Human iPSC-CMs and in-silico technologies define mechanisms and accelerate targeted pharmacogenetics in hypertrophic cardiomyopathy

Cardiomyopathies have unresolved genotype-phenotype relationships and lack disease-specific treatments. Here we identify genotype-specific pathomechanisms and therapeutic targets combining experimental hiPSC-CM modelling and human-based cardiac electromechanical in-silico modelling and simulation bridging from specific mutations to clinical biomarkers. We select hypertrophic cardiomyopathy as a challenge for this approach and study genetic variations that mutate proteins of the thick (MYH7R403Q/+) and thin filaments (TNNT2R92Q/+, TNNI3R21C/+) of the cardiac sarcomere. We show that destabilisation of myosin super relaxation drives disease in MYH7R403Q/+ with secondary effects on thin filament activation, which are corrected by Mavacamten. Thin filament variants TNNT2R92Q/+ and TNNI3R21C/+ share calcium regulation-related pathomechanisms, for which Mavacamten provides incomplete salvage. 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.