Effect of heart rate reduction in coronary artery disease and heart failure

Roberto Ferrari1 and Kim Fox2

1Department 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.

fri@unife.it

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 2

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 calcium-

channel 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 anti-

ischaemic 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 3

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 growth24thase 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.

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 4

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-of-

concept 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

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 5

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. 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

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 6

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

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 well-

known negative inotropic action of this class of drugs38,39. Whether this effect is the result of heart

7

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

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 8

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

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 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,

9

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 hyperpolarization-

activated 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.

[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 10

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 ischaemia-

induced 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.

The question remains as to why ivabradine improved the prognosis of patients with HF in

SHIFT,3214,18 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 one-third of the SHIFT population had HF 11

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 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 32 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

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 12

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.

[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 13

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.

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, 14

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 2016s 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.

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

15

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,

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.

16

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.

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.

Figure 4 | The effects of heart rate increase in various cardiovascular disease states.

29