Myofilament Calcium Sensitization Causes Pause-Dependent Ventricular Ectopy in Mouse Hearts with Acute and Chronic Myocardial Infarction

Abstract

Background. Increased myofilament Ca2+ sensitivity has been associated with cardiac arrhythmias in several cardiomyopathies. During the course of myocardial infarction (MI), myofilament Ca2+ sensitivity is reduced during acute ischemia but increases in the chronic stage. Thus, we aimed to compare the arrhythmogenic patterns during an acute MI or after chronic MI in mice.Methods. In theacute MI group, isolated hearts were investigated 15 min after left anterior descending (LAD) coronary artery ligation. In the chronic MI group, hearts were harvested 4 weeks after LAD ligation. To measure arrhythmia susceptibility, isolated hearts from both groups underwent a ventricular pacing challenge consisting of pacing trains of increasing frequency, followed by a pause and an extra stimulus, in the presence or in the absence of the Ca2+ sensitizer EMD 57033 (3 µM) or the Ca2+ de-sensitizer and contractile uncoupler Blebbistatin (3 µM).Results. Acute MI caused frequent ventricular ectopyduring the steady-state pacing, but not after a pause. Acute MI hearts became susceptible to post-pause ectopy only after Ca2+ sensitization with EMD. In contrast, chronic MI hearts exhibited only very modest ventricular ectopy during the pacing trains (33.3%, p<0.01 vs acute MI), but consistently exhibited ectopy after a pause (91.6%), which was prevented by Ca2+ de-sensitization with blebbistatin (10%, p<0.05). Compared to acute MI, the incidence of ventricular tachycardia (VT) was significantly increased in chronic MI, which could be prevented by blebbistatin (MI: 70%, MI+Bleb: 10%, p<0.05, n=10 per group).Conclusion. Different patterns of arrhythmia induction are involved in acute and chronic MI hearts. Our data suggest that increased myofilament Ca2+ sensitivity strongly promotes ventricular ectopy and VT's after a pause, but does not affect ectopy during regular pacing.