Simulating haemodynamic outcomes of pharmacological contractility reduction in obstructive hypertrophic cardiomyopathy

Obstructive hypertrophic cardiomyopathy (oHCM) is characterised by pronounced myocardial hypercontractility, hypertrophy and myofibrillar disarray. Approximately a third of patients demonstrate dynamic left ventricular outflow tract (LVOT) obstruction due to systolic anterior motion of the mitral valve with septal contact and associated mitral regurgitation. Recent clinical advances include cardiac myosin inhibitors, which reduce myocardial contractility and alleviate the LVOT pressure gradient. Despite these advances, personalised predictive models remain lacking for treatment planning in oHCM.

This study evaluates a computational Virtual Human Trial framework for predicting haemodynamic responses in oHCM, specifically examining whether a patient-specific 3D-0D electromechanical model of the heart and circulation can reproduce the clinically observed reduction in the LV-aortic pressure gradient (Δp) following pharmacologically induced contractility reduction.

A patient-derived cardiac anatomy was reconstructed from high-resolution CMR to model a representative oHCM case with ventricular hypertrophy, myocardial fiber disarray, LVOT narrowing, and mitral regurgitation. The fully coupled electromechanical model (3D finite-element cardiac simulation coupled to a 0D closed-loop lumped-parameter systemic and pulmonary circulatory model) simulated cardiac electrophysiology, tissue mechanics, and circulation. Simulations were performed for three conditions: a healthy control, the untreated oHCM case, and a treated oHCM state with a 50% reduction in myocardial contractility, simulating the effect of myosin inhibitor therapy.

The oHCM simulation exhibited elevated peak left ventricular systolic pressure (approximately 150 mmHg), regurgitant flow through the mitral valve, reduced stroke volume and ejection fraction, and a significant LV-aortic pressure gradient (Δp ≈ 67 mmHg) during systole, reflecting LVOT obstruction. In the treated state, the model captured a marked reduction in Δp. These findings qualitatively align with reported clinical effects of myosin inhibitor therapy, which similarly decreases the LV-aortic pressure gradient by reducing contractile force.

This patient-specific computational framework successfully replicated key haemodynamic features of oHCM and predicted the reduction in LV-aortic pressure gradient following contractility reduction. The approach is being extended to a cohort of six patients with pre- and post-treatment imaging to validate model predictions against clinical data. Future simulations will explore individual responses under varying degrees of contractility reduction, with a view to supporting personalised therapy planning in oHCM.

Pipeline to build the cardiac model