Download Increased heart rate as a risk factor for cardiovascular disease

European Heart Journal Supplements (2003) 5 (Supplement G), G3—G9
Increased heart rate as a risk factor for
cardiovascular disease
B.N. Singh
Department of Cardiology, VA Medical Center, West Los Angeles, and Department of Medicine, UCLA
Medical Center, and UCLA School of Medicine, Los Angeles, California, U.S.A.
KEYWORDS
Agents that exclusively
reduce heart rate;
Beta-blockade;
Cardiovascular
mortality;
Hypertension;
Increased heart rate;
Myocardial infarction;
Sudden death
Heart rate is a major determinant of oxygen consumption in patients with ischaemic
heart disease. Its pharmacological modulation is increasingly the focus of
therapeutic approaches to alleviate symptoms and prolong survival. It is the simplest
cardiovascular variable to measure accurately and reproducibly. Many long-term
follow-up studies suggest that elevated heart rate increases all-cause mortality,
cardiovascular disease and sudden death in patients with known or suspected
coronary heart disease, survivors of myocardial infarction and patients with
hypertension. These links hold for men and women, and are unrelated to ethnic
origin. The effect on sudden death or total mortality increases as a function of heart
rate such that an increase in heart rate by more than 40 beats/min doubles total
mortality. Conversely, low heart rate reduces risk for coronary artery disease and
sudden death. Primary and secondary prevention studies in myocardial infarction
indicated that elevated heart rate in susceptible patients predicts risk for
developing myocardial infarction and death. Prophylactic beta-blockers attenuate
risks for reinfarction, sudden death and total mortality; these effects correlate with
reduced heart rate, thus providing a compelling basis for developing agents that
reduce heart rate exclusively as antianginal agents for the therapy of myocardial
ischaemia with broader therapeutic implications.
© 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All
rights reserved
Introduction
Because heart rate is a critical determinant of
myocardial oxygen consumption in patients with
coronary artery disease, the relationship between
heart rate and prognosis or severity of myocardial
ischaemia has assumed major therapeutic
importance. Other factors that are also determinants of myocardial oxygen consumption are
contractility and end-systolic stress, but heart
rate is the simplest to quantify accurately and
Correspondence: Bramah N. Singh, Department of Cardiology,
VA Medical Center of West Los Angeles, 1301 Wilshire
Boulevard, Los Angeles, CA 90073, U.S.A.
reproducibly. In recent years its importance has
been highlighted by the success of heart rate
lowering drugs such as beta-blockers. They are
now recognized as major antianginal and
antiarrhythmic agents, with the property of
reducing mortality and morbidity in a wide range
of cardiac disorders.1,2 A reduction in heart rate
appears to have the closest and most consistent
favourable relation to total and cardiovascular
mortality.3,4
It is therefore not surprising that an increasing
number of prospective and retrospective primary
and secondary observational studies have been
undertaken to determine the nature of the
association between heart rate and coronary
01520-765X/03/0G0003 + 07 $35.00/0 © 2003 The European Society of Cardiology, Published by Elsevier Science Ltd. All rights reserved.
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artery disease, myocardial infarction and
hypertension.5—16 They have indicated that in
these settings, as well as in others, sustained
elevated heart rate is strongly predictive of a
significantly higher incidence of death,3,15,16 as
compared with those settings in which the heart
rate is persistently within the normal or a lower
range. The observation that the favourable effects
of beta-blockade on mortality have been found to
correlate significantly with their heart rate
lowering actions3,4 provides a compelling basis for
exploring the role of other bradycardic agents in
cardiovascular therapeutics. In this regard,
because of their pharmacological action, blockers
of the sinus pacemaker current (If, or ‘funny’
current), agents that exclusively reduce heart
rate,17 may be of particular importance as antiischaemic agents, and they have potential utility
in reducing morbidity and mortality in
cardiovascular disorders that are characterized by
sustained increases in heart rate. In the present
paper the clinical settings in which increased
heart rate may be an independent risk factor for
cardiovascular morbidity and mortality are
critically discussed.
Potential pathophysiological
mechanisms
Although there appears little doubt that a
persistently high heart rate is associated with an
increase in coronary and cardiovascular death
rates, the precise reason for this association
remains unclear. It has been attributed to overall
lack of physical fitness or poor health.7 However,
the consistently favourable effects of betablockade in patients with ischaemic heart
disease3,4 emphasizes the significance of
sympathetic
blockade
with
associated
augmentation in vagal activity,5 both of which
have been shown to increase the threshold of
ventricular fibrillation in experimental animal
models.18,19 Similarly, it might be expected that
beta-blockers could reduce infarct size, which has
been shown to increase with high heart rates.20
There is experimental and clinical evidence that
suggests that sustained elevations in heart rate
may play a direct role in the pathogenesis of
coronary atherosclerosis.21—24 For example, in
cynomolgus monkeys in which heart rates were
reduced by surgical ablation of the sinoatrial
node, the extent of coronary atherosclerosis
induced by a high-cholesterol diet over 6 months
was significantly lower than that in a group that
underwent a sham operation and with heart rates
B.N. Singh
that were significantly higher as determined by
telemetry.21 These experimental findings are
consistent with clinical studies in which the
minimum heart rate obtained from 24-h
ambulatory Holter recordings was an independent
factor that correlated with severity of coronary
atherosclerosis in young patients after myocardial
infarction23 and with rate of progression of
atherosclerotic disease.24 Thus, there is now
evidence in animals as well as in humans that
heart rate may be a significant determinant of
atherosclerotic disease progression and of its
clinical manifestation.
These observations clearly form a basis for the
continued exploration of the role of heart rate
reduction in the subsets of patients in whom
increased heart rate may be an independent risk
factor for cardiovascular disease.25
Heart rate as a predictor of risk for
cardiovascular disorders:
epidemiological observations
The integral relationship between resting heart
rate, coronary artery disease and mortality has
been documented in a number of epidemiological
studies. These studies include, but are not
confined to, the Framingham Heart Study,7,9 the
first National Health and Nutrition Examination
Survey (NHANES 1),10 the NHANES 1 Epidemiological Follow-up Study (NNHEFS),11 the Chicago
Employee Studies6 and the Göteborg Primary
Prevention Trial.14 The Chicago Employee study is
mentioned in passing because it is one of the
oldest in the series, and its directional data are, in
general, consistent with the results of the
subsequent studies. In the discussion that follows,
only aspects of the findings in those studies that
address the impact of increased heart rate
relative to mortality and morbidity are mentioned.
Heart rate and cardiovascular mortality
The longest follow-up was reported from the
Framingham Heart Study — a prospective study
that was started in 1948.9 The report on the
relationship between heart rate and cardiovascular mortality focused on 5070 individuals who
were free of cardiac disease at entry into the
study. They were subjected to biennial examinations of a wide range of variables, including the
following: cardiovascular examination and history;
an ECG; measurement of vital capacity, body
weight and skin-fold thickness; various blood
Heart rate and cardiovascular disease
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Table 1 Sudden death by heart rate according to age in men: 30-year follow-up in the Framingham study
Age-adjusted annual incidence/1000
Persons free of prior
coronary artery disease
30—67
68—75
76—83
84—91
92—220
All persons alive
35—64 years**
65—94 years**
36—64 years***
65—94 years*
1
1
1
2
3
2
3
4
7
6
1
1
2
3
5
4
4
7
12
6
Trends for significance: *P < 0.05, **P < 0.01,
***P
< 0.001.
chemistry and blood pressure determinations; and
history of smoking. The resting ECG was used for
the determination of heart rate. Over the followup period of 30 years there were 1876 total
deaths, of which 894 were cardiovascular in origin.
For both sexes, all-cause, cardiovascular and
coronary disease mortality increased progressively
relative to the antecedent resting heart rates
determined biennially. There was no suggestion of
critical values or thresholds that could be labelled
as safe or hazardous. The trend significance was at
P < 0.01, as it was for sudden death (Table 1). The
effect of heart rate on mortality or sudden death
was independent of associated cardiovascular risk
factors, and death rate was higher in man than in
women.
The relationship between heart rate, coronary
artery disease and death was also investigated
systematically in NHEFS.11 The participants in that
study were screened from those who were 25—
74 years old at the time of the initial survey,
which was conducted during the period 1971—
1975. From the initial 7594 patients at baseline,
5136 white and 859 black people (age range 45—
74 years) remained for analysis after all defined
exclusion criteria were met and follow-up
variables established. The duration of follow-up
for this analysis was 6—13 years, with an average
of 9.9 years for white subjects and 10.3 years for
the black survivors. It is noteworthy that, in
contrast to the Framingham Study, heart rates
were not quantified by ECG but were obtained by
a physician who counted the radial pulse for 30 s.
The relative risk for the incidence of coronary
heart disease (CHD) was significantly elevated in
white men with pulse rate greater than
84 beats/min as compared with those with rates
under 74 beats/min, after correcting for multiple
risk factors. The incidence of CHD was also
increased in white women with elevated pulse
rate. The risks for death from all causes,
Study population
961
2277
2120
1202
576
319
16
Total mortality
Coronary heart disease
Other deaths
Cancer
Stroke
12
Incidence (%)
Resting heart rate
(beats/min)
8
4
0
≤59
60—69 70—79 80—89 90—99
Heart rate (beats/min)
≥100
Fig. 1 The incidence of mortality from various causes over a
mean period of 11.8 years of follow-up as a function of heart
rate at entry to the Göteborg Primary Prevention Trial. The
study population refers to the number of patients within a
range of heart rates at entry. Adapted from Wilhelmsen et al.14
cardiovascular diseases and non-cardiovascular
diseases were also elevated for white men with
raised pulse rate, and these findings was
independent of other factors. It should be
emphasized that risks for death and cardiovascular
diseases were also increased in the case of black
men and women with elevated pulse rate, but the
association with cardiovascular diseases and high
pulse rate was particularly striking in the case of
black women, even after adjustment for all of the
baseline risk factors.
Similar data on the incidence of all-cause
mortality as well as CHD mortality were reported
in the Göteborg Primary Prevention Trial,
conducted in Sweden.14 In that study, 7455
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B.N. Singh
Age-adjusted 2-year rate
per 1,000
60
50
40
CHD
CVD
All cause
30
20
10
0
<65
65—74
75—84
85+
Heart rate (beats/min)
Fig. 2 Relationship between heart rate and mortality among men with hypertension. The data that form the basis of this bar diagram were derived from a 36-year follow-up of the Framingham Heart Study. See text for details. Adapted from Gillman et al.12
CHD=coronary heart disease; CVD=cardiovascular heart disease.
patients were enrolled and followed as a function
of heart rate at entry for a mean of 11.8 years.
Deaths were stratified into total mortality, and
death due to coronary artery disease, cancer and
stroke, and other deaths. The follow-up data are
presented in Fig. 1. It is noteworthy that the rate
of death from all causes and from cardiovascular
disease increased as a function of increasing heart
rate or when pulse rate increased beyond
84 beats/min, as was reported in NNHEFS.11
Finally, heart rate as a prognostic factor for CHD
and mortality was also determined in three distinct
epidemiological studies conducted 20 years ago.6
The associations between heart rate and death
from cardiovascular diseases, coronary artery
disease and sudden cardiac death from CHD, as well
as mortality from all causes, were studied
prospectively in middle-aged white male
employees: 1233 men aged 40—59 years from the
Chicago Peoples Gas Company followed for
15 years; 1899 men aged 40—55 years from the
Chicago Western Electric Company followed for
17 years; and 5784 men aged 45—64 years of age
from the Chicago Heart Association Detection
Project in Industry followed for 5 years. Despite the
relatively short period of follow-up, in a univariate
analysis mortality from cardiovascular or noncardiovascular causes increased with increasing
heart rate. In a multivariate Cox regression
analysis, controlling for hypertension, age, serum
cholesterol, number of cigarettes smoked per day
and relative weight, heart rate emerged as a
significant risk factor for sudden death in two of the
three studies. In sum, the authors concluded that
the results of the three studies suggested that high
heart rate may be an independent risk factor for
sudden death from CHD.
Risk for high heart rate in hypertension
and in the elderly
It has been shown that hypertensive patients
generally have a higher heart rate than do
comparable normotensive persons.10 Gillman
et al.12 followed 4530 hypertensive persons (blood
pressure ≥140 mmHg systolic and ≥90 mmHg
diastolic; age range 35—74 years) from the
Framingham Heart Study for 36 years; those
investigators found that, for the individuals who
had increases in heart rates exceeding
40 beats/min, the total mortality more than
doubled over this period. The details are
summarized in Fig. 2. The rapid heart rate that
the individuals had was not related to pre-existing
illness but appeared to be an independent risk
factor for cardiovascular death in those with
hypertension. Thus, the heart rate data relative to
the impact on mortality are consistent with those
reported for patients with known CHD9,11 and
those for patients who had sustained but survived
myocardial infarction, as discussed below.15 The
data suggest that treatment regimens for
hypertension may need to include heart rate
lowering drugs.
Of interest also is the outcome of the study
reported by Aronow et al.,26 who evaluated the
risk for high heart rate in elderly patients (60—
100 years, mean age 81 years) who had
hypertensive or other forms of heart disease and
were in sinus rhythm. That study was prospective
and conducted in 1311 patients in whom mean
heart rates were quantified from 24-h Holter
recordings. The data indicated that male sex,
increasing age and mean 24-h heart rates were
independent risk factors for new coronary events.
Heart rate and cardiovascular disease
50
G7
50
Maximum heart rate
40
% Mortality
% Mortality
40
Final heart rate
30
20
10
30
20
10
0
0
<50
50
59
60
69
70
79
80
89
90
99
100 110 ≥120
109 119
<50
50
59
60
69
70
79
80
89
90
99
≥100
Heart rate (beats/min)
Heart rate (beats/min)
Fig. 3 Mortality from discharge to 1 year at maximal heart rate values observed at discharge physical examination. Adapted from
Hjalmarson.16
Table 2 Clinical consequences of high heart rate and implications of reducing heart rate
Heart rate
Impact
Population
>84 beats/min at rest
Elevated risk for CHD
Increase of 40 beats/min
50—69 beats/min on admission
≥90 beats/min on admission
>110 beats/min on admission
<90 beats/min
≥90 beats/min on admission
14 beats/min decrement within
12 h of symptom onset
5 beats/min increment in heart rate
>Twofold higher all-cause mortality
15% total mortality at 1 year post-MI
41% total mortality at 1 year post-MI
48% total mortality at 1 year post-MI
5—7% severe heart failure
24% severe heart failure
25—30% decreased infarct size
White men aged 65—74 years;
white women aged 45—74 years
Hypertensive persons
AMI patients
AMI patients
AMI patients
AMI patients
AMI patients
AMI patients
12
12
15
15
15
15
15
4
Men and women, mean age 81 years
26
1.14 higher probability of
coronary events
Reference
AMI=acute myocardial infarction; CHD=coronary heart disease; MI=myocardial infarction. Adapted from Habib.25
The probability of developing new coronary events
was 1.14 times higher for an increment of
5 beats/min in heart rate after the effects of
other confounding risk factors were controlled.
Myocardial infarction, high heart rate
and mortality
A number of studies have documented two
features that are of clinical importance: the
overall heart rate in patients sustaining
myocardial
infarction
is
higher
(mean
78.5 beats/min) than that (69.5 beats/min) in
matched control individuals;27 and elevated heart
rate is predictive of risk for development of acute
myocardial infarction and sustaining complications
while having a greater risk for death.15 Furthermore, a sustained elevated heart rate in patients
after acute myocardial infarction is well
correlated with higher mortality.8 Of particular
interest are the results of a large study involving
1807 post-myocardial infarction patients reported
by Hjalmarson.16 In a multicentre study heart rate
was examined on admission to the coronary care
unit and after discharge, and total mortality was
determined from day 2 to one year in patients
with and without heart failure. The mortality data
relative to heart rate are shown in Table 2;25 the
mortality figures from hospital discharge to 1 year
at increasing maximal heart rate values and values
observed at discharge physical examination are
presented in Fig. 3. Cumulative mortality was high
(61—68%) in patients with severe grades of heart
failure, regardless of the level of heart rate at
admission.
Conclusion
The experimental21,22 and clinical observations6—16
reviewed here provide a convincing basis for the
link between elevated heart rate and development of coronary atherosclerosis, with an
associated increase in all-cause, non-cardiovascular and cardiovascular mortality. Aspects of
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the data are summarized in Table 2. The link
between sudden cardiac death and elevated heart
rate is perhaps the most compelling. Although
most studies support the notion that the effect of
augmented heart rate is an independent risk
factor for cardiovascular mortality and morbidity,
this has not been uniform.6,9 For example, heart
rate was significantly associated with the
incidence of any form of CHD after adjustment
was made for age in men but not in women; in
neither was it significant when adjustment was
made for multiple risk factors.11 On the other
hand, the association between CHD and death and
sudden death in men remained significant after
adjustment of multiple risk factors.9,11,27 This was
also the case in the Chicago cohorts study6 with
regard to sudden CHD death in men aged 45—
64 years. The issue with regard to sudden death
remained uncertain because of the lack of
accurate classification of deaths into sudden
versus non-sudden in NHEFS.11
There have been some indications regarding sex
differences relative to the elevated heart rate as
a risk for cardiovascular morbidity and mortality.
For example, age-adjusted all-cause mortality and
that from cardiovascular diseases were positively
correlated with heart rate in the Framingham
Heart Study and in the Chicago cohort studies.6,9
This association was also significant in the case of
women in the Framingham Heart Study.9 It is of
interest that, in both the Framingham and Chicago
studies, there was a positive association between
non-cardiovascular mortality and elevated heart
rate. The findings from NHEFS11 are consistent
with data from the studies in which there were
associations between CHD and death from all
causes and from cardiovascular and noncardiovascular diseases, independently of other
risk factors. Clearly, further studies are necessary
to define more definitively the nature of the
relationship between elevated heart rate and risk
for CHD and mortality in women and in African
Americans. As suggested by Gillum et al.,11 we
require a clearer delineation of the mechanisms of
known associations relative to physical activity,
cholesterol status, insulin resistance and left
ventricular hypertrophy, as well as continuous
measurements of heart rate and blood pressure.
In sum, there is now a substantive body of
evidence that sustained elevated heart rate is
associated with an increased incidence of
mortality in persons with suspected or known
coronary artery disease, in those with documented
myocardial infarction, in those with hypertension
and in those who are elderly. Sudden cardiac death
has been the consistent finding in patients with
B.N. Singh
elevated heart rate.6—16,28,29 Prophylactic betablockers at doses that significantly reduce heart
rate attenuated the risk attendant with elevated
heart rate, as well as reducing the severity of
myocardial ischaemia, in subsets of patients in
whom they have been tested.1,2 Specific heart
rate lowering agents have been developed as
antianginal compounds on the basis of their major
effects
in
reducing
myocardial
oxygen
consumption, but they may have broader clinical
therapeutic applications, which merits serious
scrutiny in relevant clinical trials. Their selective
property of slowing the heart rate will permit
testing of the critical hypothesis that heart rate
reduction per se may prolong survival in certain
subsets of patients.
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