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Heart rate management: a therapeutic goal throughout the cardiovascular continuum
Jose Luis Zamorano*
Hospital Clinico San Carlos, Plaza de Cristo Rey, 28040 Madrid, Spain
* Corresponding author. Tel: +34 91 3303290; fax: + 34 91 3303292. E-mail address: jlzamorano{at}vodafone.es
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Abstract
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A number of physiological pathways and risk factors leading
to cardiovascular disease (CVD) are now well identified, although
there are still aspects to be investigated. An interesting concept
has been developed called the CVD continuum which frames CVD
as a chain of events initiated by a number of risk factors leading
to end stage of the disease with the hypothesis that any interruption
along this chain of events may interrupt the pathological process
thereby conferring cardiovascular prevention. In recent years,
heart rate (HR), a simple and familiar clinical finding, has
been shown to be an independent risk factor of mortality and
morbidity in various populations including patients with CVDs.
This review shows that high HRs intervene along the chain of
events which constitutes the cardiovascular continuum promoting
CVD. Experimental data and clinical observations that demonstrate
the major role played by resting HR in the pathophysiology of
atherosclerosis through the stress exerted on the vascular endothelium
leading to atherosclerotic lesion formation and plaque rupture
are reviewed. Therefore, HR reduction should lead to prevention
of atherosclerosis and therefore to the reduction of cardiovascular
events. Trials have been undertaken to answer this question
and the results are expected in the near future.
Key Words: Heart rate • Risk factors • Cardiovascular disease continuum • Coronary artery disease
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Introduction
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Cardiovascular disease (CVD) is common in the general population
and represents an important public health problem. A number
of physiological pathways leading to CVD have been identified,
although there are still a number of processes which remain
to be clarified. Dzau
et al.
1 came out in 1991 with a concept
called the CVD continuum which framed CVD as a chain of events
initiated by a number of risk factors leading to end stage of
the disease and hypothesized that any interruption along this
chain of events may interrupt the pathological process thus
conferring cardiovascular prevention.
2 In recent years, heart
rate (HR), a simple and familiar clinical finding, has been
shown to be an independent risk factor of mortality and morbidity
in various populations including CVD.
3–6
The aim of this paper is to show how high HR may intervene to promote CVD along the chain of events which constitute the cardiovascular continuum.
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The cardiovascular disease continuum
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Epidemiological studies have identified well-known risk factors
such as dyslipidaemia, arterial hypertension, diabetes mellitus,
smoking, and obesity, mainly visceral adiposity as part of the
so-called metabolic syndrome.
7,8 These risk factors may promote
atherosclerosis and/or left ventricular (LV) hypertrophy. The
most common and life-threatening manifestation of atherosclerosis
is coronary artery disease which has two major clinical presentations,
i.e. stable angina pectoris related to myocardial ischaemia
and acute myocardial infarction. Among the possible complications
of myocardial infarction, ventricular arrhythmias with the risk
of sudden cardiac death and loss in myocardial tissue inducing
ventricular remodelling and ventricular enlargement leading
to heart failure and end-stage heart disease are life-threatening
(
Figure 1). This review article aims to demonstrate how
HR may intervene in the cascade of events that constitute the
CVD continuum.
1
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Heart rate and cardiovascular mortality
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Many clinical or epidemiological studies have shown that resting
HR is an independent risk factor of total mortality and cardiovascular
mortality. These studies have been analysed by Aboyans
et al.
and others.
9–12 Overall, they include 15 500 patients
followed up for 8–36 years. For example, the ‘Chicago
Peoples Gas Company study’ included 1233 men followed
up for 15 years. Two other cohorts of patients belonging to
the ‘Chicago Western Electric Company’ and to the
‘Chicago Heart Association Detection Project’ included
1899 and 5784 men followed up for 17 and 5 years, respectively.
3 A relation was found between HR and cardiovascular mortality
and total mortality. Similarly, the Framingham study showed
with a 30-year follow-up that a significant relationship exists
in men as in women, between high resting HR and the increase
in cardiovascular mortality, coronary heart disease, and sudden
coronary death.
4 The MATISS Project included 2533 men aged 40–69
followed up for a total of 24 457 subject-years and showed that
HR was an independent predictive factor for total mortality,
cardiovascular mortality and non-cardiovascular mortality.
5 Jouven
et al.
6 reported a French population of 5713 asymptomatic
working men (between the ages of 42 and 53 years) with a 23-year
follow-up and found that after adjustment for potential confounding
variables resting HR was significantly associated with an increase
in sudden death and non-sudden death from myocardial infarction.
Wide variations of HR were analysed in these studies. Some compared
HR of
60 bpm with HR above 90 or even 100 bpm Jouven
et al.
6 compared those subjects with a resting HR above 75 bpm with
those with a HR below 60 bpm and found that those with high
HR had a relative risk of sudden death from a myocardial infarction
of 3.92 (95% CI).
The question of the optimal HR often arises and faces the difficulty of the wide variation seen over a 24-h period with a circadian rhythm, the fact that HR decreases with age, that HR is generally higher in women than in men, and that it varies with the position (sitting vs. supine) in which it is measured.10 Palatini et al.13 recommend in a consensus that HR should be measured by pulse palpation over two periods of 30 s each after 5 min in a quiet room in a sitting position.
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Cardiovascular disease and the pathophysiological continuum
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The pathophysiological processes known to initiate CVD include
oxidative stress, endothelial dysfunction, inflammation, and
vascular remodelling (
Figure 1). Knowledge gained in the
understanding of these processes has promoted the development
of new therapeutic strategies. These processes may lead to tissue
damage characterizing atherosclerotic disease. Oxidative stress
results in reduction in nitric oxide (NO) activity and endothelial
dysfunction. The latter induces pathological vascular responses,
e.g. vasoconstriction, inflammation, muscle cell proliferation,
and thrombosis.
1,2 The renin–angiotensin–aldosterone
system plays an important role in the CVD continuum. Inhibition
of angiotensin-converting enzyme and angiotensin II through
the AT1 receptors is used in the management of CVD, particularly
the treatment of hypertension and of congestive heart failure
(CHF). Other hormones such as atrial natriuretic peptide and
brain natriuretic peptide, endothelin, prostacyclin, and prostaglandin
E are also involved in the pathophysiology of CVD.
1 Inflammation
is associated with endothelial injury and with the development
of atherosclerosis to the point that C-reactive protein has
become a marker of CVD risk. Vascular remodelling represents
the structural transformation resulting from changes of haemodynamic
conditions as seen in arterial hypertension. It is important
to underline that several processes are taking place simultaneously
to generate CVD.
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Experimental evidence of the role of heart rate in the cardiovascular continuum
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In order to understand the role of HR in endothelial dysfunction
and atherosclerotic lesions, basic knowledge of local haemodynamic
forces imposed on the arterial wall is necessary. These forces
include flow-generated shear stress which is the tangential
forces due to the friction of the blood flowing on the endocardial
surface and blood-pressure-derived tensile stress, also called
circumferential stress, which represent the blood-pressure-derived
force imposed on the circumference of the arterial wall.
14 Low
shear stress stimulates mechanoreceptors located on the surface
of endothelial stress transducing them into biochemical signals
(mechanicotransduction) which cannot be developed in detail
here but which are well explained in the excellent review of
Giannoglou
et al.
14 Tensile stress is also sensed by mechanoreceptors
which trigger a cascade of signalling molecules. Elevated tensile
stress is thought to induce direct endothelial injury and to
increase endothelial permeability to LDL and to circulating
inflammatory mediators. Very high HR (>120 bpm) by reducing
the diastolic phase reduces the stroke volume and the cardiac
output. Moderate tachycardia (close to 100 bpm) increases blood
pressure and the tensile stress and may promote endothelial
injury and wall stiffness.
The role of HR in myocardial ischaemia as seen in patients with stable angina and those who suffered a myocardial infarction is also well established (Figure 2). It is well known that increased HR is present in angina pectoris and myocardial ischaemia as a consequence of exercise or emotional stress. Several mechanisms may account for the increase in HR including catecholamine discharge. Kop et al.15 analysed HR variability (HRV) 1 h before and after ischaemic events in 19 patients who underwent 24 h ambulatory recordings and assessed the role of exercise and mental stress on pre-ischaemic autonomic changes. Ischaemic events at high mental stress were preceded by depressed high frequency HRV levels compared with events at low mental activity, whereas the effects of mental activities were not observed during non-ischaemic control periods.
HR may be involved at different phases of the development of
atherosclerosis, in plaque erosion, and plaque rupture resulting
in thrombosis and in acute coronary event (
Figure 3).
Experimental evidence supports the role of HR reduction in the
progression of atherosclerosis. Beere
et al.
16 investigated
the role of HR reduction in six monkeys (
Macaca fascicularis)
fed with an atherogenic high cholesterol diet for 6 months.
These animals underwent sinus node ablation and compared with
eight animals which had the same operation without sinus node
ablation. Coronary atherosclerosis was less than half in the
group with low HR related to sino-atrial ablation when compared
with the control group without sino-atrial ablation suggesting
a protective effect of lower HR. Yamamoto
et al.
17 in an isolated
sino-atrial preparation in hypertensive rats showed that the
increase in HR with cardiac pacing, therefore independent of
sympathetic nerve activity, enhances cardiac oxidative stress
and activates mitogen-activated protein kinases, which seem
implicated in cardiac hypertrophy and cardiac remodelling. Guth
et al.
18 evaluated the beneficial effect of intravenous atenolol
on exercise-induced regional myocardial ischaemia and contractile
dysfunction in conscious dogs with single-vessel coronary stenosis.
The regional dysfunction was reduced with atenolol but the improvement
is prevented if HR is kept constant with atrial pacing. Therefore,
HR reduction may play an important role in the CVD continuum.
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Heart rate reduction and cardiovascular risk reduction in man
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Beta-blockers have been shown to reduce total mortality and
sudden cardiac death after myocardial infarction. At least part
of their beneficial effects has been ascribed to their effect
on HR.
19 Furthermore, a recent meta-regression of randomized
clinical trials of beta-blockers and calcium channel blockers
in post-myocardial infarction patients strongly suggests that
the beneficial effect of these agents is proportionally related
to resting HR reduction.
20 A statistically significant relationship
was found between resting HR reduction and reduction in cardiac
death, all-cause death, sudden death, and non-fatal MI recurrence.
Each 10 bpm reduction in the HR is estimated to reduce the relative
risk of cardiac death by 30% (
Figure 4). This meta-regression
of the randomized clinical trials strongly suggests that resting
HR reduction could be a major determinant of the clinical benefit
in these trials. Recently, this hypothesis was tested within
randomized controlled trials of beta-blockers in systolic CHF.
There was a close relation between all-cause annualized mortality
rate and HR. A strong correlation between change in HR and change
in LV ejection fraction was also observed.
21
These data suggest that HR reduction is indeed a major component
of the prognostic benefit in post-MI and CHF trials with beta-blockers
and therefore should be an important therapeutic goal for the
improvement of prognosis.
The mechanisms by which HR influences the outcome has not been completely unravelled. It is well known that exercise training is associated with lower resting HR. In fact, exercise capacity was found to be a strong predictor of mortality.22 HR is also determined by the influence of the autonomic nervous system balance. The major effect of beta-blockers is HR reduction but other actions may operate. A significant proportion of patients with myocardial infarction or myocardial ischaemia do not receive beta-blockers, probably because the common occurrence of side effects or contraindication in patients with asthma, hypotension, and atrioventricular conduction disorders, together with their negative inotropic effect, limit their use. Therefore, there is a need for developing new agents to obtain HR reduction in vast majority of patients.
Ivabradine is a new medication that has HR-lowering properties without other direct cardiovascular effects. Ivabradine is the first of a new class of agents that act specifically on the sino-atrial node by inhibiting the If current of cardiac pacemaker cells without affecting other cardiac ionic currents. Ivabradine has a unique pharmacodynamic profile as HR reduction is not associated with negative inotropic effects or vasodilation.23
Ivabradine has been investigated in patients with stable coronary artery disease. A double-blind, placebo-controlled study in patients with chronic stable angina showed that ivabradine produced dose-dependent improvements in exercise duration and time to development of exercise-induced ischaemia.24 Ivabradine showed anti-anginal and anti-ischaemic efficacy compared with such well-established reference anti-anginal drugs, such as beta-blockers and calcium antagonists.25,26 Ivabradine was also found to have beneficial effects on cardiac remodelling, capillary density, and LV dysfunction.27,28 In a rat model of CHF, Mulder et al. showed that chronic administration of ivabradine induced a dose-dependent reduction in HR without modification in systemic haemodynamics. Cardiac output was preserved despite the decrease in HR because stroke volume is increased owing to a decrease in LV end-systolic diameter.28 This improvement in LV function was attributed to a possible modification of LV structure and/or of myocyte properties. Therefore, patients with coronary artery disease and LV systolic dysfunction may derive benefit from additional HR reduction with ivabradine. Whether the use of ivabradine in patients with coronary artery disease or heart failure results in the reduction in cardiovascular morbidity-mortality remains to be demonstrated. This prompted the BEAUTIFUL study, a large, international, randomized, placebo-controlled mortality trial in a high-risk population of coronary artery disease patients with LV dysfunction.29 The ongoing SHIFT trial was designed to assess the prognostic value of pure HR reduction in patients with heart failure.30
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Conclusions
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The concept of the CVD continuum based on the hypothesis that
CVD is the result of a chain of events initiated by risk factors
leading to end stage of the disease and that any interruption
along this chain of events may interrupt the pathological process
thus conferring cardiovascular prevention has been validated
by large clinical trials. HR intervenes in different phases
of the CVD continuum as supported by epidemiological studies,
experimental data and clinical observations showing the role
that HR plays in the pathophysiology of atherosclerosis and
the stress exerted on the vascular endothelium leading to atherosclerotic
lesion formation and plaque rupture. Therefore, HR reduction
by the new HR-lowering agent ivabradine should lead to the prevention
of atherosclerosis via reduction in endothelial dysfunction
and result in the reduction in cardiovascular events. Trials
have been undertaken to answer this question and the results
are expected in the near future.
Conflict of interest: none declared.
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Abstract
Introduction
