Dr. Rengasayee Veeraraghavan, Virginia Tech Carilion

"Exploring the Machinery of Cardiac Conduction: From Single Molecule to Whole Organ"

For over half a century, the mechanisms of electrical excitation spread in heart muscle and neural tissue were thought to be distinct from each other: In nerves, electrical excitation jumps across narrow extracellular clefts from one cell to another. In the heart, electrical current was thought to flow from cell to cell via low resistance pathways afforded by gap junction channels. However, experimental observations that could not be well explained by this paradigm suggested that ‘ephaptic’ mechanisms involving extracellular fields might allow electrical excitation to jump the narrow cleft separating cardiac myocytes. A key requirement for the investigation of this hypothesis was the identification of a structural unit of ephaptic coupling. I was able to identify just such a structure within the intercalated disks, sites of electrical and mechanical coupling between cardiac myocytes. Specifically, super-resolution gSTED and STORM microscopy revealed the enrichment of cardiac sodium channels to the perinexus, a nanodomain located at the edge of gap junctions, where the membranes of adjacent cells are mere nanometers apart. Importantly, whole heart optical voltage mapping revealed arrhythmogenic conduction slowing when the perinexal membrane spacing was increased during cardiac edema. In silico investigation of these results pointed to sodium channels directly participating in electrical communication between cardiac myocytes. In subsequent work, I have identified the sodium channel auxiliary subunit β1 (encoded by SCN1b), which doubles as a cell adhesion molecule, as a key determinant of perinexal membrane spacing. Acutely compromising β1-mediated adhesion using a novel peptide inhibitor βadp1 resulted in significant perinexal widening, anisotropic conduction slowing and spontaneous arrhythmias. These results point to fundamentally novel roles for sodium channel α and β subunits and suggest that cardiac electrical conduction may have more in common with neural conduction than previously thought. Simultaneously these results form the basis for novel, potentially transformative antiarrhythmic therapies.

Bio:

Dr. Rengasayee (Sai) Veeraraghavan obtained his undergraduate degree in Chemical Engineering from Anna University, India and his doctorate in Bioengineering from the University of Utah. His research has focused on the mechanisms of electrical activity in the heart in health and in disease. Specifically, he is interested in the relationship between the nano-scale milieus of ion channel macromolecular complexes and whole heart electrophysiology. In pursuing this research question, he employs a diverse array of imaging techniques, ranging from the whole organ level down to the single molecule, in conjunction with novel quantitative analytical approaches. As a post-doctoral trainee, he was awarded The Clinical Research Award in Honor of Mark Josephson and Hein Wellens for 2013-14 from the Heart Rhythm Society and a Postdoctoral Research Fellowship for 2013-15 from American Heart Association. He has authored 17 peer-reviewed publications (261 citations, h-index 10), and holds a Scientist Development Grant from the American Heart Association (2016-2019).