Use of Advanced Echocardiographic Modalities to Discriminate Preclinical Hypertrophic Cardiomyopathy Mutation Carriers From Non-Carriers

BACKGROUND: It remains challenging to determine which hypertrophic cardiomyopathy (HCM) family members will subsequently develop HCM. Standard 2-dimensional and conventional Doppler echocardiography have been unable to reliably distinguish HCM genotype-positive and phenotype-negative (G+P−) from genotype-negative and phenotype-negative (G−P−) family members. We aimed to determine if advanced echocardiographic modalities can discriminate HCM G+P− from G−P− individuals. METHODS: Comprehensive echocardiography including speckle tracking evaluation of myocardial deformation and color M-mode were performed in 199 participants aged ≥16 years who had undergone genetic testing from families with a known HCM pathogenic variant: 58 G+P−, 39 G−P−, and 102 overt patients with HCM (genotype-positive and phenotype-positive). The primary analysis compared these measures in all G+P− and G−P− individuals. A secondary analysis was undertaken in younger subjects (age ≤40 years). RESULTS: Comparing G+P− and G−P− individuals, there were no significant differences in left ventricular ejection fraction, cavity size, wall thickness and outflow tract gradient, and tissue Doppler-derived myocardial velocities; however, septal/posterior wall thickness ratio was higher (1.06±0.09 versus 1.02±0.04, P =0.007). G+P− individuals had significantly lower color M-mode flow propagation velocity (color M-mode velocity propagation, 42.6 cm/s [interquartile range, 34.5–48.5 cm/s] versus 51.0 cm/s [interquartile range, 45.2–61.0 cm/s]; P <0.001) and higher global longitudinal strain ( P =0.021), circumferential strain ( P =0.003), and peak apical rotation ( P =0.005). Multivariable logistic regression identified 2 independent predictors (color M-mode velocity propagation and peak apical rotation). A derived regression equation allowed reasonable discrimination of G+P− individuals with a sensitivity of 82.6% and specificity of 72.2% ( P <0.0001) at the optimal cutoff. Similar findings were demonstrated when the analysis was restricted to younger subjects, although in addition to color M-mode velocity propagation and apical rotation, left ventricular ejection fraction was also independently predictive. CONCLUSIONS: In HCM family members, color M-mode velocity propagation and apical rotation provide good sensitivity and specificity for identifying mutation carriers and may represent early disease markers before the onset of hypertrophy. Longitudinal studies involving larger cohorts are required to validate these findings.