Genetic status and response patterns to mavacamten: an echocardiographic signature of reverse remodeling from 3 portuguese centers

Background Mavacamten is an effective targeted therapy for symptomatic obstructive hypertrophic cardiomyopathy (oHCM). However, real-world data on the extent and trajectory of cardiac reverse remodeling, based on comprehensive echocardiography, remains scarce. Additionally, the influence of genetic background on treatment response is still incompletely understood. Objective To characterise echocardiographic markers of reverse remodelling in mavacamten-treated oHCM patients from three Portuguese centres and to assess whether genotype influences treatment response patterns. Methods A retrospective multicentre study was conducted including consecutive mavacamten-treated oHCM patients across three Portuguese centres. Clinical, laboratory, ECG, cardiopulmonary exercise, and multimodality imaging (echocardiography and CMR when available) data were collected at baseline, weeks 4, 8, and 12, and at each patient’s optimal dose. Measurements included maximal wall thickness, LV mass index, LVOT gradients (rest and Valsalva), systolic and diastolic function (LVEF, GLS, E/e′), and left atrial size. A composite response endpoint was defined as (i) haemodynamic improvement (normalization or marked LVOT gradient reduction) or (ii) clinical response (≥1 NYHA class). Associations between baseline features, including genotype, and response were assessed using contingency analyses and logistic regression. Results A total of 83 patients were included (mean age 65 ± 12 years; 68.7% female). Baseline functional status was poor (NYHA 2.86), improving markedly at follow-up (NYHA 1.4). Mavacamten induced progressive structural reverse remodeling: (1) maximal wall thickness decreased at 12 weeks (-1.7 mm, p<0.001) and further at optimal dosing (-2.93 mm, p<0.001), (2) indexed LV mass decreased significantly at 12 weeks (-16.8 g/m², p=0.006) and at optimal dose (-24.5 g/m², p=0.002). Hemodynamics improved significantly: resting LVOT gradient fell by -26.4mmHg at 12 weeks and -59.9mmHg at optimal dosing, while provoked gradients decreased by -43.0 mmHg and -92.3 mmHg, respectively (all p<0.001). Diastolic unloading was evident through reductions in E/e′ at 12 weeks (-2.92) and at optimal dose (-4.26) (both p<0.001). LVEF and GLS showed small, expected reductions but remained within clinically preserved ranges. Genetic testing results were available for 73 patients (88%) - 57 patients (78%) negative result or VUS, and 16 patients (22%) P/LP variant. The composite response rate was high across groups: 93.0% in the negative/VUS group vs 100% in the P/LP group (p=0.57). Conclusion Mavacamten led to substantial and progressive improvements in symptoms, haemodynamics, and cardiac structure, with similarly strong responses across all genotypic groups and no evidence of reduced efficacy in patients carrying pathogenic or likely pathogenic variants.