title: 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.affiliation: Department of Biomedical Engineering and Physics, Vanderbilt University, Nashville, TN 37232-0575, USA.
authors.forename: Raghav
authors.initials: R
authors.lastname: Venkataraman
authors.forename: Marcelo Perim
authors.initials: MP
authors.lastname: Baldo
authors.forename: Hyun Seok
authors.initials: HS
authors.lastname: Hwang
authors.forename: Tiago
authors.initials: T
authors.lastname: Veltri
authors.forename: Jose Renato
authors.initials: JR
authors.lastname: Pinto
authors.forename: Franz J
authors.initials: FJ
authors.lastname: Baudenbacher
authors.forename: Björn C
authors.initials: BC
authors.lastname: Knollmann
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002908:Chronic Disease; D004195:Disease Models, Animal; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D008297:Male; D051379:Mice; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009210:Myofibrils / Q000378:metabolism* / Q000473:pathology; D017180:Tachycardia, Ventricular / Q000378:metabolism* / Q000473:pathology
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; C472645:blebbistatin; D002118:Calcium