Ivabradine Protects Against Ventricular Arrhythmias in Acute Myocardial Infarction in the Rat

Ventricular arrhythmias are an important cause of mortality in the acute myocardial infarction (MI). To elucidate effect of ivabradine, pure heart rate (HR) reducing drug, on ventricular arrhythmias within 24h after non-reperfused MI in the rat. ECG was recorded for 24h after MI in untreated and ivabradine treated rats and episodes of ventricular tachycardia/fibrillation (VT/VF) were identified. Forty-five minutes and twenty-four hours after MI epicardial monophasic action potentials (MAPs) were recorded, cardiomyocyte Ca2+ handling was assessed and expression and function of ion channels were studied. Ivabradine reduced average HR by 17%. Combined VT/VF incidence and arrhythmic mortality were higher in MI versus MI+Ivabradine rats. MI resulted in (1) increase of Ca2+ sensitivity of ryanodine receptors 24h after MI; (2) increase of HCN4 expression in the left ventricle (LV) and funny current (I-F) in LV cardiomyocytes 24h after MI, and (3) dispersion of MAP duration both 45min and 24h after MI. Ivabradine partially prevented all these three potential proarrhythmic effects of MI. Ivabradine is antiarrhythmic in the acute MI in the rat. Potential mechanisms include prevention of: diastolic Ca2+-leak from sarcoplasmic reticulum, upregulation of I-F current in LV and dispersion of cardiac repolarization. Ivabradine could be an attractive antiarrhythmic agent in the setting of acute MI. J. Cell. Physiol. 229: 813-823, 2014. (c) 2013 Wiley Periodicals, Inc.