Key result
Mavacamten abolishes contractile differences and reverses cardiomyocyte hypertrophy in TPM1 E192K engineered heart tissues.
Why the study?
Thin filament mutations are associated with severe HCM phenotypes, but the mechanisms of the TPM1 E192K variant of uncertain significance remained poorly understood.
Does mavacamten reverse hypertrophy and contractile abnormalities in patient-derived engineered heart tissues expressing the TPM1 E192K mutation?
Does mavacamten reverse hypertrophy and contractile abnormalities in patient-derived engineered heart tissues expressing the TPM1 E192K mutation?
Mavacamten reverses cellular hypertrophy and contractile abnormalities in patient-derived engineered heart tissues with the TPM1 E192K mutation, providing direct evidence that myosin inhibition can counteract the effects of mutant tropomyosin.
Hypothesis-generating for mavacamten in TPM1 E192K models; leaves open clinical translation to mutation-specific HCM.
Hypertrophic cardiomyopathy (HCM) is an inherited disorder caused primarily by mutations to thick and thinfilament proteins. Although thin filament mutations are less prevalent than their oft-studied thick filament counterparts, they are frequently associated with severe patient phenotypes and can offer important insight into fundamental disease mechanisms. We have performed a detailed study of tropomyosin (TPM1) E192K, a variant of uncertain significance associated with HCM. Molecular dynamics revealed that E192K results in a more flexible TPM1 molecule, which could affect its ability to regulate crossbridges. In vitro motility assays of regulated actin filaments containing TPM1 E192K showed an overall loss of Ca2+ sensitivity. To understand these effects, we used multiscale computational models that suggested a subtle phenotype in which E192K leads to an inability to completely inhibit actin-myosin crossbridge activity at low Ca2+. To assess the physiological impact of the mutation, we generated patient-derived engineered heart tissues expressing E192K. These tissues showed disease features similar to those of the patients, including cellular hypertrophy, hypercontractility, and diastolic dysfunction. We hypothesized that excess residual crossbridge activity could be triggering cellular hypertrophy, even if the overall Ca2+ sensitivity was reduced by E192K. To test this hypothesis, the cardiac myosin-specific inhibitor mavacamten was applied to patient-derived engineered heart tissues for 4 d followed by 24 h of washout. Chronic mavacamten treatment abolished contractile differences between control and TPM1 E192K engineered heart tissues and reversed hypertrophy in cardiomyocytes. These results suggest that the TPM1 E192K mutation triggers cardiomyocyte hypertrophy by permitting excess residual crossbridge activity. These studies also provide direct evidence that myosin inhibition by mavacamten can counteract the hypertrophic effects of mutant tropomyosin.
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Sewanan et al. (2021) studied Hypertrophic cardiomyopathy (HCM). Mavacamten vs. Control engineered heart tissues was evaluated on Contractile differences and cellular hypertrophy. Mavacamten treatment abolished contractile differences between control and TPM1 E192K patient-derived engineered heart tissues and reversed hypertrophy in cardiomyocytes.
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