BPS2025 - Long-term effect of Mavacamten impact force and sarcomere density in a MYBPC3 iPSC-cardiomyocyte model of hypertrophic cardiomyopathy

(Mava)camten, a first-in-class allosteric inhibitor of myosin, demonstrated efficacy and safety in obstructive hypertrophic cardiomyopathy (oHCM). In patients, Mava was able to reduce maximum left ventricular wall thickness in a relative short-term (30 weeks). We recently reported that the MYBPC3:c.772G>A variant causes HCM through cMyBP-C haploinsufficiency. In both patient-myocardium and induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), the mutation leads to faster sarcomere kinetics and higher energetics, however, counterbalanced by prolonged action potentials and slower Ca2+ transients, which preserve twitch duration but may expose to greater arrhythmic propensity. Therefore, Mava may prevent myocardial energetic defects in HCM. Here we used hiPSC-CMs and engineered heart tissues (EHTs) from one patient compared to its isogenic CRISPR-Cas9 corrected line to verify the long-term effect of Mava. After chronic treatment for 20 days using Mava 0.3 μM and 0.75 μM, reduced force under isometric conditions was observed with mild reduction of the twitch duration vs. untreated EHTs. Sarcomere content and myofilament organization strongly impact cardiac contractile properties. For studying this, single control cardiomyocytes expressing GFP-tagged α-actinin were treated with Mava for 20 days and compared to untreated CMs. We observed that the cell area and sarcomere network were reduced in the Mava-treated cells with reversion after 4 days of washout. In addition, long-term Mava effect was studied on electrophysiological properties. Prolonged APD and Ca2+ transients were observed in HCM-EHTs, confirming what previously observed in single cardiomyocytes, but no change after Mava treatment. In addition, transcriptome analysis is ongoing to assess any molecular alterations. In conclusion, Mava reversibly influences sarcomere structure/function after long-term treatment. This mechanism may account for the favorable cardiac structure remodeling observed in oHCM patients after chronic treatment.