Ventricular HCN channels decrease the repolarization reserve in the hypertrophic heart

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

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)


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 I(f) 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 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.

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 I(f) and a diminished repolarization reserve in cardiac hypertrophy.

Original languageEnglish
Pages (from-to)317-26
Number of pages10
JournalCardiovascular Research
Issue number3
Publication statusPublished - 1 Aug 2012


  • Action Potentials
  • Animals
  • Aorta
  • Arrhythmias, Cardiac
  • Cyclic Nucleotide-Gated Cation Channels
  • Disease Models, Animal
  • Electrocardiography
  • Gene Expression Regulation
  • Heart Ventricles
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Hypertrophy, Left Ventricular
  • Ion Channels
  • Ligation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocytes, Cardiac
  • Potassium Channels
  • RNA, Messenger
  • Time Factors
  • Ventricular Remodeling


Dive into the research topics of 'Ventricular HCN channels decrease the repolarization reserve in the hypertrophic heart'. Together they form a unique fingerprint.

Cite this