1. health and fitness
2. disease

European Heart Journal Supplements (2009) 11 (Supplement D), D8–D12
doi:10.1093/eurheartj/sup018
Heart rate and atherosclerosis
Jean-Claude Tardif*
Department of Medicine, Montreal Heart Institute and University of Montreal, 5000 Belanger Street, Montreal H1T
1C8, Canada
KEYWORDS
Heart rate;
Atherosclerosis;
Coronary artery disease;
Plaque rupture
Epidemiological studies indicate that a lower heart rate
(HR) is associated with decreased cardiovascular and allcause mortality.1–4 Clinical trials suggest that HR
reduction is an important component of the benefits of
beta-blockers in stable angina pectoris, after myocardial
infarction and in heart failure.5–12 Pharmacological inhibition of the If current13–15 now provides the opportunity
for pure HR reduction, with potential benefits from coronary artery disease to heart failure.16–24 This article
summarizes the links between HR and atherosclerosis.
Heart rate as a risk factor for cardiovascular
disease
All-cause and cardiac mortality increased steadily with
resting and exercise HR in a prospective study of 5713
healthy men, aged 42–53 years, and followed up for 23
years.1 The relationship was much steeper for sudden
cardiac death. Men with a resting HR .75 b.p.m. had a
* Corresponding author. Tel: þ1 514 376 3330, Fax: þ1 514 593 2500,
E-mail address: [email protected].
relative risk of sudden cardiac death of 3.46 by comparison with men whose HR was ,60 b.p.m., even after
adjustment for age, use of tobacco, physical activity, diabetes, body mass index, blood pressure, cholesterol, parental history of sudden death or myocardial infarction,
and exercise duration. Heart rate has also been shown
to predict mortality in hypertensive populations2,3 and
in elderly patients.3
We have reported the results of a study that evaluated
the relationship between resting HR and future cardiovascular events in 24 913 patients included in the Coronary Artery Surgery Study registry undergoing coronary
arteriography because of suspected or proven coronary
artery disease, with a median follow-up of 14.7 years.4
After adjusting the multivariable Cox proportional
hazard model for age, sex, diabetes, hypertension, cigarette smoking, left ventricular ejection fraction, number
of clinically significant diseased coronary vessels, type of
recreational activity, and concomitant treatments
(including b-blockers), total mortality was increased in
patients with resting HR between 77 and 82 b.p.m.
(hazard ratio 1.16; 99% CI, 1.04–1.28) and those
83 b.p.m. (hazard ratio 1.32; CI, 1.19–1.47) when
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Heart rate (HR) is a potent predictor of major cardiovascular events in both the
general population and the patients with various cardiovascular diseases. An increased
HR has been shown to be associated with increased progression of coronary atherosclerosis in animal models and patients. A high HR has also been associated with a
greatly increased risk of plaque rupture in patients with coronary atherosclerosis.
Pure HR reduction has slowed atherosclerosis progression in experimental models.
Endothelial function may be an important link between HR and atherosclerosis. An
increased HR has been shown experimentally to cause endothelial dysfunction. The
protective effect on the endothelium of long-term pure HR reduction with ivabradine
that we have shown in a dyslipidaemic mouse model of endothelial dysfunction could
provide an important mechanism for the potential vascular benefits of the If current
inhibitor ivabradine. These results, in addition to those of the BEAUTIFUL study, constitute a strong rationale for further clinical investigation of the cardioprotective
effects of pure HR reduction.
HR and atherosclerosis
Table 1 Pathophysiological mechanisms relating an
increased heart rate and coronary heart disease
Greater myocardial oxygen consumption (MVO2)
Decreased myocardial perfusion (shortened duration of
diastole)
Increased severity and progression of coronary atherosclerosis
Lesser development of collaterals
Increased risk of coronary plaque disruption
Increased arterial rigidity
Marker and possible mediator of sympathetic overactivity
Pathophysiological mechanisms relating
heart rate and coronary heart disease
The importance of HR in cardiovascular prognosis can be
explained by its relationship with major pathophysiological determinants (Table 1). A high HR is a major determinant of myocardial ischaemia, because it leads both to
greater myocardial oxygen consumption and decreased
myocardial perfusion, the latter because of the shortening in the duration of diastole. The likelihood of the
occurrence of an ischaemic episode increases at higher
baseline HRs. With a baseline HR less than 60 b.p.m.,
the likelihood of occurrence of ischaemic episodes with
HR acceleration was 8.7%, whereas at rates in excess of
90 b.p.m., the likelihood increased to 18.5%.25 In
addition, HR can also directly influence the underlying
atherosclerotic process as described below.
Heart rate, progression of atherosclerosis,
and plaque rupture
Experimental and clinical evidence also suggests that sustained elevations in HR may also play a direct role in the
pathogenesis of coronary atherosclerosis and its complications. Heart rate was significantly correlated with the
severity and progression of atherosclerosis on coronary
angiography among men who had developed myocardial
infarction at a young age.26 Accelerated atherogenesis
resulting from increased HR may be due to both mechanical and metabolic factors. Increased vascular wall stress
may contribute to endothelial injury, potentially promoting the complex cascade of events leading to increased
atherosclerosis. Experimental data also show that a
reduction in HR can delay the progression of coronary
atherosclerosis in monkeys.27 Male cynomolgus monkeys
subjected to sinus node ablation or those with innately
low HRs had significantly less coronary atherosclerosis
than animals with higher HRs. These observations are
supported by results from the Beta-Blocker CholesterolLowering Asymptomatic Plaque Study randomized trial,
which have shown that a b-blocker reduced the rate of
progression of carotid intima-media thickness in asymptomatic patients.28
A high HR has also been associated with an increased
risk of coronary plaque disruption.29 In this retrospective
angiographic study evaluating patients who underwent
two coronary angiograms within 6 months, logistic
regression analysis identified a positive and independent
association between plaque disruption and a mean HR
.80 b.p.m. This association again indicates that haemodynamic forces may play a critical role in the process of
plaque disruption. A high HR is also strongly associated
with increased arterial rigidity, reduced vascular distensibility, and elevated pulse-wave velocity, characteristics
that are all associated with an increased risk of myocardial infarction and cardiac death.30 In a retrospective
study, a larger number of patients with obstructive coronary artery disease whose HRs were ,50 b.p.m. had
developed collateral vessels (potentially decreasing the
ischaemic burden) compared with patients with HRs
.60 b.p.m.31 The presence of collaterals was independent of the history of angina or the use of b-blockers. A
high HR may also reflect an imbalance of the autonomic
nervous system and may therefore be a marker of sympathetic overactivity.32 The metabolic syndrome and
insulin resistance are also associated with sympathetic
overactivity.33,34
Heart rate and endothelial dysfunction
A number of studies point to endothelial dysfunction as
the missing link between HR and cardiovascular events.
The hypothesis is that a higher HR could increase the
twisting of large epicardial arteries during systole as
well as the number of times per minute that forces are
applied to the vascular wall leading to fatigue, causing
endothelial damage to these vital arteries, and a simultaneous increase in the probability of atherosclerotic
plaque rupture in the coronary arteries, thereby leading
to myocardial infarction. Endothelial dysfunction is considered an integral part of the events leading to atherosclerosis initiation and progression and has been shown
to be associated with adverse cardiovascular events.
We now review the evidence linking HR and endothelial
function.
Endothelial dysfunction is central to the pathogenesis
of atherosclerosis. It is the first step, leading to the
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compared with the reference quintile (62 b.p.m.). Cardiovascular mortality also increased in the 77–82 b.p.m.
(hazard ratio 1.14, CI, 1.00–1.29) and in the
83 b.p.m. (hazard ratio 1.31, CI, 1.15–1.48) groups.
The association between HR and total mortality held
true in all analysed subgroups: old (.65 years) vs.
young, diabetics vs. non-diabetics, hypertensives vs. normotensives, BMI .27 or ,27, those with ejection fraction .50% or ,50%, and patients treated with
b-blockers vs. those without such treatment. The predictive power of HR for mortality remained true both in men
and in women. A gender-related difference in the association between HR and mortality has been found in some
studies in hypertensive subjects2 or in patients with myocardial infarction.5 Data from our study in patients with
stable coronary artery disease indicates that a higher
HR can also be deleterious in women.
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J.-C. Tardif
Figure 1 Ivabradine prevents endothelial dysfunction associated with dyslipidaemia in mice. Adapted from Drouin et al.35
Pure heart rate reduction to preserve
endothelial function
We performed a study in dyslipidaemic mice to document
the effects of pure heart reduction on endothelial function.35 The If current inhibitor ivabradine was chosen
because it reduces HR in mice independently of sympathetic activation, and it does not affect blood pressure,
myocardial contractility, or intracardial conduction.36,37
Endothelial vasodilator capacity was used as the means
to show preservation of endothelial function. The experiments were conducted in dyslipidaemic mice expressing
the human apoprotein-B 100 as they develop changes in
endothelial-dependent arterial dilation.38,39 Dyslipidaemic mice were assigned to 3 months of treatment with
ivabradine, metoprolol, or no treatment. The outcomes
in terms of vessel dilation in renal and posterior communicating cerebral arteries were compared between these
groups and those of wild-type C57BI/6 mice.
Throughout the experiments, it was found that HR
remained stable in wild-type mice whereas it increased
in untreated dyslipidaemic mice. The use of ivabradine
reduced HR in dyslipidaemic mice by 17%. Endothelium-
dependent dilation in response to acetylcholine was
decreased in untreated dyslipidaemic mice compared
with those treated with ivabradine, which maintained
maximal dilation (Figure 1). The use of ivabradine completely prevented the impaired dilator response to
acetylcholine in dyslipidaemic mice. The use of the antioxidant N-acetylcysteine fully restored dilation in
response to acetylcholine in dyslipidaemic mice,
whereas it did not affect the response to acetylcholine
in wild-type mice or in mice treated with ivabradine.39–
41
This shows that the endothelial dysfunction in dyslipidaemic mice is caused in large part by oxidative stress,
which was not increased in wild-type mice and dyslipidaemic mice treated with ivabradine. Therefore, ivabradine protected the treated dyslipidaemic mice against
oxidative stress. Given that ivabradine has no direct antioxidant effects, the protection it afforded might be due
to alternative mechanisms, such as improvement of the
shear stress-dependent stimulation of the endothelium,
which favours endothelial nitric oxide synthase and/or
prevents nitric oxide or hydrogen peroxide degradation,
or decreased mechanical fatigue of the arterial wall
associated with pure heart reduction. The use of
L-NNA, a nitric oxide synthase inhibitor, reduced vasodilation in wild-type and in dyslipidaemic mice treated
with ivabradine. Since ivabradine has no direct vascular
effect, this finding suggests that chronic pure heart
reduction preserved the nitric oxide pathway for
vasodilation.
Endothelium-dependent dilation of cerebral arteries
induced by acetylcholine was impaired in dyslipidaemic
mice compared with wild-type mice. The use of ivabradine also completely prevented this impairment of vasodilatory capacity in cerebral arteries. Treating
dyslipidaemic mice with metoprolol reduced HR to the
same extent as ivabradine. In contrast, ivabradine provided superior preservation of endothelial function in
renal and cerebral arteries in dyslipidaemic mice compared with metoprolol. In renal arteries, metoprolol did
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formation of fatty streaks, in a series of events that could
eventually lead to the formation of atherosclerotic
plaques and thrombus. Endothelial dysfunction allows
lipoproteins to enter the intima and be modified in situ
by oxidation and glycation. These events will exacerbate
endothelial dysfunction and promote macrophage
adhesion to the endothelium and migration into the
intima. Subsequently, the generation of extracellular
matrix will promote the formation of a fibrofatty
lesion, the atherosclerotic plaque. Under conditions of
haemodynamic stress and degradation of the extracellular matrix, the plaque can rupture and promote the formation of an intra-luminal thrombus leading to an
acute coronary syndrome.
HR and atherosclerosis
Figure 2 Metoprolol does not prevent cerebral endothelial dysfunction
associated with dyslipidaemia. Adapted from Drouin et al.35
Conclusion
An increased HR has been shown to be associated with
greater atherosclerosis progression and a higher risk of
coronary plaque rupture. Pure HR reduction has slowed
atherosclerosis progression and improved endothelial
function in experimental models. These results, in
addition to those of the BEAUTIFUL study, constitute a
strong rationale for further clinical investigation of the
cardioprotective effects of pure HR reduction.
Funding
Dr Tardif has received honoraria from Servier.
Conflict of interest: none declared.
References
1. Jouven X, Empana JP, Schwartz PJ, Desnos M, Courbon D,
Ducimetiere P. Heart-rate profile during exercise as a predictor of
sudden death. N Engl J Med 2005;352:1951–1958.
2. 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.
3. Palatini P, Thijs L, Staessen JA et al. Predictive value of clinic and
ambulatory heart rate for mortality in elderly subjects with systolic
hypertension. Arch Intern Med 2002;162:2313–2321.
4. 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.
5. Disegni E, Goldbourt U, Reicher-Reiss H et al. 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.
6. 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.
7. Cucherat M. Quantitative relationship between resting heart rate
reduction and magnitude of clinical benefits in post-myocardial
infarction: a meta-regression of randomized clinical trials. Eur
Heart J 2007;28:3012–3019.
8. Gibbons RJ, Chatterjee K, Daley J et al. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina:
executive summary and recommendations. A Report of the American
College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Chronic
Stable Angina). Circulation 1999;99:2829–2848.
9. Van Der Vring JA, Daniels MC, Holwerda NJ et al. Combination of
calcium channel blockers and beta-adrenoceptor blockers for
patients with exercise-induced angina pectoris: a double-blind
parallel-group comparison of different classes of calcium channel
blockers. Netherlands Working Group on Cardiovascular Research
(WCN). Br J Clin Pharmacol 1999;47:493–498.
10. Lechat P, Escolano S, Golmard JL et al. Prognostic value of
bisoprolol-induced hemodynamic effects in heart failure during the
Cardiac Insufficiency BIsoprolol Study (CIBIS). Circulation 1997;96:
2197–2205.
11. Metra M, Torp-Pedersen C, Swedberg K et al. Influence of heart rate,
blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in
patients with chronic heart failure: results from the COMET trial.
Eur Heart J 2005;26:2259–2268.
12. Gullestad L, Wikstrand J, Deedwania P et al. What resting heart rate
should one aim for when treating patients with heart failure with a
beta-blocker? Experiences from the Metoprolol Controlled Release/
Extended Release Randomized Intervention Trial in Chronic Heart
Failure (MERIT-HF). J Am Coll Cardiol 2005;45:252–259.
13. DiFrancesco D. Characterization of single pacemaker channels in
cardiac sino-atrial node cells. Nature 1986;324:470–473.
14. Bois P, Bescond J, Renaudon B, Lenfant J. Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells.
Br J Pharmacol 1996;118:1051–1057.
15. Thollon C, Cambarrat C, Vian J, Prost JF, Peglion JL, Vilaine JP. Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison
with UL-FS 49. Br J Pharmacol 1994;112:37–42.
16. Tardif JC. Clinical results of I(f) current inhibition by ivabradine.
Drugs 2007;67(Suppl. 2):35–41.
17. Borer JS, Fox K, Jaillon P, Lerebours G. Antianginal and antiischemic
effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation 2003;107:817–823.
18. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in
patients with chronic stable angina. Eur Heart J 2005;26:2529–2536.
19. Simon L, Ghaleh B, Puybasset L, Giudicelli JF, Berdeaux A. Coronary
and hemodynamic effects of S 16257, a new bradycardic agent, in
resting and exercising conscious dogs. J Pharmacol Exp Ther 1995;
275:659–666.
20. Ruzyllo W, Tendera M, Ford I, Fox KM. Antianginal efficacy and safety
of ivabradine compared with amlodipine in patients with stable
effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial. Drugs 2007;67:393–405.
21. Mulder P, Barbier S, Chagraoui A et al. Long-term heart rate reduction
induced by the selective I(f) current inhibitor ivabradine improves
left ventricular function and intrinsic myocardial structure in congestive heart failure. Circulation 2004;109:1674–1679.
22. Fox K, Ferrari R, Tendera M, Steg PG, Ford I. Rationale and design of a
randomized, double-blind, placebo-controlled trial of ivabradine in
patients with stable coronary artery disease and left ventricular systolic dysfunction: the morBidity-mortality EvAlUaTion of the I(f)
Downloaded from by guest on October 28, 2014
not increase renal artery sensitivity to acetylcholine to
the same extent as ivabradine. In cerebral arteries,
metoprolol did not prevent the decrease in dilator
response to acetylcholine seen in dyslipidaemic mice,
unlike ivabradine (Figure 2). The mitigated effects of
metoprolol may be related to the coupling between
endothelial beta-adrenoceptors and endothelial nitric
oxide synthase.40
D11
D12
23.
24.
25.
26.
27.
28.
29.
30.
31.
J.-C. Tardif
32. Palatini P, Julius S. Heart rate and the cardiovascular risk.
J Hypertens 1997;15:3–17.
33. Festa A, D’Agostino R Jr, Hales CN, Mykkanen L, Haffner SM. Heart
rate in relation to insulin sensitivity and insulin secretion in nondiabetic subjects. Diabetes Care 2000;23:624–628.
34. Grassi G, Dell’Oro R, Quarti-Trevano F et al. Neuroadrenergic and
reflex abnormalities in patients with metabolic syndrome. Diabetologia 2005;48:1359–1365.
35. Drouin A, Gendron ME, Thorin E, Gillis MA, Mahlberg-Gaudin F,
Tardif JC. Chronic heart rate reduction by ivabradine prevents
endothielial dysfunction in dyslipidaemic mice. Br J Pharmacol
2008;154:749–757.
36. Du XJ, Feng X, Gao XM, Tan TP, Kiriazis H, Dart AM. If Channel Inhibition Ivabradine Lowers Heart Rate in Mice with Enhanced Sympathoadrenerdic activities. Br J Pharmacol 2004;142:107–112.
37. Vilaine JP. The Discovery of the Selective If Current Inhibitor Ivabradine. A New Therapeutic Approach to Ischemic Heart Disease. Pharmacol Res 2006;53:424–434.
38. Sanan DA, Newland DL, Tao R, Marcovina S, Wang J, Mooser V et al.
Low density lipoprotein receptor-negative mice expressing human
apolipoprotein B-100 develop complex atherosclerotic lesions on a
chow diet: no accentuation by apolipoprotein (a). Proc Natl Acad
Sci USA 1998;95:4544–4549.
39. Krummen A, Falck JR, Thorin E. Two Distinct Pathways Account for
EDHF-Dependent Dilatation in the Gracilis Artery of Dyslipidaemic
hApoBþ/þ mice. Br J Pharmacol 2005;145:264–270.
40. Krummen S, Drouin A, Gendron ME, Falck JR, Villeneuve L, Thorin E.
ROS-sensitive cytochrome P450 activity maintains endothelial dilatation in ageing but is transitory in dyslipidaemic mice. Br J Pharmacol
2006;147:897–904.
41. Gendron ME, Thorin-Trescases N, Villeneuve L, Thorin E. Aging associated with mild dyslipidemia reveals that COX-2 preserves dilation
despite endothelial dysfunction. Am J Physiol 2007;292:H451–H458.
Downloaded from by guest on October 28, 2014
inhibitor ivabradine in patients with coronary disease and left
ventricULar dysfunction (BEAUTIFUL) study. Am Heart J 2006;152:
860–866.
Jondeau G, Korewicki J, Vasiliauskas D. Effect of ivabradine in
patients with left ventricular systolic dysfunction and coronary
artery disease. Eur Heart J 2004;25:451.
Kjekshus J, Gullestad L. Heart rate as a therapeutic target in heart
failure. Eur Heart J 1999;1:H64–H69.
Andrews TC, Fenton T, Toyosaki N et al. Subsets of ambulatory myocardial ischemia based on heart rate activity. Circadian distribution
and response to anti-ischemic medication. The Angina and Silent
Ischemia Study Group (ASIS). Circulation 1993;88:92–100.
Perski A, Olsson G, Landou C, de Faire U, Theorell T, Hamsten A.
Minimum heart rate and coronary atherosclerosis: independent
relations to global severity and rate of progression of angiographic
lesions in men with myocardial infarction at a young age. Am Heart
J 1992;123:609–616.
Beere PA, Glagov S, Zarins CK. Retarding effect of lowered heart rate
on coronary atherosclerosis. Science 1984;226:180–182.
Hedblad B, Wikstrand J, Janzon L, Wedel H, Berglund G. Low-dose
metoprolol CR/XL and fluvastatin slow progression of carotid intimamedia thickness: Main results from the Beta-Blocker CholesterolLowering Asymptomatic Plaque Study (BCAPS). Circulation 2001;
103:1721–1726.
Heidland UE, Strauer BE. Left ventricular muscle mass and elevated
heart rate are associated with coronary plaque disruption. Circulation 2001;104:1477–1482.
Sa Cunha R, Pannier B, Benetos A et al. Association between high
heart rate and high arterial rigidity in normotensive and hypertensive
subjects. J Hypertens 1997;15:1423–1430.
Patel SR, Breall JA, Diver DJ, Gersh BJ, Levy AP. Bradycardia is associated with development of coronary collateral vessels in humans.
Coron Artery Dis 2000;11:467–472.