• Heart Failure
• Pharmacology

Ivabradine selectively blocks the I_f channel by binding to a site in the channel pore, reducing the f-current and thereby reducing the slope of the slow diastolic depolarisation phase of the action potential in the sinoatrial node cells, increasing the time required to reach the voltage threshold for action potential initiation. This slows the spontaneous firing of the sinoatrial node cells and, therefore, the heart rate (HR). The drug is licensed for the treatment of angina and of systolic heart failure in sinus rhythm. At therapeutic doses the drug does not act on other cardiac ion currents and there appears to be no direct effects on myocardial contractility or relaxation, cardiac output, coronary haemodynamics, blood pressure or peripheral resistance in humans.

The molecular subunits of the I_f channel are the hyperpolarisation-activated cyclic-nucleotide gated (HCN) channels. Polymorphism in these proteins may explain some of the variation in resting HR in human populations. Several genetic alterations of the HCN4 channel gene have been reported to be associated with asymptomatic sinus bradycardia, sinus arrhythmia and atrial fibrillation (AF).

There is some evidence of more widespread I_f channel expression in disease states, and in other species, including in pulmonary vein myocytes in the rabbit.1 Ruairidh and colleagues2 raise the possibility that ivabradine may affect the electrical properties of pulmonary venous myocardium, increasing the risk of AF. They have conducted a meta-analysis of randomised trials with this drug, and report a 15% increase in the relative risk of AF. They postulate that there may be individual variation in susceptibility to this side effect, related to polymorphisms in HCN4 or other HR regulating genes.