Abstract 17269: Increased Myofilament Ca2+ sensitivity Causes Pacing-Rate Dependent QRS Widening and Conduction Slowing Associated with Rapid Connexin43 De-phosphorylation
Carriers of the troponin T (TnT) I79N mutation linked to familial hypertrophic cardiomyopathy often die of sudden cardiac death at a young age. Mice expressing TnT-I79N have structurally normal hearts, but are susceptible to ventricular tachycardia (VT). In isolated hearts reentrant activation patterns can be reproduced by treating non-transgenic hearts (NTG) with the myofilament Ca sensitizer EMD57033 and can be prevented by reducing the increased Ca sensitivity to control level. We hypothesized that slow excitation spread (conduction velocity (CV)) due to altered regulation of the gap junction protein connexin43 (Cx43) generates a substrate able to sustain reentry.
Results: In vivo programmed intraventricular stimulation frequently induced episodes of VT in TnT-I79N mice (88% vs 27% in control, n=8–11, p<0.05) that were also longer than in control (1.9±1.5 vs 0.5±0.8s), but baseline electrophysiological parameters were not different. Similarly, under baseline conditions QRS duration was unchanged in isolated perfused hearts with increased myofilament Ca sensitivity (TnT-I79N, EMD-treated) compared to control (TnT-WT, NTG). However, with fast pacing (12+Hz), but not slow pacing (8Hz), QRS progressively widened only in hearts with increased Ca sensitivity (up to 177±17%, p<0.05 within 13 min). Optical mapping confirmed CV slowing (lateral CV −21.4±4%, n=11, p<0.05) and demonstrated increased anisotropy ratio in all Ca sensitized hearts. The QRS widening was highly predictive of VT induction (80% VT at 160±13% QRS, n=10). In EMD-treated hearts QRS widening was reversible within ∼8 min, indicating that fast pacing had a lasting effect. Consistent with the functional data, no difference in Cx43 expression or phosphorylation was found under baseline conditions, but relative Cx43 phosphorylation (measured as gel-shift isoform ratio) rapidly decreased during fast pacing in all Ca sensitized hearts compared to control (p<0.05). This shift was prevented when myofilament Ca sensitivity was decreased.
Conclusion: Rapid Cx43 de-phosphorylation associated with QRS widening and CV slowing during high heart rates may contribute to arrhythmogenesis in hypertrophic cardiomyopathy and other conditions with increased myofilament Ca sensitivity.
- © 2010 by American Heart Association, Inc.