Referenced in: none

Automatically associated channels: HCN2

Title: Ectopic automaticity induced in ventricular myocytes by transgenic overexpression of HCN2.

Authors: Kensuke Oshita, Masayuki Itoh, Shingo Hirashima, Yoshihiro Kuwabara, Keiko Ishihara, Koichiro Kuwahara, Kazuwa Nakao, Takeshi Kimura, Kei-ichiro Nakamura, Kazuo Ushijima, Makoto Takano

Journal, date & volume: J. Mol. Cell. Cardiol., 2015 Mar , 80, 81-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25562801

Abstract
Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) are expressed in the ventricles of fetal hearts but are normally down-regulated as development progresses. In the hypertrophied heart, however, these channels are re-expressed and generate a hyperpolarization-activated, nonselective cation current (Ih), which evidence suggests may increase susceptibility to arrhythmia. To test this hypothesis, we generated and analyzed transgenic mice overexpressing HCN2 specifically in their hearts (HCN2-Tg). Under physiological conditions, HCN2-Tg mice exhibited no discernible abnormalities. After the application of isoproterenol (ISO), however, ECG recordings from HCN2-Tg mice showed intermittent atrioventricular dissociation followed by idioventricular rhythm. Consistent with this observation, 0.3 μmol/L ISO-induced spontaneous action potentials (SAPs) in 76% of HCN2-Tg ventricular myocytes. In the remaining 24%, ISO significantly depolarized the resting membrane potential (RMP), and the late repolarization phase of evoked action potentials (APs) was significantly longer than in WT myocytes. Analysis of membrane currents revealed that these differences are attributable to the Ih tail current. These findings suggest HCN2 channel activity reduces the repolarization reserve of the ventricular action potential and increases ectopic automaticity under pathological conditions such as excessive β-adrenergic stimulation.