Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Turning Basic Research into Clincal Success

Editor's Choice - Free Access

Heart Rate, Life Expectancy and the Cardiovascular System: Therapeutic Considerations

Boudoulas K.D.a · Borer J.S.b · Boudoulas Ha,c,d

Author affiliations

aDivision of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio, and bDivision of Cardiovascular Medicine, The Howard Gilman Institute for Heart Valve Diseases and the Schiavone Institute for Cardiovascular Translational Research, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York, N.Y., USA; cBiomedical Research Foundation, Academy of Athens, Athens, and dAristotelian University of Thessaloniki, Thessaloniki, Greece

Corresponding Author

Harisios Boudoulas, MD

Division of Cardiovascular Medicine

The Ohio State University

4185 Mumford Ct, Columbus, Ohio 43220 (USA)

E-Mail boudoulas@bioacademy.gr

Related Articles for ""

Cardiology 2015;132:199-212

Abstract

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.

© 2015 S. Karger AG, Basel


Introduction

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.

Fig. 1

Semilogarithmic relation between resting heart rate and life expectancy in mammals [1].

http://www.karger.com/WebMaterial/ShowPic/415640

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 [7]. 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].

Fig. 2

a Schematic presentation of coronary flow in relation to the cardiac cycle. Note that the greater proportion of coronary flow occurs in diastole. Left ventricular (LV) work is related to the duration of systole and LV systolic pressure. First and second heart sounds, and the electrocardiogram (ECG) are also shown [11]. b Upper panel: relationship between heart rate, total electromechanical systole, i.e. systolic time, relative risk interval and diastolic period. Two factors determine the duration of diastolic time: heart rate and the duration of systole. Lower panel: relationship between heart rate and percent diastole. Due to a nonlinear relationship, small changes in heart rate produce dramatic changes in diastolic time, especially at a slower heart rate. The relationship between the systolic time and heart rate is linear, thus changes in heart rate produce substantially smaller changes in systolic versus diastolic times [7]. QS2 = Systolic time; R-R = relative risk.

http://www.karger.com/WebMaterial/ShowPic/415639

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 [7]. The effects of heart rate on the heart are summarized in table 1.

Table 1

Effects of fast heart rate on the heart

http://www.karger.com/WebMaterial/ShowPic/415642

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).

Fig. 3

a Pulse wave velocity (PWV) is shown schematically with large arrows. When the aorta is stiff, PWV increases, resulting in stretching of the peripheral arterioles and vascular damage. b Reflected wave velocity in a stiff aorta is faster than in a normal aorta, so reflected waves reach the root of the aorta at the end of systole; this results in an increase in the systolic pressure and the disappearance of the diastolic wave. The pulse pressure waves of the carotid artery or the central aorta in both a normal and a stiff aorta are also shown schematically (see text for detail) [18].

http://www.karger.com/WebMaterial/ShowPic/415638

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].

Fig. 4

a Slow heart rate may result in an increase in central aortic pressure due to a significant increase in diastolic time compared to an aorta with the same length and the same elastic properties, but a normal heart rate. b Note that diastolic time increased from 374 to 761 ms but systolic time increased only to 439 from 376 ms when the heart rate decreases from 80 to 50 bpm. The central aortic pressure waves with a heart rate of 80 or 50 bpm are also shown schematically (see text for detail). PWV = Pulse wave velocity.

http://www.karger.com/WebMaterial/ShowPic/415637

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 [34] (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 [35]. 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.

Fig. 5

a Relative risk of death from any cause, sudden death and nonsudden death due to myocardial infarction (MI) in relation to resting heart rate in healthy men [34]. b All-cause mortality in relation to resting heart rate adjusted for age, physical activity, fitness, maximal myocardial oxygen consumption (MVO2 max), leisure time, tobacco consumption, alcohol intake, body mass index, systolic/diastolic pressure, serum cholesterol and triglycerides (constructed using data from [35]).

http://www.karger.com/WebMaterial/ShowPic/415636

Heart Rate and Mortality in Arterial Hypertension

The Framingham study [36] 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).

Fig. 6

Resting heart rate as a predictor of all-cause mortality in patients with arterial hypertension in the Framingham Study, which included 2,037 men with a 36-year follow-up.

http://www.karger.com/WebMaterial/ShowPic/415635

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 [40]), 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 [41] (fig. 7b).

Fig. 7

a Mortality in relation to resting heart rate in coronary artery disease adjusted for age, gender, hypertension, diabetes mellitus, cigarette smoking, clinically significant coronary artery disease, left ventricular (LV) ejection fraction, recreational activity and treatment with antiplatelets, diuretics, β-blockers and lipid-lowering drugs (modified from [40]). b Heart rate as a predictor of cardiovascular events and hospitalization for heart failure (HF) in patients with coronary artery disease and LV systolic dysfunction. Note that cardiovascular death and hospitalization for heart failure were greater in those with a heart rate ≥70 bpm than in those with a heart rate <70 bpm [41].

http://www.karger.com/WebMaterial/ShowPic/415634

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 [42] (fig. 8a). In another trial, the same relationship was found between a reduction in heart rate in the treatment group and nonfatal myocardial infarction [43]. 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 [12] (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].

Fig. 8

a Relationship between reduction in heart rate due to therapy with β-blocking agents and reduction in mortality in large, prospective, randomized trials on patients with coronary artery disease [42]. b Relationship between increase in diastolic time due to therapy with β-blocking agents and reduction in mortality in patients with coronary artery disease in large, prospective, randomized trials [13].

http://www.karger.com/WebMaterial/ShowPic/415633

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 [47]. 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 [49]. 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].

Fig. 9

a Proportion of patients with stable coronary artery disease and a heart rate >70 bpm at baseline who were hospitalized for myocardial infarction (MI). Therapy with ivabradine that decreased heart rate was associated with a decreased incidence of myocardial infarction [41]. b In patients with coronary artery disease (CAD) and arterial hypertension, the relationship between follow-up resting heart rate and the incidence of adverse outcomes is shown. Adverse outcomes include all-cause death, nonfatal myocardial infarction, or nonfatal stroke (modified from [53]).

http://www.karger.com/WebMaterial/ShowPic/415632

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 [53]. 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 [49]. 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 [54].

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 [63]. 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].

Fig. 10

a Distribution of patients in the ivabradine group (upper panel) and placebo group (lower panel) according to heart rate achieved at day 28. b Kaplan-Meier cumulative-event curves for primary end point (cardiovascular death or hospital admission for worsening heart failure) in the ivabradine group according to heart rate achieved at day 28 [63].

http://www.karger.com/WebMaterial/ShowPic/415631

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 [1] (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% [2]. 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. [2].

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 [2] (fig. 11).

Fig. 11

Life expectancy is related to metabolic rate; an increase in metabolic rate leads to the production of free radicals and oxidative stress. Increased metabolic rate is also associated with a faster heart rate. Fatty acids that are involved in the structure of the cell membrane are also related to the degree of oxidative stress that leads to cell damage, aging and death. One theory is complementary to the other.

http://www.karger.com/WebMaterial/ShowPic/415630

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 [3]. 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).

Fig. 12

Effects of heart rate on the cardiovascular system (schematic presentation). Increase in heart rate will result in a decrease in diastolic time and an increase in systolic time (increase in systolic time is proportionally less than the decrease in diastolic time); these changes result in decreased myocardial perfusion and increased LV work that in the long run, may result in LV hypertrophy (LVH), myocardial damage and congestive heart failure (CHF). Increased heart rate may also be associated with endothelial damage, oxidative stress, inflammation and stiff vessels, all of which may contribute to aging, the development of atherosclerosis, arterial hypertension and a stiff aorta. A stiff aorta results in an increase in pulse wave velocity (PWV) and reflected wave velocity that results in systolic hypertension, decreased myocardial blood flow and organ damage. All these effects of a fast heart rate on the cardiovascular system may contribute to the development of cardiovascular diseases and increase cardiovascular morbidity and mortality. MVO2 = Myocardial oxygen consumption.

http://www.karger.com/WebMaterial/ShowPic/415629

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 [7] (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 [75].

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.

Table 2

Fast heart rate: therapeutic considerations

http://www.karger.com/WebMaterial/ShowPic/415641


References

  1. Levine HJ: Rest heart rate and life expectancy. J Am Coll Cardiol 1997;30:1104-1106.
  2. Hulbert AJ, Ramplona R, Buffenstein R, Buttemer WA: Life and death: Metabolic rate, membrane composition, and life span of animals. Physiol Rev 2007;87:1175-1213.
  3. DiFrancesco D, Borer JS: The funny current: cellular basis for the control of heart rate. Drugs 2007;67:15-24.
  4. Olshansky B, Sullivan RM: Inappropriate sinus tachycardia. J Am Coll Cardiol 2013;61:793-801.
  5. Eigelsheim M, Newton-Cheh C, Sotoodehnia, et al: Genome-wide association analysis identifies multiple loci related to resting heart rate. Hum Mol Genet 2010;19:3385-3394.
  6. Vaanholt LM, Daan S, Schubert KA, Visser GH: Metabolism and aging: effects of cold exposure on metabolic rate, body composition, and longevity in mice. Physiol Biochem Zool 2009;82:314-324.
  7. Boudoulas H, Rittgers SE, Lewis RP, Leier CV, Weissler AM: Changes in diastolic time with various pharmacologic agents: implication for myocardial perfusion. Circulation 1979;60:164-169.
  8. Obdahl A, Venkatesh BA, Fernandes VRS, Wu CO, Nasir K, Choi EY, Almeida AL, Rosen B, Carvalho B, Edvardsen T, Bluemke DA, Lima JAC: Resting heart rate as predictor for left ventricular dysfunction and heart failure. MESA (Multiethnic Study of Atherosclerosis). J Am Coll Cardiol 2014;63:1182-1189.
  9. Levy R, White PD, Stroud WD, Cha BG: Transient tachycardia. Prognostic significance alone and in association with transient hypertension. JAMA 1945;129:585-588.
    External Resources
  10. Boudoulas H, Leier CV: Clinical perspective: myocardial perfusion pressure in the age of afterload reduction. ACC Curr J Rev 2000;9:27-29.
    External Resources
  11. Boudoulas H, Karayannacos PE, Kien N, Lewis RP, Kakos GS, Leir CV, Vasco JS: Noninvasive method of estimating relative subendocardial flow employing diastolic time; in Dietrich E (ed): Noninvasive Assessment of the Cardiovascular System. Littleton, John Wright-PSG Inc, 1982, pp 211-217.
  12. Boudoulas H: Diastolic time: the forgotten dynamic factor. Implications for myocardial perfusion. Acta Cardiol 1991;46:61-71.
    External Resources
  13. Boudoulas H: Diastolic time: implications for myocardial perfusion and ventricular filling. Hell J Cardiol 1991;32:400-409.
  14. Boudoulas H, Dervenagas S, Fulkerson PK, Bush CA, Lewis RP: Effect of heart rate on diastolic time and left ventricular performance in patients with atrial fibrillation; in: Noninvasive Cardiovascular Diagnosis, ed 2. Littleton, Mass PSG Inc, 1981, pp 433-445.
  15. Ling L, Khammy O, Byne M, Amirahmadi F, Foster A, Li G, Zhang L, Remedios C, Chen C, Kaye DM: Irregular rhythm adversely influences calcium handling in ventricular myocardium. Circ Heart Fail 2012;5:786-793.
  16. Boudoulas KD, Vlachopoulos C, Raman SV, Sparkas EA, Triposkiadis F, Stefanadis C, Boudoulas H: Aortic function: from the research laboratory to the clinic. Cardiology 2012;121:31-42.
  17. Boudoulas H, Stefanadis C: The Aorta: Structure, Function, Dysfunction, and Diseases. New York, Informa Healthcare, 2009.
  18. Boudoulas H, Toutouzas P, Wooley CF: Functional Abnormalities of the Aorta. Futura, Armonk, 1996.
    External Resources
  19. Nichols WW, O'Rourke MF, Vlachopoulos C (eds): McDonald's Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles, ed 6. London, Hoder Arnold, 2011.
  20. Thorin E, Thorin-Trescases N: Vascular endothelial aging, heartbeat after heartbeat. Cardiovasc Res 2009;84:24-32.
  21. Custodis F, Schirmer SH, Baumhakel M, Heusch G, Böhm M, Laufs U: Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol 2010;56:1973-1983.
  22. Giannattasio C, Vincenti A, Failla M, Capta A, Ciro A, De Ceglia S, Getile G, Brambilla R, Mancia G: Effects of heart rate changes on arterial distensibility in humans. Hypertension 2003;42:253-256.
  23. Wilkinson IB, MacCallum H, Flint L, Cockcroft JR, Newby D, Webb DJ: The influence of heart rate on augmentation index and central arterial pressure in humans. J Physiol 2000;525:263-270.
  24. Tartiere-Kesri L, Tartieri JM, Logeart D, Bwauvais F, Solal C: Increased proximal arterial stiffness and cardiac response with moderate exercise in patients with heart failure and preserved ejection fraction. J Am Coll Cardiol 2012;59:455-461.
  25. Borlaud BA: Heart rate reduction. It is not just for ventricles anymore. J Am Coll Cardiol 2013;62:1986-1987.
  26. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, Hughes AD, Thuster A, O'Rourke M: Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes. Principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006;113:1213-1225.
  27. Benetos A, Adamopoulos C, Bureau JM, Temmar M, Labat C, Bean K, Thomas F, Pannier B, Asmar R, Zureik M, Safar M, Guize L: Determinants of accelerated progression of arterial stiffness in normotensive subjects and in treated hypertensive subjects over a 6-year period. Circulation 2002;105:1202-1207.
  28. Böhm M, Reil JC, Danchin N, Thoenes M, Bramlage P, Volpe M. Association of heart rate with microalbuminuria in cardiovascular risk patients: data from I-SEARCH. J Hypertens 2008;26:18-25.
  29. Palatini P, Casiglia E, Pauletto P, Staessen J, Kaciroti N, Jukius S: Relationship of tachycardia with high blood pressure and metabolic abnormalities. Hypertension 1997;30:1267-1273.
  30. O' Hartaigh B, Bosch JA, Carroll D, Hemming K, Pilz S, Loebroks A, Kleber ME, Grammer TB, Fisher JE, Boehm B, Marz W, Thomas NG: Evidence of a synergistic association between heart rate, inflammation, and cardiovascular mortality in patients undergoing coronary angiography. Eur Heart J 2013;34:932-941.
  31. Zulfigar U, Jurivich DA, Singer DH: Relation of high heart rate variability to healthy longevity. Am J Cardiol 2010;105:1181-1185.
  32. Grassi G, Vailati S, Bertinieri G, Seravalle G, Stella ML, Dell'Oro R, Mancia G: Heart rate as marker of sympathetic activity. J Hypertens 1998;16:1635-1639.
  33. Rogowski O, Shapira I, Shirom A, Melamed S, Toker S, Berliner S: Heart rate and microinflammation in men: a relevant atherothrombotic link. Heart 2007;93:940-944.
  34. Jouven X, Empana JP, Schwartz PJ, Desmos M, Courbon D, Ducimeltiere P: Heart rate profile during exercise as a predictor of sudden death. N Engl J Med 2005;152:1915-1958.
  35. Jesen MT, Suadicani O, Hein HO, Gynderlberg F: Elevated resting heart rate, physical fitness and all-cause mortality: a 16-year follow-up in the Copenhagen Male Study. Heart 2013;99:882-887.
  36. Gillman MW, Kannel WB, Belanger A, D'Agostino RB: Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J 1993;125:1148-1154.
  37. Fox K, Borer JS, Camm J, Danchin N, Ferrari R, Sendon JLL, Steg PG, Tardif JC, Tavazzi L, Tendera M; Heart Rate Working Group: Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007;50:823-830.
  38. Palatini P, Benetos A, Grassi G, Julius S, Kjeldsen SE, Mancia G, Narkiewicz K, Parati G, Pessina AC, Ruilope LM, Zanchetti A: Identification and management of the hypertensive patients with elevated heart rate: statement of the European Society of Hypertension consensus meeting. J Hypertens 2006;24:603-610.
  39. Palatini P: Role of elevated hear rate in the development of cardiovascular disease in hypertension. Hypertension 2012;58:745-750.
  40. Diaz A, Bourassa MG, Guertin MC, Tardif JC: Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J 2005;26:967-974.
  41. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL Investigators: Heart rate as prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomized trial. Lancet 2008;372:817-821.
  42. Kjekshus J: Comments - beta blockers: heart rate reduction a mechanism of benefit. Eur Heart J 1985;6(suppl. A):29-30.
    External Resources
  43. Hjalmarson A. Gilpin EA, Kjekshus J, Schieman G, Nicod P, Henning H, Ross J Jr: Influence of heart rate on mortality after acute myocardial infarction. Am J Cardiol 1990;65:547-553.
  44. Boudoulas H: Therapeutic interventions which may improve survival in patients with coronary artery disease. Acta Cardiol 1990;45:477-487.
    External Resources
  45. Beere PA, Glagov S, Zarins CK: Retarding effects of heart rate on coronary atherosclerois. Science 1984;226:180-184.
  46. Schirmer SH, Degen A, Baumhakel M, Custodis F, Schuh L, Kohihaas M, Friedrich E, Bahlmann F, Kappl R, Maack C, Böhm M, Laufs U: Heart rate reduction by IF-channel inhibition with ivabradine restores collateral artery growth in hypercholesterolemic atherosclerosis. Eur Heart J 2011;33:1223-1231.
  47. Borer JS, Fox K, Jailon P, Lerebours G: Antianginal and anti-ischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, doubled-blind, multicentered, placebo-controlled trial. Circulation 2003;107:817-823.
  48. Fox K, Ford I, Steg GP. Tendera M, Ferrari R; BEAUTIFUL Investigators: Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomized double-blind, placebo-controlled trial. Lancet 2008;372:807-816.
  49. Fox K, Ford I, Steg GP, Tardif JC, Tendera M, Ferrari R; SIGNIFY Investigators: Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med 2014;371:1091-1099.
  50. Fox K, Komajda M, Ford I, Robertson M, Böhm M, Borer JS, Steg GS, Tavazzi L, Tendera M, Ferrari R, Swedberg K: Effect of ivabradine in patients with left-ventricular systolic dysfunction: a pooled analysis of individual patients data from BEAUTIFUL and SHIFT trials. Eur Heart J 2013;34:2263-2270.
  51. Manz M, Reuter M, Lauck G, Omran H, Jung W: A single intravenous dose of ivabradine, a novel If inhibitor, lowers heart rate but does not depress left ventricular function in patients with left ventricular dysfunction. Cardiology 2003;100:149-155.
  52. Ferrari R: Ivabradine: heart rate and left ventricular function. Cardiology 2014;128:226-230.
    External Resources
  53. Kolloch R, Legler UF, Champion A, Cooper-DeHoff RM, Handberg E, Zhou Q, Pepine CJ: Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the International Verapamil-SR/Trandolapril Study (INVEST). Eur Heart J 2008;29:1327-1334.
  54. Tsika EP, Poulimenos LE, Boudoulas KD, Manolis AJ: The J-curve in arterial hypertension: fact or fallacy? Cardiology 2014;129:126-135.
  55. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilberd EM, Shusterman NH: The effect of carvedilol on mortality and morbidity in patients with chronic heart failure. N Engl J Med 1996;334:1349-1355.
  56. Lechat P, Hulot JS, Escolano S, et al: Heart rate and cardiac rhythm relationship with bisoptol benefit in chronic heart failure in the GIBIS II trial. Circulation 2001;103:1428-1433.
  57. Hjalmarson A, Goldstein S, Fagerberg B, et al; MERIT-HF Study Group: Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL, Randomized Intervention Trial in Congestive Heart Failure (MERIT-II). JAMA 2000;283:1295-1302.
  58. Dobre D, Borer JS, Fox K, Swedberg K, Adams KF, Clelard JGF, Cohen-Solal AS Chergrade M, Gueyffier FF, O'Connor CM, Fidzet M, Patak A, Pin I, Rozano G, Sebach HN, Tavazzi L, Zannad F: Heart rate: a prognostic factor and therapeutic target in chronic heart failure. The distinct roles of drugs with heart rate lowering properties. Eur J Heart Fail 2014;10:76-85.
  59. Habal MV, Liu PP, Austin PC, Ross HJ, Newton GE, Wang X, Tu JV, Lee DS: Association of heart rate at hospital discharge with mortality and hospitalizations in patients with heart failure. Circ Heart Fail 2014;7:12-20.
  60. Dobre D, Zannad F, Keteylan SJ, Stevens SR, Rossignol O, Kitzman DW, Landzberg J, Howlett J, Krauss WE, Ellis SJ: Association between resting heart rate, chronotropic index, and long term outcomes in patients with heart failure receiving β-blocker therapy: data from the HF-ACTION trial. Eur Heart J 2013;34:2271-2280.
  61. Greene SJ, Vaduganathan M, Wilcox JE, Haristein ME, Maggioni AP, Subacius H, Zannad F, Konstam MA, Chioncel O, Yancy CW, Swedberg K, Butler J, Bonow RO, Gheorghiade M; EVEREST Investigators: The prognostic significance of heart rate in patients hospitalized for heart failure with reduced ejection fraction in sinus rhythm: insight from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) JACC Heart Fail 2013;1:488-496.
  62. Shinbane JS, Wood MA, Jensen DN, Elenbogen KA, Fitzpatrick AP, Scheinman MM: Tachycardia induced cardiomyopathy: a review of animal models and clinical studies. J Am Coll Cardiol 1997;29:709-715.
  63. Böhm M, Swedberg K, Komajda , Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; SHIFT Investigators: Heart rate as a risk factor in chronic heart failure (SHIFT). The association between heart rate and outcomes in a randomized placebo-controlled trial. Lancet 2010;376:886-894.
  64. Reil JC, Tardif JC, Ford I, Lloyd SM, O'Meara E, Komajda M, Borer JF, Tavazzi L, Swedberg K, Böhm M: Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients. J Am Coll Cardiol 2013;62:1977-1985.
  65. De Ferrari GM, Mazzuero A, Argesina I, et al: Favourable effects of heart rate reduction with intravenous administration of ivabradine in patients with advanced heart failure. Eur Heart Fail 2008;10:550-555.
  66. Ekman I, Chassany O, Komajda M, Böhm M, Borer JS, Ford I, Tavazzi L, Swedberg K: Heart rate reduction with ivabradine and health related quality of life in patients with chronic heart failure: results from the SHIFT study. Eur Heart J 2011;32:2395-2404.
  67. Tardif JC, O'Meara E, Komajda M, Böhm M, Borer JS, Ford I, Tavazzi L, Swedberg K; SHIFT Investigators: Effects of selective heart rate reduction with ivabradine on left ventricular remodeling and function: results from the SHIFT echocardiographic substudy. Eur Heart J 2011;32:2507-2515.
  68. Dyer AR, Persky V, Stamler J, et al: Heart rate as a prognostic factor for coronary heart disease and mortality: findings in Chicago epidemiologic studies. Am J Epidemiol 1980;112:736-749.
    External Resources
  69. Williams B, Lacy PS; ASCOT Investigators: Impact of heart rate on central aortic pressure and hemodynamics: analysis from the CAFÉ (Conduit Artery Function Evaluation) study. J Am Coll Cardiol 2009;54:705-713.
  70. Mittleman MA, Maclure M, Tofler GH, Sherwood JB, Goldberg RJ, Muller JE: Triggering of acute myocardial infarction by heavy physical exertion. Protection against triggering by regular exertion. Determinants of Myocardial Infarction Onset Study Investigators. N Engl J Med 1993;329:1677-1168.
  71. Tardif JC, Polikowski O, Kahan T: Efficacy of the I(f) current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial. Eur Heart J 2009;30:540-548.
  72. Borer JS, Böhm M, Ford I, Robertson M, Komajda M, Tavazzi L, Swedberg K: Efficacy and safety of ivabradine in patients with severe chronic systolic heart failure (from the SHIFT study). J Am Coll Cardiol 2014;113:497-503.
  73. Dierckx R, Cleland JGF, Parsons S, Putzu P, Pellicori P, Dicken B, Boyalla V, Clark AL: Prescribing patterns to optimize heart failure rate: analysis of 1,000 consecutive outpatient appointments to a single heart failure clinic over a six-month period. JACC Heart Fail 2015;3:224-230.
  74. Borer JS: Heart rate slowing by If inhibition: therapeutic utility from clinical trials. Eur Heart J 2005;7(suppl H):H22-H28.
    External Resources
  75. Boudoulas KD, Leier CV, Geleris P, Boudoulas H: Shortcoming of guidelines. Cardiology 2015;130:187-200.

Author Contacts

Harisios Boudoulas, MD

Division of Cardiovascular Medicine

The Ohio State University

4185 Mumford Ct, Columbus, Ohio 43220 (USA)

E-Mail boudoulas@bioacademy.gr


Article / Publication Details

First-Page Preview
Abstract of Turning Basic Research into Clincal Success

Received: May 12, 2015
Accepted: June 15, 2015
Published online: August 15, 2015
Issue release date: November 2015

Number of Print Pages: 14
Number of Figures: 12
Number of Tables: 2

ISSN: 0008-6312 (Print)
eISSN: 1421-9751 (Online)

For additional information: http://www.karger.com/CRD


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Levine HJ: Rest heart rate and life expectancy. J Am Coll Cardiol 1997;30:1104-1106.
  2. Hulbert AJ, Ramplona R, Buffenstein R, Buttemer WA: Life and death: Metabolic rate, membrane composition, and life span of animals. Physiol Rev 2007;87:1175-1213.
  3. DiFrancesco D, Borer JS: The funny current: cellular basis for the control of heart rate. Drugs 2007;67:15-24.
  4. Olshansky B, Sullivan RM: Inappropriate sinus tachycardia. J Am Coll Cardiol 2013;61:793-801.
  5. Eigelsheim M, Newton-Cheh C, Sotoodehnia, et al: Genome-wide association analysis identifies multiple loci related to resting heart rate. Hum Mol Genet 2010;19:3385-3394.
  6. Vaanholt LM, Daan S, Schubert KA, Visser GH: Metabolism and aging: effects of cold exposure on metabolic rate, body composition, and longevity in mice. Physiol Biochem Zool 2009;82:314-324.
  7. Boudoulas H, Rittgers SE, Lewis RP, Leier CV, Weissler AM: Changes in diastolic time with various pharmacologic agents: implication for myocardial perfusion. Circulation 1979;60:164-169.
  8. Obdahl A, Venkatesh BA, Fernandes VRS, Wu CO, Nasir K, Choi EY, Almeida AL, Rosen B, Carvalho B, Edvardsen T, Bluemke DA, Lima JAC: Resting heart rate as predictor for left ventricular dysfunction and heart failure. MESA (Multiethnic Study of Atherosclerosis). J Am Coll Cardiol 2014;63:1182-1189.
  9. Levy R, White PD, Stroud WD, Cha BG: Transient tachycardia. Prognostic significance alone and in association with transient hypertension. JAMA 1945;129:585-588.
    External Resources
  10. Boudoulas H, Leier CV: Clinical perspective: myocardial perfusion pressure in the age of afterload reduction. ACC Curr J Rev 2000;9:27-29.
    External Resources
  11. Boudoulas H, Karayannacos PE, Kien N, Lewis RP, Kakos GS, Leir CV, Vasco JS: Noninvasive method of estimating relative subendocardial flow employing diastolic time; in Dietrich E (ed): Noninvasive Assessment of the Cardiovascular System. Littleton, John Wright-PSG Inc, 1982, pp 211-217.
  12. Boudoulas H: Diastolic time: the forgotten dynamic factor. Implications for myocardial perfusion. Acta Cardiol 1991;46:61-71.
    External Resources
  13. Boudoulas H: Diastolic time: implications for myocardial perfusion and ventricular filling. Hell J Cardiol 1991;32:400-409.
  14. Boudoulas H, Dervenagas S, Fulkerson PK, Bush CA, Lewis RP: Effect of heart rate on diastolic time and left ventricular performance in patients with atrial fibrillation; in: Noninvasive Cardiovascular Diagnosis, ed 2. Littleton, Mass PSG Inc, 1981, pp 433-445.
  15. Ling L, Khammy O, Byne M, Amirahmadi F, Foster A, Li G, Zhang L, Remedios C, Chen C, Kaye DM: Irregular rhythm adversely influences calcium handling in ventricular myocardium. Circ Heart Fail 2012;5:786-793.
  16. Boudoulas KD, Vlachopoulos C, Raman SV, Sparkas EA, Triposkiadis F, Stefanadis C, Boudoulas H: Aortic function: from the research laboratory to the clinic. Cardiology 2012;121:31-42.
  17. Boudoulas H, Stefanadis C: The Aorta: Structure, Function, Dysfunction, and Diseases. New York, Informa Healthcare, 2009.
  18. Boudoulas H, Toutouzas P, Wooley CF: Functional Abnormalities of the Aorta. Futura, Armonk, 1996.
    External Resources
  19. Nichols WW, O'Rourke MF, Vlachopoulos C (eds): McDonald's Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles, ed 6. London, Hoder Arnold, 2011.
  20. Thorin E, Thorin-Trescases N: Vascular endothelial aging, heartbeat after heartbeat. Cardiovasc Res 2009;84:24-32.
  21. Custodis F, Schirmer SH, Baumhakel M, Heusch G, Böhm M, Laufs U: Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol 2010;56:1973-1983.
  22. Giannattasio C, Vincenti A, Failla M, Capta A, Ciro A, De Ceglia S, Getile G, Brambilla R, Mancia G: Effects of heart rate changes on arterial distensibility in humans. Hypertension 2003;42:253-256.
  23. Wilkinson IB, MacCallum H, Flint L, Cockcroft JR, Newby D, Webb DJ: The influence of heart rate on augmentation index and central arterial pressure in humans. J Physiol 2000;525:263-270.
  24. Tartiere-Kesri L, Tartieri JM, Logeart D, Bwauvais F, Solal C: Increased proximal arterial stiffness and cardiac response with moderate exercise in patients with heart failure and preserved ejection fraction. J Am Coll Cardiol 2012;59:455-461.
  25. Borlaud BA: Heart rate reduction. It is not just for ventricles anymore. J Am Coll Cardiol 2013;62:1986-1987.
  26. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, Hughes AD, Thuster A, O'Rourke M: Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes. Principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006;113:1213-1225.
  27. Benetos A, Adamopoulos C, Bureau JM, Temmar M, Labat C, Bean K, Thomas F, Pannier B, Asmar R, Zureik M, Safar M, Guize L: Determinants of accelerated progression of arterial stiffness in normotensive subjects and in treated hypertensive subjects over a 6-year period. Circulation 2002;105:1202-1207.
  28. Böhm M, Reil JC, Danchin N, Thoenes M, Bramlage P, Volpe M. Association of heart rate with microalbuminuria in cardiovascular risk patients: data from I-SEARCH. J Hypertens 2008;26:18-25.
  29. Palatini P, Casiglia E, Pauletto P, Staessen J, Kaciroti N, Jukius S: Relationship of tachycardia with high blood pressure and metabolic abnormalities. Hypertension 1997;30:1267-1273.
  30. O' Hartaigh B, Bosch JA, Carroll D, Hemming K, Pilz S, Loebroks A, Kleber ME, Grammer TB, Fisher JE, Boehm B, Marz W, Thomas NG: Evidence of a synergistic association between heart rate, inflammation, and cardiovascular mortality in patients undergoing coronary angiography. Eur Heart J 2013;34:932-941.
  31. Zulfigar U, Jurivich DA, Singer DH: Relation of high heart rate variability to healthy longevity. Am J Cardiol 2010;105:1181-1185.
  32. Grassi G, Vailati S, Bertinieri G, Seravalle G, Stella ML, Dell'Oro R, Mancia G: Heart rate as marker of sympathetic activity. J Hypertens 1998;16:1635-1639.
  33. Rogowski O, Shapira I, Shirom A, Melamed S, Toker S, Berliner S: Heart rate and microinflammation in men: a relevant atherothrombotic link. Heart 2007;93:940-944.
  34. Jouven X, Empana JP, Schwartz PJ, Desmos M, Courbon D, Ducimeltiere P: Heart rate profile during exercise as a predictor of sudden death. N Engl J Med 2005;152:1915-1958.
  35. Jesen MT, Suadicani O, Hein HO, Gynderlberg F: Elevated resting heart rate, physical fitness and all-cause mortality: a 16-year follow-up in the Copenhagen Male Study. Heart 2013;99:882-887.
  36. Gillman MW, Kannel WB, Belanger A, D'Agostino RB: Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J 1993;125:1148-1154.
  37. Fox K, Borer JS, Camm J, Danchin N, Ferrari R, Sendon JLL, Steg PG, Tardif JC, Tavazzi L, Tendera M; Heart Rate Working Group: Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007;50:823-830.
  38. Palatini P, Benetos A, Grassi G, Julius S, Kjeldsen SE, Mancia G, Narkiewicz K, Parati G, Pessina AC, Ruilope LM, Zanchetti A: Identification and management of the hypertensive patients with elevated heart rate: statement of the European Society of Hypertension consensus meeting. J Hypertens 2006;24:603-610.
  39. Palatini P: Role of elevated hear rate in the development of cardiovascular disease in hypertension. Hypertension 2012;58:745-750.
  40. Diaz A, Bourassa MG, Guertin MC, Tardif JC: Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J 2005;26:967-974.
  41. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL Investigators: Heart rate as prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomized trial. Lancet 2008;372:817-821.
  42. Kjekshus J: Comments - beta blockers: heart rate reduction a mechanism of benefit. Eur Heart J 1985;6(suppl. A):29-30.
    External Resources
  43. Hjalmarson A. Gilpin EA, Kjekshus J, Schieman G, Nicod P, Henning H, Ross J Jr: Influence of heart rate on mortality after acute myocardial infarction. Am J Cardiol 1990;65:547-553.
  44. Boudoulas H: Therapeutic interventions which may improve survival in patients with coronary artery disease. Acta Cardiol 1990;45:477-487.
    External Resources
  45. Beere PA, Glagov S, Zarins CK: Retarding effects of heart rate on coronary atherosclerois. Science 1984;226:180-184.
  46. Schirmer SH, Degen A, Baumhakel M, Custodis F, Schuh L, Kohihaas M, Friedrich E, Bahlmann F, Kappl R, Maack C, Böhm M, Laufs U: Heart rate reduction by IF-channel inhibition with ivabradine restores collateral artery growth in hypercholesterolemic atherosclerosis. Eur Heart J 2011;33:1223-1231.
  47. Borer JS, Fox K, Jailon P, Lerebours G: Antianginal and anti-ischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, doubled-blind, multicentered, placebo-controlled trial. Circulation 2003;107:817-823.
  48. Fox K, Ford I, Steg GP. Tendera M, Ferrari R; BEAUTIFUL Investigators: Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomized double-blind, placebo-controlled trial. Lancet 2008;372:807-816.
  49. Fox K, Ford I, Steg GP, Tardif JC, Tendera M, Ferrari R; SIGNIFY Investigators: Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med 2014;371:1091-1099.
  50. Fox K, Komajda M, Ford I, Robertson M, Böhm M, Borer JS, Steg GS, Tavazzi L, Tendera M, Ferrari R, Swedberg K: Effect of ivabradine in patients with left-ventricular systolic dysfunction: a pooled analysis of individual patients data from BEAUTIFUL and SHIFT trials. Eur Heart J 2013;34:2263-2270.
  51. Manz M, Reuter M, Lauck G, Omran H, Jung W: A single intravenous dose of ivabradine, a novel If inhibitor, lowers heart rate but does not depress left ventricular function in patients with left ventricular dysfunction. Cardiology 2003;100:149-155.
  52. Ferrari R: Ivabradine: heart rate and left ventricular function. Cardiology 2014;128:226-230.
    External Resources
  53. Kolloch R, Legler UF, Champion A, Cooper-DeHoff RM, Handberg E, Zhou Q, Pepine CJ: Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the International Verapamil-SR/Trandolapril Study (INVEST). Eur Heart J 2008;29:1327-1334.
  54. Tsika EP, Poulimenos LE, Boudoulas KD, Manolis AJ: The J-curve in arterial hypertension: fact or fallacy? Cardiology 2014;129:126-135.
  55. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilberd EM, Shusterman NH: The effect of carvedilol on mortality and morbidity in patients with chronic heart failure. N Engl J Med 1996;334:1349-1355.
  56. Lechat P, Hulot JS, Escolano S, et al: Heart rate and cardiac rhythm relationship with bisoptol benefit in chronic heart failure in the GIBIS II trial. Circulation 2001;103:1428-1433.
  57. Hjalmarson A, Goldstein S, Fagerberg B, et al; MERIT-HF Study Group: Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL, Randomized Intervention Trial in Congestive Heart Failure (MERIT-II). JAMA 2000;283:1295-1302.
  58. Dobre D, Borer JS, Fox K, Swedberg K, Adams KF, Clelard JGF, Cohen-Solal AS Chergrade M, Gueyffier FF, O'Connor CM, Fidzet M, Patak A, Pin I, Rozano G, Sebach HN, Tavazzi L, Zannad F: Heart rate: a prognostic factor and therapeutic target in chronic heart failure. The distinct roles of drugs with heart rate lowering properties. Eur J Heart Fail 2014;10:76-85.
  59. Habal MV, Liu PP, Austin PC, Ross HJ, Newton GE, Wang X, Tu JV, Lee DS: Association of heart rate at hospital discharge with mortality and hospitalizations in patients with heart failure. Circ Heart Fail 2014;7:12-20.
  60. Dobre D, Zannad F, Keteylan SJ, Stevens SR, Rossignol O, Kitzman DW, Landzberg J, Howlett J, Krauss WE, Ellis SJ: Association between resting heart rate, chronotropic index, and long term outcomes in patients with heart failure receiving β-blocker therapy: data from the HF-ACTION trial. Eur Heart J 2013;34:2271-2280.
  61. Greene SJ, Vaduganathan M, Wilcox JE, Haristein ME, Maggioni AP, Subacius H, Zannad F, Konstam MA, Chioncel O, Yancy CW, Swedberg K, Butler J, Bonow RO, Gheorghiade M; EVEREST Investigators: The prognostic significance of heart rate in patients hospitalized for heart failure with reduced ejection fraction in sinus rhythm: insight from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) JACC Heart Fail 2013;1:488-496.
  62. Shinbane JS, Wood MA, Jensen DN, Elenbogen KA, Fitzpatrick AP, Scheinman MM: Tachycardia induced cardiomyopathy: a review of animal models and clinical studies. J Am Coll Cardiol 1997;29:709-715.
  63. Böhm M, Swedberg K, Komajda , Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; SHIFT Investigators: Heart rate as a risk factor in chronic heart failure (SHIFT). The association between heart rate and outcomes in a randomized placebo-controlled trial. Lancet 2010;376:886-894.
  64. Reil JC, Tardif JC, Ford I, Lloyd SM, O'Meara E, Komajda M, Borer JF, Tavazzi L, Swedberg K, Böhm M: Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients. J Am Coll Cardiol 2013;62:1977-1985.
  65. De Ferrari GM, Mazzuero A, Argesina I, et al: Favourable effects of heart rate reduction with intravenous administration of ivabradine in patients with advanced heart failure. Eur Heart Fail 2008;10:550-555.
  66. Ekman I, Chassany O, Komajda M, Böhm M, Borer JS, Ford I, Tavazzi L, Swedberg K: Heart rate reduction with ivabradine and health related quality of life in patients with chronic heart failure: results from the SHIFT study. Eur Heart J 2011;32:2395-2404.
  67. Tardif JC, O'Meara E, Komajda M, Böhm M, Borer JS, Ford I, Tavazzi L, Swedberg K; SHIFT Investigators: Effects of selective heart rate reduction with ivabradine on left ventricular remodeling and function: results from the SHIFT echocardiographic substudy. Eur Heart J 2011;32:2507-2515.
  68. Dyer AR, Persky V, Stamler J, et al: Heart rate as a prognostic factor for coronary heart disease and mortality: findings in Chicago epidemiologic studies. Am J Epidemiol 1980;112:736-749.
    External Resources
  69. Williams B, Lacy PS; ASCOT Investigators: Impact of heart rate on central aortic pressure and hemodynamics: analysis from the CAFÉ (Conduit Artery Function Evaluation) study. J Am Coll Cardiol 2009;54:705-713.
  70. Mittleman MA, Maclure M, Tofler GH, Sherwood JB, Goldberg RJ, Muller JE: Triggering of acute myocardial infarction by heavy physical exertion. Protection against triggering by regular exertion. Determinants of Myocardial Infarction Onset Study Investigators. N Engl J Med 1993;329:1677-1168.
  71. Tardif JC, Polikowski O, Kahan T: Efficacy of the I(f) current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial. Eur Heart J 2009;30:540-548.
  72. Borer JS, Böhm M, Ford I, Robertson M, Komajda M, Tavazzi L, Swedberg K: Efficacy and safety of ivabradine in patients with severe chronic systolic heart failure (from the SHIFT study). J Am Coll Cardiol 2014;113:497-503.
  73. Dierckx R, Cleland JGF, Parsons S, Putzu P, Pellicori P, Dicken B, Boyalla V, Clark AL: Prescribing patterns to optimize heart failure rate: analysis of 1,000 consecutive outpatient appointments to a single heart failure clinic over a six-month period. JACC Heart Fail 2015;3:224-230.
  74. Borer JS: Heart rate slowing by If inhibition: therapeutic utility from clinical trials. Eur Heart J 2005;7(suppl H):H22-H28.
    External Resources
  75. Boudoulas KD, Leier CV, Geleris P, Boudoulas H: Shortcoming of guidelines. Cardiology 2015;130:187-200.
ppt logo Download Images (.pptx)


Figures
Thumbnail
Thumbnail
Thumbnail
Thumbnail
Thumbnail
Thumbnail
Thumbnail
Thumbnail
Thumbnail
Thumbnail
Thumbnail
Thumbnail

Tables
Thumbnail
Thumbnail