Key result
The targeted myosin ATPase inhibitor MYK-461 completely rescued abnormal contractility, relaxation, calcium transients, and ATPase activity in pediatric HCM iPSC-cardiomyocytes with MYH7 and MYBPC3 missense variants.
Why the study?
Targeted myosin ATPase inhibitors have shown efficacy in adult hypertrophic cardiomyopathy, but they have not been evaluated in children.
Does a targeted myosin ATPase inhibitor rescue the abnormal phenotype in pediatric HCM iPSC-cardiomyocytes compared to standard therapies?
Does a targeted myosin ATPase inhibitor rescue the abnormal phenotype in pediatric HCM iPSC-cardiomyocytes compared to standard therapies?
A targeted myosin ATPase inhibitor completely rescued the hypercontractile phenotype in pediatric HCM iPSC-cardiomyocytes, outperforming standard therapies like verapamil and metoprolol.
Pediatric HCM iPSC-CMs recapitulate hypertrophy and disarray; leaves open whether myosin inhibitors benefit children.
SUMMARY Hypertrophic cardiomyopathy (HCM) is mainly caused by sarcomere gene variants in MYH7 and MYBPC3. Targeted drugs like myosin ATPase inhibitors have shown efficacy in adult HCM but have not been evaluated in children. We generated iPSC-cardiomyocytes (CMs) from four children with HCM harboring variants in MYH7 ( V606M; R453C) or MYBPC3 (G148R; P955fs and TNNI3_A157P ), variant-corrected controls, and a healthy individual. All CMs showed hypertrophy and sarcomere disorganization. All 3 single variant CMs showed higher contractility, slower relaxation, higher calcium transients and higher ATPase activity. Only MYH7 variant CMs showed stronger myosin-actinin binding. Targeted myosin ATPase inhibitor showed complete rescue of the phenotype in affected CMs and in cardiac Biowires to mirror isogenic controls. The response was stronger compared to verapamil or metoprolol, highlighting the need for clinical trials of myosin targeted therapy in pediatric HCM patients. The phenotype and response to drug therapy are influenced by the underlying genotype.
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Kinnear et al. (2023) studied Hypertrophic cardiomyopathy (n=4). MYK-461 vs. Pre-treatment baseline, variant-corrected isogenic controls, verapamil, metoprolol was evaluated on Rescue of functional abnormalities (contractility, relaxation, Ca2+ transients, ATPase activity). The targeted myosin ATPase inhibitor MYK-461 completely rescued abnormal contractility, relaxation, calcium transients, and ATPase activity in pediatric HCM iPSC-cardiomyocytes with MYH7 and MYBPC3 missense variants.
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