Association of HDL composition and functionality with markers of subclinical vascular disease in individuals with extremely high HDL
Bibliographic record
Abstract
Abstract Background Extremely elevated High-Density Lipoprotein cholesterol (HDL-c) concentrations, defined as hyperalphalipoproteinemia (HALP), have paradoxically been associated with increased cardiovascular (CV) risk. Emerging evidence suggests a U-shaped relationship between HDL-c and CV risk, suggesting that in HALP, HDL particles may exhibit altered composition or impaired functionality. Purpose To evaluate the association between HDL composition and functionality and altered markers of subclinical vascular disease (SVD) in individuals with HALP. Methods A total of 45,000 individuals from a large population cohort and a specialized cardiology center database were screened, identifying 62 participants (0.14%) aged 45–75 years, with HDL-c levels ≥90 mg/dL and no established clinical CV disease. Coronary artery calcium (CAC) quantification and carotid intima-media thickness (cIMT) were assessed, while pulse wave velocity (PWV) was measured using applanation tonometry, with all considered markers of SVD. Plasma lipid profile and apolipoprotein (apo) A-IV levels were measured using commercial assays. The simultaneous transfer of cholesteryl ester (CE) and unesterified cholesterol (UC) to the HDL fraction, along with its anti-inflammatory properties, assessed by the inhibition of IL-6 and TNF-α, were evaluated. Following the in vitro tests, HDL3 and HDL2 subfractions were characterized in terms of lipid composition, antioxidant capacity, and cholesterol efflux capacity. Results Among the 62 participants, 79.0% were female, with a median HDL-c level of 96 mg/dL (IQR 90–105) and a body mass index (BMI) of 23.5 kg/m² (IQR 21.4–26.3). Thirty-one participants exhibited at least one altered marker of SVD and were older than those without (64.2 ± 8.0 vs. 57.7 ± 9.1 years; p = 0.0043). Hypertension was more prevalent in the SVD group (p = 0.0209). While diabetes prevalence was similar across groups, glucose was higher in the SVD group (p = 0.0404). No differences were observed in the plasma lipid profile, apo A-IV levels, or HDL functionality-related parameters, in addition to the transfer of CE and UC to the HDL fraction. However, the SVD group showed increased concentrations of phospholipids and triglycerides in the HDL3 subfraction compared to the non-SVD group (p = 0.0113 and p = 0.0227, respectively). After multivariate adjustment for sex, BMI, hypertension, diabetes, glucose, and smoking, only age (OR 1.11, 95% CI 1.03–1.20; p = 0.0075) and phospholipid concentration in the HDL3 subfraction (OR 1.00, 95% CI 1.00–1.23; p = 0.0422) remained independently and positively linked to SVD. Conclusion Besides age, specific features of HDL composition, such as increased phospholipid concentrations in the HDL3 subfraction, are independently associated with SVD. This suggests that the protective role of HDL may be compromised in these individuals, regardless of their highly elevated HDL-c concentrations.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".