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. / Doctor of Philosophy / The ability of the heart to function as a pump is dependent on the successful coordination of electrical activity throughout the heart. Disruptions to this intricate electrical system result in cardiac arrhythmias, which in turn prevent the heart from effectively perfusing the body with oxygenated blood. The present dissertation investigates ways in which we can modulate cell-cell communication within the heart, and how this may in turn influence disease states with a high propensity for arrhythmia. We show that reducing electrical coupling between cells using simple interventions like reducing serum sodium or increasing osmolarity may be a viable technique for diagnosing "concealed" disease states (i.e. disease states that are asymptomatic for much of a patient's life). We then explore ways in which elevated serum potassium, known as hyperkalemia, may alter the heart's ability to recover from electrical activation (repolarization). Finally, we show that the relationship between cardiac activation and repolarization is not as dependent on cell-cell communication as was once thought.
Taken together, this dissertation provides evidence that transiently disrupting cell-cell communication may hold promise for development of diagnostics for some congenital cardiac diseases, and yet does not appear to disrupt the relationship between electrical conduction and repolarization across the heart.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/115892 |
| Date | 27 July 2023 |
| Creators | Blair, Grace Anna |
| Contributors | Graduate School, Poelzing, Steven, Gourdie, Robert, Chappell, John Christopher, Lahmers, Sunshine M. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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