High burden of subclinical coronary artery disease in asymptomatic adults with heterozygous familial hypercholesterolemia

Aims To characterize the burden and severity of subclinical coronary artery disease (CAD) detected by coronary computed tomographic angiography (CCTA) in asymptomatic adults with heterozygous familial hypercholesterolemia (HeFH) without prior atherosclerotic cardiovascular disease (ASCVD), to identify demographic and disease-related factors associated with greater CAD burden, and to assess whether CCTA-detected CAD is associated with subsequent coronary revascularization and ASCVD events. Methods Asymptomatic adults with genetically confirmed or clinically diagnosed HeFH (Dutch Lipid Clinic Network score ≥8) enrolled in the French REFERCHOL registry who underwent CCTA were included. The registry prospectively collects standardized data from lipid clinics nationwide. CAD burden was categorized according to the presence and severity of coronary stenosis. Demographic and clinical factors, including markers of lifetime LDL-C exposure, were assessed in relation to CAD severity. Incident coronary revascularization and ASCVD events were recorded during follow-up and analyzed according to baseline CCTA findings. Results Between 2015 and 2025, 435 asymptomatic HeFH patients (mean age 48.2 years; 56% women; 96% genetically confirmed) underwent CCTA. Normal coronary arteries were found in 161 (37.0%) patients, non-obstructive CAD in 185 (42.5%), and obstructive CAD in 89 (20.4%). CAD was detected as early as 24 years of age, with obstructive disease observed from 30 years. Coronary artery calcium (CAC) scores correlated with CAD severity, yet 7.5% of patients with a CAC score of zero had CAD on CCTA. Male sex, older age, and higher untreated LDL-c values were independently associated with increase CAD severity whereas age at diagnosis was inversely associated with CAD. Over a median 24-months follow-up, 33 patients required coronary revascularization and 9 experienced ASCVD events, all occurring in individuals with abnormal CCTA results. Conclusion CCTA revealed a substantial burden of subclinical CAD in asymptomatic HeFH adults, associated with higher untreated LDL-c value and age at diagnosis and leading to subsequent coronary revascularization or ASCVD events. These findings support further evaluation of targeted CCTA-based risk stratification to improve primary prevention in HeFH.