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

Abstract

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.