MYH7 mutation increased EF to 60% from 56%, but remodelling reduced EF to 51%; Mavacamten dose-dependently reduced hypercontractility with variable efficacy.
Does mavacamten and progressive remodeling affect cardiac electromechanical function in a computational model of MYH7-mutated hypertrophic cardiomyopathy?
Computational modeling demonstrates that while MYH7 mutations enhance contractility, progressive remodeling reduces diastolic filling and stroke volume, and mavacamten's efficacy varies based on the extent of remodeling.
Absolute Event Rate: 0% vs 0%
Abstract Background Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease, affecting at least 1 in 500 individuals worldwide and a leading cause of sudden cardiac death in young adults. MYH7 gene mutations, encoding the β-myosin heavy chain, account for ~40% of familial HCM cases and contribute to hypercontractility, diastolic dysfunction, and arrhythmia risk. However, the interplay between MYH7 mutations, ionic remodelling, and hypertrophy in disease progression remains unclear, limiting targeted therapy development. Purpose This study aims to investigate the mechanistic contributions of MYH7 mutation, hypertrophic growth, and secondary ionic remodelling in HCM using multiscale computational electromechanical models. Additionally, we evaluate the therapeutic efficacy of novel cardiac myosin inhibitors across different pathological stages of HCM to support the development of precision therapies. Methods A multi-scale computational model, based on established cellular electromechanical frameworks 1, was developed to simulate cardiac electromechanical function under four conditions: (i) Control (healthy cardiac function), (ii) MYH7 mutation alone (hypercontractility and diastolic dysfunction), (iii) MYH7 + ionic remodelling (altered calcium sensitivity and impaired relaxation), and (iv) MYH7 + ionic + anatomical remodelling (combined effects of hypertrophy and ionic remodelling). Figure 1 illustrates the progressive structural, ionic, and electromechanical alterations across these conditions. The dose-dependent effects of Mavacamten 2, a novel cardiac myosin inhibitor, on contractility and relaxation dynamics were assessed across these conditions. Results The MYH7 mutation increased ejection fraction (EF) to around 60% from 56% in the control, indicating hypercontractility. With ionic remodelling, EF remained at 58%, while geometric remodelling reduced it to 51%. Stroke volume (SV) progressively declined with remodelling, from 86.7 mL in the control to 82.2 mL with ionic remodelling and 62.2 mL with geometric remodelling. Similarly, end-diastolic volume (EDV) followed a decreasing trend, from 154.4 mL in the control to 142.4 mL with ionic remodelling and 123.3 mL with hypertrophic remodelling. These results suggest that while MYH7 mutations enhance contractility, remodelling progressively reduces diastolic filling and stroke volume, lowering EF. Mavacamten reduced hypercontractility dose-dependently but only partially restored relaxation, with efficacy varying based on remodelling extent, suggesting a need for personalised treatment. Conclusion This study provides novel insights into the pathophysiology of HCM, demonstrating the distinct and combined effects of MYH7 mutations, ionic remodelling, and hypertrophy. Our computational findings underscore the value of in-silico modelling in precision medicine, highlighting the potential of cardiac myosin inhibition as a targeted therapy for HCM management.
Hasaballa et al. (Sat,) reported a other. MYH7 mutation increased EF to 60% from 56%, but remodelling reduced EF to 51%; Mavacamten dose-dependently reduced hypercontractility with variable efficacy.