Preclinical results with I(f) current inhibition by ivabradine.

Ivabradine, a highly selective I(f) current inhibitor acting directly on the sinoatrial node, induces a rapid, sustained and dose-dependent reduction of heart rate at rest and during exercise, without significant effects on atrioventricular conduction, left ventricular (LV) contraction-relaxation or vascular tissues. These properties, associated with an improvement in LV loading related to bradycardia, resulted in an increase in stroke volume and preservation of cardiac output at rest and during exercise. Reducing myocardial oxygen consumption and improving oxygen supply, ivabradine reduced the severity of ischaemia and associated regional contractile dysfunction of the stunned myocardium. Long-term administration of ivabradine in rats with chronic heart failure improved cardiac haemodynamics associated with a progressive remodelling of LV structure. In dyslipidaemic mice, ivabradine prevented the renal and cerebrovascular endothelial dysfunction associated with atherosclerosis. These preclinical data suggest that long-term reduction in heart rate with ivabradine might interact with multiple a priori unexpected mechanisms involved in cardiac and vascular remodelling processes associated with chronic heart diseases.