PO94
Beyond Genotype in Hypertrophic Cardiomyopathy: CMR and Biomarkers Drive Risk, Genetics Shapes Phenotype

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy, usually caused by sarcomeric gene variants. However, genotype–phenotype correlations remain debated, and the incremental prognostic value of genetic testing is uncertain.

To evaluate relationships between genotype and clinical, imaging, and outcome features in HCM.

We studied 300 consecutive HCM patients (median age 68 years, IQR 57-76 years; 31% female) referred for cardiac magnetic resonance (CMR) from 2012 to 2024. All underwent ECG, 24-hour Holter ECG, echocardiography, CMR, measurement of cardiac biomarkers, and Next Generation sequencing. Variants were classified as pathogenic/likely pathogenic (P/LP), variants of uncertain significance (VUS), or negative. Analyses included comparisons by genotype category, thick vs thin filament variants, and the presence of myocardial oedema on T2-weighted STIR sequencing. The primary endpoint was a composite of cardiac death or sustained ventricular arrhythmias.

P/LP variants were detected in 116 subjects (39%), VUS in 67 (22%), and negative in 117 (39%). Compared with VUS/negative, P/LP carriers were younger at diagnosis (57 vs 63 years, p=0.002), more often female (36% vs 27%, p<0.001), had more family history of HCM (31% vs 12%, p<0.001), and more often non-sustained ventricular tachycardia (32% vs 19%, p=0.004). They showed greater maximal wall thickness (19 vs 17 mm, p=0.029), more myocardial crypts (27% vs 11%; p<0.001), and a higher prevalence of a hyperkinetic LV (36% vs 21%; p=0.002). Apical and concentric phenotypes were more frequent in VUS/negative, whereas asymmetric septal hypertrophy predominated in P/LP. Late gadolinium enhancement (LGE) prevalence was similar, but P/LP carriers had higher LGE burden (2.1% vs 1.0%, p<0.001). Among 153 patients with T2-STIR imaging, 47 (31%) had myocardial oedema. Oedema was associated with greater wall thickness (20 vs 17 mm; p<0.001), lower left ventricular ejection fraction (LVEF; 65% vs 69%; p=0.024), and more extensive LGE (3.0% vs 0.9%; p<0.001), independent of genotype. Within P/LP carriers, thick filament variants (87%; mainly MYBPC3 and MYH7) were more common than thin filament (11%). MYBPC3 was linked to later onset and milder hypertrophy, whereas rare MYL3 variants (5%) were associated with earlier and more severe disease. Among patients with VUS, 22 (33%) carried non-sarcomeric variants. Over a median follow-up of 4.0 years (IQR 1.5-7,8), 23 primary events occurred. In multivariable analyses, higher N-terminal pro-B-type natriuretic peptide (hazard ratio [HR] 2.24, 95% CI 1.54-3.26) and troponin (HR 3.21, 95% CI 1.75-5,89), and lower LVEF (HR 2.75, 95% CI 1.47-5.16) and tricuspid annular plane systolic excursion (HR 0.06, 95% CI 0.01-0.62) independently predicted the endpoint. Overall genotype category was not independently associated with outcomes, although MYL3 variants independently conferred higher risk.

P/LP sarcomeric variants are linked to a more advanced structural phenotype, while apical forms are predominantly genotype-negative. Myocardial oedema tracks with disease severity irrespective of genotype. Prognosis is driven mainly by biomarkers and functional parameters rather than by genotype alone, with the notable exception of MYL3 variants. These findings support integrated genetic, clinical, and CMR assessment for personalised risk stratification in HCM.