Figure 2
From: Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy
Mechanistic explanation of the MYH7R403Q/+ cellular phenotype of hypercontractility and diastolic dysfunction through human-based modelling and simulation informed by biophysical evidence. (a,b) Proportion of myosin heads in SRX and DRX conformations in WT and MYH7R403Q/+ hiPSC-CMs. Data are presented as mean and SD, significance was tested by two-tailed unpaired t test (N = 9 in control and N = 10 in MYH7R403Q/+). (c) Comparison of simulated active tension waveforms in control and under MYH7R403Q/+. (d,e) Simulated MYH7R403Q/+ cardiomyocytes with larger myosin availability develop higher tension amplitude compared to control (d) in line with experimental hiPSC-CM data (e) which present increased sarcomere shortening. Data are presented as mean and SD, significance was tested by two-tailed unpaired t test for experimental data (N = 92 in control and N = 109 in MYH7R403Q/+) and Mann Whitney test for simulation data (N = 348 in control and MYH7R403Q/+). (f) Hypothesis tested in simulations to explain the pathway behind impaired relaxation in MYH7R403Q/+, i.e. the myosin-based contribution to thin filament activation. The scaling factor of Ca50 is reported. Ca50 represents the calcium concentration at half maximal thin filament activation and has \(\upmu\)M unit. Therefore, a larger Ca50 value means lower calcium sensitivity and vice versa. (g) Effect of myosin contribution to thin filament activation on simulated active tension relaxation: relaxation times are prolonged (dark blue) compared to the absence of feedback (light blue). Data are presented as mean and SD, significance was tested by Kruskal–Wallis with post hoc Dunn correction (N = 348 in control and MYH7R403Q/+). (h,i) Simulation results (h) that consider the myosin contribution to thin filament activation replicate the prolongation of the calcium transient decay observed experimentally (i).Experimental data presented as average trace (average over N = 113 for WT and N = 128 for MYH7R403Q/+) and simulation data presented as trace of the baseline model. (j,k) The combination of larger myosin availability and the myosin-based contribution to thin filament activation leads to a prolongation in the relaxation of simulated active tension (j) similar to experimental data (k). Data are presented as mean and SD, significance was tested by two-tailed unpaired t test for experimental data (N = 92 in control and N = 109 in MYH7R403Q/+) and Mann Whitney test for simulation data (N = 348 in control and MYH7R403Q/+).
