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

Abstract

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.

• Authors: Raghav Venkataraman, Marcelo Perim Baldo, Hyun Seok Hwang, Tiago Veltri, Jose Renato Pinto, Franz J Baudenbacher, Björn C Knollmann
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 60 Pg. 8-15 (Jul 2013) ISSN: 1095-8584 [Electronic] England
• PMID: 23570978 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Heterocyclic Compounds, 4 or More Rings
• blebbistatin
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Chronic Disease
• Disease Models, Animal
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Male
• Mice
• Myocardial Contraction
• Myocardial Infarction (metabolism, pathology)
• Myocardium (metabolism, pathology)
• Myofibrils (metabolism, pathology)
• Tachycardia, Ventricular (metabolism, pathology)