MRI-derived wall thickness heterogeneity in hypertrophic cardiomyopathy and in carriers of sarcomeric gene mutations

BACKGROUND: Hypertrophic cardiomyopathy (HCM) shows variable left ventricular hypertrophy, yet current diagnostic criteria rely on absolute wall thickness (WT) cut-offs that may miss early or subtle phenotypes, particularly in sarcomere mutation carriers. OBJECTIVES: To determine whether wall thickness standard deviation (WTSD), reflecting WT heterogeneity, improves identification of HCM and mutation carriers. METHODS: Cardiac magnetic resonance was performed in 382 healthy controls, 297 patients with HCM, 82 sarcomere mutation carriers without overt hypertrophy, and 180 patients with other cardiac conditions (75 with and 105 without LV hypertrophy). End-diastolic WT was measured in 16 myocardial segments, and WTSD was computed. Diagnostic performance was compared with other WT-derived parameters using age- and sex-specific thresholds. RESULTS: WTSD was higher in HCM (4.3 ± 1.1 mm) and mutation carriers (2.3 ± 0.3 mm) than in controls (1.3 ± 0.3 mm; p<0.0001). WTSD identified 97% of HCM and 64% of carriers with 99% specificity. In females, WTSD achieved 98.9% sensitivity and 100% specificity for HCM and detected 74% of carriers. WTSD outperformed demographic-based thresholds and BSA-indexed maximal WT in all subgroups. Mutation carriers showed heterogeneous remodeling with both hypertrophic and thinned segments despite normal absolute WT. WTSD was significantly higher in HCM than in all cardiac conditions with LV hypertrophy and in mutation carriers versus non-hypertrophic conditions, except post-ischemic severe LV dysfunction. CONCLUSIONS: WTSD is a robust imaging biomarker that detects both overt and early sarcomeric HCM with high accuracy. Incorporating WT heterogeneity into diagnostic algorithms may enhance early identification, especially in women and mutation carriers.