Background: Cardiac voltage-gated sodium channel gain-of-function prolongs repolarization in the Long-QT Syndrome Type 3 (LQT3). Previous studies suggest that narrowing the perinexus within the intercalated disc, leading to rapid sodium depletion, attenuates LQT3-associated action potential duration (APD) prolongation. However, it remains unknown whether extracellular sodium concentration modulates APD prolongation during sodium channel gain-of-function. We hypothesized that elevated extracellular sodium concentration and widened perinexus synergistically prolong APD in LQT3. Methods and Results: LQT3 was induced with anemone toxin type II (ATXII) in Langendorff-perfused guinea pig hearts (n=20). Sodium concentration was increased from 145 to 160 mM. Perinexal expansion was induced with mannitol or the sodium channel β1-subunit adhesion domain antagonist (βadp1). Epicardial ventricular action potentials were optically mapped. Individual and combined effects of varying clefts and sodium concentrations were simulated in a computational model. With ATXII, both mannitol and βadp1 significantly widened the perinexus and prolonged APD, respectively. The elevated sodium concentration alone significantly prolonged APD as well. Importantly, the combination of elevated sodium concentration and perinexal widening synergistically prolonged APD. Computational modeling results were consistent with animal experiments. Conclusions: Concurrently elevating extracellular sodium and increasing intercalated disc edema prolongs repolarization more than the individual interventions alone in the LQT3. This synergistic effect suggests an important clinical implication that hypernatremia in the presence of cardiac edema can markedly increase LQT3-associated APD prolongation. Therefore, this is the first study to provide evidence of a tractable and effective strategy to mitigate LQT3 phenotype by managing patient sodium levels and preventing cardiac edema.
Age-Dependent Intercalated Disc Perinexal Narrowing Conceals Long-Qt Syndrome Type 3 Phenotype
