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

<jats:sec xml:lang="en"> <jats:title>Background</jats:title> <jats:p xml:lang="en"> The 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 ( <jats:styled-content style="fixed-case">HCN</jats:styled-content> ) channels in hypertrophied and failing hearts contributes to their arrythmicity. Still, the role of induced <jats:styled-content style="fixed-case">HCN</jats:styled-content> channel expression in the enhanced arrhythmicity associated with heart failure and the capacity of <jats:styled-content style="fixed-case">HCN</jats:styled-content> channel blockade to prevent lethal arrhythmias remains undetermined. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Methods and Results</jats:title> <jats:p xml:lang="en"> We examined the effects of ivabradine, a specific <jats:styled-content style="fixed-case">HCN</jats:styled-content> channel blocker, on survival and arrhythmicity in transgenic mice (dn <jats:styled-content style="fixed-case">NRSF</jats:styled-content> ‐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 dn <jats:styled-content style="fixed-case">NRSF</jats:styled-content> ‐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 dn <jats:styled-content style="fixed-case">NRSF</jats:styled-content> ‐Tg ventricular myocytes. Moreover, cardiac‐specific overexpression of <jats:styled-content style="fixed-case">HCN</jats:styled-content> 2 in mice ( <jats:styled-content style="fixed-case">HCN</jats:styled-content> 2‐Tg) made hearts highly susceptible to arrhythmias induced by chronic β‐adrenergic stimulation. Indeed, ventricular myocytes isolated from <jats:styled-content style="fixed-case">HCN</jats:styled-content> 2‐Tg mice were highly susceptible to β‐adrenergic stimulation‐induced abnormal automaticity, which was inhibited by ivabradine. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Conclusions</jats:title> <jats:p xml:lang="en"> <jats:styled-content style="fixed-case">HCN</jats:styled-content> channel blockade by ivabradine reduces lethal arrhythmias associated with dilated cardiomyopathy in mice. Conversely, cardiac‐specific overexpression of <jats:styled-content style="fixed-case">HCN</jats:styled-content> 2 channels increases arrhythmogenicity of β‐adrenergic stimulation. Our findings demonstrate the contribution of <jats:styled-content style="fixed-case">HCN</jats:styled-content> channels to the increased arrhythmicity seen in failing hearts and suggest <jats:styled-content style="fixed-case">HCN</jats:styled-content> channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure. </jats:p> </jats:sec>