Metabolic regulation of the cardiac sodium channel

Sudden cardiac death, an unexpected death by the loss of heart function (cardiac arrest), is a major health problem in the United States and in the rest of the world, accounting for 50% of all heart disease-related deaths and 15%-20% of all deaths. Cardiac arrest results from malfunctioning of the heart’s electrical system where the rate and/or rhythm of the heart becomes irregular, in what is known as an arrythmia. One of the primary regulators of the heart’s electrical system is the cardiac voltage-gated sodium channel NaV1.5. Dysfunction in NaV1.5 contributes to fatal arrhythmias. My research examines the regulation of NaV1.5 by metabolic influences that can be leveraged as anti-arrhythmic strategies in inherited and acquired heart disease. I demonstrate that NAD⁺ supplementation utilizing Nicotinamide Riboside can modulate NaV1.5 currents and cardiac electrophysiology in a way that may prevent arrhythmias in heart disease. Additionally, the known NaV1.5 modifying protein α-actinin 2 was studied and I demonstrated a novel form of α-actinin 2. I further showed that these different forms of α-actinin 2 are dysregulated in inherited cardiomyopathies. Together this research further builds our knowledge on the metabolic regulation of the cardiac sodium channel and lays the foundation for NAD⁺ supplementation as an anti-arrhythmic strategy in the prevention of sudden cardiac death.