De battre mon coeur s'est arrêté—Movie by Jacques Audiard.

Resting heart rate (RHR) is one of the simplest cardiovascular parameters, which usually averages 60 to 80 beats per minute (b.p.m.), but can occasionally exceed 100 b.p.m. in unconditioned, sedentary individuals and be as low as 30 b.p.m. in highly trained endurance athletes. Epidemiological evidences demonstrate that RHR, or its corollaries, namely post-exercise heart rate recovery, which is mediated primarily by vagal tone, and heart rate variability (HRV, beat-to-beat variability also mediated by autonomic nervous system, especially parasympathetic) correlates with cardiovascular morbidity and suggests that RHR determines life expectancy. Multiple studies have identified RHR as an independent risk factor for cardiovascular disease (comparable with smoking, dyslipidemia or hypertension). However, it is often overlooked.

Heart rate: an independent cardiovascular risk factor

Since 1980, it is known that resting heart rate (RHR) is a prognostic factor in coronary diseased patients.1,2 Data from the Coronary Artery Surgery Study (CASS) published last year underline the prognostic importance of RHR for morbidity (time to rehospitalization), as well as total and cardiovascular mortality.3 Heart rate proves to be the best predictor after myocardial infarction,4,5 in patients with congestive heart failure, as well as in patients with diabetes mellitus or hypertension.

In addition, it was found that elevated RHR is also strongly associated with mortality in the general population. For instance, in the Framingham Study, in a cohort composed of 5070 subjects who were free from cardiovascular disease at the time of entry into the study, cardiovascular and coronary mortality increased progressively with RHR6 (Figure 1). In a subset of 4530 untreated hypertensive (>140 mmHg systolic or >90 mmHg diastolic) patients included in this study, using 36-year follow-up data, odds ratio (OR) for each increment in heart rate of 40 b.p.m. were 1.68–1.70 (CI: 1.08–2.67) for cardiovascular mortality and fascinatingly also 2.14–2.18 (CI: 1.59–2.88) for all-cause mortality. This latter study, however, also underlines a key concept: because high RHR is associated with elevated sympathetic activity, it is also frequently related to arterial hypertension. A crucial step is therefore to know whether high RHR is also associated with cardiovascular mortality when controlling for potential confounding cardiovascular risk factors, such as arterial hypertension or age.7 Subsequent analysis demonstrated that rapid RHR was not an indicator of pre-existing illness, but was rather an independent risk factor.8 Moreover, four studies involving hypertensive subjects demonstrated that this effect was sustained in this subset of patients.711 This abundant literature was further incremented by data also demonstrating this effect in elderly.1214

Figure 1

Dependency of heart failure events and sudden cardiac death on RHR divided in quartiles or quintiles. Included are men in a 36-year follow-up in the Framingham Heart Study.6,8

Figure 1

Dependency of heart failure events and sudden cardiac death on RHR divided in quartiles or quintiles. Included are men in a 36-year follow-up in the Framingham Heart Study.6,8

Multiple follow-up studies confirmed these data, as the Cordis trial, the Paris Prospective Study or the MATISS project: Kristal-Boneh et al. (CORDIS)15 found that RHR was strongly associated with both all-cause (RR: 2.23, CI: 1.4–3.6, RHR >90 vs. <70 b.p.m.) and cardiovascular mortality after controlling (in various statistical models) for manifold recognized risk factors. Filipovsky et al. (PPS)16 found that mortality could be predicted by resting heart frequency in 4907 middle-aged males followed during 17 years. Seccareccia et al. (MATISS)17 verified that in a low-risk Italian population, heart rate increment was associated with a relative risk increase from 1.52 (CI: 1.29–1.78) for all-cause mortality, 1.63 (CI: 1.26–2.10) for cardiovascular mortality, and 1.47 (CI:1.19–1.80) for non-cardiovascular mortality.

As with cholesterol levels, the risk is graded;9,18 i.e. the risk rises with increasing RHR. In the French IPC trial, Benetos et al.9 evaluated the prognostic value of RHR on mortality in more than 19 000 healthy subjects and found a continuous, graded effect of RHR during a mean follow-up duration of 18.2 years. In men, the relative risk for cardiovascular death was 1.35 (CI: 1.01–1.80) in the group with RHR 60–80 b.p.m. to 2.18 (CI: 1.37–3.47) in the group with RHR >100 b.p.m. Data from the National Health and Nutrition Examination Survey (NHANES I) Epidemiologic follow-up study confirmed this association in white men (RR: 1.37, CI: 1.02–1.84, RHR >84 vs. <74 b.p.m.) and extended this observation to black men and women.19 This is an important finding because it has been considered that high RHR was only a weak predictor in the female gender. The key studies on the topic are listed on the Table 1.13,2027

Table 1

Main studies on high RHR as cardiovascular risk factor

Reference Study population subset(s) Study name Year 
CAD    
 Wong et al.20  Framingham 1989 
 Disegni et al.4  SPRINT 1995 
 Copie et al.1   1996 
 Hathaway et al.5  GUSTO-I 1998 
 Diaz et al.3  CASS 2005 
General population    
 Dyer et al.2  Chicago 1980 
 Kannel et al.6  Framingham 1985–87 
 Gillum et al.19  NHANES I 1991 
 Filipovsky et al.16  Paris Prospective 1992 
 Shaper et al.21  British Men Study 1993 
 Goldberg et al.22  Framingham 1996 
 Benetos et al.9  French IPC 1999 
 Jouven et al.23  Paris Prospective 1999 
 Kristal-Boneh et al.15  CORDIS 2000 
 Seccareccia et al.17  MATISS 2001 
Hypertensive individuals    
 Benetos et al.9  French IPC 1999 
 Gillmann et al.8  Framingham 1993 
 Thomas et al.10  French IPC 2001 
Female gender    
 Perk et al.25  Jerusalem 70-year-old Longitudinal Study 2003 
 Diaz et al.3 +CAD CASS 2005 
 Diaz et al.3 +diabetes CASS 2005 
 Chang et al.26 +elderly Women's Health and Aging Study I (WHAS I) 2003 
 Gillman et al.8 +arterial hypertension Framingham 1993 
 Palatini et al.11 +elderly+arterial hypertension Syst-Eur 2002 
Elderly    
 Aronow et al.27   1996 
 Palatini et al.14  CASTEL 1999 
 Menotti et al.13  FINE 2001 
 Benetos et al.12  French IPC 2003 
 Palatini et al.11 +arterial hypertension Syst-Eur 2002 
Reference Study population subset(s) Study name Year 
CAD    
 Wong et al.20  Framingham 1989 
 Disegni et al.4  SPRINT 1995 
 Copie et al.1   1996 
 Hathaway et al.5  GUSTO-I 1998 
 Diaz et al.3  CASS 2005 
General population    
 Dyer et al.2  Chicago 1980 
 Kannel et al.6  Framingham 1985–87 
 Gillum et al.19  NHANES I 1991 
 Filipovsky et al.16  Paris Prospective 1992 
 Shaper et al.21  British Men Study 1993 
 Goldberg et al.22  Framingham 1996 
 Benetos et al.9  French IPC 1999 
 Jouven et al.23  Paris Prospective 1999 
 Kristal-Boneh et al.15  CORDIS 2000 
 Seccareccia et al.17  MATISS 2001 
Hypertensive individuals    
 Benetos et al.9  French IPC 1999 
 Gillmann et al.8  Framingham 1993 
 Thomas et al.10  French IPC 2001 
Female gender    
 Perk et al.25  Jerusalem 70-year-old Longitudinal Study 2003 
 Diaz et al.3 +CAD CASS 2005 
 Diaz et al.3 +diabetes CASS 2005 
 Chang et al.26 +elderly Women's Health and Aging Study I (WHAS I) 2003 
 Gillman et al.8 +arterial hypertension Framingham 1993 
 Palatini et al.11 +elderly+arterial hypertension Syst-Eur 2002 
Elderly    
 Aronow et al.27   1996 
 Palatini et al.14  CASTEL 1999 
 Menotti et al.13  FINE 2001 
 Benetos et al.12  French IPC 2003 
 Palatini et al.11 +arterial hypertension Syst-Eur 2002 

On the basis of this evidence, it has been proposed that, as in animals, life span could be predetermined using allometric scales based on RHR.28 Longevity determination is a key element in biogerontology. Within the animal kingdom, the mammalians' heart rate represents an inverse semi-logarithmic relation to life expectancy: small animals have a higher heart rate and shorter lifespan than do larger2830 (Figure 2). The average number of heart beats per lifetime in mammalians is unexpectedly constant within one order of magnitude, 7.3+/−5.6×108 despite a >40-fold difference in longevity (Figure 3). As a corollary, the basal energy consumption per heart beat and heart mass may be the same for all animals. This suggests that the life span is predetermined by the basic energetics of the living cells, and that the apparent inverse relation between life span and heart rate reveals the heart rate to serve as a marker of the metabolic rate. This may be exemplified by considering the vast range of physiological cardiac parameters between one of the smallest, the shrew weighing 2 g, and the largest extant mammalian, the blue whale of 100 000 kg (Table 2 with data compiled from Dobson31). Despite a difference of many millions in body weight, heart weight, stroke volume, and total blood pumped per lifetime, the total oxygen consumption and ATP usage per unit mass and lifetime are almost identical together with the total number of the heart beats per lifetime.

Figure 2

Inverse linear relation between RHR and life expectancy in mammals and humans. Redrawn from Levine28 with permission from American College of Cardiology Foundation.

Figure 2

Inverse linear relation between RHR and life expectancy in mammals and humans. Redrawn from Levine28 with permission from American College of Cardiology Foundation.

Figure 3

Relation between life expectancy and total heart beats per lifetime in mammals and humans. Redrawn from Levine28 with permission from American College of Cardiology Foundation.

Figure 3

Relation between life expectancy and total heart beats per lifetime in mammals and humans. Redrawn from Levine28 with permission from American College of Cardiology Foundation.

Table 2

Cardiac parameters of one of the smallest and one of the largest living mammalians

Parameter Shrew Blue whale Fold difference 
Body weight 2 g 100 000 kg 50 000 000 
Heart weight 12 mg 600 kg 50 000 000 
Heart weight over body weight 0.006 0.006 1.0 
Heart rate per minute 1000 170 
Life span (years) 118 118 
Heart beats per lifetime 6.6×108 11×108 1.7 
Stroke volume (litres) 1.2×10−6 350 300 000 000 
Cardiac output (litres per min) 0.001 2098 2 200 000 
Total blood pumped per lifetime (litres) 800 1.3×1011 163 000 000 
Blood pumped (litres) per lifetime per kg heart 6.7×107 22×107 3.3 
Total oxygen consumption (litres per kg per lifetime) 35 000 39 300 1.1 
Moles ATP per kg per lifetime 7813 8771 1.1 
Parameter Shrew Blue whale Fold difference 
Body weight 2 g 100 000 kg 50 000 000 
Heart weight 12 mg 600 kg 50 000 000 
Heart weight over body weight 0.006 0.006 1.0 
Heart rate per minute 1000 170 
Life span (years) 118 118 
Heart beats per lifetime 6.6×108 11×108 1.7 
Stroke volume (litres) 1.2×10−6 350 300 000 000 
Cardiac output (litres per min) 0.001 2098 2 200 000 
Total blood pumped per lifetime (litres) 800 1.3×1011 163 000 000 
Blood pumped (litres) per lifetime per kg heart 6.7×107 22×107 3.3 
Total oxygen consumption (litres per kg per lifetime) 35 000 39 300 1.1 
Moles ATP per kg per lifetime 7813 8771 1.1 

Data of column one and two were collected from Dobson.31

Only humans make an exception to the rule by living longer and thus accumulating a larger mean number of heart beats of around 30×108 per lifetime (Figure 3). One might speculate how modern humans have stretched the biological boundaries by pushing the life expectancy to 80 years and beyond. The most likely explanations may be changes in life-style, drugs (in particular, antibiotics), prevention, and nutrition.28 However, the question should still be raised: does the RHR causally determine the life span, or is it only an epiphenomenon?

High RHR: genetics vs. environmental factors?

The last decade has witnessed key discoveries on mechanisms leading to isolated high RHR. Singh et al.32 highlighted the contribution of genetic factors as a substantial determinant of RHR. Heritability analyses have been done by studying correlations between siblings and between spouse pairs after adjusting for important covariates within the Framingham Heart Study. They estimated the heritability of RHR to be 21%, which was similar to the subsequent report by Martin et al.'s33 estimate of 26%. Using a candidate gene approach for looking at the genetic determination of RHR, Ranade et al.34 found a ser49-to-gly (S49G) polymorphism in the beta-1 adrenergic receptor (ADRB1) associated with RHR. Serine homozygotes subjects had the highest mean RHR. A finding, which was supported by results from a genome scan study by Wilk for quantitative trait loci influencing RHR in about 1000 Caucasians and 1000 African Americans. Wilk et al.35 (Hypertension Genetic Epidemiology Network-HyperGEN) also demonstrated that the highest logarithm of the odds (LOD) score was detected on chromosome 4. Further investigations by Martin et al.33 from the Metabolic Risk Complications of Obesity Genes project, obtained significant evidence of linkage (LOD=3.9) for RHR on chromosome 4q, in the same region as for long QT syndrome 4 and within the 1-LOD unit support interval of two candidates: ankyrin-B and myozenin.

So is it only genetics? The response is clearly NO. Singh et al.32 demonstrated (apart from the genetic factors) that environmental causes (body mass index, systolic and diastolic blood pressure, smoking, and alcohol consumption) play at least such a large role in the determination of the RHR/HRV (13–40% vs. 13–23%). Martin et al.33 observed that individuals (especially females) with elevated RHR exhibited significantly elevated insulin and glucose levels, waist circumference, BMI, and diastolic blood pressure and suggestively elevated triglyceride levels and systolic blood pressure, all different clusters from the well known insulin resistance syndrome.36,37 The question is, therefore, whether high RHR also represents a member of this family. In line with these findings, recent studies have contributed importantly to generate the new concept that a defect in ‘bioavailability’ of nitric oxide (NO) plays a central role in the pathogenesis of this disorder. Interestingly, NO has been implicated in autonomic regulation of various aspects of cardiovascular system and could, thus, be the missing link between metabolic syndrome and high RHR (for review, see Sartori et al.38). In the coronary arteries, NO participates in parasympathetic vasodilation39 and inhibition of its sympathetic vasoconstriction.40 NO also modulates myocardial contractility in response to both cholinergic41,42 and beta-adrenergic stimulation.43 More importantly, NO is considered to modulate the autonomic control of heart rate, and, thus, RHR. Studies in humans suggest that NO augments cardiac vagal control in healthy subjects, as well as in patients with heart failure.44 Studies in animals established that this effect was mediated by the neuronal isoform of NO synthase (nNOS): mice (intact animals or isolated atria harvested from such animals) with complete deletion of the gene display impairment in the parasympathetic control of heart rate.45,46 So, is high RHR an epiphenomenon of the same spectrum of disease, yet known as metabolic syndrome?47 The answer is probably affirmative.

Because virtually all widespread ‘common’ diseases, such as diabetes or hypertension, result from the complex interaction of genetic susceptibility factors and modifiable environmental factors, one should postulate that this is also the case for the pathogenesis of elevated RHR. In line with this concept, animals fed with high-fat diet (unfortunately a not-so-infrequent diet in humans) rapidly develop a loss of nocturnal dipping of both blood pressure and heart rate48,49 and then all the pattern of metabolic syndrome. This effect is exaggerated in animal with NO deficiency,36,37,50 but could also happen with other gene deficiency, as demonstrated by PPARγ conditional E-null mice.51

HR-lowering therapy on the myth of eternal youth

If heart rate conditioned the fate of basal energy consumption and that the total energy per life is predetermined, life span should depend on heart rate (as in everyday chassis battery): average (battery) life has become shorter as energy requirements have increased. Taking advantage of this theory, techniques aiming to lower RHR should increase the life span. In wildness, hibernation acts in this way: hibernation markedly lowers RHR and prolongs life. For example, hibernating bats' heart rate decrease by 45-fold to 10–20 b.p.m. Hibernating bats live 70% longer (39 vs. 23 years) than its non-hibernating counterparts.52 In humans, modification of coronary heart disease risk factors play a key role in the control and alteration of the atherosclerotic process. Because hibernation is hardly possible (although some failed attempts have been reported53), we should know whether artificial lowering of an abnormally high heart rate (resting and non-resting) will aid primary and secondary prevention of coronary heart disease and, thus, decrease its related mortality. Exercise is a well-known intervention to lower RHR and increase survival. In the long term, endurance training increases parasympathetic activity and decreases sympathetic activity in the human heart at rest. These two training-induced autonomic effects, coupled with a possible reduction in intrinsic heart rate, decrease RHR. Interestingly, regular exercise training and RHR were strongly correlated with late survival in elderly patients from the French IPC-Study.12

In CAD patients, reducing heart rate is a generally accepted treatment modality; it directly minimizes the myocardial oxygen demand and enhances its supply by improving subendocardial blood flow.54,55 Moreover, it may reduce the risk of plaque rupture56 and decrease the risk of sudden cardiac death after myocardial infarction. In both animal and human, the anti-ischaemic benefits of beta-blockade can be abolished by atrial pacing,57,58 which argues for an important role of heart rate control in the positive effects of this class of drug. In addition, the favourable effects of beta-blockers (BB) on mortality in CAD patients are at least partially mediated to their HR-lowering effects.5961

In patients with chronic heart failure (CHF), rate-lowering therapies have shown to reduce both the morbidity (risk of hospitalization) and the mortality.6266 Multivariate analysis of CIBIS II showed that under beta-blockade, larger the discard of RHR was associated with, higher the survival and freedom of hospital admissions.67

Should we prescribe HR-lowering drugs to patients with high RHR, but without known CAD or CHF?

In the general population, a pulse rate higher than 90 b.p.m. may be harmful. So, should we treat it with the same strength as other components of the metabolic syndrome (hypercholesterolemia, arterial hypertension, or obesity)? To date, no human study has been performed to demonstrate the efficacy, the risk-benefit ratio, or even less, the cost-effectiveness of heart-rate lowering treatment in patients without cardiac disorders. Few evidences exist, however, based on animal studies. In monkeys, heart rate reduction by sinoatrial node ablation68,69 or administration of propranolol70 is associated with a noticeable reduction of atherogenesis. In mice, administration of digoxin slowed the heart rate and prolonged the life span.71

In humans, how should we currently manage high RHR? Since it could unmask hypoxaemia, anaemia, alcoholism, chronic stress or depression, or be the consequence of already prescribed drugs, a careful investigation should be done to exclude and, if necessary, treat secondary causes. Furthermore, lifestyle changes should be recommended with special emphasize on preventing anxiety, stress and toxics (caffeine, alcohol, nicotine, amphetamines, or cocaine), screen for drugs (hydralazine, thyroid hormones, catecholamines, aminophylline, etc.), and prescribe exercise or rational behaviour therapies. For instance, one should consider that pet ownership can lower RHR.72

Besides the BB, some of the calcium channel blockers (CCB), such as diltiazem and verapamil (non-dihydropyridines), also potently reduce the heart rate. BB reduce both RHR and the response of the heart rate to exercise. The reduction of heart rate by BB is accompanied by a decrease in peripheral blood pressure with consequently reduced cardiac oxygen consumption and a longer diastolic filling time allowing for increased coronary perfusion. BB have consistently been shown to reduce cardiovascular mortality, sudden cardiac death, and reinfarction in patients recovering from previous infarction61,73,74 (Figure 4). In common with BB, the CCB of the non-dihydropyridine type also lower the heart rate and blood pressure as well as the risk of reinfarction. In principle, both classes of drugs operate by lowering the intracellular calcium signalling (although by different mechanisms), reduce conductance velocity and cardiac inotropism.73,74 Since it is known that the heart rate is primarily determined by the hyperpolarization-activated cation current, termed If (f stands for funny because of its unusual activation by hyperpolarization at voltages in the diastolic range), Ih or Iq, the search for drugs that reduce the heart rate without the aforementioned unwanted effects of BB or CCB is going on. In the heart, the pacemaker current is carried by a family of hyperpolarization-activated, cyclic adenosine monophosphate (cAMP)-mediated cation channels (HCN1–HCN4, cloned in the late 1990s) in the sinoatrial node.75 HCN4 is the main isoform in the heart with smaller amounts of HCN1 and HCN2. These channels carry either an inward current (mainly Na+) at strongly negative (−80 mV) or an outward current (mainly K+) at mildly positive voltage (+5 mV) inducing membrane depolarization following the action potential. By mediation of cAMP their activity is subject to beta-adrenergic regulation. Mutations in HCN4 have recently been found in patients with idiopathic sinus node dysfunction.76 Of several drugs tested, ivabradine proved to be the most specific without almost any noticeable side effects. Ivabradine specifically inhibits the HCN4 channel in the open state displaying pronounced ‘use dependence’.77 This latter property supports its therapeutic effectiveness, since with higher heart rate more channels are open and might, thus, become inhibited by the drug. Ivabradine is presently in phase-III clinical tests and may soon become available.

Figure 4

Effect of variations in RHR on cardiovascular mortality in several studies on heart failure. Generally, those studies with an increase in heart rate (positive inotropic substances) augment mortality, whereas those with a decrease in heart rate (ACE-inhibitors or BB) reduce mortality. PROFILE, Prospective Randomized Flosequinan Longevity Evaluation Study; XAMOTEROL, Xamoterol in Severe Heart Failure Study; PROMISE, effects of oral milrinone on mortality in severe chronic heart failure; VHeFT, Vasodilator-Heart Failure Trials; CIBIS, Cardiac Insufficiency Bisoprolol Study; BHAT, Beta-blocker Heart Attack Trial; SOLVD, effect of enalapril on mortality and development of heart failure in asymtomatic patient with reduced LV ejection fractions; NOR, Norwegian Study Group: TIMOLOL, induced reduction in mortality and reinfarction; ANZ, Australia–New Zealand Heart Failure Research Collaborative Group; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; US CARVEDILOL, United States Carvedilol Heart Failure Trials; MOCHA, Multicenter Oral Carvedilol Heart Failure Assessment. Redrawn from Kjekshus77 with permission.

Figure 4

Effect of variations in RHR on cardiovascular mortality in several studies on heart failure. Generally, those studies with an increase in heart rate (positive inotropic substances) augment mortality, whereas those with a decrease in heart rate (ACE-inhibitors or BB) reduce mortality. PROFILE, Prospective Randomized Flosequinan Longevity Evaluation Study; XAMOTEROL, Xamoterol in Severe Heart Failure Study; PROMISE, effects of oral milrinone on mortality in severe chronic heart failure; VHeFT, Vasodilator-Heart Failure Trials; CIBIS, Cardiac Insufficiency Bisoprolol Study; BHAT, Beta-blocker Heart Attack Trial; SOLVD, effect of enalapril on mortality and development of heart failure in asymtomatic patient with reduced LV ejection fractions; NOR, Norwegian Study Group: TIMOLOL, induced reduction in mortality and reinfarction; ANZ, Australia–New Zealand Heart Failure Research Collaborative Group; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; US CARVEDILOL, United States Carvedilol Heart Failure Trials; MOCHA, Multicenter Oral Carvedilol Heart Failure Assessment. Redrawn from Kjekshus77 with permission.

In conclusion, because current evidences are enough to demonstrate its efficacy, drugs that lower heart rate should be prescribed in patients with myocardial infarction, diabetes mellitus, and/or heart failure. In hypertensive patients, an approved consensus has been published recently by Palatini et al.7 This publication presents a comprehensive review of clinical significance and prognosis of RHR as independent cardiovascular risk factor, especially in subsets of patients, such as women and elderly, its measurement and its management.

Lastly and because, to date, it is not known whether any drug-induced diminution of heart rate will efficiently extend life expectancy, heart rate reduction should be left to physician's discretion, hoping that large-scale, multicentre, double-blinded, placebo-controlled clinical studies will address this issue.

Conflict of interest: none declared.

References

1
Copie
X
Hnatkova
K
Staunton
A
Fei
L
Camm
AJ
Malik
M
Predictive power of increased heart rate versus depressed left ventricular ejection fraction and heart rate variability for risk stratification after myocardial infarction. Results of a two-year follow-up study
J Am Coll Cardiol
 
1996
27
270
276
2
Dyer
AR
Persky
V
Stamler
J
Paul
O
Shekelle
RB
Berkson
DM
Lepper
M
Schoenberger
JA
Lindberg
HA
Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies
Am J Epidemiol
 
1980
112
736
749
3
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
4
Disegni
E
Goldbourt
U
Reicher-Reiss
H
Kaplinsky
E
Zion
M
Boyko
V
Behar
S
The predictive value of admission heart rate on mortality in patients with acute myocardial infarction. SPRINT Study Group. Secondary Prevention Reinfarction Israeli Nifedipine Trial
J Clin Epidemiol
 
1995
48
1197
1205
5
Hathaway
WR
Peterson
ED
Wagner
GS
Granger
CB
Zabel
KM
Pieper
KS
Clark
KA
Woodlief
LH
Califf
RM
Prognostic significance of the initial electrocardiogram in patients with acute myocardial infarction. GUSTO-I Investigators. Global utilization of streptokinase and t-PA for occluded coronary arteries
JAMA
 
1998
279
387
391
6
Kannel
WB
Kannel
C
Paffenbarger
RS
Jr
Cupples
LA
Heart rate and cardiovascular mortality: the Framingham Study
Am Heart J
 
1987
113
1489
1494
7
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 patient with elevated heart rate: statement of a European Society of Hypertension Consensus Meeting
J Hypertens
 
2006
24
603
610
8
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
9
Benetos
A
Rudnichi
A
Thomas
F
Safar
M
Guize
L
Influence of heart rate on mortality in a French population: role of age, gender, and blood pressure
Hypertension
 
1999
33
44
52
10
Thomas
F
Rudnichi
A
Bacri
AM
Bean
K
Guize
L
Benetos
A
Cardiovascular mortality in hypertensive men according to presence of associated risk factors
Hypertension
 
2001
37
1256
1261
11
Palatini
P
Thijs
L
Staessen
JA
Fagard
RH
Bulpitt
CJ
Clement
DL
de Leeuw
PW
Jaaskivi
M
Leonetti
G
Nachev
C
O'Brien
ET
Parati
G
Rodicio
JL
Roman
E
Sarti
C
Tuomilehto
J
Predictive value of clinic and ambulatory heart rate for mortality in elderly subjects with systolic hypertension
Arch Intern Med
 
2002
162
2313
2321
12
Benetos
A
Thomas
F
Bean
KE
Pannier
B
Guize
L
Role of modifiable risk factors in life expectancy in the elderly
J Hypertens
 
2005
23
1803
1808
13
Menotti
A
Mulder
I
Nissinen
A
Giampaoli
S
Feskens
EJ
Kromhout
D
Prevalence of morbidity and multimorbidity in elderly male populations and their impact on 10-year all-cause mortality: the FINE Study (Finland, Italy, Netherlands, Elderly)
J Clin Epidemiol
 
2001
54
680
686
14
Palatini
P
Casiglia
E
Julius
S
Pessina
AC
High heart rate: a risk factor for cardiovascular death in elderly men
Arch Intern Med
 
1999
159
585
592
15
Kristal-Boneh
E
Silber
H
Harari
G
Froom
P
The association of resting heart rate with cardiovascular, cancer and all-cause mortality. Eight year follow-up of 3527 male Israeli employees (the CORDIS Study)
Eur Heart J
 
2000
21
116
124
16
Filipovsky
J
Ducimetiere
P
Safar
ME
Prognostic significance of exercise blood pressure and heart rate in middle-aged men
Hypertension
 
1992
20
333
339
17
Seccareccia
F
Pannozzo
F
Dima
F
Minoprio
A
Menditto
A
Lo Noce
C
Giampaoli
S
Heart rate as a predictor of mortality: the MATISS project
Am J Public Health
 
2001
91
1258
1263
18
Fujiura
Y
Adachi
H
Tsuruta
M
Jacobs
DR
Jr
Hirai
Y
Imaizumi
T
Heart rate and mortality in a Japanese general population: an 18-year follow-up study
J Clin Epidemiol
 
2001
54
495
500
19
Gillum
RF
Makuc
DM
Feldman
JJ
Pulse rate, coronary heart disease, and death: the NHANES I Epidemiologic Follow-up Study
Am Heart J
 
1991
121
172
177
20
Wong
ND
Cupples
LA
Ostfeld
AM
Levy
D
Kannel
WB
Risk factors for long-term coronary prognosis after initial myocardial infarction: the Framingham Study
Am J Epidemiol
 
1989
130
469
480
21
Shaper
AG
Wannamethee
G
Macfarlane
PW
Walker
M
Heart rate, ischaemic heart disease, and sudden cardiac death in middle-aged British men
Br Heart J
 
1993
70
49
55
22
Goldberg
RJ
Larson
M
Levy
D
Factors associated with survival to 75 years of age in middle-aged men and women. The Framingham Study
Arch Intern Med
 
1996
156
505
509
23
Jouven
X
Desnos
M
Guerot
C
Ducimetiere
P
Predicting sudden death in the population: the Paris Prospective Study I
Circulation
 
1996
99
1978
1983
24
Thomas
F
Bean
K
Provost
JC
Guize
L
Benetos
A
Combined effects of heart rate and pulse pressure on cardiovascular mortality according to age
J Hypertens
 
2001
19
863
869
25
Perk
G
Stessman
J
Ginsberg
G
Bursztyn
M
Sex differences in the effect of heart rate on mortality in the elderly
J Am Geriatr Soc
 
2003
51
1260
1264
26
Chang
M
Havlik
RJ
Corti
MC
Chaves
PH
Fried
LP
Guralnik
JM
Relation of heart rate at rest and mortality in the Women's Health and Aging Study
Am J Cardiol
 
2003
92
1294
1299
27
Aronow
WS
Ahn
C
Mercando
AD
Epstein
S
Association of average heart rate on 24-hour ambulatory electrocardiograms with incidence of new coronary events at 48-month follow-up in 1,311 patients (mean age 81 years) with heart disease and sinus rhythm
Am J Cardiol
 
1996
78
1175
1176
28
Levine
HJ
Rest heart rate and life expectancy
J Am Coll Cardiol
 
1997
30
1104
1106
29
Azbel
M
Universal biological scaling and mortality
Proc Natl Acad Sci USA
 
1994
91
12453
12457
30
Ferrari
R
Editorial: heart rate
Eur Heart J Suppl
 
2003
5
G1
G2
31
Dobson
GP
On being the right size: heart design, mitochondrial efficiency and lifespan potential
Clin Exp Pharmacol Physiol
 
2003
30
590
597
32
Singh
BN
Increased heart rate as a risk factor for cardiovascular disease
Eur Heart J Suppl
 
2003
5
G3
G9
33
Martin
LJ
Comuzzie
AG
Sonnenberg
GE
Myklebust
J
James
R
Marks
J
Blangero
J
Kissebah
AH
Major quantitative trait locus for resting heart rate maps to a region on chromosome 4
Hypertension
 
2004
43
1146
1151
34
Ranade
K
Jorgenson
E
Sheu
WH
Pei
D
Hsiung
CA
Chiang
FT
Chen
YD
Pratt
R
Olshen
RA
Curb
D
Cox
DR
Botstein
D
Risch
N
A polymorphism in the beta1 adrenergic receptor is associated with resting heart rate
Am J Hum Genet
 
2002
70
935
942
35
Wilk
JB
Myers
RH
Zhang
Y
Lewis
CE
Atwood
L
Hopkins
PN
Ellison
RC
Evidence for a gene influencing heart rate on chromosome 4 among hypertensives
Hum Genet
 
2002
111
207
213
36
Cook
S
Coronary artery disease, nitric oxide and oxidative stress: the ‘Yin-Yang’ effect—a Chinese concept for a worldwide pandemic
Swiss Med Wkly
 
2006
136
103
113
37
Cook
S
Hugli
O
Egli
M
Vollenweider
P
Burcelin
R
Nicod
P
Thorens
B
Scherrer
U
Clustering of cardiovascular risk factors mimicking the human metabolic syndrome X in eNOS null mice
Swiss Med Wkly
 
2003
133
360
363
38
Sartori
C
Lepori
M
Scherrer
U
Interaction between nitric oxide and the cholinergic and sympathetic nervous system in cardiovascular control in humans
Pharmacol Ther
 
2005
106
209
220
39
Shen
W
Ochoa
M
Xu
X
Wang
J
Hintze
TH
Role of EDRF/NO in parasympathetic coronary vasodilation following carotid chemoreflex activation in conscious dogs
Am J Physiol
 
1994
267
H605
H613
40
Goodson
AR
Leibold
JM
Gutterman
DD
Inhibition of nitric oxide synthesis augments centrally induced sympathetic coronary vasoconstriction in cats
Am J Physiol
 
1994
267
H1272
H1278
41
Hare
JM
Keaney
JF
Jr
Balligand
JL
Loscalzo
J
Smith
TW
Colucci
WS
Role of nitric oxide in parasympathetic modulation of beta-adrenergic myocardial contractility in normal dogs
J Clin Invest
 
1995
95
360
366
42
Hare
JM
Kim
B
Flavahan
NA
Ricker
KM
Peng
X
Colman
L
Weiss
RG
Kass
DA
Pertussis toxin-sensitive G proteins influence nitric oxide synthase III activity and protein levels in rat heart
J Clin Invest
 
1998
101
1424
1431
43
Keaney
JF
Jr
Hare
JM
Balligand
JL
Loscalzo
J
Smith
TW
Colucci
WS
Inhibition of nitric oxide synthase augments myocardial contractile responses to beta-adrenergic stimulation
Am J Physiol
 
1996
271
H2646
H2652
44
Chowdhary
S
Vaile
JC
Fletcher
J
Ross
HF
Coote
JH
Townend
JN
Nitric oxide and cardiac autonomic control in humans
Hypertension
 
2000
36
264
269
45
Choate
JK
Danson
EJ
Morris
JF
Paterson
DJ
Peripheral vagal control of heart rate is impaired in neuronal NOS knockout mice
Am J Physiol Heart Circ Physiol
 
2001
281
H2310
H2317
46
Jumrussirikul
P
Dinerman
J
Dawson
TM
Dawson
VL
Ekelund
U
Georgakopoulos
D
Schramm
LP
Calkins
H
Snyder
SH
Hare
JM
Berger
RD
Interaction between neuronal nitric oxide synthase and inhibitory G protein activity in heart rate regulation in conscious mice
J Clin Invest
 
1998
102
1279
1285
47
Palatini
P
Casiglia
E
Pauletto
P
Staessen
J
Kaciroti
N
Julius
S
Relationship of tachycardia with high blood pressure and metabolic abnormalities: a study with mixture analysis in three populations
Hypertension
 
1997
30
1267
1273
48
Antic
V
Van Vliet
BN
Montani
JP
Loss of nocturnal dipping of blood pressure and heart rate in obesity-induced hypertension in rabbits
Auton Neurosci
 
2001
90
152
157
49
Carroll
JF
Thaden
JJ
Wright
AM
Strange
T
Loss of diurnal rhythms of blood pressure and heart rate caused by high-fat feeding
Am J Hypertens
 
2005
18
1320
1326
50
Cook
S
Hugli
O
Egli
M
Menard
B
Thalmann
S
Sartori
C
Perrin
C
Nicod
P
Thorens
B
Vollenweider
P
Scherrer
U
Burcelin
R
Partial gene deletion of endothelial nitric oxide synthase predisposes to exaggerated high-fat diet-induced insulin resistance and arterial hypertension
Diabetes
 
2004
53
2067
2072
51
Nicol
CJ
Adachi
M
Akiyama
TE
Gonzalez
FJ
PPARgamma in endothelial cells influences high fat diet-induced hypertension
Am J Hypertens
 
2005
18
549
556
52
Wilkinson
GS
South
JM
Life history, ecology and longevity in bats
Aging Cell
 
2002
1
124
131
53
Giles
J
Could astronauts sleep their way to the stars?
Science news
 
2004
August
3
8
54
Colin
P
Ghaleh
B
Monnet
X
Hittinger
L
Berdeaux
A
Effect of graded heart rate reduction with ivabradine on myocardial oxygen consumption and diastolic time in exercising dogs
J Pharmacol Exp Ther
 
2004
308
236
240
55
Colin
P
Ghaleh
B
Monnet
X
Su
J
Hittinger
L
Giudicelli
JF
Berdeaux
A
Contributions of heart rate and contractility to myocardial oxygen balance during exercise
Am J Physiol Heart Circ Physiol
 
2003
284
H676
H682
56
Heidland
UE
Strauer
BE
Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption
Circulation
 
2001
104
1477
1482
57
Guth
BD
Heusch
G
Seitelberger
R
Ross
J
Jr
Mechanism of beneficial effect of beta-adrenergic blockade on exercise-induced myocardial ischemia in conscious dogs
Circ Res
 
1987
60
738
746
58
Simonsen
S
Ihlen
H
Kjekshus
JK
Haemodynamic and metabolic effects of timolol (Blocadren) on ischaemic myocardium
Acta Med Scand
 
1983
213
393
398
59
Hjalmarson
A
Significance of reduction in heart rate in cardiovascular disease
Clin Cardiol
 
1998
21
II3
II7
60
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
61
Kjekshus
JK
Importance of heart rate in determining beta-blocker efficacy in acute and long-term acute myocardial infarction intervention trials
Am J Cardiol
 
1986
57
43F
49F
62
CIBIS Investigators and Committees
The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial
Lancet
 
1999
353
9
13
63
The MERIT-HF Study
Group
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)
Lancet
 
1999
353
2001
2007
64
Hjalmarson
A
Goldstein
S
Fagerberg
B
Wedel
H
Waagstein
F
Kjekshus
J
Wikstrand
J
El Allaf
D
Vitovec
J
Aldershvile
J
Halinen
M
Dietz
R
Neuhaus
KL
Janosi
A
Thorgeirsson
G
Dunselman
PH
Gullestad
L
Kuch
J
Herlitz
J
Rickenbacher
P
Ball
S
Gottlieb
S
Deedwania
P
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 (MERITHF). MERIT-HF Study Group
JAMA
 
2000
283
1295
1302
65
Packer
M
Bristow
MR
Cohn
JN
Colucci
WS
Fowler
MB
Gilbert
EM
Shusterman
NH
The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group
N Engl J Med
 
1996
334
1349
1355
66
Packer
M
Coats
AJ
Fowler
MB
Katus
HA
Krum
H
Mohacsi
P
Rouleau
JL
Tendera
M
Castaigne
A
Roecker
EB
Schultz
MK
DeMets
DL
Effect of carvedilol on survival in severe chronic heart failure
N Engl J Med
 
2001
344
1651
1658
67
Lechat
P
Hulot
JS
Escolano
S
Mallet
A
Leizorovicz
A
Werhlen-Grandjean
M
Pochmalicki
G
Dargie
H
Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial
Circulation
 
2001
103
1428
1433
68
Beere
PA
Glagov
S
Zarins
CK
Retarding effect of lowered heart rate on coronary atherosclerosis
Science
 
1984
226
180
182
69
Beere
PA
Glagov
S
Zarins
CK
Experimental atherosclerosis at the carotid bifurcation of the cynomolgus monkey. Localization, compensatory enlargement, and the sparing effect of lowered heart rate
Arterioscler Thromb
 
1992
12
1245
1253
70
Kaplan
JR
Manuck
SB
Adams
MR
Weingand
KW
Clarkson
TB
Inhibition of coronary atherosclerosis by propranolol in behaviorally predisposed monkeys fed an atherogenic diet
Circulation
 
1987
76
1364
1372
71
Coburn
AF
Grey
RM
Rivera
SM
Observations on the relation of heart rate, life span, weight and mineralization in the digoxin-treated A-J mouse
Johns Hopkins Med J
 
1971
128
169
193
72
Allen
K
Shykoff
BE
Izzo
JL
Jr
Pet ownership, but not ace inhibitor therapy, blunts home blood pressure responses to mental stress
Hypertension
 
2001
38
815
820
73
DeWitt
CR
Waksman
JC
Pharmacology, pathophysiology and management of calcium channel blocker and beta-blocker toxicity
Toxicol Rev
 
2004
23
223
238
74
Zaugg
M
Schaub
MC
Cellular mechanisms in sympatho-modulation of the heart
Br J Anaesth
 
2004
93
34
52
75
DiFrancesco
D
Cardiac pacemaker I(f) current and its inhibition by heart ratereducing agents
Curr Med Res Opin
 
2005
21
1115
1122
76
Bucchi
A
Tognati
A
Milanesi
R
Baruscotti
M
DiFrancesco
D
Properties of ivabradine-induced block of HCN1 and HCN4 pacemaker channels
J Physiol
 
2006
572
335
346
77
Kjekshus
J
Gullestad
L
Heart rate as a therapeutic target in heart failure
Eur Heart J
 
1999
1
H64
H69

Comments

0 Comments