A Human-Based Computational Investigation into Sarcomeric and Ionic Remodelling in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM), an inherited cardiac disease, is one of the leading causes of sudden cardiac death in the young. There is no pharmacological therapy in use that specifically targets HCM pathophysiology. HCM caused by mutations in the gene coding for the sarcomeric protein troponin T is particularly arrhythmogenic; the mechanisms remain unknown. Guided by human experimental data, we investigate sarcomeric re-modelling caused by the R92Q troponin T mutation and HCM ionic remodelling using a human-based computational model of an adult ventricular cardiomyocyte. Arrhythmogenic triggers in the form of early afterdepolarisations (EADs) were absent when considering R92Q sarcomeric remodelling alone, but sarcomeric remodelling increased the frequency of EADs associated with HCM ionic remodelling. An arrhythmogenic ionic mechanism was identified: the sarcomeric mutation increased calcium myofilament sensitivity which led to prolonged calcium transient decay, resulting in prolonged inward $I_{NCX}$ which generated EADs. This pathway was targeted in the simulations with a sarco/endoplasmic reticulum $Ca^{2+}$ -ATPase activator, which reduced EAD frequency. This highlights the potential of computational precision medicine to investigate mutation-specific pathomechanisms and identify therapeutic targets in inherited cardiomyopathies.