Myofilament calcium de-sensitization and contractile uncoupling prevent pause-triggered ventricular tachycardia in mouse hearts with chronic myocardial infarction.

Venkataraman R, Baldo MP, Hwang HS, Veltri T, Pinto JR, Baudenbacher FJ, Knollmann BC
J Mol Cell Cardiol. 2013 60: 8-15

PMID: 23570978 · PMCID: PMC3683590 · DOI:10.1016/j.yjmcc.2013.03.022

Myocardial infarction (MI) is a major risk for ventricular arrhythmia. Pause-triggered ventricular arrhythmia can be caused by increased myofilament Ca binding due to sarcomeric mutations or Ca-sensitizing compounds. Myofilament Ca sensitivity is also increased after MI. Here we hypothesize that MI increases risk for pause-triggered ventricular arrhythmias, which can be prevented by myofilament Ca-desensitization and contractile uncoupling. To test this hypothesis, we generated a murine chronic MI model using male B6SJLF1/J mice (n=40) that underwent permanent ligation of the left anterior descending coronary artery. 4 weeks post MI, cardiac structure, function and myofilament Ca sensitivity were evaluated. Pause-dependent arrhythmia susceptibility was quantified in isolated hearts with pacing trains of increasing frequency, followed by a pause and an extra stimulus. Coronary ligation resulted in a mean infarct size of 39.6±5.7% LV and fractional shortening on echocardiography was reduced by 40% compared to non-infarcted controls. Myofilament Ca sensitivity was significantly increased in post MI hearts (pCa50: Control=5.66±0.03; MI=5.84±0.05; P<0.01). Exposure to the Ca desensitizer/contractile uncoupler blebbistatin (BLEB, 3 μM) reduced myofilament Ca sensitivity of MI hearts to that of control hearts and selectively reduced the frequency of post-pause ectopic beats (MI 0.12±0.04 vs MI+BLEB 0.01±0.005 PVC/pause; P=0.02). BLEB also reduced the incidence of ventricular tachycardia in chronic MI hearts from 59% to 10% (P<0.05). We conclude that chronic MI hearts exhibit increased myofilament Ca sensitivity and pause-triggered ventricular arrhythmias, which can be prevented by blebbistatin. Decreasing myofilament Ca sensitivity may be a strategy to reduce arrhythmia burden after MI.

Copyright © 2013 Elsevier Ltd. All rights reserved.

MeSH Terms (12)

Animals Calcium Chronic Disease Disease Models, Animal Heterocyclic Compounds, 4 or More Rings Male Mice Myocardial Contraction Myocardial Infarction Myocardium Myofibrils Tachycardia, Ventricular

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