Effect of Heart Rate Reduction in Coronary Artery Disease and Heart Failure
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, ItalyUniversity Hospital of Ferrara and Maria Cecilia Hospital, GVM Care&Research, E.S: Health Science Foundation, Cotignola, Italy
2NHLI National Heart and Lung Institute, Imperial College and, ICMS Institute of Cardiovascular Medicine and Science, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK
Address for cCorrespondence to: R.oberto F. errari, MD, Chair of Cardiology, Azienda Ospedaliero-Universitaria di Ferrara, Ospedale di Cona, Via Aldo Moro 8, 44124 (Cona) Ferrara, Italy
Email:
Telephone: +39 0532 239882
Abstract |
Elevated heart rate in coronary artery disease (CAD) is known to induce myocardial ischaemia in patients with coronary artery disease (CAD), and its 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. EIn addition, elevated heart rate is an established risk factor for cardiovascular events in patients with CAD and in those with chronic heart failure (HF) and CAD. Accordingly, reducing heart rate improves prognosis in HF patients with HF, as demonstrated in SHIFfT (sSystolic hHeart fFailure treatment with If inhibitor iIvabradine tTrial). However, By contrast, however, recent data from SIGNIFfY (sStudy assessingInG the morbidity– mortality beneNefits of the If inhibitor ivabradine in patients with coronaryY artery disease) indicate this is not the case in CAD patients without clinical HF. Thus, at heart rate is not a modifiable risk factor in this clinical settingpatients with CAD who do not also have, contrary to HF. Meanwhile, new clinical evidence has confirmed the benefits of heart rate reduction on angina symptoms, by improving microcirculation and coronary flow reserve, and stimulating arteriogenesis. Heart rate is also an important determinant of cardiac arrhythmias;: a low heart rate canmay be associated with atrial fibrillation, and a high heart rate after exercise canmay be associated with sudden cardiac death. Here, we critically review these new clinical findings and the role of heart rate along the cardiovascular continuum, and propose hypotheses for the variabledifferential effect of heart rate reduction in cardiovascular diseasecardiovascular disease.
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
- The role of heart rate in coronary artery disease and heart failure can be explored using ivabradine, a drug that selectively targets heart rate.
- Increased heart rate can provoke myocardial ischaemia
- Heart rate, and its reduction canhas symptomatic,reduce the symptoms of antianginal effects.
- Increased heart rate is just a risk marker in patients with coronary artery disease, but as heart rate its reduction does not improve prognosis in this clinical setting.
- In the setting of heart failure, elevated heart rate is a modifiable risk factor — reducing, i.e. heart rate its reduction is accompanied by an improvesment in prognosis in these patients.
Keywords: heart rate; ischaemia; coronary artery disease; heart failure; cardiac arrhythmias; ivabradine.
In 2011
Introduction
Four years ago, when our Rwe wrote a review on the role of heart rate in coronary artery disease (CAD)1 was published, . The title was Heart rate: a forgotten link in coronary artery disease?1 At the time, the recognition of the rolethe effect of heart rate over the whole spectrum of cardiovascular disease continuum was receiving new impetusrecognition. The impetus was the 2005, mainly as a consequence of the approvalintroduction in Europe of the specific heart rate–lowering agent ivabradine for patients with angina into routine clinical practice.2. Ivabradine — in contrast to the other widely used drugs widely used in for the treatment of CAD, such as eta-blockers and non-dihydropyridine calcium channel blockers — has no direct effect on the cardiovascular system other than reducing heart rate reduction. In addition to making an impact in the clinical setting, ivabradineit also 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 at the timein 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 a detrimental role of heart rate can causeon cardiac arrhythmias and coronary artery shear stress.1,3-9. This observation naturally led to the hypothesis of an association between increased heart rate and the development and instability of atherosclerotic plaque.1. On the basis of Supported by preclinical data from animals and humans, as well as byand the results of a prespecified subgroup of the BEAUTIFfUL (mMorbBidity-mortality eEvaAluatUaTion of the If inhibitor ivabradine in patients with coronary disease and left vVentriculULar dDysfunction) trial,10, we anticipated —but with no definitive proof—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 because of the impressive number ofon the basis of several epidemiological studies that showeding an interaction between elevated heart rate and cardiac events in this population in CAD patients.11-13.
Over the plast 54 years, however, new information has become available that has allowed us to clarify some of the 2011 hypotheses we postulated in 2011 and produce a more precise picture of the role of heart rate in the cardiovascular diseasecontinuum. In addition to several new experimental dataresults from basic science, the results of the SIGNIFfY study (sStudy assessiIngG the morbidity – mortality benNefits of the If inhibitor ivabradine in patients with coronaryY artery disease)14 have greatly contributed to the understanding of the role of heart rate in CAD. In this Rreview, we critically analyse these new findings, mainly from a clinical perspective, following the phases of the ivabradine development programme that encompass the effect of heart rate lowering along all of the different steps on the in cardiovascular continuumdisease. Whenever new basic scienceexperimental data are relevant to the clinical results, we report these in detail. Otherwise, we refer the reader to our previous 2011 Rreview.1.
[L1] Effects of hHeart rate lowering reduction andin angina
It is well established that anI increased heart rate can provoke myocardial ischaemia in a patients with CAD. setting. This well-established mechanism is the basis — at least in part — of the symptomatic antianginal effect of eta-blockers and the calcium- channel blockers that lower heart rate, (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 may contribute to their anti--ischaemic and antianginal actions. N, notably, b-blockers lower blood pressure (BP) lowering and, for the calcium- channel blockers cause, dilatation of the coronary arteries. The development programme for ivabradine in angina included over 6000 patients in a variety of studies in which >6,000 patients were enrolled, and has allowed us to establish the role of pure heart rate reduction in this contextangina to be established.15-17. In all the studies, exercise test parameters improved and the number of angina attacks decreased, confirming that selective heart rate reduction prevents and/or attenuates the short period of myocardial ischaemia that causes angina.15-17. In 2014, tThis finding was has recently been confirmed by the results of in the SIGNIFfY14,18. trial: in In 12 000 randomised patients with angina ((Canadian Cardiovascular Society class ≥II or above), heart rate reduction with ivabradine resulted in a reduction inof class of angina class at 3 months,14, and in an improvement inof quality of life at 12 months.14,18.
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 diastole.1. The interaction between heart rate and myocardial perfusion in the presence of substantial coronary stenosis is, however, more complex. An accurate description was presented in our previous r2011 Review,1, including the role of the so-called “collateral steal” phenomenon (, due to a redistribution of flow away from post-stenotic myocardium,19); the possibility of “paradoxical vasoconstriction” induced by acute heart rate increase,20,21; and the “accelerated deterioration” of the vessel elastin fibres, with fraying, fragmentation, and functional deterioration leading to increased arterial stiffness.22,23.
In the past 5 yearsmeantime, 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, Schirmer et al used 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 eta-receptor blockade with metoprolol on collateral artery growth in both wildtype and dyslipidaemic apolipoprotein E–deficient mice.24. The hypothesis behind these experiments was that collateral arteries protect from ischaemia and that heart rate reduction could improve arteriogenesis and perfusion, thus reducing ischaemia and, eventually, vascular events. Schirmer et al The researchers demonstrated that heart rate reduction with ivabradine, but not with metoprolol, stimulated adaptive collateral artery growth.24 This effect was present o only in the dyslipidaemic apolipoprotein E–deficient mice, and not in the wildtypes24.. The molecular mechanism involved is most 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 (ILinterleukin-6, tumour necrosis factor–alpha, and tumour growth factor–beta), and the angiotensin II receptor, type 1) (AT1).24.
The clinical relevance of these experimental findings into the coronary arteries of these experimental findings was subsequently evaluated in a single-blind study of 46 CAD patients with CAD, who were randomly allocated to ivabradine or placebo.25. The main primary outcome was the measurement of collateral flow index, obtained measured invasively during a 1- minute 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 CAD patients with CAD. Of course, these data have only a proof- of- concept value but, if confirmed, this could be provide an additional explanation for the symptomatic effect of heart rate reduction in angina.26 In an elegant study of 21 CAD patients with CAD, Skalidis et al showed that 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 pacing.27. A recent 2015 study of coronary flow velocity reserve in angina patients with angina confirmed supported these data and showed the superiority of pure heart rate reduction with ivabradine over that achieved with the -blocker bisoprolol to enhance coronary flow reserve.28. Taken together, these data indicate that it appears that slowing heart rate improves microcirculation and allows better coronary flow reserve, most likelyprobably as a result of enhanced ventricular diastolic relaxation time, which is more pronounced with ivabradine than with eta-blockade.29,30.
These new clinical and experimental and clinical data confirm the usefulness ofthat reducing heart rate to improves the symptoms of angina, and expand our knowledge ofn the mechanisms involved (FIGUREigure 1). On the one hand, hHeart 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. On the other handIn 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 patients
Our knowledge has changed substantially since our previous review in 2011,1 mainly due to the results of the SIGNIfY study, which were published in the New England Journal of Medicine in 2014.14 In our previous 2011 Rreview, we statedhypothesized that elevated resting heart rate in CAD patients with CAD was a modifiable risk factor for cardiovascular events and mortality.1. 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, a worseadverse outcomes.1. 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 rates of mortality and rates of cardiac events in patients with cardiovascular disease.1,12,13,30. The results of BEAUTIfUL were already available when we wrote our review.10,11 In BEAUTIFfUL,10,11 the relative risk of cardiovascular death was increased by 34% in placebo patients receiving placebo who hadwith a heart rate ≥70 bpmeats/min compared with those with a heart rate <70 bpmeats/min, 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 bpmeats/min, reducing heart rate with ivabradine was associated with significant 73% and 59% risk reductions for myocardial infarction (MI) (MI) and coronary revascularizsation, respectively.31 In view of these data, it seemed perfectly reasonable at that time to hypothesize that selective heart rate reduction would lead to an improvement of outcomes in CAD patients with CAD was reasonable.
Theis was the objective inof the SIGNIFfY14 trialwas to put this theory to the test. Enrolled p, a study that recruited 19 102 patients (n = 19,102) with had stable CAD plus and additional cardiovascular risk factors, a resting heart rate ≥70 bpm,eats/min with no symptoms of heart failure (HF) or left ventricular (LV) systolic dysfunction (left ventricular ejection fraction ([LVEF)] at baseline: 56.5% ± 8.6%), and were receiving guideline-based background therapy for their condition. Contrary to the initial assumption, after a median follow-up of 27.8 months, heart rate reduction with ivabradine had no effect on the primary end point —, a composite of cardiovascular death or non-fatal MIMI — with an event rate of 6.8% with for ivabradine, and 6.4% with for placebo (median follow-up 27.8 months; HhRazard ratio 1.08, 95% confidence interval [CI] 0.96– to 1.20, P = 0.20)14. There was nNo significant difference between the groups was observed in terms of any secondary end points including cardiovascular death, non-fatal MI, or all-cause death.