Investigating the coordination of cardiac conduction and repolarization in ventricular myocardium
Aberrations in conduction or repolarization are established prerequisites for arrhythmogenesis. The following dissertation investigates how reducing either ephaptic (EpC) or gap junctional (GJ) coupling between cardiomyocytes can modulate cardiac conduction, repolarization, or the relationship between these two phenomena. Our lab has previously demonstrated that EpC can be modified in the ventricular epicardium using ionic and osmotic challenges to the Langendorff-perfused heart. In the first series of experiments, we show that reducing EpC via treatment with mannitol or hyponatremia can unmask conduction deficits that are otherwise below the resolution of detection in Scn5a+/- mice. Interestingly, we also observe that combination of the two treatments resolves severe conduction delay due to hyponatremia in the heterozygous animal. These data suggest it may be valuable to pursue the use of mannitol or hyponatremia as novel diagnostics for sodium channel loss of function diseases. The importance of extracellular perfusate is also highlighted by the second investigation, which evaluates how sodium and calcium concentration modulate repolarization in the context of hyperkalemia, a common comorbidity of hospitalized patients that increases the risk of arrhythmia. Calcium may potentially play a role in modulating APD adaptation to pacing rate in the context of this disease state, though more research is needed to clarify the exact mechanism of this effect. Finally, we investigate the relationship between conduction and repolarization in the epicardium, and conclude that this relationship does not appear to be dictated by the degree of cell-cell coupling in the myocardium, but instead is driven by endogenous gradients of action potential duration within the tissue. Taken together, these data demonstrate ways in which both conduction and repolarization are sensitive to modulations of EpC, though we also find that the relationship between these two phenomena is not influenced by such changes in electrical coupling.