Arun Sridhar

My Story:

Thesis title:
Regulation of cardiac voltage gated potassium currents in health and disease

Abstract:
Cardiovascular disease (CVD) is a major cause of mortality and morbidity worldwide. Hypertension, Heart Failure and Atrial Fibrillation are the most common diagnosis, hospitalization cause and the sustained cardiac arrhythmia respectively in the US. Sudden cardiac death is the one of the most common causes of cardiovascular mortality after myocardial infarction. High impetus has been placed on identifying novel therapeutic targets via translational research. This dissertation addresses these important therapeutic issues from the standpoint of cellular electrophysiology Atrial-specific ion channel blockers have been proposed as a major therapeutic target to treat atrial fibrillation without the risk of ventricular proarrhythmia. All experiments were amphotericin-B perforated whole cell patch-clamp experiments performed on isolated cardiac myocytes at 36 0.5C. Chapter 2 addresses a very important issue of identification of a purportedly atrial-specific ion current in the canine ventricle. The findings suggest that the current is not atrial-specific and has properties similar to the atrial ultra-rapid delayed rectifier current (IKur). This might have important implications for the use of IKur blockers for the treatment of atrial fibrillation. Hypertension leads to ventricular hypertrophy, and ionic and structural remodeling, leading to heart failure. Chapter 3 focuses on alterations in diastolic currents (IK1 and If) and their contribution to altered cardiac excitability in hypertensive heart failure. Chapter 4 documents ionic remodeling in a canine model of sudden cardiac death. This study provides a basis for examining the potential benefits of IKr activators as a therapeutic target to prevent arrhythmias and sudden death. Chapter 5 assesses ventricular ionic remodeling in chronic heart failure and after electrophysiologic reverse remodeling after cardiac resynchronization therapy. Chapter 6 focuses on atrial ionic remodeling in chronic heart failure. Preliminary data suggesting specific oxidative processes that regulate atrial K+ currents are presented. These studies provide a foundation for examining a future research direction where the use of specific anti-oxidant interventions for prevention of atrial remodeling, atrial fibrillation can be tested. We propose that these studies aid in understanding of important processes of K+ current remodeling in CVD. Understanding these mechanisms is important to devise new therapeutic targets for prevention/treatment of arrhythmias in CVD.