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Association of HDL subclass components with all-cause and cardiovascular mortality: a prospective cohort study based
Xuan Liu1, Siqi Lin1, Hao Zhang1
1National Clinical Research Center for Cardiovascular Diseases, National Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Insights
Larger high-density lipoprotein cholesterol (HDL) subclasses correlate with increased mortality risk, while smaller, denser HDL particles offer protection. This explains the U-shaped relationship between HDL cholesterol and mortality risk.
Area of Science:
- Cardiovascular Research
- Lipid Metabolism
- Mortality Risk Factors
Background:
- The U-shaped association between HDL cholesterol (HDL-C) and mortality is known, but HDL subclass contributions are unclear.
- Understanding HDL subclasses is crucial for explaining HDL-C's complex relationship with mortality.
Purpose of the Study:
- To analyze HDL subclass component variations across HDL-C levels.
- To assess HDL subclass associations with all-cause and cardiovascular mortality risk.
Main Methods:
- 1,585 participants (35-75 years) from the ChinaHEART study.
- Nuclear magnetic resonance for lipoprotein analysis (HDL subclasses, TG, CH, FC, PL, Apo-A1, Apo-A2).
- Cox regression and competing risk models, with restricted cubic splines for nonlinear associations.
Main Results:
- Larger, buoyant HDL components (e.g., H1CH, H1A1) linked to higher all-cause mortality.
- Smaller, denser HDL components (e.g., H4CH, H4A1) showed protective effects.
- H1PL, H1A1, H1A2 were independent cardiovascular mortality risk factors.
Conclusions:
- HDL subclasses differentially impact mortality risk.
- Smaller, denser HDL particles are protective against mortality.
- The U-shaped HDL-C-mortality curve may be explained by extreme levels of specific HDL subclasses.
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.
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