Diastolic reserve restoration drives functional improvement under mavacamten in obstructive hypertrophic cardiomyopathy: a real-world CPET–echocardiography study

Background Cardiac myosin inhibition improves symptoms and exercise capacity in obstructive hypertrophic cardiomyopathy (oHCM), yet the physiological drivers of functional benefit remain debated. Beyond relief of LVOT obstruction, it is unknown whether exercise improvement reflects enhanced systolic performance, structural remodeling, or restoration of diastolic reserve and atrioventricular coupling. Methods In this prospective real-world study, 95 oHCM patients initiated mavacamten; 82 with paired baseline and 6-month assessments were analyzed. Cardiopulmonary exercise testing (CPET) and comprehensive transthoracic echocardiography were performed at baseline and 6 months. Functional response was defined as peak VO2 increase ≥ 1.5 mL/kg/min or ≥ 10% rise in oxygen pulse without VE/VCO2 deterioration (> 2 units). Associations between CPET and echocardiographic changes were examined, and baseline predictors of response were identified using bootstrap-validated multivariable modelling. Results At 6 months, 31/82 patients (37.8%) met functional response criteria. Mean peak VO2 remained stable (19.3 ± 5.9 vs 19.1 ± 5.6 mL/kg/min), whereas ventilatory efficiency improved (VE/VCO2 slope 32.5 ± 5.5 to 30.1 ± 4.8; p<0.001) and oxygen pulse increased (11.9 to 12.2 mL/beat; p<0.001), indicating enhanced stroke volume response. Echocardiography demonstrated marked improvement in diastolic indices (septal and lateral e′ ↑, both p<0.001; E/e′ 10.8 to 9.2; p<0.001) with significant left-atrial volume reduction (LAVImin and LAVImax, both p<0.001). In contrast, left-atrial strain and LV systolic parameters were unchanged. Baseline predictors of functional response were left-atrial volume index (nonlinear relationship) and global longitudinal strain (optimism-corrected AUC 0.72). No baseline variable predicted absolute peak VO2 change. Conclusions In real-world oHCM treated with mavacamten, functional improvement is not mediated by peak VO2 increase but by improved ventilatory efficiency and stroke volume reserve. These gains closely track reductions in filling pressures and atrial unloading, supporting restoration of diastolic reserve and atrioventricular coupling—rather than systolic or structural remodeling—as the dominant mechanism of clinical benefit.VE/VCO2LAVmin