Coronary atherosclerotic burden in severe dyslipidemia: heterogeneity beyond genetic status

Background Severe dyslipidemia is a common indication for cardiovascular risk stratification, yet coronary atherosclerotic burden varies widely among affected patients. Whether genetic status, particularly familial hypercholesterolemia, meaningfully identifies individuals with greater coronary involvement beyond metabolic phenotype remains uncertain. Purpose To assess coronary anatomical heterogeneity in severe dyslipidemia and determine whether FH confers greater atherosclerotic burden than non-genetic dyslipidemia. Methods We studied consecutive patients from a tertiary cardiovascular hospital with severe dyslipidemia (LDL >190 mg/dL at any time or genetically confirmed FH) who underwent coronary CT angiography. Coronary burden was assessed using three complementary outcomes: obstructive coronary artery disease defined as lesions considered clinically significant by the reporting radiologist; coronary calcium burden modeled as log(CAC+1); and CAC severity strata (0, 1–99, 100–399, ≥400). Associations between FH and obstructive coronary disease were evaluated using logistic regression, continuous CAC burden using linear regression, and CAC severity strata using ordinal regression models. Hierarchical adjustment sequentially incorporated clinical risk factors, LDL measured within 180 days of imaging, and statin therapy. Results The cohort included 1,468 patients, of whom 309 had genetically confirmed FH. FH patients were younger and had lower prevalence of hypertension and diabetes, while high-intensity statin use was more frequent. Despite these differences, coronary anatomical burden was comparable between groups. In hierarchical multivariable analyses, FH was not independently associated with obstructive coronary disease (adjusted OR 0.80, 95% CI 0.48–1.36), continuous CAC burden (β −0.17, 95% CI −0.59 to 0.25), or CAC severity strata (adjusted OR 0.93, 95% CI 0.69–1.26). Conclusion FH did not independently identify greater coronary atherosclerotic burden among patients with severe dyslipidemia after adjustment for clinical and metabolic factors. These findings emphasize substantial heterogeneity within severe dyslipidemia and support the role of coronary imaging to refine risk assessment beyond genetic status.Table 1Table 2