Mechanism based therapies enable personalised treatment of hypertrophic cardiomyopathy

Abstract

Cardiomyopathies have unresolved genotype–phenotype relationships and lack disease-specific treatments. Here we provide a framework to identify genotype-specific pathomechanisms and therapeutic targets to accelerate the development of precision medicine. We use human cardiac electromechanical in-silico modelling and simulation which we validate with experimental hiPSC-CM data and modelling in combination with 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. Using in-silico techniques we show that the destabilisation of myosin super relaxation observed in hiPSC-CMs drives disease in virtual cells and ventricles carrying the MYH7R403Q/+ variant, and that secondary effects on thin filament activation are necessary to precipitate slowed relaxation of the cell and diastolic insufficiency in the chamber. In-silico modelling shows that Mavacamten corrects the MYH7R403Q/+ phenotype in agreement with hiPSC-CM experiments. Our in-silico model predicts that the thin filament variants TNNT2R92Q/+ and TNNI3R21C/+ display altered calcium regulation as central pathomechanism, for which Mavacamten provides incomplete salvage, which we have corroborated in TNNT2R92Q/+ and TNNI3R21C/+ hiPSC-CMs. 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.

Cardiac troponin T N-domain variant destabilizes the actin interface resulting in disturbed myofilament function

“…Using human in-silico models of the variants TNNT2 R92Q/+ and TNNI3 R21C/+ , Margara et al ( 68 ) predicted that HCM-linked thin-filament variants lead to a decrease in DRX myosins in contrast to our experimental findings in murine myocardium–containing cTnT-I79N, which displays an increase in DRX myosins. A consistent finding from experimental X-ray studies of thick filament–based mutations ( 64 , 69 ) associated with HCM, however, is an increase in DRX/ON state myosins under relaxed conditions, so the predictions of Margara et al ( 68 ) are surprising. In silico predictions, however, at their present state of development, while very valuable as hypothesis-generating tools, do not take into consideration several aspects of the disease that can be captured in an animal model.…”

“…It has been proposed that variants in other thin filament proteins (TnT and TnI) may affect the SRX/DRX equilibrium ( 68 ). Using human in-silico models of the variants TNNT2 R92Q/+ and TNNI3 R21C/+ , Margara et al ( 68 ) predicted that HCM-linked thin-filament variants lead to a decrease in DRX myosins in contrast to our experimental findings in murine myocardium–containing cTnT-I79N, which displays an increase in DRX myosins.…”

“…It has been proposed that variants in other thin filament proteins (TnT and TnI) may affect the SRX/DRX equilibrium ( 68 ). Using human in-silico models of the variants TNNT2 R92Q/+ and TNNI3 R21C/+ , Margara et al ( 68 ) predicted that HCM-linked thin-filament variants lead to a decrease in DRX myosins in contrast to our experimental findings in murine myocardium–containing cTnT-I79N, which displays an increase in DRX myosins. A consistent finding from experimental X-ray studies of thick filament–based mutations ( 64 , 69 ) associated with HCM, however, is an increase in DRX/ON state myosins under relaxed conditions, so the predictions of Margara et al ( 68 ) are surprising.…”

Advancing clinical translation of cardiac biomechanics models: a comprehensive review, applications and future pathways

“…Modelling can provide insight into the impact of genetic variants of sarcomeric proteins and their manifestation under pathological conditions. In [ 109 ], the authors constructed an electromechanical cardiomyocyte model to reproduce phenotypes in hypertrophic cardiomyopathy, linking alterations in model parameters with mutations in myosin heavy chain and troponin genes. When the cell model is coupled with in-vitro measurements, they carried out an in silico clinical trial of the drug mavacamten, a contraction inhibitor used to treat hypertrophic cardiomyopathy.…”

“…We use the definition of in silico trial used before in [ 176 ]: a research study that uses computer models of cells, tissues, organs, or systems of human subjects, assigned to one or more interventions (which may include some form of control group) to evaluate the effects of those interventions on health-related biomedical or behavioural outcomes. In [ 109 ] Margara et al performed a set of in silico trials using ventricular mechanics to investigate the effect of specific mutations in hypertrophic cardiomyopathy. This setup was based on the one presented by Wang et al [ 177 ].…”