PubMed 22652004

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: HCN1 , HCN2 , HCN3 , HCN4

Title: Ventricular HCN channels decrease the repolarization reserve in the hypertrophic heart.

Authors: Florian Hofmann, Larissa Fabritz, Juliane Stieber, Joachim Schmitt, Paulus Kirchhof, Andreas Ludwig, Stefan Herrmann

Journal, date & volume: Cardiovasc. Res., 2012 Aug 1 , 95, 317-26

PubMed link:

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 I(f) which has been hypothesized to contribute to arrhythmogenesis in the hypertrophied ventricle.We used transverse aortic constriction in mice to induce ventricular hypertrophy. This resulted in an increased number of I(f) positive ventricular myocytes as well as a strongly enhanced and accelerated I(f) when compared with controls. Of the four HCN (hyperpolarization-activated cyclic nucleotide-gated channels) isoforms mediating I(f), 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 I(f) completely. The lack of I(f) 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.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 I(f) and a diminished repolarization reserve in cardiac hypertrophy.