Projectdetails

Influx of sodium ions through cardiac voltage-gated sodium channels is responsible for the initial upstroke of the action potential and consequently plays a central role in excitability of myocardial cells. Sodium channel dysfunction causes cardiac conduction disturbances, ventricular arrhythmias, and sudden death, both during common pathological conditions such as myocardial ischemia and heart failure, and in the setting of inherited mutations in the SCN5A gene encoding the cardiac sodium channel. Recent evidence indicates that sodium channels not only determine the electrophysiological characteristics of the myocardium, but also exert regulatory effects on myocyte structural integrity and viability. Cardiac sodium channel dysfunction has been associated with the development of structural abnormalities within the myocardium. Indeed, in a previous study by the applicant, transgenic mice carrying the Scn5a-1798insD+/- mutation were shown to develop dilatation of the right ventricle in addition to severe left ventricular cardiac fibrosis with increasing age. These structural changes further predispose these hearts to development of ventricular arrhythmias. However, the underlying mechanisms involved are not known, and it remains unclear how the cardiac sodium channel regulates cardiomyocyte integrity and viability. Proposed mechanisms include: (1) abnormal intracellular sodium/calcium handling, (2) destabilization of cytoskeletal integrity resulting from altered sarcolemmal sodium channel expression, and/or (3) electrical activity-dependent stimulation of pro-fibrotic factors of the transforming growth factor β (TGFβ) pathway. In the current project, the applicant aims to test these hypotheses in three different models of sodium channel dysfunction, allowing for in-depth assessment of the contributing role in this process of reduced sodium current, decreased number of functional sodium channels at the cell membrane, and increased persistent inward current. Results from this project are expected to elucidate the mechanisms underlying the detrimental effects of sodium channel dysfunction on myocyte viability and function, and establish a functional role as signal transducer for the cardiac sodium channel.