Ventricular HCN channels decrease the repolarization reserve in the hypertrophic heart

Abstract

Aims: Cardiac hypertrophy is accompanied by reprogramming of gene expression, where the altered expression of ion channels decreases electrical stability and increases the risk of life-threatening arrhythmias. However, the underlying mechanisms are not fully understood. Here, we analysed the role of the depolarizing current If which has been hypothesized to contribute to arrhythmogenesis in the hypertrophied ventricle. Methods and results: We used transverse aortic constriction in mice to induce ventricular hypertrophy. This resulted in an increased number of If positive ventricular myocytes as well as a strongly enhanced and accelerated If when compared with controls. Of the four HCN (hyperpolarization-activated cyclic nucleotide-gated channels) isoforms mediating If, HCN2 and HCN4 were the predominantly expressed subunits in healthy as well as hypertrophied hearts. Unexpectedly, only the HCN1 transcript was significantly upregulated in response to hypertrophy. However, the combined deletion of HCN2 and HCN4 disrupted ventricular If completely. The lack of If in hypertrophic double-knockouts resulted in a strong attenuation of pro-arrhythmogenic parameters characteristically observed in hypertrophic hearts. In particular, prolongation of the action potential was significantly decreased and lengthening of the QT interval was reduced. Conclusions: We suggest that the strongly increased HCN channel activity in hypertrophied myocytes prolongs the repolarization of the ventricular action potential and thereby may increase the arrhythmogenic potential. Our results provide for the first time a direct link between an upregulation of ventricular If and a diminished repolarization reserve in cardiac hypertrophy. © The Author 2012.