UC San Diego

It is well established that cardiac electrophysiology can be altered by changes in mechanical loading of the heart, through processes of mechanoelectric feedback (MEF). However, the cellular mechanisms and particular strain dependence of these processes have not been determined, partly due to the difficulty in assessing complex mechanical and electrophysiological phenomena in active cardiac tissue, and also to challenges in linking observations in single cells to organ-level effects. To circumvent these challenges, there is need for electrophysiological studies multicellular platforms with capability for precise, physiologic mechanical loading. In this dissertation, biaxial stretch of micropatterned cardiomyocyte preparations is employed in conjunction with electrophysiological measurement, particularly via optical mapping of changes in membrane potential as well as by patch clamp recording, to discover how mechanoelectric interactions at the cell level may give rise to stretch- dependent alterations in cardiac conduction. Chapter 1 introduces cardiac mechanoelectric feedback starting with the clinical and tissue-scale observations, describing candidate cellular mechanisms and discussing the need for multicellular experiments to bridge the gap between single -cell and whole-organ experiments. Chapter 2 describes a multicellular system for testing electrophysiology under biaxial loading, and reports data from a range of stretch magnitudes. Chapter 3 probes cellular mechanisms for conduction slowing at large physiologic loads, and demonstrates that slowing is due to caveolae-dependent increases in cell membrane capacitance. Chapter 4 utilizes the system to test a transgenic murine model of clinical arrhythmia for conduction block and interbeat variability, demonstrating the capability of the system in examining multicellular electrophysiological phenomena that develop on a spatial scale reflecting human tissue