Download Heart rate as a treatable cardiovascular risk factor

Published Online May 27, 2009
Heart rate as a treatable cardiovascular
risk factor
Jean-Claude Tardif*†‡
†
Montreal Heart Institute, Montreal, QC, Canada, and ‡Université de Montreal, Montreal,
QC, Canada
Background: Although several epidemiological studies demonstrate the
association between resting heart rate (HR) and cardiovascular morbidity and
mortality, an elevated HR remains a neglected cardiovascular risk factor.
Sources of data: This review summarizes the results of published studies on the
relationship between elevated HR and cardiovascular risk.
Areas of agreement: The role of HR in myocardial ischaemia in coronary patients
is well known. Experimental data and clinical observations support the
importance of HR in the pathophysiology of atherosclerosis and plaque rupture.
A large body of evidence points to high resting HR as a risk factor for mortality
in various populations, including coronary patients.
Areas of controversy: HR reduction is suggested to be a mechanism explaining
the prognostic benefit of beta-blockers after myocardial infarction or in heart
failure patients. However, it was unclear whether HR reduction per se directly
affects cardiovascular prognosis. Treatment with ivabradine, a pure HR-reducing
agent, provides an opportunity to assess the effects of selectively lowering HR
without altering other aspects of cardiac function.
Growing points: The results of the recent Morbidity –Mortality Evaluation of the
If Inhibitor Ivabradine in Patients with Coronary Disease and Left Ventricular
Dysfunction study underline the importance of HR reduction in the
management of stable coronary artery disease. The prospective analysis of data
from the placebo arm demonstrated that elevated resting HR (70 bpm) is a
strong independent predictor of clinical outcomes. Consistent with these data,
ivabradine significantly improved coronary outcomes in patients with a HR of
70 bpm or more.
Accepted: April 21, 2009
*Correspondence to:
Jean-Claude Tardif,
Montreal Heart Institute,
5000 Belanger Street,
Montreal, QC, Canada
H1T 1C8.
E-mail: [email protected]
Areas timely for development: These data support the importance of HR in the
management of stable coronary artery disease to assess prognosis and to guide
optimal therapy.
Keywords: heart rate/risk factors/cardiovascular disease/coronary artery
disease
British Medical Bulletin 2009; 90: 71–84
DOI:10.1093/bmb/ldp016
& The Author 2009. Published by Oxford University Press. All rights reserved.
For permissions, please e-mail: [email protected]
J.-C. Tardif
Introduction
Coronary artery disease (CAD) represents a major cause of morbidity
and mortality in industrialized countries and its prevalence makes it a
public health problem worldwide.1 Despite modern therapy including
intensive pharmacological treatment and interventional revascularization procedures, affected patients still suffer high event rates, including
angina pectoris, myocardial infarction (MI), heart failure (HF) and cardiovascular death.2 Patients with left ventricular dysfunction or ischaemic cardiomyopathy are even at a higher risk of ischaemic events and/
or cardiovascular death. Therefore, identification and treatment of risk
factors are essential for improving the prognosis and quality of life of
coronary patients.
Heart rate (HR), a simple and easily measurable clinical parameter,
has been found to be a risk predictor of mortality and morbidity in
various populations. The aim of this paper is to review the value of
HR as a prognostic factor of mortality and morbidity and the effect of
HR reduction on the prognosis of patients with CAD. Although HR
reduction can be achieved with beta-blocker or non-dihydropyridine
calcium antagonists, the recent development of the If current inhibitor
ivabradine capable of achieving pure HR reduction is important to
consider in light of the recently published results of the BEAUTIFUL
(morBidity –mortality EvAlUaTion of the If inhibitor ivabradine in
patients with coronary disease and left ventricULar dysfunction) trial.
HR as a risk factor of cardiovascular and all-cause mortality
Epidemiological studies have consistently shown that resting HR is a
predictive factor of all-cause mortality and cardiovascular mortality.3 – 6
Dyer et al. 7 observed statistically significant relationships between
resting HR and both cardiovascular mortality and total mortality in
men followed for 15 years in the Chicago People Gas Company study
and for 17 and 5 years, respectively, in the Chicago Western Electric
Company (n ¼ 1899) and Chicago Heart Association Detection Project
(n ¼ 5784). HR was also an independent risk predictor of sudden coronary death, even when other CAD risk factors, such as age, blood
pressure, total blood cholesterol, smoking and body weight, were taken
into account in a multivariate analysis. A significant relationship was
also found in the Framingham study between a high resting HR and
increased rates of cardiovascular mortality, coronary heart disease and
sudden coronary death both in men and women followed for
30 years.8 In a study of 19 386 French “white collar” employees
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Heart rate—a treatable risk factor
followed for more than 20 years, Benetos et al. 9 assessed cardiovascular mortality and non-cardiovascular mortality in four groups of HR
based on the electrocardiogram: HR1 was ,60 bpm, HR2 between 60
and 80 bpm, HR3 between 81 and 100 bpm and HR4 .100 bpm. In
men, the relative risks of cardiovascular mortality in groups with
resting HR of 60– 80 bpm, 81– 100 bpm and .100 bpm were 1.35,
1.44 and 2.18, respectively, as compared with the group with an HR
of ,60 bpm. HR was an independent risk factor in men, independent
of age, hypertension, total cholesterol level, body mass index, smoking
and level of exercise activity. In this cohort of women, HR did not
influence cardiovascular mortality.
The Malattie Cardiovascolari Aterosclerotiche Istituto Superiore di
Sanita (MATISS) study included 2533 men aged 40 –69 years followed
for a total of 24 457 subject-years and showed that HR was an independent predictive factor for total mortality and cardiovascular mortality.10 In a French population of 7079 subjects aged 42– 53 years and
followed for an average 23 years, there were 603 cardiovascular deaths
including 118 sudden deaths and 192 following MI.11 The risk of
sudden death increased linearly with the level of resting HR in men.
Taking into account age, body mass index, systolic blood pressure,
tobacco consumption, parental history of MI and parental history of
sudden death, cholesterol level, diabetic status and sport activity, an
elevated HR remained an independent risk factor for sudden death.
The latest data in this French population of healthy men showed that
resting HR and its change over 5 years were both predictors of death,
independent of the standard cardiovascular risk factors.12 This observational study followed up 5139 asymptomatic men (aged 42 –53
years) who had their HR measured at rest in standardized conditions
every year for 5 consecutive years. Subjects were divided into following
tertiles of HR changes: decrease .4 bpm, unchanged (from 24 to
þ3 bpm) or increase .3 bpm. After adjustments were made for confounding factors, including baseline HR at rest, and compared with
subjects with unchanged HR, those with HR that decreased during the
5 years had a 14% decrease in mortality risk (P ¼ 0.05), whereas men
whose HR increased over 5 years had a 19% increase in mortality risk
(P , 0.012). The association between high resting HR and mortality is
consistent with the published data from a number of epidemiological
studies in the general population, but the study provides the first observation that change in HR over a 5-year period conferred additional
information beyond HR at rest and was an independent predictor of
mortality in middle-aged men.
In the 4530 hypertensive patients (defined as a systolic blood pressure
140 mm Hg or a diastolic 90 mm Hg) of the Framingham study
(age 35– 74 years) who were not on antihypertensive medications,13 an
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J.-C. Tardif
increment of HR of 40 bpm was associated with an odds ratio for total
mortality of 2.18 (95% CI: 1.68–2.83) for men and 2.14 (95% CI:
1.59– 2.88) in women. For cardiovascular mortality, the odds ratios
were 1.68 (1.19, 2.37) for men and 1.70 (1.08, 2.67) for women. It
was therefore concluded that HR is an independent risk marker of cardiovascular death in patients with hypertension.
In patients with CAD, increased HR is a well-known precipitating
factor of myocardial ischaemia and of angina. Tardif and his
colleagues14 from the Montreal Heart Institute analysed a registry of
24 913 patients with suspected or proven CAD referred for coronary
angiography and followed for an average of 14.1 years. They found
that resting HR is an independent risk factor for total and cardiovascular mortality both in men and women. Commenting on this study,
Palatini15 pointed out that the better prognosis observed in patients
with lower resting HR was not due to beta-blockers as this was also
observed in patients not receiving this therapy. The prognostic value of
HR held true when controlling for hypertension, diabetes and smoking
as well as powerful markers such as the left ventricular ejection fraction
and the number of diseased coronary vessels. Patients with an HR of
83 bpm also had a significantly higher risk of hospital admissions for
cardiovascular causes than those with an HR of 62 bpm.
Hjalmarson et al. 16 characterized, in 1807 patients with acute MI,
the relationship between HR on hospital admission and after discharge
from hospital and respectively total mortality from admission to discharge and mortality at 1 year. In-hospital mortality and post-discharge
mortality increased with increasing HR on admission. Total mortality
was 15% for patients with an admission HR ranging between 50 and
60 bpm, 41% for HR .90 bpm and 48% for HR 110 bpm.
Mortality from hospital discharge to 1 year was also related to the
maximal HR observed in the coronary care unit and to HR at discharge. In patients with moderate HF, the cumulative mortality for
patients with an admission HR of 90 bpm was more than twice that
of patients with an admission HR of ,90 bpm (39% versus 18%).
A similar relationship was observed in patients with mild or no HF
(18% versus 10%).
The prognostic significance of HR was also assessed in 8915 patients
with acute MI of the GISSI-2 study and treated with fibrinolytic
therapy.17 In this study, increased HR on admission was associated
with a progressive increase in in-hospital mortality (from 7.1% for HR
,60 bpm to 23.4% for HR .100 bpm). HR at discharge from the
hospital was available in 7831 patients. A progressive increase of
6-month mortality was noted with increasing HR (from 0.8% for HR
,60 bpm to 14.3% for HR .100 bpm). Multivariate analysis showed
that HR was an independent prognostic factor of mortality. Similar
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Heart rate—a treatable risk factor
results were observed in the Secondary Prevention Reinfarction Israeli
Nifedipine trial, performed before the thrombolytic era, which showed
that HR on admission in the coronary care unit was related to total mortality and to the occurrence of complications.18 In the CIBIS II trial,
which randomized patients with HF to bisoprolol or placebo, the
relationships between baseline HR, HR changes and outcomes, such as
mortality and hospitalization for HF, were evaluated in the placebo
group. Multivariate analysis showed that baseline HR and HR changes
were both significantly related to survival and hospitalization for worsening HF.19 The lowest baseline HR and the largest HR changes were
associated in the placebo group with the best survival and with a
reduction of hospital admissions. Bisoprolol further improved survival at
any level of baseline HR or HR changes to a similar extent. In the
International Verapamil-SR/Trandolapril study, the relationships between
resting HR at baseline and at follow-up and adverse outcomes (all-cause
death, non-fatal MI and non-fatal stroke) were evaluated in 22 192
patients with hypertension and CAD treated either with verapamil or atenolol. Resting HR was found in this study to predict adverse events, and
on-treatment HR was even more predictive than baseline resting HR.20
Role of HR in the development of atherosclerosis and coronary
events
Risk factors can trigger a complex chain of events leading to the continuum of cardiovascular diseases.21 Any modification along this chain
of events may interrupt the pathological process, conferring cardiovascular protection.22 The most common coronary manifestations of
atherosclerosis are stable angina pectoris and acute coronary syndromes. Experimental evidence support the role of HR in endothelial
dysfunction and the progression of atherosclerotic lesions.23 Briefly,
pressure wave-derived vascular stress sensed by mechanoreceptors triggers a cascade of signalling molecules. Elevated tensile stress is thought
to induce direct endothelial injury and to increase endothelial permeability to LDL particles and to circulating inflammatory mediators.
The role of HR in myocardial ischaemia as seen in patients with
stable angina and those who suffer a MI is well known (Fig. 1). An
increased HR contributes to an imbalance between myocardial oxygen
demand and supply, by causing both an increase in myocardial oxygen
demand and a decrease in coronary blood supply (the latter via a
shorter duration of diastole, the period during which most of the myocardial perfusion occurs). An increased HR may also be involved at the
later stages of atherosclerosis including plaque rupture resulting in
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Fig. 1 Mismatch between myocardial oxygen demand and oxygen supply by coronary
blood flow leading to myocardial ischaemia.
Fig. 2 Role of HR in the development and progression of atherosclerosis.
coronary thrombosis (Fig. 2). Therefore, HR reduction may play an
important role in the cardiovascular disease continuum.
HR reduction and decreased cardiovascular risk
Several studies have shown that beta-blockers are able to reduce total
mortality and sudden cardiac death after MI. These beneficial effects
have been ascribed at least in part to the reduction of HR.24
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Heart rate—a treatable risk factor
Furthermore, a recent meta-regression of randomized clinical trials of
beta-blockers and calcium channel blockers in post-acute MI patients
strongly suggest that the beneficial effects of these agents are proportionally related to the reduction of resting HR.25 A statistically significant relationship was found between resting HR reduction and
decreases in cardiac death, all-cause death, sudden death and non-fatal
MI recurrence. This meta-regression strongly suggests that resting HR
reduction could be a major determinant of the clinical benefits seen in
these trials. This hypothesis was also tested more recently in randomized controlled trials of beta-blockers in HF due to left ventricular systolic dysfunction. There was a close relation between all-cause
annualized mortality rate and HR in these studies, and a strong correlation between change in HR and change in left ventricular ejection
fraction was also observed.26 Beta-blockers are a cornerstone of HF
treatment, but their efficacy in elderly patients is less known as such
patients are often excluded from clinical trials. According to recent
findings from the Organized Program to Initiate Lifesaving Treatment
in Hospitalized Patients With Heart Failure Registry, beta-blocker
therapy reduces mortality and rates of re-hospitalization among elderly
patients with HF who have left ventricular systolic dysfunction, but
does not appear to have any beneficial effects in those with preserved
systolic function.27
In contrast to the beneficial effect of beta-blockers on mortality in
post-MI and HF settings, Messerli28 has recently described an inverse
relationship between HR reduction with beta-blockers and cardiovascular end points in patients with hypertension. However, this hypertension paradox observed with beta-blockers (mainly atenolol) cannot be
explained solely by pharmacological HR slowing, and findings should
not be extrapolated to pharmacological interventions aiming at pure
HR reduction. Beta-blockers not only reduce HR, but also have a
number of other effects. The novel specific HR-lowering agent ivabradine therefore provides an opportunity to assess the effects of lowering
HR without directly altering other aspects of cardiac function.
Ivabradine is the first of a new class of agents that act specifically on
the sinoatrial node by inhibiting the If current of cardiac pacemaker
cells without affecting other cardiac ionic currents at therapeutic concentrations. Ivabradine is a new medication that has HR-lowering
properties without other direct cardiovascular effects.29 A doubleblind, placebo-controlled study in patients with chronic stable angina
showed that ivabradine produces dose-dependent improvements in
exercise tolerance and time to development of exercise-induced ischaemia.30 Ivabradine was also compared with the b-adrenoceptor antagonist atenolol in the International Trial of the Antianginal effect of
Ivabradine study compared with atenolol.31 Ivabradine 7.5 mg twice
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J.-C. Tardif
daily resulted in substantial and consistent HR reduction at rest that
was fairly similar to that of beta-blockade. No relevant between-group
differences were observed at rest. At peak exercise, HR decrease from
baseline to end-of-study was less pronounced in both ivabradine
groups than in the atenolol 100 mg o.d. group. Although atenolol
showed greater HR reduction, ivabradine was non-inferior to the betablocker in terms of prolonging total exercise duration (primary end
point) as well as time to limiting angina and time to angina onset
during exercise tolerance testing. Thus, ivabradine induced a similar or
greater improvement in exercise capacity while causing less reduction
in rate-pressure product and HR when compared with atenolol.
According to these findings, ivabradine increased exercise capacity to a
greater extent for every beat of HR reduction. This might be linked to
ivabradine’s lack of negative inotropic, peripheral vascular or coronary
vasoconstrictor effect as well as the greater prolongation of diastole
obtained with ivabradine compared with a beta-blocker. Data from the
recently published assessment of efficacy and safety of oral ivabradine
compared to placebo on top of atenolol (ASSOCIATE) study demonstrate that addition of ivabradine 7.5 mg bid to atenolol at the dose
commonly used in clinical practice in patients with chronic stable
angina pectoris produced additional HR reduction and further
improvement in all exercise testing parameters, with no untoward
effect on safety or tolerability.32
Ivabradine was also found to have beneficial effects on cardiac remodelling, capillary density and left ventricular dysfunction. In a rat
model of congestive HF, Mulder et al. 33 showed that chronic administration of ivabradine induced a dose-dependent reduction in HR
without modification in systemic haemodynamics. Cardiac output was
preserved despite the decrease in HR because stroke volume was
increased owing to a decrease in left ventricular end-systolic diameter.
In animals with dyslipidaemia, selective HR reduction with ivabradine
decreases markers of vascular oxidative stress, improves endothelial
function and reduces atherosclerotic plaque formation.34 Therefore,
these data support the potential of HR reduction as an intervention to
improve endothelial function, to attenuate progression of atherosclerosis and ultimately to prevent coronary events. Whether lowering HR
with ivabradine in patients with stable CAD receiving optimal background therapy could result in reduction of cardiovascular events had
to be demonstrated. This prompted the BEAUTIFUL study, the results
of which have been recently reported.35 BEAUTIFUL is a large, international, randomized, placebo-controlled morbidity –mortality trial in
a high-risk population of patients with CAD and left ventricular systolic dysfunction (ejection fraction ,40%), conducted between
December 2004 and December 2006. The study enrolled 10 917
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Heart rate—a treatable risk factor
Fig. 3 Elevated HR (70 bpm) as a predictor of cardiovascular outcomes in a population
with stable CAD and left ventricular dysfunction. Kaplan– Meier curves for cardiovascular
death in the placebo arm of the BEAUTIFUL study.
eligible patients. About 5479 patients were randomized to receive the
initial dose of 5 mg of ivabradine bid, with the aim to reach the target
dose of 7.5 mg bid on top of conventional cardiovascular treatments as
recommended by guidelines, and 5438 patients were randomly assigned
to the placebo group. The mean age of the study patients was 65 years.
The mean HR at baseline was 71.6 bpm and the mean left ventricular
ejection fraction was 32.4%. The use of background evidence-based
therapy was very high (including 87% of patients for beta-blockers).
The BEAUTIFUL investigators have added substantially to current
knowledge concerning the prognostic value of elevated HR by also
conducting a prospective analysis of the data from the placebo arm of
the study to assess the association of HR with different clinical outcomes.36 Patients with an HR of 70 bpm or more had increased risks
of cardiovascular death (34%, P ¼ 0.0041, Fig. 3), admission to hospital for HF (53%, P , 0.0001), admission to hospital for MI (46%,
P ¼ 0.0066) and coronary revascularization (38%, P ¼ 0.037) after
adjustment for other predictors of outcome.
Although the primary end point of the study (composite of cardiovascular mortality, admission to hospital for acute MI and admission to
hospital for new onset or worsening HF) was not met in the overall
population, ivabradine reduced the risk of coronary events by 22%
(P ¼ 0.023), fatal and non-fatal MI by 36% (P ¼ 0.001, Fig. 4) and
coronary revascularization by 30% (P ¼ 0.016) in the pre-specified
subgroup of patients with baseline HR 70 bpm. These benefits were
observed despite the fact that 84% of these patients received
beta-blockers.
Ongoing and future clinical studies will provide further evidence on
the presence and extent of cardioprotective benefits of HR lowering
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J.-C. Tardif
Fig. 4 In stable CAD patients with left ventricular systolic dysfunction and an elevated
resting HR (70 bpm), ivabradine reduced the risk of hospitalization for myocardial infarction in BEAUTIFUL. RRR ¼ relative risk reduction.
with ivabradine in patients with cardiovascular disease. The Systolic
Heart failure study with the If inhibitor ivabradine trial, which is currently investigating the effects of ivabradine in congestive HF, will
provide important information concerning the importance of pure HR
reduction in this patient population. This large-scale, randomized,
placebo-controlled trial has recruited over 7000 patients with moderate
to severe HF and resting HR 70 bpm. Throughout the study, all
patients have continued their current standard treatments for HF and
any other cardiovascular conditions. The aim is to evaluate the effects
of adding treatment with ivabradine versus placebo in terms of
reduction in cardiovascular events in HF.
Applying current knowledge to practice
In spite of the large body of evidence on the evaluation of cardiovascular risk, little attention has been paid to the measurement of HR for
cardiovascular risk assessment in daily practice. There might be two
main reasons for this: first, HR has been considered to be a poorly
reproducible clinical variable, and, second, HR has been seen as a mere
marker of sympathetic activity rather than a cardiovascular risk factor
per se.
Recent evidence has fuelled the concept that increased resting HR is
probably an independent cardiovascular risk factor. The new evidence
from the BEAUTIFUL study constitutes the first prospective demonstration that an elevated resting HR (70 bpm) places coronary
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Heart rate—a treatable risk factor
patients at risk for cardiovascular events, even if they are well treated
according to current guidelines including treatment with beta-blockers.
Thus, resting HR should be considered in every patient with CAD,
especially since it is an easily measurable parameter. To standardize
measurement of resting HR, a consensus meeting and recent Guidelines
for the Management of Arterial Hypertension recommended measurement of HR by pulse palpation during two 30-s periods, performed in
a sitting position, after 5 min sitting in a quiet room.37,38
There are several methods for HR measurement. ECG is the most
routinely used technique in clinical settings. Whether more precise
measurement of HR with ECG translates into more meaningful data is
not clear. According to Erikssen and Rodahl,39 these two types of
measurement are highly correlated (R . 0.9) and provide similar information. Data on the prognostic value of home or 24-h HR measurement performed with electrocardiographic Holter recording are
currently lacking. In a study by Aronow et al.,40 the risk of death
increased by 14% for each 5 bpm increase in mean 24-h HR in both
men and women, but no comparison with clinical HR was provided.
Hozawa et al. 41 reported a 17% increase in the risk of mortality for a
5 bpm increase in home HR, but their study failed to compare the predictive power of out-of-office HR with that of outpatient clinic HR.
There is no available evidence demonstrating an advantage of HR
measured out of the office over outpatient clinic HR. In times of major
health care burden, HR measurement can be utilized with no
additional cost in the overall strategy of cardiovascular risk assessment
in daily practice.
HR has already appeared in European guidelines for the prevention
of cardiovascular disease.42 The idea that high HR places patients at
risk is by no means new, but previous studies generally confined themselves to comparing quartiles or quintiles of high versus low HR
values. The BEAUTIFUL study has lowered the cutoff at which HR
may pose a risk to 70 bpm. Resting HR is easy and inexpensive to
measure in the clinic, and this should clearly become a component of
the risk stratification of patients with stable CAD. Thus, the important
implication of BEAUTIFUL is that HR .70 bpm is deleterious in
patients with stable CAD and this issue needs to be addressed.
Conclusions
A large body of evidence supports high resting HR as a risk factor for
total mortality and cardiovascular mortality in various populations
including patients with CAD. Experimental evidence supports the role
of high HR in endothelial dysfunction and atherosclerosis progression.
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J.-C. Tardif
Recent evidence has extended current knowledge of the role of HR as a
potential risk factor in CAD. Elevated HR (70 bpm) increases cardiovascular risk and this measurement should be used to guide optimal
therapy in coronary patients.
Funding
Dr Tardif has previously received honoraria from Servier.
References
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
82
McGovern PG, Pankow JS, Shahar E et al. (1996) Recent trends in acute coronary heart
disease-mortality, morbidity, medical care and risk factors. The Minnesota Heart Survey
Investigators. N Engl J Med, 334, 884 –890.
Steg PG, Bhatt DL, Wilson PW et al. (2007) One year cardiovascular event rates in outpatients with atherothrombosis. JAMA, 297, 1197– 206.
Aboyans V, Criqui MH (2006). Can we improve cardiovascular risk prediction beyond risk
equations in the physician’s office? J Clin Epidemiol, 59, 547– 558.
Fox K, Borer JS, Camm AJ et al. (2007) Resting heart rate in cardiovascular disease. J Am
Coll Cardiol, 50, 823– 830.
Lévy S, Guize L (2006) Heart rate, a major prognostic factor of cardiovascular risk.
Therapie, 61, 115– 119.
Palatini P (2007) Heart rate as an independent risk factor for cardiovascular disease: current
evidence and basic mechanisms. Drugs, 67(Suppl 2), 3– 13.
Dyer AR, Persky V, Stamler J et al. (1980) Heart rate as a prognostic factor for coronary
heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol,
112, 736 –749.
Kannel WB, Kannel CE, Paffenbarger R et al. (1987) Heart rate and cardiovascular mortality
in the Framingham study. Am Heart J 113, 1489– 1494.
Benetos A, Rudnichi A, Thomas F et al. (1999) Influence of heart rate on mortality in a
French population: role of age, gender and blood pressure. Hypertension, 33, 44– 52.
Seccareccia F, Pannozzo F, Dima F et al. (2001) Heart rate as a predictor of mortality: the
MATISS project. Am J Public Health 91, 1258– 1263.
Jouven X, Zureik M, Desnos M et al. (2001) Resting heart rate as a predictive risk factor for
sudden cardiac death in middle-aged men. Cardiovasc Res, 50, 373 –378.
Jouven X, Empana JP, Escolano S et al. (2009) Relation of heart rate at rest and long-term
(.20 years) death rate in initially healthy middle-aged men. Am J Cardiol, 103, 279–283.
Gillman MW, Kannel WB, Belanger A et al. (1993) Influence of heart rate on mortality
among persons with hypertension: the Framingham Study. Am Heart J, 125, 1148–1154.
Diaz A, Bourassa MG, Guertin MC et al. (2005) Long-term prognostic value of resting heart
rate in patients with suspected or proven coronary artery disease. Eur Heart J, 26, 967– 974.
Palatini P (2005) Heart rate: a strong predictor of mortality in subjects with coronary artery
disease. Eur Heart J, 26, 943– 945.
Hjalmarson A, Gilpin EA, Kjekshus J et al. (1990) Influence of heart rate on mortality after
acute myocardial infarction. Am J Cardiol, 65, 547– 553.
Zuanetti G, Mantini L, Hernández-Bernal F et al. (1998) Relevance of heart rate as a prognostic factor in patients with acute myocardial infarction: insights from the GISSI-2 study.
Eur Heart J, Suppl F, F19 –F26.
Disegni E, Goldbourt U, Reicher-Reiss H et al. (1995) The predictive value of admission
heart rate on mortality in patients with acute myocardial infarction. J Clin Epidemiol, 48,
1197–1205.
British Medical Bulletin 2009;90
Heart rate—a treatable risk factor
19 Lechat P, Hulot JS, Escolano S et al. (2001) Heart rate and cardiac rhythm relationships with
bisoprolol benefit in chronic heart failure in CIBIS II Trial. Circulation, 103, 1428– 1433.
20 Kolloch R, Legler UF, Champion A et al. (2008) Impact of resting heart rate on outcomes in
hypertensive patients with coronary artery disease: 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, 29, 1327–1334.
21 Dzau VJ, Antman EM, Black HR et al. (2006) The cardiovascular disease continuum
validated: clinical evidence of improved outcome. Part I. Pathophysiology and clinical trial
evidence (risk factors through stable coronary artery disease). Circulation, 114, 2850– 2870.
22 Dzau VJ, Antman EM, Black HR et al. (2006) The cardiovascular disease continuum validated: clinical evidence of improved outcome. Part II. Clinical trial evidence (Acute coronary
syndromes through renal disease. Circulation, 114, 2871–2891.
23 Giannoglou GD, Chatzizisis YS, Zamboulis C et al. (2008) Elevated heart rate and atherosclerosis: an overview of the pathogenetic mechanisms. Int J Cardiol, 126, 302–312.
24 Kjekshus J (1986) Importance of heart rate in determining beta-blocker efficacy in acute and
long-term myocardial infarction intervention trials. Am J Cardiol, 57, 43F– 49F.
25 Cucherat M (2007) 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, 28, 3012–3019.
26 Flannery G, Gehrig-Mills R, Billah B et al. (2008) 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, 101, 865 –869.
27 Hernandez AF, Hammill BG, O’Connor CM, Schulman KA, Curtis LH, Fonarow GC (2009)
Clinical effectiveness of beta-blockers in heart failure. Findings from the OPTIMIZE-HF
(Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart
Failure) Registry. J Am Coll Cardiol, 53, 184–192.
28 Bangalore S, Sawhney S, Messerli FH (2008) Relation of beta-blocker– induced heart rate
lowering and cardioprotection in hypertension. J Am Coll Cardiol, 52, 1482–1489.
29 Di Francesco D, Camm AJ (2004) Heart rate lowering by specific and selective If current
inhibition with ivabradine. Drugs, 64, 1757–1765.
30 Borer JS, Fox K, Jaillon P et al. (2003) Antianginal and antiischemic effects of ivabradine, an
If inhibitor, in stable angina. A randomized, double blind, multicentered, placebo-controlled
trial. Circulation, 107, 817 –823.
31 Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K (2005) Efficacy of ivabradine, a new
selective I(f ) inhibitor, compared with atenolol in patients with chronic stable angina. Eur
Heart J, 26, 2529–236.
32 Tardif JC, Ponikowski P, Kahan T for the ASSOCIATE study investigators (2009) Efficacy of
the If current inhibitor ivabradine in patients with chronic stable angina receiving betablocker therapy: a 4 month, randomized, placebo-controlled trial. Eur Heart J, 30, 540–548.
33 Mulder P, Barbier S, Chagraoui A et al. (2004) Long-term heart rate reduction induced by
the selective If current inhibitor ivabradine improves left ventricular function and intrinsic
myocardial structure in congestive heart failure. Circulation, 109, 1674–1679.
34 Custodis F, Baumahakel M, Schlimmer N et al. (2008) Heart rate reduction with ivabradine
reduces oxidative stress, improves endothelial function and prevents atherosclerosis in apolipoprotein E deficient mice. Circulation, 117, 2377.
35 Fox K, Ford I, Steg PG et al. (2008) Ivabradine for patients with stable coronary artery
disease and left ventricular dysfunction (Beautiful): a randomized, double-blind, placebocontrolled trial. Lancet, 372, 807– 816.
36 Fox K, Ford I, Steg PG et al. (2008) 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, 6, 372, 817– 821.
37 Palatini P, Benetos A, Grassi G et al. (2006) Identification and management of the hypertensive patient with elevated heart rate: statement of a European Society of Hypertension
Consensus Meeting. J Hypertens, 24, 603–610.
38 Guidelines for the management of arterial hypertension (2007) The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the
European Society of Cardiology (ESC). J Hypertens, 25, 1105–1187.
British Medical Bulletin 2009;90
83
J.-C. Tardif
39 Erikssen J, Rodahl K (1979) Resting heart rate in apparently healthy middle-aged men. Eur J
Appl Physiol, 42, 61– 69.
40 Aronow WS, Ahn C, Mercando AD, Epstein S (1996). Association of average heart rate on
24-hour ambulatory electrocardiograms with incidence of new coronary events at 48-month
follow-up in 1311 patients (mean age 81 years) with heart disease and sinus rhythm. Am J
Cardiol, 78, 1175–1176.
41 Hozawa A, Ohkubo T, Kikuya M et al. (2004) Prognostic value of home heart rate for
cardiovascular mortality in the general population: the Ohasama study. Am J Hypertens, 17,
1005–1010.
42 Graham I, Atar D, Borch-Johnsen K et al. (2007) European guidelines on cardiovascular
disease prevention in clinical practice: executive summary. Eur Heart J, 28, 2375–2414.
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British Medical Bulletin 2009;90