Optical Assessment and Modulation of Electrophysiology in Perfused Hearts
Open Access DepositedAlmost 50% of adults in the US are affected by some form of heart disease, including arrhythmia. The objective of this dissertation was to identify new ways to treat heart disease by investigating how both disease and therapy alter cardiac electrophysiology.Atrial fibrillation (AF) is a prevalent arrhythmia that increases the risk of stroke and heart failure. Persistent AF is treated using ablation therapy yet conduction gaps between ablation lesions are difficult to detect and require repeat ablation procedures. We tested a novel pulsed field ablation (PFA) catheter with the ability to create lesions while also measuring NADH fluorescence to assess the formation of lesion. Clinically relevant PFA energies were applied to perfused rabbit hearts to create sets of lesions that were optically mapped to track changes in intracellular Ca2+ and NADH fluorescence as lesions developed over an hour. Lesions had high baseline Ca2+ but low Ca2+ transient amplitude and low NADH at their centers, indicating tissue damage. Next, we studied autonomic conflict by measuring changes in heart rate during sudden simultaneous activation of cardiac sympathetic and parasympathetic autonomic pathways. A custom microLED photostimulated sympathetic neurons in perfused hearts from mice that expressed channelrhodopsin in sympathetic neurons. Heart rate increases were faster and more controlled during photostimulation than that of wild-type mice after administering norepinephrine. Simultaneous autonomic activation was tested with increasing doses of acetylcholine (ACh) added to the perfusate. High doses of ACh significantly diminished heart rate increases during photostimulation and induced atrioventricular block at lower doses than without sympathetic activation, demonstrating that arrhythmias during autonomic conflict could be caused by severe AV block. Multiple sclerosis (MS) is a complex autoimmune disease with no cure. Although inflammation is a cause of cardiac disease, it is generally unknown whether MS alters cardiac electrophysiology. We tested the hypothesis that the experimental autoimmune encephalomyelitis (EAE) mouse model of MS will exhibit altered electrophysiological characteristics, specifically increased LV action potential duration. This is supported by recent echocardiography data showing dysfunction in EAE mice. To interrogate this dysfunction, disease controls (CFA) and EAE mice were optically mapped to measure differences in Ca2+ transient duration (CTD) and action potential duration (APD). Male EAE mice presented no differences in CTD or APD compared to CFA. Female EAE mice presented elongated APD but no significant difference in CTD compared to CFA. This preliminary data suggests that female EAE mice may exhibit an arrhythmogenic phenotype of longer APD, possibly caused by a reduction in repolarizing potassium currents.
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