![]() ![]() 9 Hearts from dnNRSF‐Tg mice show increased expression of fetal type ion channel genes, including HCN2 and HCN4, which is consistent with what has been observed in other animal models of heart disease and in human failing hearts. 8 Transgenic mice that selectively express a dominant‐negative form of NRSF (dnNRSF) in their hearts (dnNRSF‐Tg) develop progressive cardiomyopathy leading to sudden arrhythmic death beginning at about 8 weeks of age. We recently reported that a transcriptional repressor, neuron‐restrictive silencer factor (NRSF, also named REST) is an important regulator of the fetal cardiac gene program. Nor has blockade of HCN channel been shown to prevent malignant arrhythmias or sudden death associated with heart failure independently of heart rate reduction. 3, 4, 5, 6, 7 Direct evidence showing the contribution of induced ventricular expression of HCN channels to enhanced myocardial arrhythmicity in vivo is lacking, however. 6 However, HCN channels, especially HCN2 and HCN4, are re‐expressed in hypertrophied and failing hearts in both rodents and humans, and the resultant increase in I f currents in ventricular myocytes is thought to provide an important trigger that initiates clinically significant arrhythmias in those hearts. ![]() ![]() 3, 4, 5 During development, HCN channels are abundantly expressed in the embryonic ventricle, but their expression progressively declines after birth, and is restricted to the conduction system in healthy adult hearts. 3 HCN channels (HCN1‐4) are also expressed in ventricular myocytes, where HCN2 is the dominant isoform, though expression of HCN channels in the healthy adult ventricular myocardium is generally much weaker than in the conduction system, so that I f currents are rarely detectable in normal ventricular myocytes. 2, 3 In the healthy adult heart, HCN channels are predominantly expressed in the conduction system, especially in the sinoatrial node, where HCN4 is the major isoform and controls cardiac rhythmicity. Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels comprise an ion channel family (HCN1‐4) that carries a current termed I f or I h, which has been recorded in both the heart and nervous system. 1 Thus, identification of potential therapeutic targets based on knowledge of the molecular mechanism underlying the enhanced arrhythmicity in failing hearts would be highly desirable. Indeed, as many as 50% of deaths among heart failure patients are sudden and unexpected, presumably caused by lethal arrhythmias. Stroke: Vascular and Interventional Neurologyĭespite recent progress, the efficacy of available pharmacological interventions aimed at preventing lethal arrhythmias associated with chronic heart failure remains limited.Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes. ![]() Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB). ![]()
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