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Effect of heart rate reduction in coronary artery disease and heart failure
Roberto Ferrari1 and Kim Fox2
1
Department of Cardiology and LTTA Centre, Azienda Ospedaliero-Universitaria di Ferrara,
Ospedale di Cona, Via Aldo Moro 8, 44124 (Cona) Ferrara, Italy
2
National Heart and Lung Institute, Imperial College and Institute of Cardiovascular Medicine and
Science, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK
Correspondence to R. F.
[email protected]
Abstract | Elevated heart rate is known to induce myocardial ischaemia in patients with coronary
artery disease (CAD), and heart rate reduction is a recognized strategy to prevent ischaemic
episodes. In addition, clinical evidence shows that heart rate reduction reduces the symptoms of
angina, by improving microcirculation and coronary flow. Elevated heart rate is an established risk
factor for cardiovascular events in patients with CAD and in those with chronic heart failure (HF).
Accordingly, reducing heart rate improves prognosis in patients with HF, as demonstrated in SHIFT
(systolic heart failure treatment with If inhibitor ivabradine trial). By contrast, however, data from
SIGNIFY (study assessing the morbidity–mortality benefits of the If inhibitor ivabradine in patients
with coronary artery disease) indicate that heart rate is not a modifiable risk factor in patients with
CAD who do not also have HF. Heart rate is also an important determinant of cardiac arrhythmias;
low heart rate can be associated with atrial fibrillation, and high heart rate after exercise can be
associated with sudden cardiac death. Here, we critically review these clinical findings and propose
hypotheses for the variable effect of heart rate reduction in cardiovascular disease.
1
Key points
-
The role of heart rate in coronary artery disease and heart failure has been explored using
ivabradine, a drug that selectively targets heart rate
-
Increased heart rate can provoke myocardial ischaemia
-
Heart rate reduction can reduce the symptoms of angina
-
Increased heart rate is a risk marker in patients with coronary artery disease, but heart rate
reduction does not improve prognosis in this clinical setting
-
In the setting of heart failure, elevated heart rate is a modifiable risk factor — reducing
heart rate improves prognosis in these patients
In 2011, when our Review on the role of heart rate in coronary artery disease (CAD)1 was
published, the effect of heart rate over the whole spectrum of cardiovascular disease was receiving
new recognition. The impetus was the 2005 approval in Europe of the specific heart rate–lowering
agent ivabradine for patients with angina2. Ivabradine — in contrast to other drugs widely used for
the treatment of CAD, such as -blockers and nondihydropyridine calcium channel blockers — has
no direct effect on the cardiovascular system other than heart rate reduction. In addition to making
an impact in the clinical setting, ivabradine captured the interest of the scientific community as a
tool to investigate the epidemiological, pathophysiological, and clinical role of heart rate in
cardiovascular disease.
The information available in 2011 allowed us to define the negative effects of increased
heart rate on both myocardial oxygen consumption and arterial stiffness, as well as suggest that
elevated heart rate can cause cardiac arrhythmias and coronary artery shear stress1,3-9. This
observation naturally led to the hypothesis of an association between increased heart rate and the
development and instability of atherosclerotic plaque1. On the basis of preclinical data from animals
and humans, and the results of a prespecified subgroup of the BEAUTIFUL (morbidity-mortality
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evaluation of the If inhibitor ivabradine in patients with coronary disease and left ventricular
dysfunction) trial10, we anticipated that reducing heart rate in patients with CAD would improve
their prognosis. Equally, the scientific community started to consider elevated heart rate as a
modifiable risk factor for cardiovascular events and mortality in patients with CAD on the basis of
several epidemiological studies that showed an interaction between elevated heart rate and cardiac
events in this population11-13.
Over the past 5 years, however, new information has become available that has allowed us
to clarify some of the hypotheses we postulated in 2011 and produce a more precise picture of the
role of heart rate in cardiovascular disease. In addition to new experimental data, the results of
SIGNIFY (study assessing the morbidity – mortality benefits of the If inhibitor ivabradine in
patients with coronary artery disease)14 have greatly contributed to the understanding of the role of
heart rate in CAD. In this Review, we critically analyse these new findings, following the phases of
the ivabradine development programme that encompass the effect of heart rate lowering in
cardiovascular disease. Whenever new experimental data are relevant to the clinical results, we
report these in detail. Otherwise, we refer the reader to our 2011 Review1.
[L1] Heart rate reduction and angina
Increased heart rate can provoke myocardial ischaemia in patients with CAD. This well-established
mechanism is the basis — at least in part — of the antianginal effect of -blockers and calciumchannel blockers (such as verapamil and diltiazem) that lower heart rate. Both of these classes of
drugs, however, exert effects other than heart rate reduction that can contribute to their antiischaemic and antianginal actions. Notably, -blockers lower blood pressure and calcium-channel
blockers cause dilatation of the coronary arteries. The development programme for ivabradine in
angina included a variety of studies in which >6,000 patients were enrolled, and allowed the role of
pure heart rate reduction in angina to be established15-17. In all the studies, exercise test parameters
improved and the number of angina attacks decreased, confirming that selective heart rate reduction
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prevents or attenuates the short period of myocardial ischaemia that causes angina15-17. In 2014, this
finding was confirmed by the results of SIGNIFY14,18. In patients with angina (Canadian
Cardiovascular Society class ≥II), heart rate reduction with ivabradine resulted in a reduction in
angina class at 3 months14, and in an improvement in quality of life at 12 months18.
Classically, the antianginal effect of heart rate lowering is explained in terms of reduction of
myocardial oxygen consumption, and increased time available for coronary perfusion, which occurs
predominantly during diastole1. The interaction between heart rate and myocardial perfusion in the
presence of substantial coronary stenosis is, however, more complex. A description was presented
in our 2011 Review1, including the role of the “collateral steal” phenomenon (due to a redistribution
of flow away from poststenotic myocardium19); the possibility of “paradoxical vasoconstriction”
induced by acute heart rate increase20,21; and the “accelerated deterioration” of the vessel elastin
fibres, with fraying, fragmentation, and functional deterioration leading to increased arterial
stiffness22,23.
In the past 5 years, new information has become available and our understanding of the
interaction between heart rate and myocardial perfusion in CAD has been refined. In one study, a
murine model of hindlimb collateral arteriogenesis was used to test the effects of heart rate
reduction by If channel inhibition with ivabradine versus that with adrenergic -receptor blockade
with metoprolol24. The hypothesis was that collateral arteries protect from ischaemia and that heart
rate reduction could improve arteriogenesis and perfusion, thus reducing ischaemia and, eventually,
vascular events. The researchers demonstrated that heart rate reduction with ivabradine, but not
with metoprolol, stimulated adaptive collateral artery growth only in dyslipidaemic apolipoprotein
E–deficient mice, not in wildtypes24. The molecular mechanism is likely to be improved endothelial
function, as shown by upregulation of endothelial nitric oxide synthase expression and activity, as
well as downregulation of gene expression of classical inflammatory cytokines (IL-6, tumour
necrosis factor, and tumour growth factor–beta), and the angiotensin II receptor type 1)24.
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The clinical relevance to the coronary arteries of these experimental findings was
subsequently evaluated in a single-blind study of 46 patients with CAD, who were randomly
allocated to ivabradine or placebo25. The primary outcome was collateral flow index, measured
invasively during a 1 min coronary artery balloon occlusion at baseline, and repeated at 6 months'
follow-up. Ivabradine significantly increased collateral flow index, suggesting a proarteriogenic
effect of heart rate reduction in patients with CAD. Of course, these data have only proof-ofconcept value but, if confirmed, could provide an additional explanation for the symptomatic effect
of heart rate reduction in angina.26 In an elegant study of 21 patients with CAD, heart rate reduction
with ivabradine reduced resting coronary blood flow and increased hyperaemic coronary flow,
leading to a net improvement of coronary flow reserve, which remained improved after restoration
of baseline heart rate with pacing27. A 2015 study of coronary flow velocity reserve in patients with
angina supported these data and showed the superiority of pure heart rate reduction with ivabradine
over that achieved with the -blocker bisoprolol28. Taken together, these data indicate that slowing
heart rate improves microcirculation and coronary flow reserve, probably as a result of enhanced
ventricular diastolic relaxation time, which is more pronounced with ivabradine than with blockade29,30.
These new experimental and clinical data confirm that reducing heart rate improves the
symptoms of angina, and expand our knowledge of the mechanisms involved (FIGURE 1). Heart
rate is an important regulator of oxygen consumption by mitochondrial oxidation of the myocytes,
and its reduction increases the ischaemic threshold and maintains myocyte viability. In addition, the
effect of heart rate reduction at the level of the coronary arteries can stimulate arteriogenesis and
improve coronary flow reserve. These beneficial effects on coronary arteries could help prevent
microvascular angina and, theoretically, contribute to reducing cardiovascular events.
[L1] Heart rate and clinical outcome in CAD
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In our 2011 Review, we hypothesized that elevated resting heart rate in patients with CAD was a
modifiable risk factor for cardiovascular events and mortality1. We also discussed the adverse
effects of elevated heart rate on the balance between antiatherogenic and proatherogenic genes, by
modulating the ratio between detrimental oscillatory shear stress (during systole), and protective
unidirectional, high shear stress (during diastole)1. Finally, we speculated that, in the presence of
risk factors such as smoking, hyperlipidaemia and hyperglycaemia, elevated heart rate results in
endothelial oxidative stress, inflammation, and increased thrombogenicity, favouring progression of
atherosclerosis, plaque rupture and, eventually, adverse outcomes1. This biological hypothesis was
supported by a large amount of clinical data. Epidemiological studies and substudies of large
clinical trials have consistently shown that elevated heart rate is associated with increased mortality
and rates of cardiac events in patients with cardiovascular disease1,12,13,30. In BEAUTIFUL,10,11 the
relative risk of cardiovascular death was increased by 34% in patients receiving placebo who had a
heart rate ≥70 bpm compared with those with a heart rate <70 bpm, and the rate of cardiovascular
death increased progressively with baseline heart rate. Moreover, in a post hoc analysis of patients
with life-limiting angina and heart rate ≥70 bpm, reducing heart rate with ivabradine was associated
with significant 73% and 59% risk reductions for myocardial infarction (MI) and coronary
revascularization, respectively.31 In view of these data, to hypothesize that selective heart rate
reduction would lead to an improvement of outcomes in patients with CAD was reasonable.
The objective in SIGNIFY14 was to put this theory to the test. Enrolled patients (n = 19,102)
had stable CAD and additional cardiovascular risk factors, a resting heart rate ≥70 bpm, with no
symptoms of HF or left ventricular systolic dysfunction (left ventricular ejection fraction (LVEF) at
baseline: 56.5% ± 8.6%), and were receiving guideline-based background therapy. Contrary to the
initial assumption, heart rate reduction with ivabradine had no effect on the primary end point — a
composite of cardiovascular death or nonfatal MI — with an event rate of 6.8% for ivabradine and
6.4% for placebo (median follow-up 27.8 months; HR 1.08, 95% CI 0.96–1.20, P = 0.20)14. No
significant difference between the groups was observed in terms of any secondary end points
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including cardiovascular death, nonfatal MI, or all-cause death. SIGNIFY14 unequivocally showed
that pure heart rate reduction does not prevent cardiovascular death or MI in patients with CAD
who have no clinical signs of HF and so, evidently, does not slow the progression of atherosclerosis
or prevent plaque rupture leading to MI. The study also showed that, in patients with CAD and no
left ventricular dysfunction or overt HF, increased heart rate is not a modifiable risk factor, but only
a marker of other processes that influence the progression of CAD (for example, hyperlipidaemia,
diabetes mellitus, or smoking)14.
The question now is, how do we explain the unexpected and counterintuitive results of
SIGNIFY14,18? Indeed, the findings contrast with those of SHIFT (systolic heart failure treatment
with If inhibitor ivabradine trial)32, in which improved outcomes were reported for patients with
systolic HF who received ivabradine. Therefore, the data from SIGNIFY14,18 cannot be interpreted
without first discussing the role of elevated heart rate in patients with HF.
[L1] Heart rate and clinical outcome in HF
The role and relevance of increased heart rate in patients with HF is more complex than in those
with CAD33. In the setting of HF, heart rate reflects the degree of neuroendocrine stimulation (that
is, activation of the sympathetic nervous system and renin–angiotensin system), which is known to
be beneficial in the short-term, but detrimental in the long-term. The elevation of heart rate is
closely associated with the stroke volume, and its early increase is considered a compensatory
mechanism34. Depletion of catecholamines in failing myocytes, first described in 196635, is another
mechanism that could protect the heart from ischaemic injury in HF36. Prolonged neuroendocrine
activation, however, has a direct deleterious effect on the myocytes, leading to hypertrophy and
apoptotic death which, in turn, cause left ventricular remodeling37. Remodeling is another complex,
and not fully understood, phenomenon in which the ventricle progressively enlarges with a
reduction in LVEF. Heart rate reduction with -blockers is known to improve the outcome of
patients with HF, partly by reducing — and even reversing — the progression of left ventricular
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remodeling, as demonstrated by the increase in LVEF with chronic -blockade. Paradoxically,
therefore, long-term -blockade in the setting of HF exerts positive inotropism, despite the wellknown negative inotropic action of this class of drugs38,39. Whether this effect is the result of heart
rate reduction, or other actions mediated by -adrenergic receptor blockade such as prevention of
the detrimental effects of catecholamines on the myocytes, is difficult to establish.
The results of SHIFT32 improved our understanding of the role of heart rate in HF; elevated
heart rate has now been established as an independent risk marker and a prognostic risk factor in
patients with HF. SHIFT32 included 6,558 patients in sinus rhythm with stable symptomatic chronic
HF, LVEF <35%, and a resting heart rate ≥70 bpm. The aetiology of HF was either ischaemic
(68%) or nonischaemic (32%). Patients were randomly assigned to ivabradine or placebo, and
received optimal guideline–driven standard treatment for HF. Notably, 89% of participants were
already taking -blockers at the maximum-tolerated dose. The primary composite end point of
cardiovascular death or hospital admission for worsening HF was significantly reduced by 18% in
the ivabradine group (P <0.0001), largely driven by a reduction in HF death and hospitalization for
HF, which were reduced by 26% (P = 0.014) and 26% (P <0.0001), respectively.32
A further analysis of the results from SHIFT40 showed that, the higher the heart rate at
baseline, the worse the outcome. This finding suggests that heart rate is a marker of the severity of
HF. Moreover, in SHIFT40 the greater the heart rate reduction achieved with ivabradine, the lower
the mortality. This result shows that the marker is also a risk factor, meaning that the increase in
heart rate itself has pathological effects including deterioration of left ventricular function, which, in
turn, increases neuroendocrine activation creating a vicious cycle of decline. Therefore, a heart rate
≥70 bpm actively contributes to adverse outcome in patients with HF, and should be reduced with
therapy. This phenomenon of ‘tachycardia–mediated cardiomyopathy’ is not new, and has been
reported in several animal models and clinical studies41,42. Trials of patients with HF who have
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implanted pacemakers has demonstrated that heart rate per se impacts left ventricular function;
increasing the rate of pacing leads to increases in volumes and reduction of LVEF43,44.
The benefits of slowing the heart rate in patients with HF are likely to be the result of a
combination of factors (FIGURE 2). Firstly, the relationship between force and frequency, by which
the heart regulates cardiac function, is altered in patients with HF. The force of healthy papillary
muscle increases proportionally to the increase in heart rate. By contrast, the force developed by
papillary muscle in the presence of HF becomes negative and decreases in response to the same
increment of heart rate45,46. As a result, in HF, the compensatory mechanism of heart rate is not only
lost, but actually reversed — increasing heart rate coincides with a reduction in contractility and
negative inotropism, and vice versa34,47. Secondly, the pressure–volume relationship is also altered
in HF, leading to an increased afterload.48 Arterial stiffness is increased in the setting of HF,
whereas arterial compliance and elasticity, which represent resistant and pulsatile afterload to the
heart, are reduced. Selective heart rate reduction has been shown, in both animals and humans, to
improve total arterial compliance and effective arterial elasticity, therefore, unloading the ventricle
and improving remodeling48-50. In animals, however, this effect is not achieved by heart rate
reduction with metoprolol.51 Thirdly, high heart rate increases myocardial energy requirement and
often induces local hypoxia, which stimulates the production of cytokines, free radicals, and
vasoconstrictors implicated in the development of left ventricular remodeling.37 Heart rate reduction
decreases energy expenditure, as shown by higher energy phosphate availability, and improves
cardiac metabolism and remodeling in experimental models52,53.
As in the experimental setting, the progression of left ventricular remodeling was
significantly reversed by reducing heart rate with ivabradine in both BEAUTIFUL54 and SHIFT55.
In line with the clinical results, new experimental data show that remodeling is specifically
attenuated by selective heart rate reduction with ivabradine. In a model of angiotensin II–induced
HF in mice, ivabradine, but not metoprolol, improved systolic and diastolic left ventricular function,
despite a similar reduction in heart rate with each drug56. Angiotensin II infusion induced
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upregulation of several proinflammatory cytokines, levels of all of which were reduced to values
similar to control animals by both ivabradine and metoprolol56. Therefore, the different effects of
ivabradine and metoprolol cannot be explained by different effects on inflammation. Ivabradine, but
not metoprolol, attenuated the upregulation of the mRNA of metalloproteinase and collagen I and
II, and slowed the increases in apoptosis and hypertrophy induced by angiotensin II infusion56.
These effects are the most likely explanation for the different effects of the two drugs.
Hypertrophy and apoptosis are two well-regulated and opposite processes, one representing
life and the other death57. Both are activated by the same triggers, such as mechanical stretch, tissue
neuroendocrine activation, and upregulation of hyperpolarization channels58. The simultaneous
presence of apoptosis and hypertrophy in the failing heart has been suggested to be the result of a
shift from the adult to embryonic genetic programme of the myocyte, resulting in embryonic
phenotypes where the life and death cycle is present and active37. Interestingly, the If
hyperpolarization channels, which are the target for ivabradine, might be involved in (and could
even be the cause of) the shift to embryonic programme through changes in notch signalling, the
system that ultimately decides the fate of the cell58. In addition, the If current and hyperpolarizationactivated cyclic nucleotide-gated channel (HCN) isoform have been shown to be upregulated in
atrial and ventricular myocytes from rats and humans with severe HF59-61. These
electrophysiological alterations in nonpacemaker cells resemble the embryonic programme, because
the embryonic heart expresses hyperpolarization channels and If current62. In rats with
postinfarction left ventricular remodeling, long-term ivabradine treatment reversed
electrophysiological and haemodynamic remodeling through a decrease in functional and molecular
overexpression of HCN in ventricular and atrial cardiomyocytes through transcriptional and
posttranscriptional effects (FIGURE 3)63-65. Whether overexpression of the If current in
nonpacemaker cells in individuals with HF contributes to remodeling and to adverse outcomes is
uncertain and difficult to establish. What is certain, however, is that none of these alterations occur
in the healthy ventricle, as in the patients enrolled in SIGNIFY14,18.
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[L1] Explaining the results of SIGNIFY
The results of SIGNIFY14,18 came as a surprise to the scientific community; reducing heart rate was
widely believed to provide cardiac protection, particularly in patients with CAD. Consistent
experimental data supported the notion that heart rate reduction produces direct benefit on myocytes
by saving energy, and indirect benefit on the coronary arteries by limiting the development of
atherosclerotic plaque, resulting in improved myocardial perfusion1. In a pig model of ischaemiainduced ventricular fibrillation, ivabradine provided cardioprotection by increasing regional
myocardial blood flow, preserving cardiomyocyte viability, mitochondrial structure, Ca2+
homeostasis, and energy status, and limiting formation of reactive oxygen free radicals66,67. The
cardioprotective effects of ivabradine were also demonstrated in rodent models68-70. However, no
cardioprotection was observed when heart rate was reduced by propranolol, suggesting a possible
pleiotropic action of ivabradine, beyond heart rate reduction66,71. Evidence of ivabradine-induced
cardioprotection through a beneficial effect on the arteries in mice was originally shown in 2008 by
Custodis et al.5,19,72. The results were replicated by other groups, extending to several animal
models with different arterial systems and settings of endothelial dysfunction73-77. Nevertheless, as
with other promising drugs whose experimental cardioprotective effects did not translate to humans,
ivabradine did not improve the outcomes of patients with CAD in SIGNIFY.14,18,78 A full account
of the complex mechanisms behind the lack of benefit for ivabradine in SIGNIFY are beyond the
scope of this Review. Briefly, differences in ischaemic duration, residual blood flow, and coronary
perfusion territory could contribute to this lack of translation in benefits between animals and
humans. Moreover, the complex and long-lasting pathophysiology of CAD, and the use of
concomitant treatments in humans are difficult to reproduce in animal models. The results of
SIGNIFY14,18 emphasize the importance of testing hypotheses derived from experimental studies
and subgroup analyses in well-designed clinical trials.
11
The question remains as to why ivabradine improved the prognosis of patients with HF in
SHIFT,32 but not those with CAD in SIGNIFY.14,18 At least two possible explanations, which are
not mutually exclusive, have been put forward79,80. The first explanation is based on the results of
BEAUTIFUL10 and SHIFT32; the patient populations of these trials overlap in many aspects, except
for the aetiology of left ventricular dysfunction79. Investigators estimated that approximately onethird of the SHIFT population had HF of nonischaemic origin31,79, and heart rate reduction with
ivabradine produced the best outcome in this subgroup of patients. Ivabradine significantly reduced
the primary composite outcome in both subgroups with a HR of 0.72 (95% CI 0.60–0.85) in
patients with nonischaemic HF, versus 0.87 (95% CI 0.78–0.97) in those with ischaemic HF. In
patients with CAD and left ventricular dysfunction in BEAUTIFUL,11 ivabradine had no effect on
the composite end point of cardiovascular death or HF hospitalization, or either of its components,
in the subgroup with heart rate ≥70 bpm. However, ivabradine did reduce the incidence of the
secondary end points — admission to hospital for fatal and nonfatal MI (HR 0.64, 95% CI 0.49–
0.84) and coronary revascularization (HR 0.70, 95% CI 0.52–0.93)11. One possible biological
explanation for these data is that, in patients with ischaemic left ventricular dysfunction, the loss of
myocytes resulting from infarction leaves too little surviving myocardium for meaningful
improvement. However, in nonischaemic left ventricular dysfunction, more viable myocardial
tissue is available and could contribute to improvement in cardiac function. The patients enrolled in
SIGNIFY32 had preserved LVEF, leaving no room for improvement in cardiac function. Similarly,
digoxin and some -blockers have been shown to have differential effects depending on the
underlying aetiology in patients with HF81-83.
The second explanation for the opposing results observed in SHIFT14,18 and SIGNIFY32 is
that elevated heart rate is an important risk factor, but only when left ventricular function is
reduced80. In SIGNIFY, elevated heart rate might have exerted a deleterious effect only on the
progression of coronary artery atherosclerosis. However, the results do not support this theory, as
ivabradine had no effect on the incidence of cardiovascular death or MI14. This finding questions
12
whether an increase in heart rate in absence of left ventricular dysfunction is a risk factor, an
epiphenomenon of the underlying pathological process, or simply a physiological response.
Regardless, in patients with CAD unlike those with HF, elevated heart rate is not an index of
neuroendocrine activation.
The results of BEAUTIFUL10 seem to go against the second hypothesis (that the benefit of
heart rate reduction depends on left ventricular function). In the subgroup of patients with elevated
heart rate and left ventricular dysfunction, ivabradine did not reduce the incidence of the primary
end point or hospitalization for HF, despite having effects on left ventricular remodeling that were
similar to those in SHIFT54. On the other hand, a subgroup analysis from SHIFT seems to
contradict the first hypothesis (that the effect of heart rate depends on the aetiology of left
ventricular dysfunction). In the subgroup of patients of SHIFT who had angina (and probably
CAD), ivabradine improved prognosis, with results similar to those observed in the subgroup of
patients with angina in BEAUTIFUL84. Notably, these data come from post hoc, not prespecified,
subgroup analyses, raising the possibility of invalid results. Moreover, BEAUTIFUL is a neutral
study for which, from a purely statistical point of view, subgroup analyses have little or no validity
and should not even be considered. However, for every large trial a temptation — if not a duty —
exists to extensively analyse the data in the hope of finding plausible explanations of the results.
In stable CAD, elevated heart rate is a well-established determinant of ischaemia, and its
reduction is a recognized strategy to prevent ischaemic episodes and the symptoms of angina.
Accordingly, ivabradine had symptomatic benefits in SIGNIFY14, despite the lack of prognostic
benefit. In SIGNIFY14, patients with life-limiting angina seemed to fare less well in terms of
outcome with ivabradine than with placebo. An explanation for this finding has not been
forthcoming, and some concern has arisen in the medical community. However, the regulatory
authorities maintained the benefit:risk ratio of ivabradine as a treatment to relieve the symptoms of
angina.
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[L1] Implications for -blocker therapy
The discovery that reducing heart rate in patients with CAD does not affect prognosis came as a
surprise, because -blockers are widely thought to be the best first-line therapy in these patients96.
This supposition is based on the potent antianginal effects of -blockers, as well as extrapolation of
the prognostic benefit demonstrated in patients who have experienced an MI97 and in those with
HF98. However, the studies supporting the efficacy of -blockers in patients with CAD but without
HF were performed before the current era; that is, before use of coronary revascularization and
contemporary medical therapy with antiplatelets, statins, and angiotensin-converting enzyme (ACE)
inhibitors96. The same is true for studies of calcium-channel blockers, such as verapamil and
diltiazem, that also reduce heart rate99,100. To suppose that the CAD phenotype has changed over the
years is not unreasonable. A reperfused myocardium is less arrhythmogenic, and its function is less
affected by timely revascularization than necrotic, scared muscle. Many of the agents in common
current use (that were background therapy in SIGNIFY14), such as aspirin, statins, and ACE
inhibitors, exert beneficial effects on the coronary artery endothelium with reduction in
atherosclerosis progression and plaque stabilization96.
Analysis of data from contemporary registries suggest that, in daily clinical practice, blockers do not improve the prognosis of patients, irrespective of whether or not they have had an
MI101,102. This evidence, however, comes from observational, non-prospective, randomised clinical
trials and should, therefore, be considered with caution. Accordingly, in the latest version of the
European (2013)103 and American (2012)104 guidelines, recommendations for the long-term use of
-blockers have been downgraded in patients with CAD, restricting them for those who also have
HF or left ventricular dysfunction. Controversy also exists surrounding the efficacy of -blockers
during noncardiac surgery105,106 and after CABG surgery in patients with good left ventricular
function107,108.
14
Current reports on -blockers are essentially retrospective analyses of prospectively
collected data with multivariate adjustments and propensity matching, and -blockers could exert
effects other than heart rate reduction. However, the lack of prognostic benefit for -blockers
provides an additional line of evidence supporting the concept that heart rate reduction carries
prognostic benefit only when the ventricle is damaged and its function is reduced.
[L1] Heart rate and cardiac arrhythmias
In 2011, when our previous Review1 was published, elevated heart rate rather than bradycardia
seemed to be associated with an increased risk of supraventricular and ventricular arrhythmias,
including atrial fibrillation (AF), especially in patients with CAD. This association was
demonstrated in experimental models using dogs85 and pigs86, a large trial7, and an epidemiological
survey8. In 2016, we know that the opposite might also be true; that is, heart rate reduction can
under certain circumstances be linked to AF. BEAUTIFL10, SIGNIfY14, and SHIfT32 all showed a
trend towards a slight increase in emergent AF in the ivabradine group, which was statistically
significant in SIGNIFY14. Several reasons exist for such an association. Bradycardia can cause
dispersion of atrial repolarization which, in turn, can initiate AF (the recognized mechanism of
vagal-mediated AF)87. Interestingly, an increased risk of AF has been reported in elderly Norwegian
men with a history of long-term endurance sport practice leading to bradycardia88. Polymorphisms
of the HCN channel, the molecular subunit for If, are associated with asymptomatic sinus
bradycardia, sinus arrhythmia, and AF89. Moreover, in disease states such as in HF, HCN channels
are not restricted to the sinus node, and are expressed in a large portion of the myocardium.
However, inhibition of If by ivabradine could also be beneficial in AF, as demonstrated by a
reduction in the spontaneous activity of cardiomyocytes in the pulmonary vein of rabbits77. Whether
these findings can be extrapolated to humans is uncertain, particularly when the data were obtained
using a concentration of ivabradine much higher than that used clinically or in SIGNIFY89.
15
In SIGNIFY90, the incidence of emergent bradycardia was higher than in the other
ivabradine trials, because of the higher dosage regimen. Treatment with ivabradine also increased
the rate of AF events, the majority of which were paroxysmal, by 0.7% per year. Although — as
would be expected — the outcome in patients who developed AF was worse than those who did
not. In SIGNIFY90, neither bradycardia nor AF impacted outcomes. The safety of heart rate
reduction with ivabradine in patients with congenital or acquired long QT syndromes, who were
excluded from the ivabradine trials, has been a subject of debate91-94. However, we should recall
that ivabradine does not increase heart rate–corrected QT interval95.
[L1] Conclusions
Heart rate is no longer a forgotten link in CAD1. In just 5 years, our knowledge of the role of heart
rate in cardiovascular disease has greatly improved. When left ventricular function is maintained,
increased heart rate seems to be a marker of processes that might influence the progression of
atherosclerosis towards serious and irreversible damage in the coronary arteries, such as MI. In
these early stages of cardiovascular disease, reducing heart rate is not beneficial in terms of
reducing the progression of atherosclerosis in the coronary arteries. Therefore, contrary to popular
belief, reducing heart rate does not have a prognostic impact in these patients. However, in the
presence of coronary plaque or a defect in coronary microcirculation, a further short-term increase
in heart rate (such as during exercise or with emotion) is a determinant of ischaemia. In this case,
heart rate reduction is relevant to enhance the ischaemic threshold of hypoperfused myocytes and
prevent angina (FIGURE 4). For this reason, agents with negative chronotropic capacities — such
as -blockers, nondihydropyridine calcium-channel blockers, and ivabradine — are indicated to
reduce the symptoms of angina. To improve prognosis, antiplatelet agents, statins, and ACE
inhibitors, which act on recognized CAD risk factors, are required.
With the progression of CAD resulting in MI, left ventricular dysfunction and, eventually,
HF, the role of increased heart rate changes. When left ventricular function is already impaired,
16
increased heart rate itself contributes to left ventricular deterioration. Under these circumstances,
heart rate is both a marker of the progression of CAD and a determinant of adverse prognosis, and
heart rate reduction has been proven to improve prognosis (FIGURE 4). For this reason, -blockers
are indicated as first-line treatment to reduce mortality of patients with HF. Reduction of heart rate
with ivabradine further to that achieved with -blockers has been recognised in the ESC guidelines
for the diagnosis and treatment of HF109 as useful to improve outcome, confirming the prognostic
benefit of pure heart rate reduction in HF. Interestingly, the negative chronotropic effect of
ivabradine on top of -blocker therapy could be linked to specific actions of the drug on the
overexpressed If channel in the failing heart.
Undoubtedly, the availability of a tool such as ivabradine has added a great deal to our
knowledge of the role of heart rate in CAD. Discrepancies between experimental and clinical data
still exist and merit further exploration. Equally, deeper evaluation of the results from registries and
clinical trials are expected to lead to a better understanding of the interaction between heart rate and
left ventricular function in settings other than CAD. This is the beauty of medicine — our
knowledge changes as science progresses.
Conflict of interest statement
Roberto Ferrari reported that he received honorarium from Servier for steering committee
membership consulting and speaking, and support for travel to study meetings from Servier. In
addition, he received personal fees from Amgen, Boehringer-Ingelheim, Novartis, Merck Serono
and Irbtech. Kim Fox reported fees, honoraria, and research grants from Servier.
Author contributions
Both authors contributed equally to the article in terms of discussion of content, writing, and
reviewing and editing the manuscript before submission, and after peer review and editing.
17
Acknowledgments
This work was supported by a grant from Fondazione Anna Maria Sechi per il Cuore (FASC), Italy.
FASC had no role in the decision to publish or the preparation of the manuscript.
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Figure 1 | The beneficial effects of heart rate reduction in angina. A summary of the
mechanisms acting at the level of the myocyte and the coronary artery, and their outcomes.
Figure 2 | The beneficial effects of heart rate reduction in heart failure. A summary of the
mechanisms acting at the level of the mitochondria, myocyte, and aorta, and their outcomes.
Figure 3 | Molecular explanation for the effects of ivabradine independent of heart rate
reduction. HCN, hyperpolarization-activated cyclic nucleotide-gated channel.
29
Figure 4 | The effects of heart rate increase in various cardiovascular disease states.
30