Ivabradine in Cardiovascular Disease: Heart Rate Isn't Everything

The funny or hyperpolarization-activated cyclic nucleotide-gated channel (HCN) modulates cardiac excitability and heart rate by regulating the If or IKf current in sinoatrial cells. The 4 HCN channel isoforms (HCN1–4) are unique in that they are activated by both cyclic adenosine monophosphate (AMP) and hyperpolarized membrane channels. Thus, sympathetic activation of b-adrenergic receptors (b-AR) on the cardiac sarcolemma and the resultant increase in cellular levels of cyclic AMP shift the activation potential of the channel thereby increasing heart rate. Channel activity is also modified by phosphoinositides including phosphatidylinositol-4,5bisphosphate and by Src kinase–mediated phosphorylation in an isoform-specific manner. HCN channels also play a role in regulating excitability in neurons, and changes in channel activity have been associated with the development of epilepsy and seizures. Much of what we know about HCN channels in the heart comes from studies in which the channels were knocked out. For example, animals in which HCN1 had been knocked out had sinus pauses and reduced cardiac output, whereas mice with knockout of HCN3 had abnormal action potentials. Global knockout of HCN4 was lethal, presumably because of a profound decrease in heart rate, whereas conditional deletion of HCN2 and HCN4 was associated with an increase in ventricular arrhythmias. Although adult ventricular myoctes do not express appreciable levels of HCN channels under normal conditions, HCN expression is increased in cardiac hypertrophy and failure although the physiological relevance is uncertain. Either pharmacologic blockage of the HCN channels or selective knockdown of HCN2 or 4 channels affected cardiac remodeling or ventricular function during the development of cardiac hypertrophy and a loss of function mutation in HCN4 in families with bradycardia was also associated with structural abnormalities of the myocardium. Therefore, in aggregate, these results suggested that any salutary benefits of HCN inhibition were likely because of an effect on heart rate and not on the biology of the myocardium. Despite the lack of basic science data supporting a role for cardiac HCN channels in the pathobiology of left ventricular dysfunction, the recognition that there was an inverse relationship between heart rate and survival in patients with cardiovascular disease led to the development of the selective sinus note If channel inhibitor ivabradine. 19,20 Ivabradine has been evaluated in large multicenter trials assessing its efficacy in the treatment of a variety of cardiovascular disease including stable coronary artery disease with left ventricular dysfunction, chronic heart failure, and stable coronary artery disease without clinical heart failure. The BEAUTIFUL (morbidity–mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricular dysfunction) trial randomized 10,917 patients with stable coronary disease and a left ventricular ejection fraction of ,40% to receive either ivabridine or placebo after a 14-day run-in period. The starting dose of ivabradine was uptitrated if the resting heart rate was 60 beats per minute (bpm) or greater. Not surprisingly, ivabradine reduced heart rate; however, it had no effect on the primary end point of cardiovascular death or admission to a hospital for new-onset or worsening heart failure. In a subgroup of patients with a heart rate of 70 bpm or greater, ivabradine treatment reduced the secondary end points of admission to a hospital for a fatal or nonfatal myocardial infarction and coronary revascularization. In a substudy of only 426 subjects, the investigators reported a significant decrease in the primary end point of left ventricular end-systolic volume index assessed by echocardiography.