| Summary: | Cardiomyopathies have unresolved genotype–phenotype relationships and lack disease-specific treatments. Here we provide a framework to identify genotype-specific pathomechanisms and therapeutic targets to accelerate the development of precision medicine. We use human cardiac electromechanical in-silico modelling and simulation which we validate with experimental hiPSC-CM data and modelling in combination with clinical biomarkers. We select hypertrophic cardiomyopathy as a challenge for this approach and study genetic variations that mutate proteins of the thick (<i>MYH7</i><sup>R403Q/+</sup>) and thin filaments (<i>TNNT2</i><sup>R92Q/+</sup>, <i>TNNI3</i><sup>R21C/+</sup>) of the cardiac sarcomere. Using in-silico techniques we show that the destabilisation of myosin super relaxation observed in hiPSC-CMs drives disease in virtual cells and ventricles carrying the MYH7<sup>R403Q/+</sup> variant, and that secondary effects on thin filament activation are necessary to precipitate slowed relaxation of the cell and diastolic insufficiency in the chamber. In-silico modelling shows that Mavacamten corrects the MYH7<sup>R403Q/+</sup> phenotype in agreement with hiPSC-CM experiments. Our in-silico model predicts that the thin filament variants TNNT2<sup>R92Q/+</sup> and TNNI3<sup>R21C/+</sup> display altered calcium regulation as central pathomechanism, for which Mavacamten provides incomplete salvage, which we have corroborated in TNNT2<sup>R92Q/+</sup> and TNNI3<sup>R21C/+</sup> hiPSC-CMs. We define the ideal characteristics of a novel thin filament-targeting compound and show its efficacy in-silico. We demonstrate that hybrid human-based hiPSC-CM and in-silico studies accelerate pathomechanism discovery and classification testing, improving clinical interpretation of genetic variants, and directing rational therapeutic targeting and design.
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