Estimated Small Dense LDL Cholesterol and Coronary Artery Disease in Familial Hypercholesterolemia

Recent evidence reports good agreement between measured and estimated small-dense low-density lipoprotein cholesterol (EsdLDL-C) using a readily applicable formula. Its clinical utility in heterozygous familial hypercholesterolemia (HeFH) has not yet been evaluated. We aimed to evaluate the sex-specific associations of pre-treatment EsdLDL-C with coronary artery disease (CAD) prevalence in adult patients with HeFH and its discriminative value beyond LDL-C.

Data from consecutively recruited adults with a clinical diagnosis of HeFH from an ongoing registry (HELLAS-FH, n = 3,276) were analyzed. Patient demographics, lipid parameters, CAD risk factors, and CAD prevalence at registry enrollment were evaluated. EsdLDL-C was calculated at pre-treatment (i.e., before any hypolipidemic therapy initiation) using the Sampson equation.

EsdLDL-C was associated with an increased prevalence of type 2 diabetes and hypertension, a higher body mass index and triglycerides, and lower high-density lipoprotein cholesterol. EsdLDL-C was also the strongest independent lipid-associated factor for CAD (OR: 1.24, p＜0.001). This association was more pronounced in women (OR 1.57, p＜0.001). EsdLDL-C showed higher CAD discrimination than LDL-C (AUC 0.611 vs. 0.522). Incorporating EsdLDL-C into the best discriminative model improved discriminative ability vs the core model (AUC 0.831 vs 0.828, p = 0.038) and overall model fit (ΔAIC) = -10.3). This incremental predictive value was driven predominantly by females (ΔAIC = -14.1; AUC 0.787 vs 0.769, p = 0.015).

In a large sample of patients with clinical HeFH, EsdLDL-C was incrementally associated with CAD beyond LDL-C. This finding was more pronounced in women. The clinical utility of this readily available lipid marker as a risk enhancer should therefore be further investigated.