur la fonction microvasculaire est confirmé dans des études équivalentes, cela signifiera alors que nous disposons d’un traitement supplémentaire pour les patients coronariens, ciblant
la fonction microvasculaire.
465
A TOUCH
OF FRANCE
ochefort, on the French Atlantic coast, is steeped in
history, boasting a Royal
dockyard, Royal Rope Factory
(once the longest building in Europe), the world’s first School of
Naval Medicine, and the extravagant “multicultural” house of novelist and navy officer Pierre Loti.
Today, history is relived as a replica
of La Fayette’s ship, the Hermione,
is being rebuilt in the same dockyard it originally came from, and
will soon be setting sail for Boston,
in America.
R
“Call back yesterday, bid time return”
Rochefort, the town
where the past comes alive
I . S p a a k , Fra n c e
The 374-meter long
Royal Rope Factory
(Corderie Royale)
in Rochefort, completed
in 1669. © Bruno Barbier/
Photononstop.
Sickness and health on the
high seas in the 18th century
The Former Rochefort School of Naval
Medicine and the birth of the French
C . R é g n i e r, Fra n c e
Navy Health Service
The School of Naval
Medicine occupied
the left wing of the
Maritime Hospital in
Rochefort. Detail of a
lithograph by Charles
Mercereau, 19th century. Private Collection.
© Archives Charmet/
Bridgeman Art Library.
467
A TOUCH
‘‘
In 1997 a group of enthusiasts
formed a nonprofit organization
(Hermione–La Fayette) dedicated
to reconstructing the dockyards of
yore and building a replica of the
Hermione, the legendary frigate
aboard which the 23-year-old Marquis de La Fayette set sail in 1780
to join forces with George Washington in fighting the English crown
and winning independence for
America. This, and much more in
Rochefort, the French sea port
built by the Sun King Louis XIV…”
OF
FRANCE
“Call back yesterday,
bid time return”
Rochefort, the town
where the past comes alive
b y I . S p a a k , Fra n c e
R
Isabelle SPAAK
Journalist
37 rue des Plantes
75014 Paris, France
(e-mail:
[email protected])
ochefort, built on a bend of the river Charente close to its estuary, owes
its fame to Louis XIV who in 1666 made it into France’s greatest and
largest military and maritime arsenal. The sea port of Rochefort has the
richest heritage of naval architecture in France, epitomized by an extraordinary limestone rope factory almost 400 meters long. It was also the site of the
prestigious Rochefort School of Surgery founded in 1722 (see companion article by Dr Christian Régnier). One of Rochefort’s most famous scions was undoubtedly Julien Viaud, (1850-1923), who enjoyed a long and distinguished
career as an officer in the French navy. Better known by his pen name Pierre
Loti, his literary career was crowned in 1891 by his election at the Académie
Française. Most intriguing was Loti’s abiding passion for the house in which
he was born and which bore the impress of his wanderings over the years,
like shifting scenery on a theater stage. Loti refurbished his home as the muse
took him, in harmony with his peregrinations around the globe, while leaving no
outward sign of the transformations taking place within. Now a museum, the
house tells the tale of his voyages, of his nostalgia, his wont to hark back to
times long past. Loti was a likeness of his birthplace, the town of Rochefort:
quiet, low-key, yet possessed of a steely determination, an eagerness to rise
to a challenge. In recent times, following the abandonment of the dockyard in
the early 20th century, of the Naval School of Medicine in 1964, and the closure of the hospital attached to it in 1983, Rochefort has resembled a sleeping
beauty. Yet something is stirring. Craftsmen and journeymen are working on
a technical and historical challenge—the recreation of an 18th-century shipyard and the building of a replica of the Hermione, the sixty-five-meter frigate
aboard which the Marquis de La Fayette crossed the Atlantic to join George
Washington in the American Revolutionary War.
ith a stroke of his pen in 1665, King Louis XIV changed forever the destiny of a sleepy little town on the right bank of the Charente River, a few
kilometers from the Atlantic Ocean. On the advice of his chief naval administrator Colbert du Terron, the king chose Rochefort in southwestern France
as the site for a new shipyard able to vie with the ports of Holland and England.
W
468
Each newcomer was allotted 200 m2 of land on which to build his house, and by
the end of the 17th century the first wooden huts for the dockyard workers had
been replaced by stone residential quarters for naval officers, and by military build-
Rochefort, the town where the past comes alive – Spaak
A TOUCH
OF
FRANCE
View of the Sea Port of Rochefort, by Joseph Vernet. 1762, oil on canvas. Paris, Musée de la Marine.
© RMN-Grand Palais/All rights reserved.
ings. A vast rope factory was erected, the longest building in
Europe at the time, and naval construction proceeded apace,
with 49 ships built between 1688 and 1692, and about 350
by 1710.
A shipyard rises from the wetlands
When the Sun King, Louis XIV, took possession of Rochefort
in 1666, it was a rural parish of some four hundred communicants. In his recommendation to the king, Colbert du Terron
called attention to the safety of the harbor protected by the
natural barrier that is the Ile d’Oléron, the ease with which the
site could be defended, the depth of the Charente, the natural barrier to a land-based attack offered by surrounding marshland, and the richness of the hinterland and its forest, which
would be a ready source of timber for shipbuilding.
As a bulwark of sorts against the Protestant town of La Rochelle a mere thirty kilometers away, the king seized the opportunity to impose a Catholic stronghold, and to build the
naval dockyard that France so sorely lacked.
By the time Louis XIV died in 1715, the dockyard had built,
armed, and repaired dozens of ships, the town had 12 to
15 000 inhabitants, and the countryside had been transformed.
These profound changes were not achieved effortlessly. The
naval dockyard arose at great cost from wetlands liable to
flooding and better suited to grazing livestock, the town constantly suffered from a lack of drinking water and from the disease-breeding unwholesomeness and “bad air” of the neighboring swamplands. No one built a decent parish church, the
countryside was stripped of its forest and blighted by the construction of a suburb, and the locals swapped tilling for work
at the naval shipyard.
Sixty thousand ropes a month
The dockyard’s production was exceptional, thanks to refits
in stone-lined dry docks on the banks of the Charente and
Rochefort’s main monument, its remarkable 374-meter-long
Royal Rope Factory (Corderie Royale), which produced cable lengths of two hundred meters. Begun in 1666 and completed in 1699, the rope factory is in itself a page of history.
469
A TOUCH
OF
FRANCE
The 374meter long
Royal Rope
Factory
(Corderie
Royale) in
Rochefort,
completed
in 1669.
© Bruno
Barbier/Photononstop.
How was such a structure raised on the vast meadowland
prone to flooding alongside the river? The soil was too loose
for the traditional building techniques of the area, in which foundations were not dug but placed directly on the grassland.
The architect François Blondel (1618-1686) raised the edifice
slightly on a sort of raft, a gigantic supporting grid fashioned
from oak beams. Some lying flat, others vertical under the main
walls, these wooden piles support the whole length of the
two magnificent galleries built one
above the other, the lower for
producing strands of fibers and
the upper for spinning. Resplendent before a huge lawn, the
palace-like frontage is reminiscent of Versailles, with its finelyworked limestone from the quarries at Crazannes, its whiteness
set against the orange tiles and
gray slates of the two-tiered roof.
The walls are pierced on the first
floor and on the second, with its
sloping roof and dormer windows
surmounted by semicircular pediments, to air the building and
thus better preserve the hemp
used in rope making. Its elegant architecture, like a “long hull
of beige stone” in the words of writer Erik Orsenna, has contributed to its fame. The rope factory also had four warehouses for the hemp used to make ropes, two others to keep the
ropes, two more for barrels of tar, and a last one for cutting,
along with a gigantic cast iron boiler. Considered the most efficient in the kingdom, the Rochefort rope factory produced
up to sixty thousand pieces of rope a month.
Rope-making cording machine
at the Royal Rope Factory in
Rochefort. © Walter Bibikow/JAI/Corbis.
470
A TOUCH
OF
FRANCE
Then came the 19th century with its larger vessels and steamships and steel cables signaling the decline of the shipyard
and its rope factory, which was closed in 1927 and set alight
by the Germans in 1944. A twenty-year hiatus followed before Admiral Maurice Dupont, Naval Commander at Rochefort,
undertook to restore the partially destroyed buildings. By 1988
the work was done, and the opening of a museum complex
of over 300 square meters devoted to the history of the naval
dockyard marked Rochefort’s first step in reclaiming its maritime past.
Curious fellow this naval officer, baptized Loti after the name
of a sweet-smelling red flower “at the age of twenty-two
years and eleven days,” by a Tahitian girl he fell for during a
stay in Polynesia. During and after a long and distinguished
career as an officer in the French navy, Loti wrote highly per-
Pierre Loti in his uniform of
the Académie Française.
The unrevealing façade of the House of Pierre Loti behind which
are “a mosaic of civilizations, dramatized decors, baroque fantasies.”
Collection Maison de Pierre Loti © Ville de Rochefort.
Photographie Maison de Pierre Loti © Ville de Rochefort.
Out- and homeward bound: pain and yearning
sonal books steeped in exoticism, accounts of his loves and
adventures at the four corners of the world, in a literary career crowned in 1891 by his election as one of the forty socalled “immortals,” or members of the Académie Française,
winning a head-to-head contest with Émile Zola (who in 19
attempts never achieved “immortality”).
Time: half an hour before the stroke of midnight on the 14th
of January 1850. Place: 141 rue Saint Pierre, Rochefort-surMer, on the Atlantic coast of France. Julien Viaud, now better
known by his pseudonym Pierre Loti, was born in a nondescript house with a freestone façade alongside others of similar ilk. Three windows on each floor, molded cornices under
the second and third floors, cream-colored wooden shutters.
Located behind the city walls, the house stands on one of
the main ruler-straight roads of the “new town” built in the
17th century in a checkerboard pattern. In exploring the town
with his father Théodore, the author of a two-volume history
of Rochefort, the young Julien Viaud heard tales of its past
and learned to observe his surroundings and to capture the
atmosphere of a place in the minutest detail. Skills he later
put to good use in his travel writings.
Frail and solitary, Loti was torn between his passion for foreign
lands and the comfort of the familiar, of childhood memories
of home life, of halcyon days. His was a lifelong struggle between the pain of leaving and the ardent desire to venture
forth. Imbued with exoticism, the writer−traveler drifted ever
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The Turkish room (above). The Renaissance room (below). House of Pierre Loti. Photographie Maison de Pierre Loti ©Ville de Rochefort.
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further afield, yet dreamed of but one thing: home, the haven
of the house where he was born in Rochefort. “A very modest provincial house where Huguenot austerity was felt,” a
peaceful atmosphere, a muffled interior, where there was “no
unruliness, we chatted, sowed, wrote, prayed. Free of distractions from the outside world, we were self-sufficient. Affection
was shared like bread…,” wrote Loti in 1890 in Le Roman d’un
Enfant, an autobiographical account of his childhood, which
greatly influenced Marcel Proust.
Bordering on fetishism, this passion for things past, for a sort
of stasis, paradoxically fueled his obsessive need to transform
his home. Returning from his travels, Loti converted his abode,
expanded in 1895 by the acquisition of the adjoining terrace
house, into a sort of museum of faraway places. It became a
mosaic of civilizations, dramatized decors, baroque fantasies,
a literary phenomenon. Between oriental bazaar and flights
of fancy, Loti transmogrified, converted, anchored his excesses, fixed his travels in amber. Memories of family and of departed loved ones—his grandmother
Berthe, his mother Nadine, his elder
brother Gustave (a naval surgeon who
died at age 29 off the coast of Ceylon, as Sri Lanka was then known)—
haunted his home, as it mutated into
settings of the Far East on the first
floor, orientalism on the second, eclectic historicism, while the house’s frontage remained untouched, such that
should his grandfather one day return to the land of the living he would
recognize his “ancient abode.”
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was a Chinese pagoda, little of which remains, described by
Loti’s private secretary as being of “unrivaled magnificence
with its yellow gold, red gold, bright or soft golden tints… a
dizzying array of colors flaming in air heavy with musk and
sandalwood.” Three altars, tiered seating, golden thrones
amidst a jumble of religious symbols presided over by “an
ancient god with six arms and five eyes, gesticulating, sniggering, ferocious.” The Empire chamber and its ceiling studded with stucco bees, his childhood bedroom transformed
into a peasant room with rustic fittings, a tomb-like chamber
of Egyptian mummies at the end of a dark corridor—women,
a child, cats, a small painted wood sarcophagus. And even a
mosque. Not forgetting the Renaissance room for which Loti
added a floor to the house, lending to the space the majesty
of a mansion, a precious tapestry from the Gobelins Manufactory, a monumental chimney, stained glass windows, armor,
and three stone lions atop columns. All of which contrasts
starkly with the abnegation and frugality of Loti’s monastic
bedchamber.
An anatomy of restlessness
Among the trunks and chests, the
closets filled with piously preserved
relics, quirkiness reigned in the image
of Loti: withdrawn, yet unbridled and
flaunty. In an everlasting fight against
Pierre Loti’s « monastic-like » bedroom. House of Pierre Loti.
the ravages of time, his obsession, Photographie Maison de Pierre Loti © Ville de Rochefort.
Loti used greasepaint, rouged his
cheeks and colored his lips, heightened his stature by a few Old Cathay comes to Rochefort
centimeters with a device inside his socks, dressed as a pasha, Fanfares of olifants and horns rang out. Disguised as Louis XI
a Chinese, a medieval lord, an acrobat, in unison with the meta- (1423-1483), his wife Blanche as the queen consort Charmorphoses of his house. “One must defend oneself against lotte of Savoy, My Lord Pierre Loti advanced, hooded falcon
old age,” he wrote to justify his primping, “one has no right to on his right fist, left hand in his lady’s. Behind the couple, a
retinue formed and proceeded to the Gothic dining room.
become an object of disgust.”
Dressed in duns and browns, “as befits people who have
Loti converted his grandmother’s former bedroom into a Turk- spent four hundred years in their clothes” advised the invitaish living room where Moorish influence dominated. Inspired tion written in old French, the guests crossed the Japanese
by the Alhambra in Granada, two columns support a poly- salon and ceremoniously took to the stairs.
lobed arch suggestive of the gallery of the Court of the Lions
as reinterpreted by Loti through his instructions to local plas- Despite appearances, this scene did not unfold “in the year
terers. The whole forms a skillful blend of predominantly blue of grace M*CCCC*L*XX under the reign of our good King
ceramics, with marbles, textiles, and hangings. Once there Louis the Eleventh,” as intimated by the invitation card, but
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Hermione and the Marquis
de la Fayette
On August 4th, 1808, Emperor Napoléon
came to Rochefort, on his return from a visit to Bayonne on the Atlantic coast, accompanied by Joséphine and his staff. Ships
of the line lay at anchor in the harbor of the
nearby Island of Aix. The Emperor’s second
and last visit, in July 1815, was a less joyful affair. Recently defeated at Waterloo,
Napoleon spent his last days on French soil
on the Island of Aix before his journey into
exile on Saint Helena.
Pierre Loti in Chinese costume. Private collection © Archives Charmet.
on the 12th of April 1888 at the unforgettable medieval banquet hosted by Loti in his home in Rochefort. Pitchers on the
tables, goblets, bowls, flaming torches, pageboys “who stood
waiting motionless”, and valets in livery to serve the interminable thirteen-course dinner. A succession of soups, sea
and freshwater fish, roast venison, squirrel, and hedgehog,
desserts, tarts, wines, barley beer, mead, candied fruits, spices,
and the showpiece, a roasted peacock, served in its feathers, borne on a golden platter by two equerries, accompanied
by torchbearers and bagpipers, and ceremoniously presented to each lady in turn before being given up to an equerry’s
carving knife. The whole meticulously staged by Loti with interludes between courses: jugglers, sorceresses, pilgrims returning from Jerusalem, yellow- and green-clad jesters leaping
through a trap door to dance a saraband, a chained Saracen
prisoner brought to the feet of the master of the house, a minstrel, table games, dice, chess, merrymaking till dawn when
“the cruel meanness of the 19th century returned to crush
the poetic and the beautiful, the noble 15th century roused
for one night from its eternal slumber.”
Rochefort experienced a joyful episode in
1966, when Jacques Demy fell in love with
the townscape and had it repainted—walls
white, shutters blue, pink, or yellow—as a
backdrop for his film Les Demoiselles de
Rochefort (The Young Girls of Rochefort),
which played to full houses around the world.
In 1997 a group of enthusiasts and French author and Academician Erik Orsenna, the founding president, formed a
nonprofit organization (Hermione–La Fayette) dedicated to reconstructing the dockyards of yore and building a replica of
As Loti wrote of the gargantuan feast of 1888 in his Journal
Intime: “I had an unadulterated vision of the Middle Ages at
two brief moments: on arrival, when I was the first to enter
the room bathed in red light from the torches held by longhaired valets, and again on the arrival of the peacock, preceded by bagpipes and the mounted servant.”
Other memorable events followed—a water sprite party and
a celebration of country life—until the last great staging in
1901, when Old Cathay came to Rochefort, and two hundred guests in Chinese garb and trappings strolled between
the port or railway station and the house, past the mild-mannered townsfolk of Rochefort gaping in awe.
474
The Marquis de La Fayette, by Louis-Léopold Boilly, 1788.
Oil on canvas 900×710 cm.
© RMN-Grand Palais (Château de Versailles)/Gérard Blot.
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Reconstruction of the frigate « Hermione » on which General La Fayette sailed to the United States during the American Revolutionary War. © Christophe Boisvieux/Corbis.
the Hermione, the legendary frigate aboard
which the 23-year-old Marquis de La Fayette
set sail in 1780 to join forces with George
Washington in fighting the English crown
and winning independence for America.
Launching ceremony of the replica of the Hermione, on July 6, 2012 in Rochefort.
Pulled by two tugboats, the hull of the frigate, with no mats, sails, or rigging, sailed
several hours on the Charente river before anchoring in front of the former Royal Rope
Factory where it will be completed in preparation of the transatlantic crossing scheduled in 2015. © Xavier Leoty/AFP.
Traditional methods are being used in a sort
of immense in situ laboratory, which has already attracted 3.4 million visitors. A few figures will suffice to illustrate the scope of this
project: a hundred or so people working onsite daily, 400 000 pieces of wood and metal, 2000 oaks selected from French forests,
1000 pulleys, 1 tonne of tow for caulking,
24 km of ropes, 2200 square meters of sail,
three masts, the tallest of which will rise 54
meters above the keel, 26 cannons for 12pound cannonballs on the gun deck, and
8 cannons on the forecastle—nonfunctional of course and lightened for safety reasons.
What would Pierre Loti have thought of today’s Hermione? Of this three-masted, 65meter, 1166-tonne frigate with a petrol blue
hull embellished with gold? Faithfully recon-
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structed step by step since July 4th, 1997 using the original
plans, the Hermione will in all regards be true to the original
when it takes to sea in 2015 to retrace La Fayette’s voyage
to Boston, with, it is true, some concessions to modernity in
the shape of a small motor system and a few computerized
navigational aids, manned by a crew of 80, compared with
the 316 seamen needed in the 18th century.
The Hermione at one end of the rope factory in one of the dry
docks on the banks of the Charente River, together with the
visitor center, attracts over 250 000 visitors a year, and guided visits fund a good part of the work, which visitors can
watch from a system of catwalks.
adapted to meet current seaworthiness regulations. From
engineering to carpentry, from the weaving of the linen sails
to the manufacture of the rigging, traditional know-how is
being used to recreate the vessel and its three decks, 2200
square meters of sail, oak hull 70 cm thick in parts (plating,
ribbing, lining), unimaginable today but vital for repelling 18thcentury cannonballs. La Fayette’s original Hermione was
built in less than a year, while today’s replica, it is true, only
emerged from its dry dock in the summer of 2012, some fifteen years after the first hammer blow was struck. The first
voyage—to the Island of Aix — is planned for 2013, and the
final touches will be made at sea in 2014 before the transatlantic crossing.
More than a reminder of the glorious maritime history of
France and of the bonds of friendship between France and
America in the early days of the War of Independence, the Hermione is above all the
fruit of an incredible technical challenge. Work on the vessel is overseen by the historical committee,
which ensures the authenticity of the building methods,
What would Loti have said? Remembering his staging of events
designed to create and sustain the illusion of time travel, to
suspend time, we can wager that he would
have been the first to rejoice in this epic return to the 18th century. To an age unhurried, to a past when the dance
to the music of time was more
sedate. In Rochefort as elsewhere. I
Fan with Polynesian scene painted by Pierre Loti
for Madame Alice Louis-Barthou, in 1910.
Private collection © Archives Charmet.
ROCHEFORT,
LA VILLE À REMONTER LE TEMPS
Rochefort, située dans un méandre de la Charente jouxtant son estuaire, doit son destin à Louis XIV qui y fit implanter, en 1666, le plus grand arsenal militaire et maritime de la France. Port maritime au patrimoine architectural
le plus riche de l’hexagone, avec son extraordinaire Corderie Royale en pierre calcaire longue de près de quatre
cent mètres, Rochefort fut également le site de la prestigieuse École de Médecine Navale fondée en 1722 (Cf. article suivant, par le Dr Christian Régnier). Un des fils les plus célèbres de Rochefort est incontestablement l’écrivain Pierre Loti (1850-1923), de son vrai nom Julien Viaud, qui poursuivit une brillante carrière d’officier de marine
dans la Royale, doublée d’une carrière d’écrivain couronnée par son élection à l’Académie Française en 1891. Ce
qui intrigua sans doute le plus dans le parcours hors normes de Loti fut la passion entretenue pour sa maison natale à Rochefort façonnée au gré de ses voyages comme un décor de théâtre. Son logis devenu musée est un résumé de ses équipées autour du globe et de son goût pour le passé. Loti est à l’image de sa ville d’origine : ville
d’apparence tranquille mais qui ne cesse de se lancer des défis. En effet, Rochefort ressemblait à une belle endormie, son arsenal abandonné au début du vingtième siècle, son École de Médecine Navale fermée en 1964,
puis l’Hôpital en 1983. Mais ce sommeil est trompeur. À Rochefort aujourd’hui, un groupe d’artisans et de compagnons est à pied d’œuvre pour un nouveau projet fou : la construction à l’identique de l’Hermione, frégate historique de soixante-cinq mètres de long sur laquelle embarqua le marquis de La Fayette pour rejoindre l’armée
insurgée de Georges Washington en Amérique. Un challenge technique et historique, un chantier à remonter le
temps, un « work in progress » sous les yeux des touristes passionnés.
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‘‘
In the mid-18th century, the
mortality rate aboard squadrons
making the two- to two-and-a-halfmonth crossing of the Atlantic to
the West Indies was an estimated
0.5% to 17.2%, and the morbidity
rate ranged from 5.4% to over
32%. These rates depended on
age (cabin boys were more resistant) and position (officers were
four times less likely to die at sea
than ordinary seamen), as well as
time of year, length of crossing,
crowding (number of sailors per
unit area of deck space), and the
type of expedition.”
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Sickness and health on the
high seas in the 18th century
The Former Rochefort School of
Naval Medicine and the birth of the
French Navy Health Service
b y C . R é g n i e r, Fra n c e
© All rights reserved
T
Christian RÉGNIER, MD
Praticien Attaché Consultant
de l’Hôtel-Dieu de Paris
Société Internationale
d’Histoire de la Médecine
9 rue Bachaumont
75002 Paris
(e-mail:
[email protected])
he life of an 18th-century navy man hung by a thread. If he escaped
death and mutilation in battle, he still had to contend with accidents,
malnutrition, dysentery, typhus, and a host of other ills, all of which accounted for many more deaths than enemy action. Scurvy alone—the “plague
of the sea”—killed tens of thousands of sailors in the navies of European nations. In France, the royal navy contracted civilian doctors to care for its
sailors until the 1700s, but in the second half of the 18th century the idea took
shape of creating a navy medical service. The navy’s need for surgeons coincided with a turbulent period in French naval history marked by a succession of conflicts: the War of the Austrian Succession, the Seven Years’ War,
the American War of Independence. Naval battles, epidemics, ignorance of
hygiene, and crowding aboard ship meant that injuries were common and diseases rife. The navy thus trained a body of medical men aware of their professional worth and organized an effective navy health service (hospitals,
surgeons, hospital ships). The foundation of the three medical schools of Rochefort (1722), Toulon (1725), and Brest (1731), of which Rochefort was the most
renowned, symbolized the advent of this medical service within the French
navy. Directed by three generations of doctors of the same family, the Rochefort School of Surgery was coupled to the naval hospital of the dockyard.
Students there trained rigorously, and on graduation as navy surgeons, most
of whom practiced their art aboard ship, they formed an elite medical corps.
ot yet five years old at his father’s death in 1643, Louis XIV reigned over France
for the next 72 years, during what Voltaire dubbed “an eternally memorable
age.” Keen to assert the maritime power of his kingdom, to defend the coasts
of France, and to develop trading links with colonies in the Americas (Quebec,
Louisiana, the West Indies, Guiana), around 1660 Louis ordered the creation of a
fine new naval dockyard on the Atlantic coast. The site chosen was Rochefort, a
nondescript village in a disease-infested swamp. Centrally located on the Atlantic
coast of France, Rochefort had strategic advantages: it afforded protection by the
islands of Ré, Aix, and Oléron, as well as being linked by the Charente River to inland forests planted to supply wood for shipbuilding.
N
The task of building the naval dockyard was entrusted to Nicolas-François Blondel,
the Royal Naval Engineer, and to Louis Nicolas de Clerville, Commissioner General
of Fortifications, and work started in May 1666. Soon branded the “navy’s grave,”
Sickness and health on the high seas in the 18th century – Régnier
477
General view of the Maritime Hospital in Rochefort. Lithograph by Charles Mercereau,
19th century. The School of Naval Medicine occupied the left wing of the building.
Private Collection. © Archives Charmet/Bridgeman Art Library.
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Outbreak of typhus onboard a ship. Woodcut by Lucien Totain,
from a popular medical science book: Hygiene and Medicine of
Both Sexes: Science Made Understandable to All. Published by
Jules Rouff in Paris, 1885. © BIU Santé Paris.
their clothes. They slept in steerage, cramped quarters choked
with the stench from buckets of excrement. Bilge water stagnated in the hold, a sort of nautical cesspool and breeding
ground for insects. Poor preservation of food and drinking
water, lack of space for foodstuffs, often led to shortages at
sea. Atlantic crossings were interminable, since a squadron
of ships could sail no faster than its feeblest laggard. With no
ports of calls to take on supplies, want of fresh produce led
to vitamin deficiencies, first and foremost scurvy. And to add
insult to injury, unlike Spanish sailors, who were issued with
warm woolen clothes, French mariners had slow-drying linen
garments which soon wore out. Captains reported that by the
end of a long voyage their men were in rags, chilled by the
rain and cold. On arrival, the sailors, their immune defenses
already much weakened, fell victim to endemic and parasitic
diseases.
Rochefort was long prey to epidemics of malaria and dysentery that wiped out thousands of shipyard workers, townspeople, and convicts from the local penal colony doing forced
labor. Yet, by 1690 the French royal navy boasted the largest
war fleet in Europe, with 110 ships of the line
and 690 other vessels crewed by 100 000
men. From 1666 to the French Revolution,
nigh on 1300 ships were commissioned at
Rochefort.1-4
In the mid-18th century, the mortality rate aboard squadrons
making the two- to two-and-a-half-month crossing of the Atlantic to the West Indies was an estimated 0.5% to 17.2%,
and the morbidity rate ranged from 5.4% to over 32%. These
rates depended on age (cabin boys were more resistant) and
position (officers were four times less likely to die at sea than
ordinary seamen), as well as time of year, length of crossing,
crowding (number of sailors per unit area of deck space), and
the type of expedition.5,6
Life before the mast
Outbreaks of disease were common in the
crowded conditions on board ship, notably
during the transport of troops or slaves:
“malignant fevers,” typhus, dysentery, pneumonia, dermatoses, typhoid. Hygiene was
woeful. Rationing of fresh water meant
sailors could wash neither their bodies nor
Title pages of two major 18th-century naval
medicine treaties. Left: How to Preserve the
Health of Ship Crews, by Duhamel du Monceau,
published in Paris by H. L. Guérin and
L. F. Delatour, in Paris, 1759. Right: Handbook
of the Most Common Surgical Operations for
the Instruction of Naval Surgical Students of the
School of Brest, by Charon de Courcelles,
published by Romain Malassis, in Brest, in 1756.
© BIU Santé Paris.
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Treatises on preserving the health of people at sea led to significant improvements in naval hygiene in the first half of the
18th century. The most famous were those by the botanist
Henri Louis Duhamel du Monceau, the navy lieutenant Sébastien François Bigot de Morogues, and the doctors AntoineMarie Poissonnier-Desperrières and Étienne Chardon de
Courcelles, the founder of the naval medical school at Brest.
Medical studies on questions of health at sea were formalized
in new naval regulations and orders.7
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over the next 105 years; some 30 000 died there—sailors, of
course, but also convicts and locals who succumbed to the
ills emanating from the disease-ridden environs.
From 1673, each of the three great ports of war—Brest, Rochefort, and Toulon—had a doctor and a navy surgeon who
were “provided for,” to wit, paid a wage. This number soon increased to two doctors and six surgeons, who took turns to
embark.
Jean-Baptiste Colbert (1619-1683), chief minister of Louis XIV,
organized the medical service of French naval hospitals and
ships. Oil on canvas, 630×520 cm, by Pierre Mignard, 1667, at
the Palais de l’Institut, Paris. © RMN–Grand Palais.
Louis XIV, the Sun King (1638-1715), who ordered the creation
of the Naval Dockyard and Rochefort School of Naval Surgery.
Oil on canvas, 277×194 cm, by Hyacinthe Rigaud (1701), at the
Louvre Museum, in Paris. © Giraudon/Bridgeman Art Library.
A navy health service is born
Around 1640, the first surgeons sailed on French ships; small
hospital ships (fluyts) sailed with squadrons; and a naval hospital opened in Marseille. Soon after, a royal order required sea
captains to take on board a good surgeon to tend to the ship’s
company. The Tonnay-Charente naval hospital (40 beds), the
first of its kind in France, was founded in the Saint-Éloi Priory
in 1666. Some 17 years later, having become too small for its
purpose, it was transferred to the vicinity of the Rochefort naval
dockyard and renamed the Charente Hospital (480 places,
ie, 240 beds). Many thousands passed through this hospital
One of Louis XIV’s principal ministers, Jean-Baptiste Colbert,
the Controller-General of Finances, issued an order stipulating that all ocean-going ships manned by over 36 men had to
have aboard a surgeon (two for crews of more than 50 men),
whose skills were tested before embarkation. Surgeons had
to attend dissection classes and acquire from a senior doctor knowledge of internal diseases and remedies. In practice,
this rule was little applied and the surgeons or “boy surgeons”
who went aboard were uneven in their skills.
Colbert sent his son to the naval dockyard at Rochefort with
clear instructions to learn what it took to be… the Secretary of
State for the Navy. Some years later, having been appointed
to this position upon the death of his father in 1683, Colbert
the younger promulgated an order which organized the medical service of the naval hospitals and of the fleet. The Col-
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Medicine cabinet used by Rochefort Port Pharmacists. 19th-century, Rochefort School of Naval Medicine Museum.
© Musée National de la Marine/Bécot.
berts, father and son, were of the view that the state should
control and supervise rather than organize health care. Colbert the younger expressed his view thus: “I consider it not in
the least necessary to increase the number of surgeons. In the
past when needed they were found when none were waged,
and I am convinced that the same will be true now, all the
more so, since as there are already eight waged, fewer will be
needed.”3,6-9
answered to the quartermaster’s office. Owners of their own
medicine chests, for which they received an allowance, surgeons were the only medical men on board ship. Placed under the authority of the captain, only the surgeon major was
The problem arose of differences in status and training between doctors, on the one hand, and surgeons and apothecaries, on the other. The former were university-trained and
bore the title of doctor; the latter, often of humbler origin and
sometimes illiterate, belonged to the world of guilds and served
a short apprenticeship to an older guild member. Surgeons
varied greatly in skill and their hierarchy was somewhat illdefined. The best boasted credentials in surgery, served the
navy for years, and when their onboard careers came to an
end were rewarded with a post in one of the three shipyards
as assistant navy surgeon or better still as a “waged surgeon.”
At the end of the 17th century doctors alone were authorized
to make diagnoses in internal medicine and to stipulate treatment; they rarely wielded a scalpel. Until the Revolution, surgeons and apothecaries prepared medical prescriptions, and
482
Naval surgeon’s instrument kit. 19th century, Rochefort School
of Naval Medicine Museum. © Musée National de la Marine/A. Fux.
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allowed access to the officers’ mess. Not all captains understood or accepted the presence of surgeons on their ship. It
is true that the care provided at this time was of limited value
in diseases and only surgery (usually amputations) could save
lives. The Navy Board was flooded with complaints about the
mediocrity of the onboard surgeons, who were accused of
rote and artless use of what little they had learnt of anatomy
and surgery.7-10 The creation of the Academy of Surgery in
1731 heralded a gradual shift of naval medical training towards joint studies with doctors.
It was against this background that the first doctor of the
port of Rochefort, Jean Cochon-Dupuy, who studied at the
Faculty of Medicine in Toulouse, proposed the foundation of
a school for the instruction of ship’s surgeons attached to the
naval hospital. The Rochefort School of Surgery was inaugurated on 5 February 1722, the first of its kind in the world.
Its success was immediate. The Minister of the Navy decided
to create schools in Toulon (1725) and Brest (1731), modeled
on Rochefort, the three schools developing their own specific features and particular practices.3
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NAMES
Referred to today as the “Former School of Naval Medicine in Rochefort” (Ancienne École de Médecine Navale
de Rochefort), now a museum, and the Hospital (the left
wing of the same building) changed names several times.
“Rochefort” may or may not be added to the names of the
school and hospital… Some names are “official,” others
not… This article makes no attempt harmonize its reference to the School and Hospital to a single name for each.
N The School: École de Chirurgie (et d’Anatomie) de Rochefort; École de Médecine Navale de Rochefort; École
de Santé Navale de Rochefort; or simply nicknamed “La
Navale.”
N The Hospital: Hôpital-Charente; Hôpital de la Butte;
Hôpital de la Fraternité (so named during the French
Revolution); Hôpital Maritime; Hôpital de la Marine de
Rochefort.
The Rochefort School of Naval Medicine
and the Cochon-Dupuy dynasty
Jean Cochon-Dupuy opened the Rochefort School of Naval
Medicine to students under 15 years of age able to read and
write, with good eyesight and healthy hands without deformities. Preference was given to children of the families of waged
surgeons or of respectable families attached to the navy. The
candidates had to be of the Catholic faith and to pass an entrance examination before the medical authorities of the naval
dockyard. The school fees were paid by the navy, except for
any auditors allowed to attend. Cochon-Dupuy organized the
life of the school according to three successive sets of regulations, and wrote the lecture notes for several courses, notably on anatomy and surgery, which he taught.
The teaching program also included bedside training to learn
the techniques of bandaging, bloodletting, and operations,
the copying out of medical prescriptions, courses at the pharmacy, and botany classes. (Regularly supplied with seeds and
plants brought from overseas, Rochefort’s botanic garden was
famous and one of its special features.) The students studied
on average for five years, and advancement to the next stage
of training was by competitive exam. Those who wished to become waged surgeons had to pass the “double masterpiece”
test, which consisted of two randomly selected questions, one
on anatomy, the other on surgery.
The school had eight ordinary surgeons and twelve students
in 1725. Two years later, the Count of Maurepas, Secretary
of State for the Navy, attended in the school’s amphitheater
two anatomy classes on the cadavers of galley slaves. Impressed by the organization, he accorded his protection to the
school. Apart from the botanic garden, the school had a rich
Boxwood urns for drawing the names of the candidates and
the questions for medical exams at the Rochefort School of
Naval Medicine. 19th century, Rochefort School of Naval Medicine Museum. © Musée National de la Marine/P. Dantec.
library with some 14 000 volumes, a cabinet of curiosities of
the natural sciences and a remarkable anatomy collection of
sections and anatomic preparations injected with wax after
the manner of the Dutchman Frederik Ruysch. In 1736, a dental surgeon was appointed at the school, notably for the treatment of people with scurvy, and this became a new specialty
at Rochefort. From its creation in 1722, the Rochefort School
of Surgery continued to the start of the French Revolution,
through the reigns of Louis XV and Louis XVI, which were
marked by three wars ruinous for the crown and punctuated by maritime disasters: the War of the Austrian Succession
(1740-1748), the Seven Years’ War (1756-1763), and the American War of Independence (1775-1783).
483
A TOUCH
OF
FRANCE
The Rochefort hospital saw a huge
influx of wounded and sick from the
squadrons engaged in the War of the
Austrian Succession. A typhus epidemic spread through the town on the
return of one such squadron, and of
the 2000 navy men who fell sick almost one third died, including 23 socalled “second-class doctors” (who
had passed certain examinations, after a six-year apprenticeship with a
doctor or five years working in a hospital or three years studying at medical
school). The school’s activities and recruitment had to be suspended for a
year, as the staff were assigned to care
for the sick. The following year another squadron arrived at Rochefort, this
time from Canada, and 8000 men died
of typhus and scurvy.1,3,4,8,10-13
the now too-cramped Charente Hospital. The school of surgical anatomy
was located in one of the wards near
the entrance. The same year, upon
the death of his cousin Gaspard, the
navy surgeon Pierre Jacques Thomas
Cochon-Duvivier took over the running
of the school. Thus it was that the same
family headed the Rochefort School
of Surgery from its founding to the start
of the French Revolution (1789), by
which time the school had trained more
than 700 navy surgeons.8,11
The Rochefort legacy
Apart from the goal of training doctors
practiced in treating the afflictions of
sailors, the naval schools of surgery led
to the inclusion of “waged personnel”
Wax model of stomatitis caused by scurvy,
in a single administration which prethe plague of the seas… Dermatological
figured a future navy health service.
Wax Model Museum of the Saint-Louis Hospital
Gaspard Cochon-Dupuy, a graduate in Paris (Musée des Moulages Dermatologiques By awarding diplomas through comde l’Hôpital Saint-Louis, Paris).
of the Paris Faculty of Medicine, took
petitive examination, the naval schools
© F. Marin Musée des Moulages
over the running of the school upon
gradually established a hierarchy beHôpital Saint-Louis APHP.
the death of his father in 1757. Two
tween navy surgeons receiving differyears later, as the Seven Years’ War was raging, the school ent emoluments: funded students, assistant surgeon (two
had 400 beds, 30 surgeons, and a 100 or so junior surgeons. classes), second surgeon, ordinary surgeon, aboard or not.
1788 saw the inauguration of the “hospital on the hill,” locat- From 1750, all commissioned navy surgeons studied at one
ed high up to guard against “pestilence” and which replaced of the three schools.
THE ROCHEFORT SCHOOL DYNASTY
Jean Cochon-Dupuy
(1674-1757)
Anonymous, 18th century. Oil on canvas
65×54 cm. Founder of the Rochefort
School of Surgery and first physician
of the port of Rochefort.
Gaspard Cochon-Dupuy
(1710-1788)
by C. Lesson, 18th century. Oil on
canvas. Son of the founder and
his successor at the head of the
Rochefort School of Surgery.
© Musée National de la Marine/P. Dantec.
© Musée National de la Marine/P. Dantec.
484
Pierre Cochon-Duvivier
(1731-1813)
Engraving by Ambroise Tardieu,
18th century. Cousin of Gaspard,
whom he succeeded in 1788.
© Bibliothèque de l’Académie
Nationale de Médecine.
A TOUCH
OF
FRANCE
The post of inspector general of the navy hospitals created in
1763 was occupied by Dr Pierre Poissonnier, the inventor of a
process of desalination of seawater, who implemented a single set of regulations for the three schools, a joint annual competitive exam for junior surgeons, and the wearing of a uniform (first step towards the inclusion in the military hierarchy
that only became effective in 1835).3,7,9,10
The second half of the 18th century saw the formation of a
specific and stable body of navy surgeons. Rather closed, it
was organized along civilian lines and defined a clear career
path. The dominant role of the doctors running the schools
was progressively challenged by the surgeons who were far
better acquainted with the diseases of sailors and had widerranging practical experience. “In their [the doctors’] eyes,
surgery was a purely mechanical art, they considered that the
surgeon was but a skillful workman, armed with iron and fire,
who employs one or other as suggested by his own or traditional experience,” lamented the surgeon Étienne Billard
in 1790, in an address to the deputies of the Constitutional
Convention.
At the end of the American War of Independence (1783), it was
reckoned that 859 surgeons and apothecaries of all grades
were needed to meet the fleet’s regulatory requirements, but
the personnel paid by the King could provide only 155 surgeons. The shortfall was made up by civilian doctors, and volunteer or conscripted surgeons.
On the eve of the French Revolution, the navy’s body of physicians lacking the official title of doctor essentially comprised
an estimated 200 well-trained surgeons accustomed to life
on board ship. Deploring that they were not integrated into a
military career, they exercised nepotism in recruiting for the
naval medical schools. What’s more, the body of ”waged surgeons” was aging and becoming costly, a good number were
unfit for life aboard, and they kept their post (and their emoluments) until they died.1,4,7-9
Pathological osteology cabinet. These bones were used as
teaching material at the Rochefort School of Naval Medicine.
© Musée National de la Marine/A.Nilderlinder.
Revolution and beyond
During the French Revolution (1789-1799), the royal navy hospital at Rochefort was renamed “Fraternity Hospital,” and the
competitive examinations and the surgeons’ certificates were
replaced by a nationwide selection process. The medicine
and surgery teaching unit was consolidated in the École de
Médecine Navale (Naval Medical School) and the program
was aligned with that of the medical faculties of Paris, Montpellier, and Strasbourg.
Medical students completed their studies with a doctoral thesis defense in one of the three faculties. Trainee apothecaries
began studies in pharmacy, but the naval medical schools were
not authorized to award doctorates after the four years of compulsory classes. At the Bourbon Restoration (1814-1830), a
bachelor’s degree was required of all those seeking admission
Collection of pathological eye models. Rochefort School of
Naval Medicine Museum. Manufactured by Duplouy, 19th century.
© Musée National de la Marine/A.Fux.
485
A TOUCH
OF
FRANCE
to these medical schools. Soon after, classes in exotic diseases
and naval medicine were included in the course of study, and
as steamships began to supplant sailing vessels the title of
“naval surgeon” was replaced by “naval doctor.” Bacteriology
and therapeutics were still little known, but the frequency of
epidemics of typhus and dysentery and the ravages of scurvy
dropped considerably thanks to stricter hygiene aboard ship.
The death rate at sea in the French navy decreased tenfold
between 1810 (one man in 30) and 1913 (one in 308).
A law passed on 11 April 1890 stipulated the setting up of a
military health service in Bordeaux, and thereafter students
did just the first year of their studies in medicine and pharmacy at Brest, Rochefort, or Toulon, before continuing their studies in Bordeaux. The three schools continued to operate up
until 1963, when they were closed. At Rochefort, this ended
241 years of prestigious history, and in 1986 the Ministry of
Defense converted the school into a museum under the authority of the National Naval Museum.4,8,9,11,14 I
References
1. Memain R. La marine de guerre sous Louis XIV. Paris, France: Hachette; 1937.
2. Desplantes F. Les cinq ports militaires de la France. Limoges, France: Ardant;
1891.
3. Sardet M. L’École de chirurgie du port de Rochefort (1722-1789) – Un modèle
sous l’Ancien Régime. Vincennes, France: Service Historique de la Marine; 2000.
4. Begouin P. Le Service de santé de la Marine à Rochefort de sa fondation jusqu’au milieu du XIX e siècle. Medical Doctoral Thesis. Bordeaux, France;1975.
5. Buchet C. Quantification des pertes dans l’espace caraïbe et retombées stratégiques. In : Buchet C et al. L’Homme, la Santé et la Mer. Actes du colloque
international, les 5 et 6 décembre 1995, à l’Institut Catholique de Paris. Paris,
France: Honoré Champion Éditeur; 1997.
6. Haudrère P. Santé et voyages au long cours : la route du cap au XVIIIe siècle.
In : Buchet C et al. L’Homme, la Santé et la Mer. Actes du colloque international, les 5 et 6 décembre 1995, à l’Institut Catholique de Paris. Paris, France:
Honoré Champion Éditeur; 1997.
7. Lefèvre A. L’histoire du Service de Santé de la Marine militaire et des Écoles
de Médecine navale en France depuis le règne de Louis XIV jusqu’à nos jours
(1666-1867). Paris, France: J.-B. Baillière; 1867.
8. Broussolle B, Masson P. La santé dans la Marine de l’Ancien Régime. In: Pluchon P et al. Histoire des médecins et pharmaciens de marine et des colonies.
Toulouse, France: Privat; 1985.
9. Suberchicot JL. Le corps des officiers de santé de la marine sous l’Ancien Régime in Buchet C et al. L’Homme, la Santé et la Mer. Actes du colloque international, les 5 et 6 décembre 1995, à l’Institut Catholique de Paris, Paris, France:
Honoré Champion Éditeur; 1997.
10. Bahaud P. Les chirurgiens navigants de la marine marchande et de la marine
royale à Rochefort dans la deuxième partie du XVIIIe siècle. Medical Doctoral
Thesis. Nantes, France; 1971.
11. Suberchicot JL. Le service de santé de la Marine royale (1661-1793). Modern
History Doctoral Thesis. Paris IV Sorbonne, France; 1998.
12. Bitaubé P. Les grandes expéditions et le jardin botanique du port de Rochefort,
Rochefort, France : Centre International de la Mer; 1988.
13. Rousseau T. Le manuel des opérations de chirurgie par le Dr Cochon-Dupuy.
Medical Doctoral Thesis. Nantes, France: 1977.
14. Niaussat P. Les santés à l’épreuve – Marine et Technique au XIXe siècle. Vincennes, France: Service Historique de la Marine; 1988.
L’ANCIENNE ÉCOLE DE MÉDECINE NAVALE DE ROCHEFORT
LA NAISSANCE D’UN SERVICE DE SANTÉ NAVALE EN FRANCE
En France, l’organisation de la marine royale connut une profonde évolution qui va de l’époque de Colbert à la fin
de l’Ancien Régime. Un « service de santé » de la marine fut progressivement mis en place. Doté de moyens matériels et humains, ce service devait assurer la prise en charge des marins malades ou blessés en mer comme à terre.
Longtemps, les chirurgiens du civil furent les seuls à être employés sous contrat par la Marine. L’idée de constituer
un corps spécifique de médecins et de chirurgiens de la marine se concrétisa dans la seconde moitié du XVIIIe
siècle. Symbole de l’avènement de cette médecine navale française, la fondation de trois écoles de santé à Rochefort (1722), Toulon (1725) et Brest (1731). Mais ce fut l’école de Rochefort qui eut la plus grande réputation. Dirigée
par trois générations de médecins appartenant à la même famille, l’école de Rochefort était couplée à l’hôpital maritime de l’arsenal. Elle formait des chirurgiens de la marine dont la plupart étaient embarqués ; les élèves faisaient
l’acquisition de connaissances complètes et formèrent bientôt un corps d’élite. De fait, le besoin en chirurgiens de la
marine coïncidait avec une période très mouvementée de l’histoire navale française dans une succession de guerres :
succession d’Autriche, guerre de Sept Ans, guerre d’indépendance américaine. Batailles navales, épidémies, ignorance de l’hygiène, promiscuité à bord des navires provoquaient de véritables hécatombes sanitaires parmi les marins, d’où la nécessité absolue de les préserver au moyen d’un Service de Santé Navale (hôpitaux, chirurgiens, navires hôpitaux) bien formé et efficace. La marine de l’Ancien Régime parvint donc à constituer une administration
sanitaire opérationnelle et un véritable corps de chirurgiens conscients de leur valeur professionnelle et bien organisés. À partir de 1798, les élèves des écoles navales intégrèrent la filière classique des études de médecine.
486
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