Numerous studies have shown that faster. The Physiological Determinants and Risk Correlations of Elevated Heart Rate Paolo Palatini and Stevo Julius

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1 AJH 1999;12:3S 8S The Physiological Determinants and Risk Correlations of Elevated Heart Rate Paolo Palatini and Stevo Julius A number of studies have shown that fast heart rate is associated with high blood pressure and metabolic disturbances, and that it is a strong precursor of hypertension, atherosclerosis, and cardiovascular events. Subjects with tachycardia often also exhibit increased plasma insulin, overweight, and higher hematocrit. These relationships have been observed also in the elderly and among hypertensive individuals and have held true after controlling for smoking, alcohol intake, and physical activity habits. In three different populations studied with a mixture analysis we demonstrated that the heart rate-blood pressure association was mostly explained by a subpopulation of subjects with high heart rates who had higher levels of blood pressure, total cholesterol, triglycerides, postload glucose, and plasma insulin. The clustering of these risk factors may explain why cardiovascular morbidity is higher in individuals with fast heart rates. Numerous studies have shown that faster resting heart rate is associated with higher blood pressure, 1 5 a relationship that has been observed either in general populations or in cohorts of hypertensive subjects. 6,7 In the Chicago studies heart rate turned out to be one of the strongest correlates of blood pressure, with correlation coefficients ranging from 0.2 to Also From the Dipartimento di Medicina Clinica e Sperimentale, University of Padova, Padova, Italy (PP), and Division of Hypertension, University of Michigan, Ann Arbor, Michigan (SJ). Address correspondence and reprints requests to Prof. Paolo Palatini, MD, Dipartimento di Medicina Clinica e Sperimentale, University of Padova, via Giustiniani, 2, Padova, Italy. Sympathetic overactivity seems to be responsible for both the increase in heart rate and blood pressure, and for the metabolic abnormalities. In addition to being a marker of sympathetic overactivity, tachycardia seems to have a direct action in the induction of risk. Studies in cholesterol-fed monkeys have shown that the reduction of heart rate could retard the development of coronary atherosclerosis. Furthermore, fast heart rate increases the pulsatile nature of the arterial blood flow and increases arterial wall stress. Antihypertensive drugs that lower the heart rate seem to have a good potential for prolonging life expectancy in humans. Am J Hypertens 1999;12:3S 8S 1999 American Journal of Hypertension, Ltd. KEY WORDS: Heart rate, tachycardia, hypertension, insulin resistance, sympathetic system, cardiovascular risk. in the Mirano and the Belgian studies 6 heart rate was significantly correlated with systolic and diastolic blood pressure, but the coefficients were higher in men than in women. In the HARVEST, a multicenter study performed in mild hypertensive individuals, the correlation between heart rate and blood pressure was also stronger in men. 6 These relationships held true in multiple linear regression analyses, where many confounding factors were used as additional independent variables. Resting heart rate has also been found to be prospectively related to the development of hypertension, as shown by Levy et al, 2 and by the results of the Kaiser-Permanente and the Framingham studies. 9,10 In the latter study the predictive power of heart rate for 1999 by the American Journal of Hypertension, Ltd /99/$20.00 Published by Elsevier Science, Inc. PII S (98)

2 4S PALATINI AND JULIUS AJH JANUARY 1999 VOL. 12, NO. 1, PART 2 FIGURE 1. Association of heart rate with mortality rate among 2037 men with hypertension. Data from 36-year follow-up of the Framingham Study. CHD indicates coronary heart disease, and CVD indicates cardiovascular disease. Reproduced from Gillman et al: Influence of heart rate on mortality among persons with hypertension: The Framingham Study. Am Heart J 1993;125: , 17 with permission of the Mosby-Year Book Inc. future development of hypertension was as great as that of obesity. In addition to predicting the development of hypertension, mounting evidence indicates that heart rate is associated with an increased risk of cardiovascular morbidity and mortality in the general population as well as within hypertensive individuals. A relation between heart rate and coronary heart disease has been shown in several studies. The first reports to describe this association were a study of 10,000 Israeli male government employees 11 and the Glostrup County study. 12 In the latter study the predictive power of heart rate for coronary events was superior to that of cholesterol. The relationship between high heart rate and the development of myocardial infarction was later found in other studies, such as the Chicago People Gas Co. study 13 and the National Health and Nutrition Examination Survey (NHANES) study. 14 The results of the Framingham study confirmed the predictive value of heart rate for coronary events, but a significant association was found only in men. 15,16 The first evidence for an association between high heart rate and cardiovascular mortality was provided as early as 53 years ago by Levy et al. 2 These authors found that coronary death was much higher in subjects with sustained tachycardia at previous examinations than in subjects with normal heart rate. In the Framingham study heart rate appeared to be significantly related to cardiovascular death in men even when many other risk factors were taken into account. 15,16 The heart rate-cardiovascular mortality association was present also within the hypertensive portion of the Framingham population (Figure 1). In fact, Gillman et al, in a 36-year follow-up of the hypertensive subjects enrolled in the Framingham study, 17 found that for an increment of 40 beats/min the age- and systolic blood pressure-adjusted odds ratio for all-cause mortality was 2.18 (P.0001). In keeping with previous results from Framingham obtained in the general population, the association was stronger in men than in women and was attenuated after adjustments for other cardiovascular risk factors. In the Framingham study as well as in the Heart Association and the People Gas Co. studies, an association was found between heart rate and sudden death. 13,15,16 Whereas in the Framingham study the relationship was linear, in the Chicago studies a J- shaped association was found, as sudden death was increased also in the subjects with a heart rate less than 60 beats/min. PATHOPHYSIOLOGIC CONSIDERATIONS Tachycardia in hypertension is a strong marker of a widespread abnormality of the autonomic control of the circulation, characterized by an increased sympathetic tone and a decreased vagal activity, which in the long run is conducive to atherosclerosis and cardiovascular morbidity. In addition to being related to high blood pressure, heart rate is associated with several other risk factors, such as increased blood glucose, hyperinsulinemia, dyslipidemia, increased body mass index, and high hematocrit. 6,7 We recently demonstrated that subjects with tachycardia have the characteristic features of the insulin resistance syndrome: high blood pressure, overweight, increased blood glucose and insulin, and abnormal lipid profile. 18 These results were obtained in three different populations using mixture analysis, a statistical test devised in the Ann Arbor laboratory that allows the identification of more than one homogeneous population within an apparently heterogeneous population. 19 The heart rate distribution within each population was studied in the men and the women separately. Within each male population, we could identify two different subpopulations, a larger one with normal heart rate and a smaller one with fast heart rate. The subgroups of men with tachycardia had high blood pressure and lipid levels, increased postload glucose (Figure 2), and high fasting insulin, showing the classical picture of the insulin resistance syndrome. Among the women, two distinct subpopulations could be identified only in the Tecumseh study, but no blood pressure and lipid differences could be found between the subjects with high and normal heart rate. These data help to explain why subjects with fast heart rates develop hypertension, atherosclerosis, and their complications in subsequent years. In this respect, heart rate appears to be a risk indicator rather than a risk factor, as tachycardia is a well-recognized marker of sympathetic activation and reduced vagal tone.

3 AJH JANUARY 1999 VOL. 12, NO. 1, PART 2 HEART RATE AS A RISK FACTOR 5S FIGURE 2. Postload glucose in the subjects with high and normal heart rate, after classification by mixture analysis, in the Belgian population. HR indicates heart rate. Based on data from Palatini et al: Relationship of tachycardia with high blood pressure and metabolic abnormalities. A study with mixture analysis in three populations. Hypertension 1997;30: The connection between autonomic dysregulation and the development of atherosclerosis has been well elucidated. 6,7 However, there is a body of evidence to show that a fast heart rate also plays a role in the induction of the risk, and that it has a direct action in producing atherosclerotic lesions. This was shown by Kaplan et al 20,21 and by Beere et al 22 (Figure 3), in studies performed in cholesterol-fed monkeys in which heart rate was decreased by -blocker administration and by ablation of the sinoatrial node, respectively. In these studies, heart rate reduction produced FIGURE 3. Severity of coronary artery lesions in a group of monkeys whose heart rate was decreased by sinoatrial node ablation (low) and a group of sham-operated animals with higher heart rate (high). The left panel relates to the average percent stenosis of lesions with the maximum stenosis for each animal within a group, and the right panel relates to the average area of the coronary lesions. Based on data from Beere et al: Retarding effect of lowered heart rate on coronary atherosclerosis. Science 1984; 226: a retardation of the development of coronary lesions. The results by Kaplan et al are of particular interest, because in that study the propranolol-induced heart rate reduction had a beneficial effect only in the animals with heightened sympathetic activity. 21 The direct atherosclerotic effect of tachycardia on the arterial wall can be explained by intensification of the pulsatile nature of the blood flow and the associated changes in the shear stress, which favor the occurrence of endothelial lesions. 6,7 Moreover, the faster the heart rate, the higher the mean blood pressure. In fact, studies in our laboratory performed with intraarterial measurement showed that for the same systolic and diastolic blood pressure level mean blood pressure steadily increases with increasing values of heart rate. 23 This is due to the progressive shortening of the diastolic phase of the cardiac cycle. CONNECTION BETWEEN TACHYCARDIA AND CARDIOVASCULAR EVENTS As mentioned above, the Framingham study and the Chicago Heart Association study found a close association between tachycardia and sudden death. 13,15,16 This may be due to several factors, including left ventricular hypertrophy, and it is known that sympathetic stimulation has a strong trophic action on the heart. 24,25 This was clearly shown by Julius et al in the experimental animal through induction of repeated neurogenic pressor episodes that were associated with increases of plasma norepinephrine. 25 An association of cardiac hypertrophy with increased plasma catecholamine values has been described in several human studies, and, interestingly enough, the association was seen only in males. 26,27 It is known that left ventricular hypertrophy favors the occurrence of ventricular arrhythmias. 28,29 In subjects with tachycardia the occurrence of cardiac arrhythmias can also be favored in a direct fashion. 30 Lown and Verrier demonstrated that the threshold for arrhythmias was greatly decreased by an increase of sympathetic tone, that it was increased by vagal stimulation, and that it was reduced by atropine administration, especially in the presence of heightened sympathetic activity. 31 This points to a role of reduced parasympathetic activity in favoring the occurrence of ventricular arrhythmias, and a decreased parasympathetic tone has been described in hypertensive subjects Elevated heart rate may be also the marker of preexisting cardiovascular disease. We recently demonstrated that an abnormal left ventricular contractility may be an early clinical finding in hypertensive individuals, and that it is accompanied by enhanced sympathetic activity. 36 In 64 of 722 mild hypertensive subjects we found that the left ventricular midwall shortening-stress relationship measured echocardiographically was less than the 95% confidence interval

4 6S PALATINI AND JULIUS AJH JANUARY 1999 VOL. 12, NO. 1, PART 2 of 50 normotensive controls, indicating impaired cardiac contractility. Subjects with depressed contractility had concentric remodeling of the left ventricle and impaired left ventricular pump function. Among these 64 subjects, left ventricular ejective performance was depressed in 35 and normal in 29. Subjects with normal ejective function had greater posterior wall, ventricular septum, and relative wall thicknesses than those with depressed ejective function. Twenty-fourhour urinary norepinephrine was 50% higher in the subjects with normal ejective performance than in those with a decreased one. Stroke volume and cardiac output were similar in the two groups. These results indicate that decreased left ventricular contractility in hypertension elicits a rise in sympathetic activity in an attempt to improve left ventricular chamber mechanics and to increase stroke volume. Similar results were obtained by the Ann Arbor group 37 which investigated patients with normokinetic borderline hypertension who had normal values of cardiac output, but had an increased heart rate. After autonomic blockade a significant decline in cardiac output and stroke volume was observed in the hypertensive subjects, indicating that compensatory tachycardia was necessary to maintain a normal pump function. HEART RATE IN THE ELDERLY It is known that the risk related to the traditional risk factors tends to lose its predictive power in old age. 38,39 Total cholesterol, smoking, and even hypertension have been shown to be unrelated to the occurrence of cardiovascular events and to all-cause and cardiovascular mortality in elderly subjects. It is therefore interesting to know whether the risk related to heart rate persists into old age or fades as years go by. This issue was explored in two studies. In 360 men and 921 women older than 60 years of age. Aronow et al found a 1.14 times higher probability of developing new coronary events for an increment of 5 beats/min of heart rate after controlling for several confounders. 40 Mean heart rate was beats/min in patients with new coronary events and beats/ min in subjects free of events (P.0001). In the Cardiovascular Study in the Elderly (CASTEL) the predictive power of heart rate for mortality was investigated in 763 men and 1175 women 65 years of age or older. 41 Subjects were divided into quintiles of heart rate. After adjustment for other risk factors including hypertension, total- and HDL-cholesterol, smoking, diabetes, alcohol intake, and other confounders, relative risk for cardiovascular mortality was 1.38 for the men with a heart rate 80 beats/min (top quintile), compared with those of the three intermediate quintiles. Conversely, men with heart rate 60 beats/min (bottom quintile) had a 0.82 lower risk of cardiovascular mortality than their counterparts in the three intermediate quintiles. Similar trends were found in the women, but the between-group differences did not achieve the level of statistical significance. In the Cox analysis, the predictive power of heart rate for mortality in men was superior to that of the major risk factors for atherosclerosis. In elderly individuals, tachycardia can be the marker of poor physical fitness or loss of vigor. However, the persistence of the association of heart rate with cardiovascular mortality after controlling for a physical activity score, and the elimination of the subjects who died within the first 2 years after the baseline evaluation, 41 indicate that other mechanisms are also responsible for the heart rate-death association. The strong relationship between heart rate and metabolic disturbances found in the CASTEL study points to a role of insulin resistance in determining cardiovascular morbidity also in older individuals. Contrary to what has been observed in adult subjects of the Heart Association study, in the CASTEL study elderly subjects with bradycardia did not show an increased risk of sudden death, but rather a decreased chance of dying from sudden death or other cardiovascular causes. The results of the above studies 40,41 indicate that heart rate also has an important clinical value in old age, at least in men. They further suggest that autonomic disturbances are still present in the elderly. Recent results from the Framingham Heart study support this hypothesis. 42 In fact, Tsuji et al 42 found that the low-frequency component of R-R variability was increased in elderly subjects and that a 1-SD decrement in the low-frequency power was associated with a 1.7-times greater hazard for all-cause mortality. This suggests that sympathetic tone can be elevated in elderly subjects, and that subjects with sympathetic overactivity are at increased risk of dying. A reduction of the high-frequency power was also related to increased mortality in the Framingham Heart study. 42 However, in a stepwise analysis the high-frequency component was not included in the model, whereas the low-frequency component was. THERAPEUTIC IMPLICATIONS As stated above, hypertension is a complex syndrome including a constellation of metabolic and hemodynamic abnormalities that may independently lead to atherosclerosis and to cardiovascular events. Both animal and human studies clearly show that sympathetic overactivity plays an important role in the coaggregation of these risk factors, 6,7 and suggest that drugs that decrease heart rate and sympathetic tone are likely to demonstrate a life-prolonging effect. In hypertensive subjects the reduction of heart rate may also be beneficial in decreasing the hemodynamic component of the atherogenetic effects of tachycardia. 43

5 AJH JANUARY 1999 VOL. 12, NO. 1, PART 2 HEART RATE AS A RISK FACTOR 7S The results obtained in postmyocardial-infarction patients, either in short-term or long-term intervention trials, also suggest the beneficial effects of heart rate reduction in this clinical setting. In analyses of all the -blocker trials, Kjekshus 44,45 found that there is a striking relationship between differences in heart rate between groups that received placebo and treated groups and the reduction in mortality rate achieved. The association between the reduction in heart rate and mortality has been shown also in subjects with congestive heart failure. In the Grupo de Estudio de la Sobrevida en la Insufficiencia Cardiaca en Argentina (GESICA) trial amiodarone improved survival in patients with congestive heart failure, but only in those who had a high heart rate. 49 Carvedilol was also reported to have produced a marked reduction in mortality in subjects with congestive heart failure, 50 but again, the beneficial effect of this drug was clear only in patients with a high heart rate. CONCLUSIONS In spite of the strong evidence provided by the numerous studies mentioned here, the clinical importance of heart rate has still been neglected, and heart rate has not yet been included among the risk factors for atherosclerosis. In no document of the Scientific Societies is information on the risk of heart rate for atherosclerosis and its sequelae provided. 51 The reason why the role of this clinical variable is so poorly recognized is difficult to understand. 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