2014 AWARDED GRANT
David Fedida, PhD
Late INa Contributes to Diastolic Dysfunction in Hypertrophic Cardiomyopathy
University of British Columbia, Vancouver, Canada
David Fedida, PhD – $50,000
The proposed research aims to better understand the ionic molecular mechanisms behind diastolic dysfunction, a hallmark of hypertrophic cardiomyopathy (HCM). In patients with diastolic dysfunction, the lower chambers of the heart, the ventricles, are unable to properly relax, and they become stiff. As a result, the ventricles may not fill completely, and blood can accumulate in other parts of the body such as the lungs causing pulmonary congestion and leading to symptoms of heart failure or arrhythmias. This study will investigate increases in the so-called "late sodium current" (INa,L), which is an influx of sodium into cells during contraction of the heart that leads to an overload of calcium inside the heart cells and an inability of the heart to relax normally. This study proposes that increases in INa,L can underlie the kinds of cellular changes in the heart cells of a animal model of HCM, as well as the entire heart, which eventually contributes to diastolic dysfunction. Single cells will be isolated from normal mouse hearts and from genetically altered mice resembling human familial HCM with impaired heart relaxation. The properties of the INa,L currents will be compared in the two groups, and the parameters of heart relaxation will be compared as the INa,L current is increased or decreased. New pharmacological agents that specifically inhibit INa,L will be used to understand the causative role of INa,L in the failure of HCM hearts to relax normally. It also may provide direction towards molecular targets for HCM therapy in adults and children.