It has long been known that life span is inversely related to resting heart rate in most organisms. This association between heart rate and survival has been attributed to the metabolic rate, which is greater in smaller animals and is directly associated with heart rate. Studies have shown that heart rate is related to survival in apparently healthy individuals and in patients with different underlying cardiovascular diseases. A decrease in heart rate due to therapeutic interventions may result in an increase in survival. However, there are many factors regulating heart rate, and it is quite plausible that these may independently affect life expectancy. Nonetheless, a fast heart rate itself affects the cardiovascular system in multiple ways (it increases ventricular work, myocardial oxygen consumption, endothelial stress, aortic/arterial stiffness, decreases myocardial oxygen supply, other) which, in turn, may affect survival. In this brief review, the effects of heart rate on the heart, arterial system and survival will be discussed.
It has long been known that resting heart rate is inversely related to average life span in most organisms that have been studied. Indeed, among mammals, where the relationship has been most intensively assessed, there is a linear, inverse semilogarithmic relationship between average resting heart rate and average life expectancy in all species except humans (who live longer than is predicted from their heart rate). This observation presumably relates to the interposition of medical care [1, 2] (fig. 1). The association between heart rate and life expectancy has been attributed to the metabolic rate, which is greater in smaller animals and is directly associated with heart rate. However, there are many other factors that affect heart rate, such as genetic influences on the cell biology of electrically active atrial tissues, autonomic nervous activity, inflammatory processes, etc. It is possible that the same factors that influence heart rate may also independently affect life expectancy. Nonetheless, heart rate itself affects the cardiovascular system in multiple ways that possibly influence survival. Consequently, heart rate may contribute to the development and acceleration of certain cardiovascular diseases, that, in turn, affect life expectancy [1, 2, 3, 4, 5, 6]. In this brief review, the effects of heart rate on the heart, arterial system and survival will be considered.
Effects of Heart Rate on the Heart
Conventionally, heart rates of 50 or 55-90 beats per minute (bpm) at rest are considered normal, but in fact, due to the wide variability of heart rate at different times of the day in relation to different activities and also to intercurrent diseases, it is difficult to precisely define the range for normal heart rate [1, 2, 7]. For example, the normal heart rate is typically much slower at night than during the day and, as a general rule, slightly faster in women than in men.
Heart Rate, Ventricular Work and Coronary Flow
Ventricular work and myocardial oxygen consumption (MVO2) are directly related to heart rate. As heart rate increases, the supply of myocardial oxygen diminishes, because the diastolic time interval during which myocardial blood flow occurs decreases relatively rapidly as heart rate increases . Diastolic time is an especially important factor when left ventricular (LV) hypertrophy and/or coronary artery disease are present. LV intramyocardial pressure during systole is equal to or greater than LV systolic pressure in the subendocardium. In patients with hemodynamically important obstructive coronary artery disease, systolic flow may be obliterated because the coronary systolic pressure distal to an obstructive lesion is less than the LV wall pressure during systole. Therefore, subendocardial blood flow, collateral flow and flow distal to an obstruction become dependent on the duration of diastole (fig. 2a). Ventricular filling also occurs during diastole. At fast heart rates, the ventricular filling time (i.e. diastolic time) shortens dramatically, left atrial pressure increases and pulmonary edema may occur. Irregular heart beat also alters the expression and activity of key proteins, regulating calcium turnover within the myocardial cells that may decrease myocardial contractility [7, 8, 9, 10, 11, 12, 13, 14, 15].
Heart Rate and Diastolic Time
Diastolic time has a nonlinear relationship to heart rate. Thus, small changes in heart rate, especially when <75 bpm, will produce a disproportionate increase in diastolic time (fig. 2b). In contrast, the relationship between heart rate and duration of systole is linear. Although the duration of systole changes according to heart rate, these changes are small and substantially fewer than the changes that occur in diastolic time . The effects of heart rate on the heart are summarized in table 1.
Effects of Heart Rate on the Arterial System
Heart Rate and Endothelial Function
LV systole results in a generation of pressure that travels from the root of the aorta into the peripheral arterial circulation as a pulse wave [16, 17, 18, 19]. The pressure waves with each ventricular systole produce a stress on the arterial endothelial cells. Intrinsic repair mechanisms maintain normal endothelial function when the applied stress is within physiologic limits. When the stress is pathologic (e.g. high arterial pressure or in the presence of other risk factors such as smoking, high levels of cholesterol, inflammatory process, aging, etc.) the intrinsic repair mechanisms are inadequate to maintain normal endothelium, and thus endothelial damage may occur. This may result in arterial aging and cardiovascular disease. The faster the heart rate, the greater the effect on the endothelium. In fact, endothelial damage and repair starts in utero with the first heart beat [20, 21].
Heart Rate, Arterial and Aortic Function
Faster heart rates also result in arterial stiffening. Increasing the rate by pacing from 60 to 90 bpm in humans results in a decrease in carotid and radial artery distensibility. In experimental animals, an increase in heart rate results in stiffening of the aorta. A fast heart rate is also a major determinant of accelerated progression of aortic stiffness in treated patients with arterial hypertension [21, 22, 23, 24, 25, 26, 27]. A stiff aorta will increase the aortic pulse wave velocity (PWV). Increased PWV results in rapid expansion of the arterioles and damage to organs, especially the kidneys and the brain (fig. 3a). A stiff aorta will also increase reflected wave velocity. Normally reflected waves arrive in the root of the aorta early in diastole and form the diastolic wave, which facilitates coronary blood flow. When reflected wave velocity is increased, reflected waves arrive in the root of the aorta late in systole. The result is the disappearance of the diastolic wave and an increase in the systolic pressure, producing an increase in LV work, MVO2 and reduced coronary blood flow [16, 17, 18, 19] (fig. 3b).
Heart Rate and Central Aortic Pressure
When the heart rate is relatively slow, reflected waves may reach the root of the aorta in systole even if the elastic properties of the aorta are normal. This may result in an increase in the central aortic pressure (fig. 4). Thus, when the heart rate slows sufficiently, the central aortic pressure will increase, assuming that the aortic function remains unchanged. When the aortic function improves and the heart rate decreases, as with regular aerobic exercise, the central aortic pressure may stay the same, despite a slower heart rate. In contrast, when the heart rate decreases with pharmacologic agents that do not alter aortic function, as with β-adrenergic blocking agents, central aortic pressure may increase. This is not related to an increase in the duration of systole, as previous investigators suggested, but mostly to an increase in the duration of diastole. The effect of a slow heart rate on the central aortic pressure may be enhanced when a slow heart rate is associated with an increase in peripheral resistance [16, 17, 18, 19, 21, 22, 23, 24].
Other Abnormalities Associated with Fast Heart Rates
Faster heart rates are also associated with other abnormalities such as inflammatory processes, oxidative stress and endothelial dysfunction that may accelerate atherosclerosis. A fast heart rate at rest is associated with increased sympathetic activity and decreased heart rate variability, which are associated with cardiovascular mortality. As heart rate increases, the likelihood of microalbuminuria also increases in patients with diabetes mellitus and arterial hypertension [28, 29, 30, 31, 32, 33]. Importantly, these associations between heart rate and various cardiovascular abnormalities do not necessarily indicate a direct causal relation. The intervening pathophysiology requires further study.
Association between Heart Rate and Survival
Heart Rate and Mortality in Apparently Healthy Individuals
In numerous epidemiologic studies, cardiovascular and all-cause mortality in healthy individuals has been directly related to heart rate. For example, in a 23-year follow-up of 5,713 asymptomatic men (age range 32-42 years) without clinical evidence of underlying cardiovascular disease, the risk of sudden death from myocardial infarction was higher in subjects with a resting heart rate >75 bpm at study entry than among those with a lower entry heart rate  (fig. 5a). In the more recent Copenhagen Male Study, 2,978 subjects in sinus rhythm without known cardiovascular disease or diabetes mellitus were followed for 16 years . Again, heart rate was directly associated with mortality, beginning with rates exceeding 55 bpm (fig. 5b). The relationship between heart rate and mortality persisted even after adjustment for physical activity, fitness, maximal MVO2, smoking, leisure time, alcohol intake, body mass index, systolic and diastolic blood pressure, and levels of serum cholesterol and triglycerides.
Heart Rate and Mortality in Arterial Hypertension
The Framingham study  evaluated 4,530 patients with arterial hypertension aged 34-74 years whose blood pressure was ≥140 mm Hg systolic or ≥90 mm Hg diastolic, and were not treated with antihypertensive medications at baseline. After 36 years of follow-up, all-cause mortality was directly related to resting heart rate at study entry [36, 37, 38, 39] (fig. 6).
Heart Rate and Mortality in Coronary Artery Disease
The relationship between resting heart rate at baseline and cardiovascular mortality/morbidity was assessed in 24,913 patients with suspected or proven coronary artery disease in the Coronary Artery Registry, established along with the CASS (Coronary Artery Surgery Study ), for a median follow-up of 14.7 years. Overall mortality and cardiovascular mortality increased with increasing baseline heart rate (fig. 7a). Heart rate as a prognostic factor for patients with coronary artery disease and LV systolic dysfunction was evaluated in the placebo group of the prospective, placebo-controlled, randomized BEAUTIFUL (Morbidity-Mortality Evaluation of the I(f) Inhibitor Ivabradine in Patients with Coronary Disease and Left Ventricular Dysfunction) trial. The 5,438 placebo-treated patients (heart rate ≥60 bpm) were prospectively dichotomized into a group with a heart rate ≥70 bpm (n = 2,693) and a group with a heart rate <70 bpm (n = 2,745). Those with a rate ≥70 bpm at entry had significant more cardiovascular events (cardiovascular death, admission for heart failure, myocardial infarction and myocardial revascularization) during the average 19-month follow-up than those with a rate <70 bpm  (fig. 7b).
Heart Rate and Survival after Therapeutic Interventions
Patients with Coronary Artery Disease
It is known that therapy with β-adrenergic blocking agents, when begun shortly after acute myocardial infarction, decreases mortality [42, 43]. In a large, prospective, randomized, double-blind trial, the difference in heart rate between the groups treated with β-blockers and the placebo groups was directly related to the reduction in mortality  (fig. 8a). In another trial, the same relationship was found between a reduction in heart rate in the treatment group and nonfatal myocardial infarction . These associations between heart rate and mortality or myocardial infarction are at least partially related to the decrease in LV work and MVO2 and to an increase in the supply of myocardial oxygen due to the increase in diastolic time at slower heart rates. An inverse relationship was present between diastolic time (in milliseconds) and mortality  (fig. 8b). In patients with silent myocardial ischemia, the number of ischemic episodes was substantially higher when the diastolic time decreased to <500 ms/beat (heart rate approximately 65-60 bpm) than when it was >500 ms/beat [10, 12, 44]. Support for the relationship of heart rate and coronary events has also been provided by experimental studies. Slower heart rates achieved with sinus node ablation in monkeys resulted in a decrease in the atherosclerotic process produced by a high-cholesterol diet when compared to monkeys whose heart rates were allowed to vary without sinus note ablation [45, 46].
β-Adrenergic blocking agents have other effects in addition to slowing heart rate. Some may be significantly beneficial, but some may be deleterious in certain patients. However, the relative importance of the effects of slowed heart rate on cardiac events can be inferred from studies with ivabradine, a drug that selectively inhibits the funny current (If), a small current that modifies the rate of the diastolic depolarization (pacemaker) current in the sinoatrial node, thereby selectively reducing the heart rate with no effect on myocardial contractility or arterial pressure . In several trials, ivabradine decreased symptoms and myocardial ischemia in patients with stable angina pectoris. In the BEAUTIFUL study, ivabradine (n = 5,479) was compared to placebo (n = 5,438) in cardiovascular events in patients with stable coronary artery disease and LV systolic dysfunction. Background therapy included drugs commonly given to subjects with known coronary artery disease. The primary end point was a composite of cardiovascular death, hospitalized myocardial infarction and hospital admission with new onset or worsening heart failure. In this trial, ivabradine decreased heart rate, but failed to demonstrate primary composite end-point reduction for the entire study cohort. However, in a prespecified subgroup analysis in patients with a heart rate >70 bpm, ivabradine reduced nonfatal myocardial infarction at the 2-year follow-up [41, 48] (fig. 9a). Most recently, in the SIGNIFY (Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease) trial, the effect of ivabradine in patients with stable coronary artery disease without clinical heart failure and a heart rate ≥70 bpm were studied . In addition to ivabradine, patients received therapy for stable coronary artery disease (antiplatelet therapy 97%, statins 92%, β-blockers 83%, angiotensin-converting enzyme inhibitors 27%, nitrates 40%, diltiazem or verapamil 4.6%, and antidiabetic agents 40%). The primary end point (a composite of death from cardiovascular causes or nonfatal myocardial infarction) was not statistically significantly different between the 2 groups (ivabradine: n = 9,550, placebo: n = 9,552). However, among those who reported exertional angina when they entered the study, the incidence of the primary end point was higher in those taking ivabradine (7.6%) than in those on placebo (6.5%, p = 0.02). Ivabradine also increased the incidence of symptomatic bradycardia compared to placebo (7.9 vs. 1.2%), asymptomatic bradycardia (11 vs. 1.3%) and atrial fibrillation (5.3 vs. 3.8%). There are several plausible explanations for these findings. Ivabradine most likely had beneficial effects in some of the patients, but some of these were offset by the adverse effects of the drug (e.g. extreme bradycardia or atrial fibrillation). It should be noted that differences may exist between heart failure and coronary artery disease [50, 51, 52].
Patients with Coronary Artery Disease and Arterial Hypertension
In the INVEST (International Verapamil-SR/Trandolapril study) trial, 22,197 patients with a mean age of 65 years with stable coronary artery disease and arterial hypertension were randomized to either verapamil-SR or atenolol . The primary end point was all-cause mortality, nonfatal myocardial infarction or nonfatal stroke; the average follow-up was 2.7 years. The study demonstrated that a relatively high baseline resting heart rate, or a relatively high or markedly slow resting heart rate during follow-up, was associated with adverse outcomes regardless of treatment strategy and underlying comorbidities (fig. 9b). Women had faster resting heart rates than men, while men for the same heart rates had a greater risk for adverse outcomes than women. The results have some similarity with the SIGNIFY trial, in which elderly patients with coronary artery disease in addition to state-of-the-art medical therapy also received ivabradine . It should be emphasized, however, that antihypertensive agents have different effects on heart rate. A faster heart rate during therapy for hypertension may be associated with adverse events, regardless of the extent of changes in blood pressure. Thus, the so-called J-curve phenomenon in arterial hypertension may at least partially be related to an increase in heart rate and not only to changes in blood pressure .
Patients with Heart Failure
Heart rate is an independent risk factor in patients with heart failure. Specifically in patients with heart failure and decreased systolic function, reducing heart rate improves outcomes, so heart rate reduction an important therapeutic target. β-Blockers are a first-line drug for the management of heart failure with decreased systolic function; they decrease heart rate and increase survival in patients with heart failure and decreased systolic function [55, 56, 57, 58, 59, 60]. However, in addition to their effect on heart rate, β-blockers affect the cardiovascular system in other ways, perhaps not all beneficial [61, 62]. In the SHIFT (Systemic Heart Failure Treatment with If Inhibitor Ivabradine) trial, which included patients with overt chronic heart failure and severe LV systolic dysfunction, 6,505 patients with LV ejection fraction (LVEF) ≤35% and a heart rate ≥70 bpm in sinus rhythm were evaluated in order to test the hypothesis that heart rate reduction with ivabradine, in addition to the background therapy suggested in the guidelines (i.e. 89% β-blockers, 91% renin-angiotensin system inhibitors and 60% mineralocorticoid receptor antagonists), can improve outcomes in patients with heart failure and decreased LV systolic function . The addition of ivabradine (n = 3,241) reduced hospitalization or cardiovascular death compared to placebo (n = 3,364) during a median follow-up of 22.9 months (fig. 10). Within the range achieved, the lower the heart rate, the better the outcome; the best outcomes were observed among patients whose final therapy heart rate was 50-55 bpm. Therapy with ivabradine also resulted in a mild, but statistically significant increase in LVEF [63, 64, 65, 66, 67]. A slower heart rate results in decreased LV work, decreased myocardial demand for intracellular high-energy substrate (deficient in the myocytes of patients with heart failure and decreased LV systolic function) and increased myocardial blood flow, especially subendocardial blood flow, thereby enhancing the capacity to produce a high-energy substrate. These beneficial effects on myocardial energetics, arterial/aortic function and ventriculovascular coupling may partially explain the reported findings [7, 10, 16].
Heart Rate and Life Expectancy
Large animals have slower heart rates and live longer than small animals [1, 2]. An inverse relationship between heart rate and life expectancy has been found in mammals  (fig. 1). This observation was attributed to the higher metabolic rate in small versus large animals. A high metabolic rate leads to the development of free radicals, oxidative stress and faster aging. A high metabolic rate is associated with a faster heart rate, so the relationship between heart rate and life expectancy has been attributed to different metabolic rates in living organisms. This was originally described as ‘the rate of living theory'.
As the size of an animal increases, although the animal requires more energy, the metabolic rate does not increase proportionally to the increase in body weight. Generally, in animals, and particularly in homeotherms, the rate of heat loss is a function of body surface area, while heat production is a function of body mass (weight). However, for a 2-fold (i.e. 100%) increase in body mass, body surface area only increases by approximately 59% . This disproportional increase in body weight in relation to body area can also be seen in humans at different stages of development. In neonates (average weight: 3.5 kg, average body surface area: 0.25 m2), the ratio of body weight to body area is 14 and at the age of 10 years (average weight: 30.5 kg, average body surface area: 1.14 m2), this ratio is 27. In adults (average weight: 75 kg, average body surface area: 1.85 m2), this ratio becomes 41. Thus, in large animals, the ratio of weight to body surface area is greater than in small animals, and the heat loss in relation to body weight is much less than in small animals. It follows that the metabolic rate per unit of mass in large animals is much smaller than in small animals.
Metabolic rate is a fundamental characteristic of all living organisms, and so life expectancy, to a certain degree, is related to metabolic rate. However, metabolic rate does not fully explain differences in life expectancy. Birds have a greater metabolic rate than mammals of similar size, but they live much longer. Metabolic rate also cannot explain the longer life expectancy of certain wild mice that live much longer than laboratory mice, certain types of rats that live up to 20-25 years (much longer than typical rats), humans, etc. .
More recent studies indicated that the oxidative stress that accelerates aging is also related to concentrations of lipids in the organism's cell membrane. A high concentration of polyunsaturated fatty acids in the cell membrane is associated with high oxidative stress and faster aging. In contrast, a low concentration of polyunsaturated fatty acids in the cell membrane is associated with lower oxidative stress and slower aging. Thus, the membrane composition theory may explain life expectancy in certain animal species in which the metabolic rate theory cannot. It appears therefore, that one theory may complement the other  (fig. 11).
Concluding Remarks and Therapeutic Considerations
MHΔΕN ΑΓΑN (Nothing in Excess)
Temple of Apollo at Delphi
Heart rate is related to survival in apparently healthy individuals and in patients with different underlying cardiovascular diseases [1, 2, 68]. A decrease in heart rate due to therapeutic interventions may result in an increase in survival. The heart rate of individuals with sinus rhythm is regulated by the sinus node. Sinus node function is controlled by several mechanisms. Potassium and calcium channels are the primary loci of the control of spontaneous diastolic depolarization and thus, of intrinsic heart rate in the sinoatrial node. Although If is quantitatively a relatively small current, it is a primary modulator of the slope of diastolic depolarization and thus, exerts an important influence over heart rate . However, there are many other factors that directly or indirectly affect sinus node rate, such as autonomic nervous system activity, metabolic rate and inflammatory processes. Since many factors regulate heart rate, it may indeed be these factors, rather than the heart rate itself, that determine survival [4, 5, 6, 28, 29, 30, 31, 32, 33]. However, heart rate has multiple direct effects on the cardiovascular system, regardless of the regulatory mechanisms. These effects directly affect the cardiovascular system in multiple ways that, in turn, may affect survival [7, 10, 11, 13, 16, 17, 18, 19, 20, 22, 23, 39, 69, 70] (fig. 12).
The effects of heart rate on LV work and MVO2 have been well-appreciated for many years. More recently, the nonlinear relationship between heart rate and the diastolic time interval (i.e. the myocardial perfusion time) has been of increasing interest  (fig. 2). Thus, it became obvious that heart rate is not only an important factor in defining MVO2 and high-energy substrate demand, but also for determining myocardial oxygen and high-energy substrate supply. For these reasons, slowing the heart rate has been a target for the management of patients with coronary artery disease. In the past, this goal was achieved with β-adrenergic blocking agents and, to a lesser degree, with verapamil-type calcium-channel blockers. These agents have several other effects on the cardiovascular system besides heart rate reduction. More recently, ivabradine, which selectively decreases heart rate without any other apparent effects on the cardiovascular system, has been introduced into clinical practice. Combinations of these drugs are often used [3, 41, 48, 49, 61, 70, 71]. Nonetheless, aggressive efforts to reduce heart rate among patients may produce substantial bradycardia, which without altering aortic function, may result in a substantial increase in central aortic pressure and the disappearance of the diastolic wave. This will result in an increase in LV work and MVO2, and a simultaneous decrease in myocardial oxygen supply [16, 17, 18, 19, 69] (fig. 4). These effects are opposite to what is expected from heart rate reduction. This may explain some of the negative results reported in patients with coronary artery disease who were treated with a combination of several bradycardic agents (β-blockers, calcium channel blockers or ivabradine).
Usually, when standard antianginal doses of β-adrenergic blocking agents are employed in patients with coronary artery disease, resting rate is maintained at <70 bpm. However, recent trials and registries indicate that among patients with heart failure and LVEF ≤35%, even when treated with β-blockers, resting heart rate exceeds 70 bpm in a substantial proportion of patients [68, 72, 73, 74]. In order to improve outcomes, these patients may need bradycardic drugs in addition to β-adrenergic blocking agents. Nonetheless, the addition of other bradycardic drugs to patients treated with β-blockers requires careful consideration from a physician who understands the physiology and pathophysiology of the coronary circulation, the effects of heart rate on the cardiovascular system, drug-drug interactions, and the medical problems of the individual patient for whom they are responsible. No clinical practice guidelines can fully address these issues .
At present, there is not enough information to justify treating individuals who have sinus tachycardia without evidence of underlying disease in order to slow the heart rate. It is reasonable, however, to instruct ‘healthy' individuals with a fast heart rate to avoid stimulants such as caffeine, smoking, alcohol, etc. Regular aerobic exercise and maintenance of normal body weight also is suggested (table 2). In patients with an underlying disease and a fast heart rate, management using current knowledge, mild-to-moderate regular aerobic exercise, and common sense are important.