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Heart rate: an independent risk factor in cardiovascular disease
Åke Hjalmarson
The Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden
Corresponding author. Tel: +46 706 290607; fax: +46 31 82 37 62. E-mail address: ake.hjalmarson{at}gu.se
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Abstract
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Large epidemiological studies have demonstrated that elevated
heart rate is an independent risk factor for mortality and morbidity
in healthy individuals with and without hypertension and in
patients with coronary artery disease (CAD), myocardial infarction,
and congestive heart failure. Elevated heart rate has been found
to be a more powerful predictor of later death than depressed
left ventricular function. This means that heart rate in patients
with congestive heart failure is not only reflecting depressed
cardiac function. Heart rate should be viewed in the same light
as other risk factors, such as elevated blood pressure or cholesterol,
smoking, cardiac dysfunction, or diabetes. It is well documented
that interventions against these risk factors improve prognosis,
in terms of both primary and secondary prevention. Several large
placebo-controlled trials of patients with acute myocardial
infarction or congestive heart failure have demonstrated that
beta-blocking agents reduce mortality and morbidity. In fact,
the effects seem to be more marked in patients with higher pre-treatment
heart rates, and these patients also demonstrate a more marked
reduction in heart rate. It seems reasonable to believe that
heart rate reduction
per se is of major importance for the effects
of beta-blockers. Beneficial effects on the prognosis after
myocardial infarction have also been shown for some calcium
antagonists, which also reduce heart rate. Heart rate should
be considered as an important risk factor in patients at risk
of CAD or with established CAD. Treatment should be started
to reduce heart rate to a normal level, similar to the aim in
the treatment of patients with hypertension.
Key Words: Coronary artery disease • Heart rate • Cardiovascular disease
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Normal population and subjects with hypertension
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Epidemiological data on the long-term follow-up of healthy individuals
have demonstrated that there is an independent association between
elevated heart rate and cardiovascular mortality and morbidity.
Published studies on the general population and subjects with
hypertension include approximately 180 000 individuals
and show that cardiovascular mortality is significantly increased
with elevated heart rate.
1–3 In the Framingham study (
n = 5070), there was a 30-year follow-up of healthy men and women.
Although the increase in the overall mortality as a consequence
of elevated resting heart rate was more marked among men, it
was also found to be significant among women and in both younger
and older individuals (
Table 1).
4 In another American study
on healthy subjects aged 25–74 years who were followed
for between 6 and 13 years (
n = 5995), elevated resting heart
rate was found to be an independent risk factor for coronary
artery disease (CAD) incidence or death among white and black
men and women.
5 In several studies of healthy men and women,
it has been found that elevated resting heart rate is not only
a predictor of all-cause mortality, but also an independent
risk predictor of sudden cardiac death.
6,7
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Coronary artery disease at baseline
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In patients with CAD at baseline, elevated heart rate is an
independent risk predictor for major ischaemic coronary events,
cardiovascular mortality, and sudden cardiac death, in a manner
very similar to that seen in healthy individuals.
8–12 In the Coronary Artery Surgery Study (CASS) registry, which
included 24 913 men and women with suspected or proven
CAD with a median follow-up time of 14.7 years, resting heart
rate was found to be a predictor of overall and cardiovascular
mortality.
11 This study population was large enough to allow
subgroup analysis, and the association between heart rate and
total mortality held true in all analysed subgroups regardless
of sex, age, hypertension, cardiac function, body weight, presence
of diabetes, or use of beta-blockers (
Figure 1). Heart
rate was also a predictor of time to first rehospitalization
because of congestive heart failure. In a large British study,
heart rate was found to be a predictor of major ischaemic heart
disease events, cardiovascular mortality, and sudden cardiac
death, both in patients with CAD and in the normal population
with or without hypertension.
9
In patients with acute myocardial infarction, the resting heart
rate on arrival in the emergency room and the average heart
rate during the hospital stay or at the time of discharge are
independent and highly significant predictors of later death.
8 In this study from hospitals in San Diego (
n = 1807), heart
rate was found to be a more powerful predictor of later mortality
than assessment of left ventricular function after arrival in
hospital. This clearly demonstrates that heart rate is not only
reflecting depressed cardiac function, which has for long been
the general assumption. Very similar observations were made
in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto
miocardico-3 (GISSI-3) study (
n = 11 020) on patients with acute
myocardial infarction, which showed that elevated heart rate
at discharge was highly significant and independently correlated
with 6-month mortality (
Figure 2).
10
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Patients with heart failure
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Large trials on patients with congestive heart failure have
demonstrated that baseline heart rate is an independent risk
predictor of all-cause mortality, cardiovascular mortality,
and hospitalization for congestive heart failure.
13–15 This was the case in the MEtoprolol CR/XL Randomized Intervention
Trial in Heart Failure (MERIT-HF,
n = 3991), but only in the
placebo-treated patients (
Table 2).
14 In this study, mean
baseline heart rate was analysed by quintiles of heart rate
[mean heart rate of the lowest quintile was 71 beats per minute
(b.p.m.) and in the highest quintile, it was 98 b.p.m.].
In this trial, with increasing baseline heart rate, age was
lower, there were more females, ejection fraction was lower,
more patients were in the New York Heart Association Classes
III and IV, more patients had a non-ischaemic aetiology, and
there was a higher presence of diabetes. This tells us that
patients with a higher heart rate are very different from those
with a lower heart rate; in general, patients with a higher
heart rate have more risk factors. Even when adjusting for these
differences, however, heart rate is an independent risk predictor
of prognosis. Data from the large Cardiac Insufficiency Bisoprolol
Study-II (CIBIS-II,
n = 2539), also carried out in patients
with chronic heart failure, showed that heart rate was a strong
predictor of 1-year mortality, was most marked in the placebo
group, and was blunted by beta-blocker treatment.
15
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Pathophysiological evidence
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High resting heart rate reflects an imbalance of the autonomic
nervous system, with increased sympathetic activity and/or reduced
vagal activity. Heart rate is a major determinant of myocardial
oxygen consumption and energy utilization; furthermore, an increase
in heart rate reduces the diastolic coronary perfusion time.
By way of these two mechanisms, an increase in heart rate may
trigger ischaemic events. An increase in sympathetic activity
and/or lowering of vagal activity are known to increase the
risk of ventricular fibrillation in experimental studies on
myocardial ischaemia. It is well known that psychosocial stress-associated
increases in heart rate can trigger the onset of acute myocardial
infarction, in addition to sudden cardiac death. This has been
well documented in the literature, and one example of an increase
in attacks of sudden death occurred during the San Francisco
earthquake in 1994.
16 During the earthquake, there was a seven-fold
increase in the risk of sudden cardiac death reported by hospitals
in the region. Elevated heart rate during mental stress may
play a key role in the development of sudden cardiac death.
It is well known that the incidence of sudden cardiac death
among patients with hypertension, myocardial infarction, or
congestive heart failure is reduced by beta-blockers.
17
Experimental data have demonstrated that elevated heart rate has a role in the development of atherosclerosis and plaque disruption. Studies in monkeys have shown that a reduction in heart rate can delay the progression of coronary atherosclerosis.18 In addition, it has been shown that monkeys subjected to sinus node ablation or treatment with beta-blockers have significantly less coronary atherosclerosis than animals not receiving these treatments and with a higher heart rate.19,20 High heart rates have been associated with coronary artery endothelial dysfunction in experimental studies.21,22 These observations are supported by results from the Beta-blocker Cholesterol lowering Asymptomatic Plaque Study (BCAPS), a randomized trial that showed that administration of a beta-blocker reduces the rate of progression of carotid artery intima thickness in asymptomatic subjects.23 Furthermore, in a multivariable analysis, it was shown that elevated heart rate is associated with coronary plaque disruption in patients.24 There is good experimental and clinical evidence that high heart rate is of importance in the development and progression of atherosclerosis, myocardial ischaemia, acute ischaemic events, and sudden cardiac death, and that a reduction in heart rate has beneficial effects.
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Effects of heart rate reduction
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In 1981, three large trials of patients with acute myocardial
infarction demonstrated that beta-blockers such as timolol,
metoprolol, and propranolol reduced all-cause mortality, cardiovascular
and sudden cardiac death, and hospitalization.
25–27 In
these studies, it was also noted that patients with a heart
rate above the median at baseline had a higher mortality during
follow-up and that the effect of the beta-blockers was most
marked in the patients with the highest heart rate at baseline.
In the Göteborg Metoprolol trial, it was also found that
all of the beneficial effects of the beta-blocker metoprolol
were most marked in patients whose heart rate was above the
median at baseline (>70 b.p.m.).
26,28 These effects
included reduction in all-cause mortality at 3–24 months
(
Figure 3), sudden cardiac death, ventricular fibrillation,
infarct development, and enzyme-estimated infarct size. By analysing
all placebo-controlled beta-blocker studies in patients with
acute myocardial infarction, it was proposed by Kjekshus and
Gullestad
29,30 that there was a significant relationship between
the reduction in resting heart rate and the decrease in all-cause
mortality. Recently new meta-regression of randomized, placebo-controlled
trials of long-term ß-blocker treatment in patients
surviving myocardial infarction has a similar significant reduction
in log odds ratio for cardiac death (
P = 0.02) (
Figure 4)
, sudden
death (
P < 0.01), and reinfarction (
P < 0.01). The same
relationship between changes in heart rate and all-cause mortality
in patients with chronic heart failure—not only with the
use of beta-blockers, but also, for example, with angiotensin-converting
enzyme inhibitors. In the two large trials on patients with
chronic heart failure, CIBIS-II and MERIT-HF, patients with
a higher heart rate at baseline had the highest mortality, and
among these patients, there was a more marked effect of the
beta-blockers disoprolol and metoprolol CR/XL.
14,15
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Figure 3 Mortality related to heart rate at baseline (below or above median) in patients with suspected acute myocardial infarction on arrival in the emergency room and in the placebo and metoprolol groups of the Göteborg Metoprolol Trial.28
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Conclusion
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It can be concluded that heart rate is an independent risk predictor
of the onset of acute coronary events, including all-cause mortality,
cardiovascular mortality, sudden cardiac death, and acute coronary
syndromes, and also the development of myocardial infarction.
Measurement of heart rate should be carried out in patients
with or without established ischaemic heart disease and should
be viewed in the same light as other risk factors, such as high
blood pressure and cholesterol, smoking, cardiac dysfunction,
and diabetes. Hypertension, smoking, depressed cardiac function,
and diabetes are all associated with an elevated heart rate.
It is known that interventions against these risk factors improve
prognosis. In several large placebo-controlled trials of patients
with acute myocardial infarction or chronic heart failure, beta-blocking
agents have shown more marked effects on mortality in patients
with higher pre-treatment heart rates. It is reasonable to believe
that the heart rate reduction
per se is of major importance
in these effects of beta-blockers. With the introduction of
ivabradine, the first selective and specific
If inhibitor, heart
rate reduction can be obtained without affecting sympathetic
activity or contractility. Whether heart rate reduction
per se with ivabradine will have the potential not only to reduce
anginal attacks and myocardial ischaemia, but also to improve
prognosis in patients with CAD and left ventricular dysfunction
and in patients with chronic heart failure is presently being
tested in the ongoing large-scale studies, BEAUT
IfUL
31 and SH
IfT.
32
Conflict of interest: none declared.
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Abstract
Normal population and subjects...
