Lipids Health Dis. 2026 Jan 27. doi: 10.1186/s12944-026-02874-w. Online ahead of print.
ABSTRACT
BACKGROUND: While the U-shaped association between high-density lipoprotein cholesterol (HDL-C) levels and the risk of all-cause and cardiovascular mortality is well-established, the underlying contributions of HDL subclasses remain poorly understood. This study aimed to comprehensively analyze the variations of HDL subclass components across different HDL-C levels and assess their associations with the risk of all-cause and cardiovascular mortality.
METHODS: This study enrolled 1,585 participants aged 35-75 years from China Health Evaluation And risk Reduction through nationwide Teamwork (ChinaHEART) (2014-2023). Lipoprotein parameters were measured by nuclear magnetic resonance, with a focus on triglycerides (TG), cholesterol (CH), free cholesterol (FC), phospholipids (PL), apolipoprotein A1 (Apo-A1) and apolipoprotein A2 (Apo-A2) within four density-separated HDL subclasses (HDL1-HDL4). Between-group comparisons were performed using analysis of variance with post-hoc least significant difference tests. Cox proportional hazards regression models and competing risk models were used to assess the association of HDL subclass components with all-cause and cardiovascular mortality. Potential nonlinear associations were examined using models with restricted cubic splines (RCS).
RESULTS: During a median follow-up of 7.6 years, 84 all-cause (5.3%) and 23 (1.5%) cardiovascular deaths were documented. As HDL-C concentration increased, most HDL subclass components (including CH, FC, PL, and Apo-A1) also increased across low (≤ 30 mg/dL), intermediate (50-60 mg/dL), and high (≥ 100 mg/dL) HDL-C groups. Regression models showed that components in larger, more buoyant HDL subclasses (such as H1TG, H2TG, H1CH, H1FC, H1PL, H1A1, H1A2 and H2A2) were positively associated with all-cause mortality, whereas smaller, denser ones (including H4CH, H4FC, H4PL, H4A1 and H4A2) exhibited protective effects. H1PL, H1A1 and H1A2 also emerged as independent risk factors for cardiovascular mortality. The RCS analysis revealed positive linear associations of H1CH and H1A1 with all-cause mortality, while H4CH and H4A1 were inversely associated.
CONCLUSIONS: Larger, more buoyant HDL subclasses showed a positive association with all-cause mortality, whereas smaller, denser ones were protectively associated. The U-shaped association between HDL-C and mortality may be primarily explained by lower levels of H4CH at very low HDL-C concentrations and higher levels of H1CH at extremely high HDL-C levels. Similar explanations could also account for the association between Apo-A1 and mortality.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT02536456. Registered 24 August 2015.
PMID:41593465 | DOI:10.1186/s12944-026-02874-w