Fellowship for Milburn: Effects of Mechanical Unloading on Myocardial Contradiction and Stiffness

Abstract Mechanical unloading from left ventricular assist devices (LVADs) can blunt cardiac remodeling in some patients with heart failure however the mechanism of how this unloading alters mechanotransduction and growth signaling is poorly understood. Heart failure affects over 6 million patients in the US and accounts for roughly 1 in 12 deaths, yet patients with heart failure have limited treatment options. Some patients with heart failure my receive an LVAD which pumps blood from the left ventricle into the aorta to maintain cardiac output. This mechanical unloading of the left ventricle can lessen the dilated growth seen in heart failure progression, but the mechanism of this altered growth is not unknown. Cardiomyocytes are passively stretched during diastolic filling and contract during systole. In the setting of heart failure, cardiomyocytes are stretched more and therefore experience increased passive tension. The large protein titin is the primary regulator of intracellular passive stiffness and likely acts as a sensor of increased passive tension and stretch. Mutations in titin and its binding proteins are associated with familial forms of dilated cardiomyopathy indicating a link between the mechanical properties of titin, titin binding proteins signaling pathways, and deleterious cardiac remodeling. Mechanical unloading with LVAD support decreases cardiomyocyte stretch which may blunt dilated growth signaling through the titin-based mechanotranduction. To understand how altered mechanical stimuli with unloading affects growth signaling our group has collected myocardial samples from patients before and after unloading for biophysical and biochemical testing. The goal of this study is to test the hypothesis that LVAD support modulates mechanotransduction and cardiac remodeling by altering (1) the mechanical properties of the myocardium and (2) titin binding proteins and their associated transcription factors. Further work will use (3) computational simulations to examine how sarcomere and organ-level function is influenced by mechanical unloading. The primary aim of this fellowship is to establish how mechanical unloading in patients with heart failure alters the mechanical properties and signal transduction pathways in myocardium, as well as provide the trainee with skills in cardiac contractile biophysics, biochemical assays, and computational modeling of cardiovascular function. These skills and training plan tailored toward the trainee’s current strengths, weaknesses, and career goals will be fundamental in supporting the trainee’s path towards an independent physician scientist