Increased Expression of HCN Channels in the Ventricular Myocardium Contributes to Enhanced Arrhythmicity in Mouse Failing Hearts

Abstract

BackgroundThe efficacy of pharmacological interventions to prevent sudden arrhythmic death in patients with chronic heart failure remains limited. Evidence now suggests increased ventricular expression of hyperpolarization‐activated cation (HCN) channels in hypertrophied and failing hearts contributes to their arrythmicity. Still, the role of induced HCN channel expression in the enhanced arrhythmicity associated with heart failure and the capacity of HCN channel blockade to prevent lethal arrhythmias remains undetermined.Methods and ResultsWe examined the effects of ivabradine, a specific HCN channel blocker, on survival and arrhythmicity in transgenic mice (dnNRSF‐Tg) expressing a cardiac‐specific dominant‐negative form of neuron‐restrictive silencer factor, a useful mouse model of dilated cardiomyopathy leading to sudden death. Ivabradine (7 mg/kg per day orally) significantly reduced ventricular tachyarrhythmias and improved survival among dnNRSF‐Tg mice while having no significant effect on heart rate or cardiac structure or function. Ivabradine most likely prevented the increase in automaticity otherwise seen in dnNRSF‐Tg ventricular myocytes. Moreover, cardiac‐specific overexpression of HCN2 in mice (HCN2‐Tg) made hearts highly susceptible to arrhythmias induced by chronic β‐adrenergic stimulation. Indeed, ventricular myocytes isolated from HCN2‐Tg mice were highly susceptible to β‐adrenergic stimulation‐induced abnormal automaticity, which was inhibited by ivabradine.ConclusionsHCN channel blockade by ivabradine reduces lethal arrhythmias associated with dilated cardiomyopathy in mice. Conversely, cardiac‐specific overexpression of HCN2 channels increases arrhythmogenicity of β‐adrenergic stimulation. Our findings demonstrate the contribution of HCN channels to the increased arrhythmicity seen in failing hearts and suggest HCN channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

Effects of ivabradine and beta-blocker therapy on dobutamine-induced ventricular arrhythmias

“…In their study, ivabradine reduced lethal arrhythmias associated with dilated cardiomyopathy in mice, and beta-adrenergic stimulation conversely increased arrhythmogenecity [21]. Also, another study showed that I f current activity increases the pro-arrhythmogenic potential in the failing myocytes through prolongation of the repolarisation phase in ventricular action potentials [22].…”

“…Furthermore, Kuwabara et al [21] examined the effect of ivabradine on survival and arrhythmicity in transgenic mice, which is a useful mouse model of dilated cardiomyopathy leading to sudden death. In their study, ivabradine reduced lethal arrhythmias associated with dilated cardiomyopathy in mice, and beta-adrenergic stimulation conversely increased arrhythmogenecity [21].…”

Ectopic automaticity induced in ventricular myocytes by transgenic overexpression of HCN2

“…We also carried out a preliminary analysis of transgenic mice overexpressing HCN2 in their hearts (HCN2-Tg) and reported that they were vulnerable to β-adrenergic-induced abnormal electrical activity [10]. In the present study, we carried out a detailed analysis of the electrocardiographic and electrophysiological properties of single ventricular myocytes from HCN2-Tg mice.…”

“…We overexpressed mouse HCN2 cDNA in the hearts of C57BL/6 mice using the α-MHC promoter (HCN2-Tg) [10]. HCN2-Tg and their wildtype (WT) littermates were used while they were between 10 and 14 weeks of age.…”

Role of NRSF/REST in the Regulation of Cardiac Gene Expression and Function

“…26 The heart rates of dnNRSF-Tg mice are slower than those of wild-type mice. Moreover, at a dose of 7 mg · kg -1 · day -1 , ivabradine signifi- .…”