Computational simulation of hypertrophic cardiomyopathy mutations in Troponin I: Influence of increased myofilament calcium sensitivity on isometric force, ATPase and [Ca2+]i

Familial hypertrophic cardiomyopathy (FHC) is an inherited disease that is characterized by ventricular hypertrophy, cardiac arrhythmias and increased risk of premature sudden death. FHC is caused by autosomal-dominant mutations in genes for a number of sarcomeric proteins; many mutations in Ca2+-regulatory proteins of the cardiac thin filament are associated with increased Ca2+ sensitivity of myofilament function. Computational simulations were used to investigate the possibility that these mutations could affect the Ca2+ transient and mechanical response of a myocyte during a single cardiac cycle. We used existing experimental data for specific mutations of cardiac troponin I that exhibit increased Ca2+ sensitivity in physiological and biophysical assays. The simulated Ca2+ transients were used as input for a three-dimensional half-sarcomere biomechanical model with filament compliance to predict the resulting force. Mutations with the highest Ca2+ affinity (lowest Km) values, exhibit the largest decrease in peak Ca2+ assuming a constant influx of Ca2+ into the cytoplasm; they also prolong Ca2+ removal but have little effect on diastolic Ca2+. Biomechanical model results suggest that these cTnI mutants would increase peak force despite the decrease in peak [Ca2+]i. There is a corresponding increase in net ATP hydrolysis, with no change in tension cost (ATP hydrolyzed per unit of time-integrated tension). These simulations suggest that myofilament-initiated hypertrophic signaling could be associated with decreased [Ca2+]i, increased stress/strain, and/or increased ATP flux.