Evaluating the Low‐Density Lipoprotein Cholesterol Paradox in Heart Failure With Reduced Ejection Fraction

Background Hypercholesterolemia is an established cardiovascular risk factor. However, studies in patients with heart failure with reduced ejection fraction (HFrEF) showed an association between low low‐density lipoprotein cholesterol (LDL‐C) and increased mortality, termed the “LDL‐C paradox.” This study examined the impact of LDL‐C on clinical outcomes in patients with HFrEF and identify distinct hypocholesterolemia subgroups using latent class analysis. Methods Consecutive patients with HFrEF (left ventricular EF <40%) from national registries (2016–2022) were stratified by LDL‐C quartiles, with the lowest quartile ≤1.73 mmol/L. Latent class analysis was performed to identify subsets of patients in the lowest quartile. Outcomes included 1‐year all‐cause mortality, cardiovascular mortality, readmission, and composite end points. Results Among 2188 patients, the lowest LDL‐C quartile had higher 1‐year all‐cause mortality than Quartile 2 and 3 ( P <0.05) but not Quartile 4, with no intergroup differences in cardiovascular mortality, readmissions, or composite outcomes between groups. Latent class analysis identified 2 hypocholesterolemia subgroups: pathological and nonpathological hypocholesterolemia. The pathological subgroup was older, lower weight, with higher comorbidity burden. Compared with patients with hypercholesterolemia, the pathological hypocholesterolemia subgroup had higher 1‐year all‐cause mortality (adjusted hazard ratio [HR], 2.14 [95% CI, 1.17–2.69], P <0.001), cardiovascular mortality (adjusted HR, 1.93 [95% CI, 1.46–2.54], P <0.001), and composite end points (adjusted HR, 1.15 [95% CI, 1.01–1.30], P =0.037), and the subgroup with nonpathological hypocholesterolemia showed comparable outcomes. Conclusions A distinct subset of patients with HFrEF with low LDL‐C demonstrates different clinical characteristics (older and higher comorbidity burden) and poorer outcomes, potentially elucidating the “LDL‐C paradox” cause in patients with HFrEF.