Heart-specific overexpression of the human short CLC-3 chloride channel isoform limits myocardial ischemia-induced ERP and QT prolongation

Int J Cardiol. 2016 Jul 1:214:218-24. doi: 10.1016/j.ijcard.2016.03.191. Epub 2016 Mar 30.

Abstract

Introduction: Ischemia causes myocardial infarction and arrhythmias. Up-regulation of cardiac CLC-3 chloride channels is important for ischemic preconditioning-induced second-window protection against myocardial infarction. But its consequences in ischemia-induced electrical remodeling are still unknown.

Methods: The recently-characterized heart-specific overexpression of human short CLC-3 isoform (hsCLC-3(OE)) mice was used to study the effects of CLC-3 up-regulation on cardiac electrophysiology under ischemia/reperfusion conditions. In vivo surface electrocardiography (ECG) and intracardiac electrophysiology (ICEP) were used to compare the electrophysiological properties of age-matched wild-type (Clcn3(+/+)) and hsCLC-3(OE) mice under control and myocardial ischemia-reperfusion conditions.

Results: QT and QTc intervals of hsCLC-3(OE) mice were significantly shorter than those of Clcn3(+/+) mice under control, ischemia and reperfusion conditions. In the ICEP, ventricular effective refractory period (VERP) of hsCLC-3(OE) mice (26.7±1.7ms, n=6) was significantly shorter than that of Clcn3(+/+) mice (36.9±2.8ms, n=8, P<0.05). Under ischemia condition, both VERP (19.8±1.3ms) and atrial effective refractory period (AERP, 34.8±2.5ms) of hsCLC-3(OE) mice were significantly shorter than those of Clcn3(+/+) mice (35.2±3.0ms and 45.8±1.6ms, P<0.01, respectively). Wenckebach atrioventricular nodal block point (AVBP, 91.13±4.08ms) and 2:1 AVBP (71.3±3.8ms) of hsCLC-3(OE) mice were significantly shorter than those of Clcn3(+/+) mice (102.0±2.0ms and 84.1±2.8ms, P<0.05, respectively). However, no differences of ICEP parameters between hsCLC-3(OE) and Clcn3(+/+) mice were observed under reperfusion conditions.

Conclusion: Heart-specific overexpression of hsCLC-3 limited the ischemia-induced QT and ERP prolongation and postponed the advancements of Wenckebach and 2:1 AVBP. CLC-3 up-regulation may serve as an important adaptive mechanism against myocardial ischemia.

Keywords: Arrhythmia; Chloride channels; ECG; Electrophysiology; Ion channels; Ischemia; Torsade de pointes.

MeSH terms

  • Animals
  • Chloride Channels / metabolism*
  • Disease Models, Animal
  • Electrocardiography
  • Electrophysiologic Techniques, Cardiac
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Myocardial Ischemia / diagnostic imaging
  • Myocardial Ischemia / metabolism*
  • Myocardial Ischemia / physiopathology
  • Myocardium / metabolism*
  • Protein Isoforms / metabolism
  • Up-Regulation

Substances

  • Chloride Channels
  • ClC-3 channel
  • Protein Isoforms