Attenuating loss of cardiac conduction during no-flow ischemia through changes in perfusate sodium and calcium

Abstract

Myocardial ischemia leads to conduction slowing, cell-to-cell uncoupling, and arrhythmias. We previously demonstrated that varying perfusate sodium (Na⁺) and calcium (Ca²⁺) attenuates conduction slowing and arrhythmias during simulated ischemia with continuous perfusion. Cardioprotection was selectively associated with widening of the perinexus, a gap junction adjacent nanodomain important to ephaptic coupling. It is unknown whether perfusate composition affects the perinexus or ischemic conduction during nonsimulated ischemia, when coronary flow is reduced or halted. We hypothesized that altering preischemic perfusate composition could facilitate perinexal expansion and attenuate conduction slowing during global ischemia. To test this hypothesis, ex vivo guinea pig hearts (n = 49) were Langendorff perfused with 145 or 153 mM Na⁺ and 1.25 or 2.0 mM Ca²⁺ and optically mapped during 30 min of no-flow ischemia. Altering Na⁺ and Ca²⁺ did not substantially affect baseline conduction. Increasing Na⁺ and decreasing Ca²⁺ both lowered pacing thresholds, whereas increasing Ca²⁺ narrowed perinexal width (W_p). A least squares mean estimate revealed that reduced perfusate Na⁺ and Ca²⁺ resulted in the most severe conduction slowing during ischemia. Increasing Na⁺ alone modestly attenuated conduction slowing, yet significantly delayed the median time to conduction block (10 to 16 min). Increasing both Na⁺ and Ca²⁺ selectively widened W_p during ischemia (22.7 vs. 15.7 nm) and attenuated conduction slowing to the greatest extent. Neither repolarization nor levels of total or phosphorylated connexin43 correlated with conduction slowing or block. Thus, perfusate-dependent widening of the perinexus preserved ischemic conduction and may be an adaptive response to ischemic stress.NEW & NOTEWORTHY Conduction slowing during acute ischemia creates an arrhythmogenic substrate. We have shown that extracellular ionic concentrations can alter conduction by modulating ephaptic coupling. Here, we demonstrate increased extracellular sodium and calcium significantly attenuate conduction slowing during no-flow ischemia. This effect was associated with selective widening of the perinexus, an intercalated disc nanodomain and putative cardiac ephapse. These findings suggest that acute changes in ephaptic coupling may serve as an adaptive response to ischemic stress.

Keywords: arrhythmia; calcium; conduction; ischemia; sodium.