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