Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Despite recent exponential growth of the field of cardiovascular genetics leading to identification of hundreds of mutations responsible for hypertrophic cardiomyopathy (HCM), the mechanism linking sarcomeric mutations to the disease progression to heart failure (HF) remains unclear. Clinical features of HCM are severe left ventricular hypertrophy (LVH), diastolic dysfunction, and an increased risk of arrhythmias. Given success in sudden death prevention, the predominant cause of HCM-related morbidity and mortality is HF. Importantly, recent reports show profound structural mitochondrial damage in patients with HCM. The goal of this proposal is to improve mitochondrial function to delay or reverse the progression of HCM. This proposal considers worsened myocardial energetics as the initial shared stimulus that, when triggered by a sarcomeric mutation, leads to the development of the clinical phenotype. HCM mutations inefficiently increase power output of the sarcomere, resulting in several-fold increased ATP demand. Mitochondria meet the excessive ATP demand, albeit at a cost of accumulation of ADP, a product of ATP hydrolysis. Elevated ADP, in turn, limits the amount of chemical energy extractable from ATP to pump sodium and calcium ions. This leads to slower removal of calcium during relaxation of the heart resulting in diastolic dysfunction. Moreover, elevated intracellular sodium further impairs mitochondrial ATP synthesis and increases reactive oxygen species (ROS) production. Excessive ROS, in turn, oxidatively inhibit mitochondrial proteins and ATP synthesis. Continuous excessive demand causes mitochondria to switch their fuel preference towards glucose oxidation. Such shift is initially beneficial, but over time supports LVH and depletes mitochondria of important metabolites. Thus, even though the primary defect is in the inefficient sarcomere, severe mitochondrial damage ensues. The central hypothesis of this proposal is that interventions that improve energy balance have the capacity to reverse mitochondrial damage in HCM. We will restore energy balance by decreasing ATP demand and increasing ATP supply. Phosphorus and carbon magnetic resonance spectroscopy and imaging will determine whether improvements in fuel preference and ROS production reverse mitochondrial damage and hypertrophy in murine models of HCM. In mice bearing two of the most lethal HCM mutations, R403Q in myosin and R92L in troponin T, we will pursue the following three Specific Aims: 1) To determine the extent to which treatment with CK-274, inhibitor of the engine of the sarcomere - myosin, improves mitochondrial function and structure in HCM mice. 2) To test the hypothesis that suppressing excessive mitochondrial ROS by overexpressing mitochondrial catalase increases ATP synthesis and prevents mitochondrial damage and hypertrophy in HCM. 3) To determine whether empagliflozin, clinically used antidiabetic medication, reverses the maladaptive cardiac substrate preference, mitochondrial damage and LVH in HCM. These results will provide immediately translatable tools to modify the disease process in HCM and other mitochondria-based cardiovascular conditions.
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