Artificial Intelligence-Enhanced Electrocardiography for Detection and Prediction of Hypertrophic Cardiomyopathy across Monogenic and Polygenic Susceptibility

BackgroundCascade screening increasingly identifies carriers of pathogenic or likely pathogenic sarcomere variants at risk for hypertrophic cardiomyopathy (HCM) in whom penetrance is incomplete, and surveillance relies on resource-intensive serial imaging. We evaluated whether a validated artificial intelligence-enhanced electrocardiography (AI-ECG) model identifies the HCM phenotype at first clinical assessment, predicts development of HCM during follow-up, and complements polygenic risk. MethodsWe assembled 1,095 genotype-positive (G+) individuals with pathogenic or likely pathogenic sarcomere variants from Yale-New Haven Hospital (n=119), Erasmus MC (n=858), and Motol University Hospital (n=118). At baseline (first clinical assessment), individuals were classified as phenotype-positive (P+) or phenotype-negative (P-). A previously validated AI-ECG model applied to 12-lead ECG images generated an HCM score. The primary outcome was detection of phenotypic positivity at baseline; secondary analyses included manifest HCM (at baseline or during follow-up) and identifying risk of developing future HCM among G+/P-individuals. In 57,007 UK Biobank participants, we assessed whether AI-ECG adds to an established polygenic risk score (PRS). ResultsAmong 1,095 G+ individuals (median age 46 years [IOR 34-56]; 52.1% female), 808 (73.8%) were P+ at baseline, 56 (5.1%) developed HCM during follow-up, and 231 (21.1%) remained P-. AI-ECG achieved an AUROC of 0.91 (95% CI 0.89-0.93) for P+ at baseline and 0.92 (95% CI 0.90-0.94) for manifest HCM. At a threshold of 0.15, sensitivity was 0.78, specificity 0.89, PPV 0.95, and NPV 0.59. Among G+/P- individuals, higher AI-ECG scores predicted development of HCM (HR 1.55 per 1-SD; 95% CI 1.28-1.88; p<0.001; adjusted HR 1.38; 95% CI 1.11-1.71; p=0.004). In the UK Biobank, individuals with both high AI-ECG and high PRS had 60-fold higher odd...