Abstract 13422: Novel Calcium Therapy for Preserving Cardiac Conduction During Myocardial Inflammation

Abstract

Introduction: Diseases like ischemia, myocarditis and heart failure are associated with myocardial inflammation and elevated cytokines such as Tumor Necrosis Factor α (TNFα). TNFα modulates gap junctional coupling (GJC) which may then alter cardiac conduction velocity (CV) . Yet, the relationship between TNFα and GJC is controversial. TNFα also modulates extracellular edema, and edema slows CV via an alternative mode of intercellular communication called ephaptic coupling (EpC). However, the relationship between TNFα, CV, GJC, and EpC remains poorly understood. Hypothesis: TNFα modulates cardiac conduction velocity (CV) by altering EpC. Methods: CV was quantified from optically mapped guinea pig ventricles. The width of the candidate cardiac ephapse called the perinexus (WP) was measured by transmission electron microscopy. Connexin43 (Cx43) expression, phosphorylation and distribution around the myocyte was determined by western blotting and confocal immunofluorescence. Results: TNFα anisotropically slowed conduction at 90 minutes relative to time controls (0.21±0.01 vs 0.24±0.01m/s). While TNFα increased WP and reduced EpC (24.2±1.12 vs 18.6±0.86 nm), TNFα did not significantly modify total Cx43 expression or phosphorylation, although Cx43 localization at the intercalated disc was reduced relative to time controls (81% vs 86%). Physiologically elevating calcium concentration in the presence of TNFα (TNFα + 2.5mM calcium) restored CV to time control values within 15 mins and further improved conduction above time control values at 90 mins. This CV increase correlated with restoration of WP to control values at both 0 and 90 mins. Interestingly, at 90 mins, TNFα + 2.5mM calcium also increased total Cx43 expression as well as intercalated disc localization relative to 90mins of TNFα alone(86%). Conclusions: TNFα reduces CV by increasing WP and redistributing Cx43. With TNFα, 2.5mM calcium acutely (15 mins) improves CV presumably by increasing EpC, and over 90 mins, improves CV above control values possibly by the increase in both EpC and GJC . Taken together, the data suggests that physiologic ionic modulation could be an effective therapy to prevent cardiac arrhythmias.