Advisory Committee Chair
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
The mechanism of triggered arrhythmia generation involves inappropriate diastolic calcium (Ca2+) releases from the sarcoplasmic reticulum that promote membrane depolarization when the released Ca2+ is transported out of the cardiomyocyte via the sodium Ca2+ exchanger (NCX). If membrane depolarization is large enough, these events can trigger an ectopic action potential. However, it is not fully understood what physiological factors facilitate triggered events at the tissue level. Pannexin 1 (Px1), a large transmembrane conductance channel, can be activated by various stimuli including increases in intracellular Ca2+. We predict that during diastolic Ca2+ releases, Px1 becomes activated and together with the NCX, facilitates membrane depolarization that leads to an action potential. We hypothesize that reducing Px1 channel function will reduce the occurrence of triggered arrhythmia in vivo. In this study, we utilized a mouse model with high susceptibility for triggered arrhythmias, the calsequestrin 2 null mouse (Casq2-/-). Heart rhythm was recorded in anesthetized Casq2-/- mice challenged with the β agonist isoproterenol and in telemetry implanted mice exercised on a treadmill (stress test). Results of this study suggest that pharmacological inhibition and the loss of Px1 in Casq2-/- mice is protective against triggered arrhythmias. For assessing Px1 channel contribution to arrhythmogenesis in the context of myocardial ischemia, we developed and implemented a method for assessing benefits of Px1 ablation against arrhythmia post-infarction and monitored consequent electrophysiology, mechanical function, as well as reported effects of Px1 loss on gross histology post-infarction. Px1 ablation in the context of myocardial infarction resulted in the reduction of triggered arrhythmia. These findings together reveal Px1 as a novel and relevant therapeutic target for reducing arrhythmogenesis in the context of inherited and ischemic arrhythmogenic disease settings.
Salzer, Grace Elizabeth, "Pannexin 1 Channel Inhibition to Prevent Triggered Arrhythmia" (2019). All ETDs from UAB. 2891.