Increased heart rate as a risk factor for cardiovascular disease

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1 European Heart Journal Supplements (23) 5 (Supplement G), G3 G9 Increased heart rate as a risk factor for cardiovascular disease 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 4 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. 23 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, 131 Wilshire Boulevard, Los Angeles, CA 973, 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 X/3/G3 + 7 $35./ 23 The European Society of Cardiology, Published by Elsevier Science Ltd. All rights reserved.

2 G4 artery disease, myocardial infarction and hypertension 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 actions 3,4 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 (I f, 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 disease 3,4 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. 2 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 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 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 infarction 23 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), 1 the NHANES 1 Epidemiological Follow-up Study (NNHEFS), 11 the Chicago Employee Studies 6 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 The report on the relationship between heart rate and cardiovascular mortality focused on 7 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

3 Heart rate and cardiovascular disease G5 Table 1 Sudden death by heart rate according to age in men: 3-year follow-up in the Framingham study Age-adjusted annual incidence/1 Persons free of prior coronary artery disease All persons alive Resting heart rate (beats/min) years ** years ** years *** years* Trends for significance: * P <.5, ** P <.1, *** P <.1. 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 3 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 <.1, 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 years old at the time of the initial survey, which was conducted during the period From the initial 7594 patients at baseline, 5136 white and 859 black people (age range 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 1.3 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 3 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, Incidence (%) Study population Total mortality Coronary heart disease Other deaths Cancer Stroke 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

4 G6 Age-adjusted 2-year rate per 1, CHD CVD All cause < 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 2 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 4 59 years from the Chicago Peoples Gas Company followed for 15 years; 1899 men aged 4 55 years from the Chicago Western Electric Company followed for 17 years; and 5784 men aged 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. 1 Gillman et al. 12 followed 453 hypertensive persons (blood pressure 14 mmhg systolic and 9 mmhg diastolic; age range years) from the Framingham Heart Study for 36 years; those investigators found that, for the individuals who had increases in heart rates exceeding 4 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 CHD 9,11 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 (6 1 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.

5 Heart rate and cardiovascular disease G7 Maximum heart rate Final heart rate 4 4 % Mortality 3 2 % Mortality < < 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 Reference >84 beats/min at rest Elevated risk for CHD White men aged years; white women aged years 12 Increase of 4 beats/min >Twofold higher all-cause mortality Hypertensive persons beats/min on admission 15% total mortality at 1 year post-mi AMI patients 15 9 beats/min on admission 41% total mortality at 1 year post-mi AMI patients 15 >11 beats/min on admission 48% total mortality at 1 year post-mi AMI patients 15 <9 beats/min 5 7% severe heart failure AMI patients 15 9 beats/min on admission 24% severe heart failure AMI patients beats/min decrement within 25 3% decreased infarct size AMI patients 4 12 h of symptom onset 5 beats/min increment in heart rate 1.14 higher probability of Men and women, mean age 81 years 26 coronary events 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 187 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 experimental 21,22 and clinical observations 6 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

6 G8 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 study 6 with regard to sudden CHD death in men aged 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 NHEFS 11 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 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. References 1. Bristow MR. β-adrenergic receptor blockade in chronic heart failure. Circulation 2;11: Reiter MJ. 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