Arrhythmogenic cardiovascular disease, which disproportionately affects individuals in the VA population with acquired cardiac and metabolic diseases, particularly heart failure, is associated with increased morbidity and mortality. The mechanisms contributing to increased risk of sudden cardiac death in individuals suffering arrhythmogenic cardiovascular disease, however, remain very poorly understood, hampering our ability to risk stratify patients and to develop novel, targeted therapeutic strategies. Although numerous experimental (animal/cellular) heart failure models have been developed and extensively studied, only limited insights into human arrhythmia mechanisms have been provided. Motivated to bridge this knowledge gap and advance the field, we have initiated a comprehensive research effort aimed at defining the mechanisms involved in the physiological regulation of membrane excitability in the human heart and the pathophysiological electrical remodeling associated with human heart failure. To enable direct molecular/biochemical and functional studies on human ventricular myocardium/myocytes, we developed the infrastructure to acquire non-failing and failing human hearts and we established robust, reliable methods for the isolation, in vitro maintenance, adenovirus- mediated transduction, and electrophysiological characterization of human ventricular myocytes. Here, we utilize these unique resources in experiments designed to define the molecular and cellular mechanisms controlling the expression, the properties and the remodeling of critical ionic currents that impact action potential repolarization, the late component of the voltage-gated Na+ (Nav) current, INa,L, and the novel non-inactivating K+ (Kv) current, IK,L, that we have recently identified in non-failing human left ventricles. We will define the roles of channel accessory subunits and post-translational modifications in controlling the cell surface expression and the biophysical and pharmacological properties of native human ventricular INa,L (aim #1) and IK,L (aim #2).
In aim #2, we shall also explore the hypothesis that there are actually two, functionally and molecularly distinct components of human ventricular IK,L. Additional experiments (aim #3) will elucidate the molecular mechanisms underlying in INa,L and IK,L remodeling in failing human ventricles. These studies will provide new, clinically relevant insights into the cellular/molecular mechanisms contributing to the physiological regulation and pathophysiological remodeling of native human ventricular Ito,f, Iss and INa channels. These insights will transform the refinement of human cardiac myocyte and whole heart models and translate to novel, mechanism-based strategies to target specific cell types to reduce the risk of life-threatening ventricular arrhythmias in VA patients suffering heart failure.
Arrhythmogenic cardiovascular disease and sudden cardiac death disproportionately affect VA patients with acquired cardiovascular disease, such as heart failure. Nationally, there are more than 350,000 VA patients who carry the diagnosis of heart failure. In the St. Louis VA system alone, over 3,000 patients have heart failure with reduced ejection fraction and an equal, if not greater, number of patients have heart failure with preserved ejection fraction. Following hospitalization, VA heart failure patients have a 22% chance of being re-admitted for worsening heart failure and 9% chance of dying within 30 days. It is increasingly recognized that the paucity of electrophysiological studies on the human heart has been a persistent barrier to advances in heart failure diagnosis and treatment. Here, we propose a powerful experimental strategy to identify the electrophysiological signature and the molecular determinants of human heart failure-related arrhythmogenic cardiovascular disease, information that will reveal new targets to treat heart failure and new strategies to prevent sudden death.
