Heart failure contributes to 1 in 9 deaths in the United States. Despite significant research efforts, therapeutic treatments for heart failure remain limited. While the causes of heart failure are multifactorial, contractile deficits at the molecular level play a major role in disease progression.This translational project uses human biospecimens procured from organ donors and patients undergoing cardiac transplant to advance understanding of a cellular-level mechanism that underpins the Frank-Starling relationship. Specifically, the project focuses on length-dependent activation, defined as the increased maximum force and Ca2+ sensitivity of contraction induced by myocardial stretch. The mechanisms that underlie length-dependent activation remain unclear, but are now thought to include dynamic transitions between the newly discovered OFF and ON states of myosin.PI Tanner has obtained pilot data which show that length-dependent increases in Ca2+ sensitivity are: (a) robust in myocardium from organ donors, (b) preserved in samples from patients with ischemic heart failure, and (c) lost in patient with non-ischemic heart failure. In collaboration with co-I Campbell, new computer modeling suggests that these effects may reflect destabilization of the myosin OFF state in non-ischemic heart failure.This AHA project builds on these exciting preliminary results and uses Mavacamten, a new pharmaceutical that is currently in clinical trials for hypertrophic cardiomyopathy, to stabilize the myosin OFF state. The working hypothesis is that this intervention will augment, and perhaps even rescue, length-dependent activation in myocardium from patients who have non-ischemic heart failure.Aim 1: Modulate the myosin OFF-ON equilibrium to control Ca2+ sensitivity of contraction in human myocardium as muscle length changes.Aim 2: Use computer modeling to predict how the length-dependent OFF-ON equilibrium and Mavacamten impact hemodynamics in organ donors and patients with heart failure.
|Program type||Transformational Project Award|
|Effective start/end date||07/01/2019 → 06/30/2022|