The Influence of Calcium Handling Variability on Cardiac Electrophysiology in Ventricular and Atrial Myocytes

Excitation-contraction coupling (ECC) in cardiomyocytes is responsible for the heartbeat through the cycling of intracellular Ca2+. The regulation of Ca2+ fluxes into and out of the bulk cytoplasm and sarcoplasmic reticulum (SR) through Ca2+ transporters (ryanodine receptors, RyR; SR Ca2+-ATPase pump, SERCA2a; Na+-Ca2+ exchanger, NCX; and L-type Ca2+ channels, LTCCs) is critical to ensuring a stable cardiac output to meet the body’s dynamic physiological demands. Variability in this Ca2+ cycling plays an important role in determining whole-cell electrophysiological behaviour and is observed to increase in heart failure (HF) and other pathologies. Advances in microscopy have evidenced sub-cellular heterogeneity in the expression of ECC channels which may explain these variabilities; however, correlating this underlying structure to function presents a major research challenge. Furthermore, the spatial heterogeneity in channel expression has not yet been systematically quantified. Image-based models present the only systematic method to directly relate spatial Ca2+ to underlying channel expression with total control. This thesis describes the development of one such novel approach to quantify the spatial profile of heterogeneity, and furthermore, correlate sub-cellular heterogeneity in channel expression and its functional implications. This novel approach was applied to quantify adaptions to SERCA2a expression in right-ventricular (RV) HF to inform a comprehensive image-based modelling study aiming to predict the functional implications of heterogeneous SERCA2a expression and its remodelling in RV-HF. This provides novel insight into the role of heterogeneous SERCA2a in ECC and arrhythmogenesis. Single-source, congruent models offer an excellent alternative approach to studying Ca2+ variability. Rabbit models are often used for studying abnormal Ca2+-related behaviours due to their electrophysiological similarities to human, and reasonable cost; however, no such model has been developed in rabbit. This thesis presents a novel, lab-specific, congruent model of rabbit atrial electrophysiology developed with the purpose of elucidating the impact of Ca2+ variability on whole-cell electrophysiology.