Benefit Of Heart Rate Reduction Research Articles

Time to benefit of heart rate reduction with ivabradine in patients with heart failure and reduced ejection fraction.

In the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure (HF) hospitalizations in patients with HF and reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate (HR) ≥70 bpm. In this study, we sought to determine the clinical significance of the time durations of HR reduction and the significant treatment effect on outcomes among patients with HFrEF. The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all-cause death, and HF death, were assessed in a post-hoc analysis of the SHIFT trial in the overall population (HR ≥70 bpm) and at HR ≥75 bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102 days, while there was no effect on cardiovascular death, all-cause death, and HF death at HR ≥70 bpm. In the population with a baseline HR ≥75 bpm, a reduction of the primary outcome occurred after 67 days, HF hospitalization after 78 days, cardiovascular death after 169 days, death from HF after 157 days and all-cause death after 169 days. Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of ≥70 bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR ≥75 bpm. At HR ≥75 bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline-directed medication, including beta-blockers at maximally tolerated doses.

Abstract 12149: Prognostic Benefit of Heart Rate Reduction of Hospitalized Heart Failure Patients is Different Between Atrial Fibrillation and Sinus Rhythm

Introduction: Heart rate (HR) reduction is a key strategy for improving clinical prognosis of patients with heart failure (HF) regardless of presenting atrial fibrillation (AF) or sinus rhythm (SR). However, the prognostic impact of HR reduction during hospitalization is still unclear. Hypothesis: The degree of HR reduction during hospitalization between HF patients with AF and SR differently contributes to the prognosis after discharge. Methods: This observational study included 1,930 hospitalized HF patients who were discharged alive. After excluding patients who were implanted pacing devices, those presenting paroxysmal AF, and those with missing data of HR, 1,137 patients were ultimately analyzed. Of them, 456 patients presented AF and 681 presented SR at admission. Change of HR was defined as the difference between HR at admission and discharge. We evaluated the association between in-hospital HR change and the incidence of a composite of cardiovascular death after discharge and HF re-hospitalization in patients with AF and SR, respectively. Results: During the observation period (median 528 (IQR: 135-736) days), the composite endpoint developed in 169 (37%) and 187 (27%) patients with AF and SR, respectively. The ROC curves for the composite endpoint showed the cut-off values of HR reduction were 0 bpm and 28 bpm in patients with AF and SR, respectively. Kaplan-Meier analysis showed a significantly lower incidence of a composite endpoint in patients who achieved HR reduction greater than the cut-off value in both groups (log-rank test: p<0.05). HR reduction greater than the cut-off value was still an independent predictor for a composite endpoint in patients with AF after adjusting age, sex, HR at admission and LVEF (hazard ratio: 0.65, 95% confidence interval: 0.45-0.96). However, this finding was not observed in patients with SR (hazard ratio: 0.81, 95% confidence interval: 0.50-1.33). Conclusions: The ideal HR reduction level during hospitalization was different between AF and SR. Target HR reduction in HF patients with AF could lead to better clinical outcomes, but the benefit is limited in patients with SR.

Heart Rate Reduction Improves Right Ventricular Function and Fibrosis in Pulmonary Hypertension.

The potential benefit of heart rate reduction (HRR), independent of β-blockade, on right ventricular (RV) function in pulmonary hypertension (PH) remains undecided. We studied HRR effects on RV fibrosis and function in PH and RV pressure-loading models. Adult rats were randomized to 1) sham controls, 2) monocrotaline (MCT)-induced PH, 3) SU5416 + hypoxia (SUHX)-induced PH, or 4) pulmonary artery banding (PAB). Ivabradine (IVA) (10 mg/kg/d) was administered from 2 weeks after PH induction or PAB. Exercise tolerance, echocardiography, and pressure-volume hemodynamics were obtained at a terminal experiment 3 weeks later. RV myocardial samples were analyzed for putative mechanisms of HRR effects through fibrosis, profibrotic molecular signaling, and Ca++ handling. The effects of IVA versus carvedilol on human induced pluripotent stem cell-derived cardiomyocytes beat rate and relaxation properties were evaluated in vitro. Despite unabated severely elevated RV systolic pressures, IVA improved RV systolic and diastolic function, profibrotic signaling, and RV fibrosis in PH/PAB rats. RV systolic-elastance (control, 121 ± 116; MCT, 49 ± 36 vs. MCT+IVA, 120 ± 54; PAB, 70 ± 20 vs. PAB+IVA, 168 ± 76; SUHX, 86 ± 56 vs. SUHX +IVA, 218 ± 111; all P < 0.05), the time constant of RV relaxation, echo indices of RV function, and fibrosis (fibrosis: control, 4.6 ± 1%; MCT, 13.4 ± 6.5 vs. MCT+IVA, 6.7 ± 2.6%; PAB, 11.4 ± 4.5 vs. PAB+IVA, 6.4 ± 5.1%; SUHX, 10 ± 4.6 vs. SUHX+IVA, 3.9 ± 2.2%; all P < 0.001) were improved by IVA versus controls. IVA had a dose-response effect on induced pluripotent stem cell-derived cardiomyocytes beat rate by delaying Ca++ loss from the cytoplasm. In experimental PH or RV pressure loading, HRR improves RV fibrosis, function, and exercise endurance independent of β-blockade. The balance between adverse tachycardia and bradycardia requires further study, but judicious HRR may provide a promising strategy to improve RV function in clinical PH.

The role of ivabradine in improving myocardial perfusion, adding to the antianginal benefits

The most common cause of oxygen demand/supply mismatch is atherosclerotic narrowing of the coronary artery, resulting in decreased coronary blood flow. However, endothelial dysfunction and/or microvascular dysfunction may be responsible for myocardial ischaemia and importantly may often coexist in patients with angina. Coronary flow reserve reflects the functional capacity of coronary circulation to adapt to the blood demand during increased cardiac work. In addition, coronary flow reserve predicts long-term adverse cardiovascular outcome. Therefore, a clear understanding of myocardial perfusion pathophysiology and a knowledge of the antianginal–anti-ischaemic drugs effect on coronary circulation are crucial for the judicious use of medications for the treatment of angina patients with coronary artery disease. This article discusses the role of ivabradine in improvement of myocardial perfusion based on data drawn from relevant preclinical and clinical investigations. Experimental data suggest that heart rate reduction with ivabradine causes greater increase in duration of diastolic perfusion time and coronary flow compared with β-blockade due to absence of impairing of left ventricular contractility and coronary vasomotion. In consequence, the full benefits of heart rate reduction for improved coronary perfusion could be realized with ivabradine. Following experimental data, clinical studies demonstrated anti-ischaemic and antianginal efficacy of ivabradine in patients with stable coronary artery disease. These clinical benefits have been supported by recent clinical data on improvement of coronary flow reserve, and coronary collateral circulation with ivabradine supports the role of ivabradine as an important anti-ischaemic and antianginal agent in patients with angina in addition to other recommended therapies or revascularization.

If blocking potency of ivabradine is preserved under elevated endotoxin levels in human atrial myocytes

Lower heart rate is associated with better survival in patients with multiple organ dysfunction syndrome (MODS), a disease mostly caused by sepsis. The benefits of heart rate reduction by ivabradine during MODS are currently being investigated in the MODIfY clinical trial. Ivabradine is a selective inhibitor of the pacemaker current If and since If is impaired by lipopolysaccharide (LPS, endotoxin), a trigger of sepsis, we aimed to explore If blocking potency of ivabradine under elevated endotoxin levels in human atrial cardiomyocytes. Treatment of myocytes with S-LPS (containing the lipid A moiety, a core oligosaccharide and an O-polysaccharide chain) but not R595 (an O-chain lacking LPS-form) caused If inhibition under acute and chronic septic conditions. The specific interaction of S-LPS but not R595 to pacemaker channels HCN2 and HCN4 proves the necessity of O-chain for S-LPS–HCN interaction. The efficacy of ivabradine to block If was reduced under septic conditions, an observation that correlated with lower intracellular ivabradine concentrations in S-LPS- but not R595-treated cardiomyocytes. Computational analysis using a sinoatrial pacemaker cell model revealed that despite a reduction of If under septic conditions, ivabradine further decelerated pacemaking activity. This novel finding, i.e. If inhibition by ivabradine under elevated endotoxin levels in vitro, may provide a molecular understanding for the efficacy of this drug on heart rate reduction under septic conditions in vivo, e.g. the MODIfY clinical trial.

Heart Rate After Cardiac Transplantation—Lessons From the Tortoise and the Shrew

There is a striking consistency in the total number of heart beats accrued over a lifetime across a range of animal species despite vast differences in size. Moreover, an inverse relationship is observed between heart rate and lifespan, leading to speculation that elevated heart rate could significantly affect longevity. It is the aim of this review to analyze heart rate as a contributing factor in defining the functional lifespan of the transplanted human heart, which may unavoidably determine the longevity of the recipient. Sinus tachycardia occurs as a result of sympathetic/parasympathetic denervation, an unavoidable consequence of transplantation. The effect of elevated heart rate in this cohort has been scarcely reported. We highlight herein multitudinous mechanisms whereby elevated heart rate accelerates the deterioration in cardiac function and arterial elasticity due to injury and stress accumulation. Additionally, we propose a significant role for heart rate in confounding the alloimmune response. Tachycardia exacerbates injurious episodes of myocardial ischemia and significantly increases the production of reactive oxygen species via increased metabolism. These factors promote immune infiltration and activation, contributing to acute and chronic rejection. Further research is required to assess the potential therapeutic benefits of heart rate reduction.

Current status: heart rate as a treatable risk factor

Resting heart is an independent predictor of all-cause mortality and cardiovascular mortality. In patients with coronary artery disease and left ventricular dysfunction, the morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) trial showed that a heart rate of 70 b.p.m. or greater is an independent predictor of cardiovascular events. In patients with moderate-to-severe heart failure, the SHIFT (Systolic Heart failure treatment with the If inhibitor Trial) showed also that heart rate was a predictor of cardiovascular death and heart failure hospitalisation. Heart rate plays an important role in the pathophysiology of atherosclerosis. The BEAUTIFUL trial and SHIFT provide evidence for the benefits of heart rate reduction using the new heart rate-lowering agent ivabradine, even in patients on beta-blockers. The BEAUTIFUL trial showed that in patients with a heart rate of 70 b.p.m. or more, ivabradine significantly reduced hospitalisation for fatal and non-fatal myocardial infarction or hospitalisation for heart failure and coronary revascularisation. In the SHIFT, heart rate reduction with ivabradine improved clinical outcomes. Therefore, high heart rate represents an important risk factor the effects of which can be reversed by ivabradine in patients with coronary artery disease or heart failure with or without background beta-blocker therapy.

Benefit of Heart Rate Reduction in Heart Failure

Epidemiological studies have suggested that life expectancy is inversely related to resting heart rate and that the risks of development of heart failure and sudden cardiac death strongly increase with higher resting heart rates [1]. After myocardial infarction, the reduction in mortality with β-blocker treatment was correlated with the extent of heart rate reduction, and in patients with heart failure, a drug-induced increase or decrease in heart rate has been associated with an increase or decrease in mortality, respectively [2, 3]. The prognostic relevance of heart rate in patients with coronary artery disease and reduced ejection fraction recently has been demonstrated in the placebo arm of the prospective BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) study. The BEAUTIFUL study included patients with coronary artery disease and a left ventricular ejection fraction of less than 40%. When patients with heart rates below and above 70 beats per minute were compared, cardiovascular death and heart failure hospitalization were significantly higher in the group of patients with higher heart rates [4].

Elevated Heart Rate: A “New” Cardiovascular Risk Factor?

A number of epidemiologic studies and several experimental lines of research point to high heart rate as a main risk factor for cardiovascular disease. However, translating research into clinical practice has been a challenge throughout medical history. From the present symposium, it appears clear that this is particularly the case for heart rate. The complex nature of atherogenesis makes it difficult to establish the role of a putative risk factor because of the correlations and complex interactions among factors. The pathogenetic mechanisms for the connection of resting heart rate with atherosclerosis and cardiovascular morbidity have been elaborated extensively in the chapter papers of this symposium, suggesting that there is a causal relationship between heart rate and cardiovascular mortality. The benefit of heart rate reduction has been proved in patients with coronary artery disease or congestive heart failure. Until now it has been difficult to determine whether modulation of heart rate is beneficial also in patients free of cardiac diseases. This concern, however, does not in any fashion suggest that health care professionals should pay less attention to this clinical variable. The impressive amount of available epidemiologic data show support for the continued effort to raise awareness of the clinical importance of resting heart rate among health care professionals.

The role of heart rate and the benefits of heart rate reduction in acute myocardial ischaemia

In myocardial ischaemia, detailed analyses of experimental data show that regional myocardial blood flow and contractile function are reduced proportionately—this being contrary to the common notion that the underlying pathological mechanism is a supply/ demand imbalance. Such perfusion–contraction matching is maintained at an increased heart rate. In the normal myocardium, metabolic regulation prevails and tachycardia results in an increased coronary blood flow. In post-stenotic myocardium that has an exhausted dilator reserve, a reduction in diastolic duration prevails, and coronary blood flow is decreased with tachycardia. In the presence of collaterals, both metabolic vasodilation of the normal microcirculation and reduced diastolic duration act in concert to decrease collateral perfusion pressure and collateral flow into the post-stenotic coronary microcirculation. Tachycardia results from sympathetic activation and activation of beta-adrenoceptors. Accordingly, beta-adrenergic blockers have been used to treat patients with stress-induced myocardial ischaemia. The benefits of heart rate reduction by beta-blockade are in part counterbalanced by unmasked alpha-adrenergic coronary vasoconstriction. Selective heart rate-reducing agents can decrease heart rate without unmasking alpha-adrenergic coronary vasoconstriction. They improve the blood flow distribution into the ischaemic myocardium and, as a consequence, improve regional myocardial function. Ivabradine is the only clinically available selective heart rate-reducing agent, and it exerts anti-ischaemic actions in patients with chronic stable angina.

Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease.

Resting heart rate is associated with cardiovascular and all-cause mortality, and the mortality benefit of some cardiovascular drugs seems to be related in part to their heart rate-lowering effects. Since it is difficult to separate the benefit of heart rate lowering from other actions with currently available drugs, a 'pure' heart rate-lowering drug would be of great interest in establishing the benefit of heart rate reduction per se. Heart rate is determined by spontaneous electrical pacemaker activity in the sinoatrial node. Cardiac pacemaker cells generate the spontaneous slow diastolic depolarisation that drives the membrane voltage away from a hyperpolarised level towards the threshold level for initiating a subsequent action potential, generating rhythmic action potentials that propagate through the heart and trigger myocardial contraction. The I(f) current is an ionic current that determines the slope of the diastolic depolarisation, which in turn controls the heart beating rate. Ivabradine is the first specific heart rate-lowering agent to have completed clinical development for stable angina pectoris. Ivabradine specifically blocks cardiac pacemaker cell f-channels by entering and binding to a site in the channel pore from the intracellular side. Ivabradine is selective for the I(f) current and exerts significant inhibition of this current and heart rate reduction at concentrations that do not affect other cardiac ionic currents. This activity translates into specific heart rate reduction, which reduces myocardial oxygen demand and simultaneously improves oxygen supply, by prolonging diastole and thus allowing increased coronary flow and myocardial perfusion. Ivabradine lowers heart rate without any negative inotropic or lusitropic effect, thus preserving ventricular contractility. Ivabradine was shown to reduce resting heart rate without modifying any major electrophysiological parameters not related to heart rate. In patients with left ventricular dysfunction, ivabradine reduced resting heart rate without altering myocardial contractility. Thus, pure heart rate lowering can be achieved in the clinic as a result of specific and selective I(f) current inhibition. Two randomised clinical studies have shown that ivabradine is an effective anti-ischaemic agent that reduces heart rate and improves exercise capacity in patients with stable angina. Ivabradine was shown to be superior to placebo in improving exercise tolerance test (ETT) criteria (n = 360) and, in a 4-month, double-blind, controlled study (n = 939), ivabradine 5 and 7.5mg twice daily were shown to be at least as effective as atenolol 50 and 100mg once daily, respectively, in improving total exercise duration and other ETT criteria, and reducing the number of angina attacks. Experimental data indicate a potential role of pure heart rate lowering in other cardiovascular conditions, such as heart failure.

Calcium antagonists andbeta-blockers: Impact on cardiovascular and cerebrovascular events

It is well established that elevated blood pressure is a major risk factor for cardiovascular and cerebrovascular events, and that controlling hypertension reduces these risks. Although most classes of antihypertensive agents play a role in risk reduction, none offers blanket reductions for all adverse events. The β-blockers, while the agents of choice for those with ischemic heart disease and for disease states requiring reducing heart rate, are inappropriate first-line therapies in patients whose primary concern is stroke risk reduction. In patients who require heart rate-lowering therapy but who cannot tolerate β-blockers, long-acting nondihydropyridine calcium antagonists offer the benefits of heart rate reduction, as well as the vasodilation that is characteristic of the calcium antagonists as a class. This article reviews the data on risk reduction involving the β-blockers and calcium antagonists, as well as other antihypertensive classes that have been shown to reduce the risk of cerebrovascular and cardiovascular disease.

Prognostic benefits of heart rate reduction in cardiovascular disease

Increased heart rate is associated with high blood pressure and metabolic disturbances that lead to hypertension, atherosclerosis and increased cardiovascular morbidity and mortality. In this respect, elevated heart rate can be considered a marker of risk. Whole body temperature and energy needs are controlled by heart activity, and the ‘language’ employed by the heart could be considered its rate, which, via the intensity and frequency of shear stress, it uses to regulate endothelial function and vascular tone. A close link between body temperature, metabolism and heart rate has been observed, and so heart rate may determine metabolic demand and ‘control’ the duration of life. In mammals, the calculated number of heart beats in a lifetime is remarkably constant, despite a 40-fold difference in life expectancy. According to this view, a reduction in heart rate would increase life expectancy also in humans. The heart produces and utilizes approximately 30 kg adenosine triphosphate each day, and slowing its rate by 10 beats/min would result in a saving of about 5 kg in a day. Considering that heart rate is a major determinant of oxygen consumption and metabolic demand, heart rate reduction would be expected to diminish cardiac workload. Clinical studies with beta-blockers have already shown a reduction in mortality and improvement in outcome as a result of reduction heart rate.

Addition of zatebradine, a direct sinus node inhibitor, provides no greater exercise tolerance benefit in patients with angina taking extended-release nifedipine: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group study

Objectives. We examined the antianginal and anti-ischemic effects of oral zatebradine, a direct sinus node inhibitor that has no blood pressure-lowering or negative inotropic effects in patients with chronic stable angina pectoris taking extended-release nifedipine.Background. Heart rate reduction is considered an important pharmacologic mechanism for providing anginal pain relief and anti-ischemic action in patients with chronic stable angina, suggesting a benefit for sinus node-inhibiting drugs.Methods. In a single-blind placebo run-in, randomized double-blind, placebo-controlled, multicenter study, patients already receiving extended-release nifedipine (30 to 90 mg once a day) were randomized to receive zatebradine (5 mg twice a day [n = 64]) or placebo (n = 60). All subjects had reproducible treadmill exercise-induced angina at baseline, and after randomization they performed a serial exercise test 3 h after each dose for 4 weeks.Results. Zatebradine reduced rest heart rate both at 4 weeks ([mean ± SEM] 12.9 ± 1.23 vs. 2.3 ± 1.6 [placebo] beats/min, p < 0.0001) and at the end of comparable stages of Bruce exercise (16.7 ± 1.2 vs. 3.4 ± 1.2 [placebo] beats/min, p < 0.0001). Despite the significant effects on heart rate at rest and exercise, there were no additional benefits of zatebradine from placebo baseline in measurements of total exercise duration, time to 1-mm ST segment depression or time to onset of angina. Subjects taking zatebradine also had more visual disturbances as adverse reactions.Conclusions. Zatebradine seems to provide no additional anti-anginal benefit to patients already receiving nifedipine, and it raises questions regarding the benefit of heart rate reduction alone as an antianginal approach to patients with chronic stable angina.

723-5 Evaluation of the Antianginal and Anti-ischemic Effects of the Sinus Node Inhibitor Zatebradine Used in Combination with Extended-Release Nifedipine In Patients with Angina Pectoris

Zatebradine (Z) is a directsinus node inhibitor which is orally active and, unlike p-adrenergic blockers, has no effect on blood pressure, vascular resistances, and ventricular contractility. We evaluated the anginal and anti-ischemic effects of Z 15 mg administered twice daily) and placebo in 124 patients (pts) already receiving 30–90 mg of extended-release nifedipine once daily, whose treadmill exercise tolerance was still limited. After 2–3 wks of single-blind placebo therapy with reproducible exercise-induced angina on the treadmill, pts were randomized to receive in double-blind fashion twice daily Z (n = 64) or twice daily placebo (n = 60) in addition to nifedipine. Subjects were followed with serial exercise tests 13 hrs post dose) for 4 wks and angina diaries were maintained. At 4 wks, Z was shown to reduce resting heart rate (HR) in contrast to placebo (12.9 ± 1,23 vs 2.3 ± 1.6 bpm, p &lt; 0.0001), and at the end of comparable stages of exercise (Bruce). Z reduced HR in contrast to placebo (16.7 ± 1.2 vs 3.4 ± 1.2 bpm, p &lt; 0.001). Despite these significant effects on HR with Z at rest and exercise, there were no additional antianginal benefits of Z from placebo baseline in measurements of total exercise duration, time to 1 mm ST segment depression, or time to onset of angina. Z appears to provide no additional antianginal benefit to pts already receiving nifedipine, and raises questions regarding the benefit of HR reduction alone as an antianginal approach in pts.