Remodeling of the heart following myocardial infarction involves the formation of scar tissue, in which myofibroblasts, an activated and differentiated form of fibroblasts, play an active and major role. This project focuses on the nature of cellular-level interactions between myofibroblasts and myocytes that can contribute to an arrhythmogenic substrate. Until recently, cardiac myofibroblasts were believed to be electrically inert, acting as passive insulators between myocytes. However, a concept that is gaining wide acceptance is that myofibroblasts can couple electrically to myocytes, thereby providing an electrical load that can mediate conduction velocity in the myocardium. Nevertheless, the existence of such functional electrical coupling remains controversial. The commonly observed close proximity of myofibroblast and myocyte membranes suggests that heterocellular communication through other signaling mechanisms is possible. Based on extensive published and preliminary results obtained by the Investigators, this project will test the hypothesis that combined mechanical and electrical interactions between myofibroblasts and myocytes is an important mechanism that leads to conduction slowing and arrhythmia. The central postulate is that these interactions arise from bidirectional tugging forces exerted between myofibroblast and myocyte that result in the activation of mechanosensitive ion channels in either cell that diminish the excitability of the myocyte, slow conduction and increase the incidence of arrhythmia. This project will couple advanced biophysical and electrophysiological techniques with multistate experimental preparations ranging from single cell to tissue slice. It will be a joint effort among three Investigators with expertise in cardiac electrophysiology, optical mapping, patterned cell growth, magnetism, microfabrication, cell mechanics, mechanotransduction, cell biology and cell-cell signaling. The project has three complementary and interconnected Aims.
Aim 1 investigates the activation of myofibroblast contraction and its influence on heterocellular coupling, on myocyte excitability, contraction and conduction, and on tissue-scale electrophysiology. Conversely, Aim 2 examines the reciprocal process in which myocyte contraction influences heterocellular coupling, myofibroblast force generation, and tissue-scale electrophysiology.
Aim 3 studies in greater detail the formation, stabilization and numbers of heterocellular adherents and gap junctions in a tissue context. The outcome of this project will be the acquisition of key information to formulate conceptual models of electromechanical signaling between myofibroblasts and myocytes.
Cardiac arrhythmias arising from heart disease and myocardial infarction are a major health concern affecting millions of individuals in the United States. This research will apply recent advances in electrophysiology, microfabrication and magnetic nanotechnology to study the mechanical and electrical interplay between the two major cell types in the infarct region. New insight will be gained regarding these interactive processes and how they may contribute to the onset of aberrant electrical activity and arrhythmia.