Diagnostic Role of Wall Thickness Heterogeneity in Hypertrophic Cardiomyopathy and in Carriers of Sarcomeric Gene Mutations

BackgroundHypertrophic cardiomyopathy (HCM) is characterized by variable left ventricular hypertrophy, but current diagnostic criteria rely on absolute wall thickness thresholds that may miss early or subtle phenotypic expressions, especially in sarcomere mutation carriers. ObjectivesThis study aimed to assess whether wall thickness standard deviation (WTSD), as a marker of wall thickness heterogeneity, improves the identification of HCM and mutation carriers. MethodsWe evaluated 382 healthy controls, 297 patients with guideline-based HCM diagnosis, and 82 sarcomere mutation carriers without overt hypertrophy using cardiac magnetic resonance imaging. End-diastolic wall thickness (WT) was measured across 16 myocardial segments, and WTSD was calculated. Diagnostic performance of WTSD and other wall thickness-derived parameters was assessed using age- and sex-specific thresholds. ResultsWTSD was significantly higher in HCM patients (4.3 {+/-} 1.1 mm) and mutation carriers (2.3 {+/-} 0.3 mm) compared to healthy controls (1.3 {+/-} 0.3 mm; p<0.0001). WTSD identified 97% of HCM patients and 64% of mutation carriers, with excellent specificity (99%). In females, WTSD achieved a sensitivity of 98.9% and specificity of 100% for HCM diagnosis, and identified 74% of female mutation carriers. WTSD outperformed demographic-based personalized thresholds and BSA-indexed maximal WT in all subgroups. Mutation carriers exhibited increased heterogeneity due to the coexistence of hypertrophic and thinned segments, despite normal absolute WT. ConclusionsWTSD is a robust imaging biomarker that detects early and overt manifestations of sarcomeric HCM with high accuracy. Incorporating WT heterogeneity into diagnostic algorithms may enhance early identification, particularly in women and mutation carriers. CONDENSED ABSTRACTWall thickness heterogeneity, quantified as wall thickness standard deviation (WTSD) by magnetic resonance, emerged as a powerful diagnostic marker of sarcomeric hypertrophic cardiomyopathy (HCM). In 297 HCM patients and 82 mutation carriers, WTSD identified nearly all overt cases and 64% of carriers without hypertrophy with excellent specificity (99%). Particularly in women, WTSD achieved near-perfect diagnostic accuracy and uncovered early disease otherwise missed by conventional thresholds. These findings support incorporating WT heterogeneity into diagnostic algorithms to enable earlier identification of at-risk individuals and refine risk stratification beyond absolute wall thickness criteria.