Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
Heart rate: from risk marker to risk factor
Jeffrey S. Borer*
Weill Cornell Medical College, Cornell University, New York, NY, USA
* Corresponding author. Tel: +212 289 7777; fax: +212 426 4353. E-mail address: canadad45{at}aol.com
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Abstract
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Several risk factors for the development of coronary heart disease
and related mortality have been identified to facilitate detection
of patients at high risk and to guide prevention of the disease
and its sequelae. This presentation will suggest that heart
rate, easily measured clinically, is evolving from its demonstrated
status as a risk marker of mortality and morbidity in various
populations, to become a risk factor in patients with established
coronary artery disease. Substantial epidemiological data support
the predictive value of resting heart rate for total mortality
and cardiovascular mortality. Indeed, this relationship was
found in the general population and in hypertensive patients
as well as in patients with clinically evident coronary artery
disease (including those with stable angina and prior myocardial
infarction). Several criteria commonly used to assess the validity
of epidemiological associations (such as those involving blood
cholesterol concentrations and development of coronary artery
disease) have been applied to resting heart rate. The relationships
between resting heart rate and the development of coronary artery
disease, as well as all-cause and cardiovascular mortality,
were found to be strong, graded and independent of other factors
such as blood pressure and physical activity. The ongoing BEAUTIFUL
and SHIFT trials will assess the therapeutic value of pure heart
rate reduction in populations with coronary artery disease with
and without heart failure (as well, in SHIFT, in patients with
heart failure in the absence of coronary disease), thus providing
the necessary evidence to support risk factor status for heart
rate in this population.
Key Words: Heart rate • Risk factor • Cardiovascular mortality
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Introduction
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Coronary artery disease (CAD) is a highly prevalent condition
with life-threatening sequelae. The disease affects a large
portion of the general population over 60 years of age. According
to the Framingham Heart Study,
1 lifetime risk of coronary heart
disease for individuals aged 40 is 48% for men and 31% for women.
Therefore, coronary heart disease represents an important public
health problem, costly for society and responsible for relatively
high mortality and morbidity in the affected patients. An obvious
medical need, therefore, is guidance in efforts at disease prevention
aided by identifying markers to detect individuals likely to
develop CAD and its clinical sequelae. Observational studies
as well as randomized trials have contributed to current understanding
of risk markers and to the identification of those which can
be modified with clinical benefit, so-called ‘risk factors’.
2,3 The major risk markers for CAD and the first identified, aside
from sex and age, were total cholesterol, systolic and diastolic
blood pressures, smoking, and diabetes. Other, less predictive,
risk markers included obesity, physical inactivity, and family
history of coronary heart disease (particularly in young individuals).
Among more recently recognized markers of CAD risk, metabolic
syndrome and resting heart rate have been acknowledged. This
review aims to present and assess the evidence now accumulating
in support of the evolution of heart rate, an easily measured
clinical parameter, from risk marker to risk factor for mortality
and morbidity from CAD.
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Difference between risk marker and risk factor
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Both risk markers and risk factors are identified from correlations
between the presence of the factor and subsequent development
of the disease. A risk marker can be considered a risk factor
if intervention to modulate this factor results in parallel
modulation of risk, provided that the analysis demonstrating
this risk modulation accounts for possible confounding factors.
For example, systemic arterial hypertension is well established
as a risk factor for CAD and its sequelae and for stroke,
4 not
only because it identifies patients at risk for cardiovascular
events but because many studies, with many different agents,
have demonstrated that, in hypertensive persons, risk is reduced
when the blood pressure is reduced.
5–12
The demonstration of the benefits of blood pressure reduction with many different agents is important: some antihypertensives, including the angiotensin-converting enzyme (ACE) inhibitors, ramipril (in HOPE, the Heart Outcomes Prevention Evaluation) and perindopril (in EUROPA, European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease), and the angiotensin receptor blocker (ARB), telmisartan (in ONTARGET, The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) appear to reduce events by pharmacological effects that add to the benefits of antihypertensive action.5,6,13 Several criteria have been developed to validate a risk marker as a risk factor, as detailed in what follows.
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Resting heart rate and cardiovascular mortality
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Several epidemiological studies support resting heart rate as
a predictor (risk marker) of total mortality and of cardiovascular
mortality. The Chicago Peoples Gas Company Study (including
1233 men followed up for 15 years), the Chicago Western Electric
Company study (including 1899 men followed up for 17 years),
and the Chicago Heart Association Detection Project (including
5784 men followed up for 5 years), reported together in 1980,
were among the earliest to demonstrate the prognostic importance
of resting heart rate for all-cause mortality in large populations.
14 Indeed, multivariate analysis using age, blood pressure, total
blood cholesterol, smoking, and body weight as covariates found
heart rate to be an independent predictor of both sudden cardiac
death and non-cardiovascular mortality in two of the three cohorts
studied. As illustrated in
Figure 1, the Framingham study,
reporting a 30-year follow-up in 1987, demonstrated a significant
relationship, in both men and women, between heart rate, cardiovascular
mortality, coronary heart disease, and sudden coronary death.
15 Paralleling these findings, a study of 19 386 ‘white collar’
employees in France, followed up over 20 years, found that resting
heart rate significantly predicted non-cardiovascular mortality
in both men and women.
16 In men, the risk of cardiovascular
death was lowest among those with heart rate <60 bpm; in
comparison with this group, relative risks among men with resting
heart rate 60–80 bpm, 81–100 bpm, and >100 bpm
were 1.35, 1.44, and 2.18, respectively (all statistically significant).
Cardiovascular deaths were primarily and predominantly due to
coronary events, and not to cerebrovascular accidents. In men,
the predictive value of heart rate was independent of age, hypertension,
total cholesterol, body mass index, smoking, and exercise activity.
In women, heart rate did not influence cardiovascular mortality.
Other parallel results were reported from the MATISS Project,
which included 2533 men aged 40–69. During 24 457 subject-years
of follow-up, heart rate independently predicted total mortality,
cardiovascular mortality, and non-cardiovascular mortality.
17 In another French cohort, including 5713 asymptomatic working
men between the age of 42 and 53 at study entry, 23-year follow-up
demonstrated a significant association between resting heart
rate and both sudden and myocardial infarction-related death.
18 As seen in
Figure 2, in this study, resting heart rate
>75 bpm defined a relative risk of 3.92 for sudden death
compared with heart rate <60 bpm. Finally, in a study preliminarily
reported at the 2006 Annual Scientific Session of the European
Society of Cardiology, the same group showed a correlation between
resting heart rate and overall mortality and, additionally,
that changes in resting heart rate during a 5-year interval
also influenced mortality rates. Those subjects who decreased
their heart rate by more than 7 bpm had a lower mortality than
those whose heart rate remained relatively stable or those whose
heart rate increased >7 bpm.
19
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Figure 1 Resting heart rate and all-cause mortality in the Framingham Study. From Kannel et al.15 with permission. The Framingham study, with a follow-up of 30 years, demonstrated that in both sexes at all ages, all-cause mortality increased progressively and significantly (P < 0.01), in relation to heart rate.
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Resting heart rate and mortality in arterial hypertension
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Heart rate is an independent predictor of total and cardiovascular
death in subjects with arterial hypertension. The Framingham
Study evaluated 4530 subjects aged 35–74 with systolic
blood pressure
140 mmHg or diastolic
90 mmHg and who were not
on antihypertensive medication. Biennial mortality rates were
determined using pooled logistic regression.
20 A heart rate
increment of 40 bpm from the group mean was associated with
odds ratios for total mortality of 2.18 (1.68, 2.83 CI: 95%)
for men and 2.14 (1.59, 2.88 CI: 95%) for women; for cardiovascular
mortality, odds ratios were 1.68 (1.19, 2.37) for men and 1.70
(1.08, 2.67) for women.
Figure 3 shows the relation between
heart rate and mortality in men.
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Figure 3 Resting heart rate and all-cause mortality in men with hypertension. From Gilman et al.20 with permission. Analysis from the Framingham Study, involving 2037 men with hypertension, demonstrates the univariate (adjusted for age) relationship between heart rate and death from all causes, cardiovascular disease, and coronary heart disease.
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Resting heart rate in patients with coronary artery disease
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The most common manifestation of CAD is stable angina pectoris.
Angina occurs when myocardial oxygen demand exceeds oxygen supply,
usually resulting from coronary artery narrowing caused by atherosclerotic
lesions (and, far less commonly, by coronary artery spasm).
Increases in heart rate are well established as precipitators
of ischaemia, both by increasing myocardial oxygen demand and
by limiting supply.
21 In addition, among patients with established
CAD, heart rate is directly related to the likelihood of sudden
arterial occlusion.
22 Thus, it is not surprising that, in an
analysis of a registry of 24 913 patients with suspected or
proven CAD referred for coronary angiography and followed for
an average of 14.1 years in the Coronary Artery Surgery (CASS)
Study, Diaz
et al.
23 found resting heart rate to be an independent
predictor of total and cardiovascular mortality in men and women.
As pointed out by Palatini,
24 the relatively better prognosis
observed in patients with lower resting heart rates may not
be ascribed solely to beta-blocker therapy, independent of heart
rate, because the effect of heart rate also was found among
patients not taking beta-blockers. The predictive value of heart
rate was independent of the effects of hypertension, diabetes,
and smoking. Importantly, the relation between heart rate and
cardiovascular mortality also was independent of ejection fraction
and of the number of diseased coronary vessels. In addition,
patients with heart rate
83 bpm had a higher risk of hospital
admission for cardiovascular cause than those with a heart rate
62 bpm.
In a parallel study aimed to assess the post-acute and early chronic period after myocardial infarction, Hjalmarson et al.25 evaluated 1807 patients to define the relation between heart rate, in hospital and after discharge, and total mortality from day 2 to 1 year post-infarction. Both in-hospital mortality and post-discharge mortality were directly related to heart rate on hospital admission. As seen in Figure 4, total mortality was 15% for patients with admission heart rate between 50 and 60 bpm, 41% for those with heart rates >90 bpm, and 48% if heart rate was 110 bpm. Mortality from hospital discharge to 1 year was also related to maximal heart rate observed in the coronary care unit and to heart rate at discharge. In patients with severe heart failure, cumulative mortality was high (60–68%) regardless of heart rate on admission. Nonetheless, in patients with moderate heart failure (grade 2 pulmonary venous congestion), cumulative mortality when admission heart rate was 90 bpm was more than twice that when admission heart rate was <90 bpm (39 vs. 18%). A similar trend was observed in patients with mild or no heart failure (18 vs. 10%).
In another study of 8915 patients first seen when acutely ill
with myocardial infarction and treated with a fibrinolytic drug
as part of the GISSI-2 study, Zuanetti
et al.
26 found that in-hospital
mortality increased progressively with increasing heart rate
(7.1% for heart rate <60 bpm to 23.4% for heart rate >100
bpm). Heart rate was available at discharge in 7831 patients
in whom 6-month mortality was directly related to discharge
heart rate (from 0.8% for heart rates <60 bpm to 14.3% for
heart rates >100 bpm). On multivariate analysis the predictive
value of heart rate for mortality was independent of other factors
assessed. In CIBIS II, a study of the impact of the beta blocker,
bisoprolol, on outcome in patients with chronic heart failure,
a relation was also found between pre-therapy heart rate and
heart rate reduction during the trial vs. clinical outcome:
multivariate analysis indicated that baseline heart rate and
heart rate reductions both were significantly and independently
related to survival and to hospitalization for worsening heart
failure.
27 In the placebo group, the lowest baseline heart rates
and the largest heart rate reduction were associated with the
best survival and with a reduction of hospital admissions. Bisoprolol
further improved survival at any level of baseline heart rate
or heart rate reduction.
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Criteria for validating heart rate as a risk factor
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Several criteria are used to assess the validity of epidemiological
associations in CAD.
28 Plausibility, based on current understanding
of pathophysiology, provides a basis for concluding that a relation
is consistent with the associated disease, in this case, CAD.
Strength is determined by the relative risk of developing an
outcome with the factor vs. the risk without.
Gradation of effect,
analogous to a dose–response curve in pharmacology, is
defined by the quantitative impact of a change in the magnitude
of the factor or the duration of exposure to the factor vs.
the outcome of interest. The clearer the gradation of effect,
the more likely the factor is, indeed, a beneficially modifiable
risk factor.
Consistency is the demonstration of the association
between factor and outcome in a variety of populations, for
example, cohorts involving various age spectra, both genders,
and different ethnic groups. Perhaps most importantly, if the
factor is modifiable by currently available strategies, diminution
of the factor should beneficially modify the outcome.
Table 1 applies these criteria to the example of blood cholesterol,
and also to resting heart rate, the latter in relation to all-cause
mortality and cardiovascular mortality. In theory, heart-rate
reduction should reduce mortality, particularly cardiovascular
mortality, for patients with CAD and, most especially, for those
suffering acute myocardial infarction. Consistent with this
hypothesis, in a review of results of beta-blocker trials for
acute infarction, Kjekshus
et al.
29 observed a relation between
the reduction in resting heart rate and the reduction in mortality.
However, as yet, data are not available based on randomized
clinical trials designed specifically to test the hypothesis
that heart rate lowering improves survival post-infarction or
in any other population with CAD. In part, this deficiency relates
to the lack, until recently, of drugs that can selectively and
specifically lower heart rate without other apparent cardiovascular
effects. The recent availability of ivabradine, an
If current
inhibitor that is the first pure heart-rate lowering agent approved
in Europe (for treatment of patients with chronic stable angina
pectoris), has facilitated assessment of the impact of heart-rate
lowering, alone, on outcome in patients with CAD. The BEAUTIFUL
study (morBidity–mortality EvAlUaTion of the
If inhibitor
ivabradine in patients with coronary disease and left ventricULar
dysfunction) to be fully analysed and reported at the 2008 Annual
Scientific Session of the European Society of Cardiology, and
the ongoing Systolic Heart failure treatment with
If inhibitor
ivabradine Trial (SHIFT) study, now ongoing and slated for completion
in 2010, employ ivabradine to test the heart-rate lowering hypothesis.
BEAUTIFUL is a 10 900-patient, multinational, randomized, placebo-controlled
mortality trial in patients with chronic stable CAD plus left
ventricular dysfunction.
30 SHIFT is a 5500-patient trial assessing
the impact of pure heart rate reduction on mortality and heart
failure hospitalizations in patients with chronic stable heart
failure due to either primary myocardial disease or CAD.
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Conclusions
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Several observational studies, registries, and trials have identified
heart rate as a risk marker for cardiovascular mortality, independent
of other risk markers, including currently validated risk factors.
Resting heart rate has been directly related to all-cause mortality,
cardiovascular mortality, and development of cardiovascular
disease in the general population, in hypertensive patients,
and in patients with CAD. These findings, as well as the suggestive
data of Kjekshus
et al.
29 from cross-sectional analysis of post-myocardial
infarction trials, strongly suggest the potential benefit of
heart rate reduction in patients with CAD, demonstration of
which would validate heart rate as a risk factor. Thus far,
the relation between heart rate and outcome has been found plausible,
21,22,31 and strong, graded, and independent of other factors including
blood pressure and physical activity.
14–18 With BEAUTIFUL
and SHIFT, all criteria accepted for validation of a risk factor
will be assessable. From the currently available data, it is
likely that heart rate will join the list of such risk factors
for CAD, thus importantly altering management strategies for
patients with CAD.
Conflict of interest: The author is a paid consultant to Servier Laboratories, manufacturer of Ivabradine.
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Funding
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None other than consultancy/honoraria fees.
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Abstract
Introduction
