Beyond Early LDL Cholesterol Lowering to Prevent Coronary Atherosclerosis in Familial Hypercholesterolemia

BACKGROUND: Familial hypercholesterolemia (FH) patients are subjected to a high lifetime exposure to low-density lipoprotein cholesterol (LDL-C), despite use of lipid-lowering therapy (LLT). This study aimed to quantify the extent of subclinical atherosclerosis and to evaluate the association between lifetime cumulative LDL-C exposure and coronary atherosclerosis in young FH patients.

METHODS: FH patients, divided into a subgroup of early treated (LLT initiated <25 years) and late treated (LLT initiated ≥25 years) patients, and an age- and sex-matched unaffected control group, underwent coronary CT angiography (CCTA) with artificial intelligence-guided analysis.

RESULTS: Ninety genetically diagnosed FH patients and 45 unaffected volunteers (mean age 41 ± 3 years, 51 (38%) female) were included. FH patients had higher cumulative LDL-C exposure (181 ± 54 vs. 105 ± 33 mmol/l*years) and higher prevalence of coronary plaque compared with controls (46 [51%] vs. 10 [22%], OR 3.66 [95%CI 1.62-8.27]). Every 75 mmol/l*years cumulative exposure to LDL-C was associated with a doubling in percent atheroma volume (total plaque volume divided by total vessel volume). Early treated patients had a modestly lower cumulative LDL-C exposure compared with late treated FH patients (167 ± 41 vs. 194 ± 61 mmol/l*years; p = 0.045), without significant difference in coronary atherosclerosis. FH patients with above-median cumulative LDL-C exposure had significantly higher plaque prevalence (OR 3.62 [95%CI 1.62-8.27]; p = 0.001), compared with patients with below-median exposure.

CONCLUSIONS: Lifetime exposure to LDL-C determines coronary plaque burden in FH, underlining the need of early as well as potent treatment initiation. Periodic CCTA may offer a unique opportunity to monitor coronary atherosclerosis and personalize treatment in FH.