Myofilament Calcium De-sensitization and Contractile Uncoupling with Blebbistatin Prevents Ventricular Tachycardia in Mouse Hearts Four Weeks after Myocardial Infarction

Abstract

Background We recently demonstrated that pharmacologic Ca 2+ sensitization increased postpause ventricular tachycardia (VT) in the setting of acute myocardial infarction (MI). Similarly, chronic infarcted hearts show increased myofilament Ca 2+ sensitivity and high arrhythmogenic activity. We hypothesized that myofilament desensitization may reduce the incidence of pause-induced arrhythmias in a mouse model of chronic MI. Methods Male B6SJLF1/J mice (n = 14) underwent permanent ligation of the left descending coronary artery. Four weeks post MI, cardiac structure, function, and myofilament Ca 2+ sensitivity were evaluated. To measure arrhythmia susceptibility, isolated hearts underwent a ventricular pacing challenge consisting of pacing trains of increasing frequency, followed by a pause and an extrastimulus. Results Coronary ligation resulted in a mean infarct size of 39.6 ± 5.7% LV, and fractional shortening on echocardiography was reduced by 30.6 ± 2.0% compared with noninfarcted controls. Myofilament Ca 2+ sensitivity was significantly increased in post MI hearts (pCa 50 : control=5.66 ± 0.03; MI=5.84 ± 0.05, P 2+ desensitizer/contractile uncoupler blebbistatin (BLEB, 3 μM) drastically reduced the frequency of postpause ectopic beats (MI 0.24 ± 0.08 vs MI+BLEB 0.02 ± 0.01 PVC/pause, P = .02) but had no effect on ectopy during the pacing trains. BLEB also reduced the incidence of VT (Figure). Conclusions Myofilament Ca 2+ desensitization in chronic infarcted hearts reduces the incidence of postpause arrhythmias. Decreasing myofilament Ca 2+ sensitivity may be a new therapeutic strategy to reduce arrhythmia burden after MI.