Figure 4

In-silico trials of Mavacamten on simulated MYH7^R403Q/+, TNNT2^R92Q/+, and TNNI3^R21C/+ cardiomyocytes and comparison with experimental evidence. (a,b) Dose-dependent effect of Mavacamten on the active tension amplitude and relaxation time of simulated MYH7^R403Q/+ cardiomyocytes, which are characterised by larger myosin availability due to a lower abundance of myosin SRX that contributes to thin filament activation. (c,d) Dose-dependent effect of Mavacamten on the active tension amplitude and relaxation time of simulated TNNT2^R92Q/+ cardiomyocytes, which are characterised by altered tropomyosin positioning and calcium sensitivity. (e,f) Dose-dependent effect of Mavacamten on the active tension amplitude and relaxation time of simulated TNNI3^R21C/+ cardiomyocytes, which are characterised by altered calcium sensitivity and dissociation rate from troponin. Simulation results recapitulated the experimentally observed responses to Mavacamten of hiPSC-CMs expressing the MYH7^R403Q/+, TNNT2^R92Q/+, and TNNI3^R21C/+ variants (g,h) and provide an explanation based on mutation-specific disease mechanisms. All data presented in (a–f) is simulation data and is presented as mean and SD. Significance with respect to untreated control (dotted grey lines) was tested with Kruskal–Wallis with post hoc Dunn correction (N = 348 for each in-silico population). Data presented in (g,h) is experimental hiPSC-CM data and is presented as mean. Significance with respect to untreated control (dotted grey lines) was tested with Kruskal–Wallis with post hoc Dunn correction (N = 109 (mutant), N = 72 (mutant + 0.3 \(\upmu\)M Mava), N = 60 (mutant + 1 \(\upmu\)M Mava), and N = 60 (mutant + 3 \(\upmu\)M Mava) for MYH7^R403Q/+; N = 98 (mutant), N = 106 (mutant + 0.3 \(\upmu\)M Mava), N = 98 (mutant + 1 \(\upmu\)M Mava), and N = 154 (mutant + 3 \(\upmu\)M Mava) for TNNT2^R92Q/+; N = 89 (mutant), N = 128 (mutant + 0.3 \(\upmu\)M Mava), N = 52 (mutant + 1 \(\upmu\)M Mava), and N = 61 (mutant + 3 \(\upmu\)M Mava) for TNNI3^R21C/+).