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

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