Grant: Operating Grant

Despite significant progress in the prevention and treatment of cardiovascular diseases, the incidence and prevalence of congestive heart failure (CHF) have been increasing steadily in recent years, especially in the elderly. CHF is the consequence of multiple pathophysiological alterations and adaptations and one of the most deleterious alterations in CHF is electrical abnormalities that can cause sudden cardiac death. Presently our knowledge about the causes for the electrical abnormalities in CHF is still rather poor though tremendous efforts have been made to improve our understanding. I believe that microRNAs, a newly discovered class of ribonucleic acids, play critical roles in controlling cardiac electrical activities contributing to the electrical abnormalities in CHF. Indeed, we and others have recently identified a subset of microRNAs that are abnormally altered in their levels in CHF and these CHF-responsive microRNAs are most likely the key microRNAs that control the vulnerability and reversibility of electrical disorders in CHF. This project is designed to test this unique hypothesis. Combined techniques involving a mice animal model of CHF, gene transfer, molecular biology, electrophysiology and pharmacology will be employed for the studies proposed. We will also distinguish the microRNAs that produce electrical disorders from those that act against electrical disorders, among the CHF-responsive microRNAs. The project will be the first experimental investigation on roles of microRNAs in repressing ion channel genes. Completion of the study will let us gain novel insight into the mechanisms for arrhythmogenesis in CHF and has the potential of finding new targets leading to novel approaches for antiarrhythmic therapy.