Abstract 15732: Chronic Mavacamten Treatment Has Opposing Effects on Contractility in Engineered Heart Tissue Models of Severe vs. Mild Hypertrophic Cardiomyopathy

Many hypertrophic cardiomyopathy (HCM) causing mutations result in myocardial hypercontractility by increasing the number of myosin crossbridges in the disordered relaxed (DRX) state, or by sensitizing the sarcomere to the effects of Ca ²⁺ . Mavacamten (Mava) recently became the first FDA-approved treatment of obstructive HCM that directly targets hypercontractility by reducing the number of DRX cross bridges. Mava improves outcomes in patients with obstructive HCM but has not been approved in children or adults without obstructive HCM. The efficacy of chronic Mava treatment at preventing phenotype development in asymptomatic HCM mutation carriers remains largely unexplored. We recently showed that ablation of cardiac myosin binding protein-C (cMyBP-C -/-) in engineered heart tissue (EHT) causes rapid phenotype development in a dish. Initial hypercontractility progresses to hypocontractility with impaired relaxation, mediated by Ca ²⁺ mishandling. Here we investigate whether chronic Mava administration prevents phenotype progression. cMyBP-C +/+, +/- and -/- EHT were treated with 100nM Mava starting on day 7 of EHT culture. Serial twitch force (TF) measurements were performed weekly for 5 weeks, using the Mantarray platform. At day 7, prior to Mava treatment, +/- and -/- produced significantly more TF than +/+ EHT (392 ± 9 μN vs. 390 ± 15 μN vs. 199 ± 13 μN). At day 14, Mava treatment reduced TF by 31% (p < 0.001) in +/+ EHT, 30% (p < 0.001) in +/- EHT and 12% (p = 0.115) in -/- EHT. After an additional 4 weeks, chronic Mava treatment reduced TF by 54% (p < 0.001) in +/+ EHT, 65% (p < 0.001) in +/- EHT but

TF by 23% (p = 0.034) in -/- EHT.These data show that chronic Mava treatment prevents/slows maladaptive remodeling in -/- EHT, but depresses contractility in +/+ and +/- ECT, suggesting that chronic Mava treatment may be detrimental to patients with mild HCM. Our ongoing studies are assessing the effect of chronic Mava treatment on other EHT models of HCM and on Ca ²⁺ -handling.