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Association Between High-Density Lipoprotein Cholesterol Levels and Adverse Cardiovascular Outcomes in High-risk
Chang Liu1,2, Devinder Dhindsa1, Zakaria Almuwaqqat1
1Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
Insights
Very high high-density lipoprotein cholesterol (HDL-C) levels paradoxically increase mortality risk in patients with coronary artery disease (CAD). This finding holds true even when accounting for genetic factors, suggesting a complex relationship beyond typical risk assessment.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Epidemiology
Background:
- Higher high-density lipoprotein cholesterol (HDL-C) levels are traditionally associated with lower cardiovascular risk.
- However, recent studies indicate a potential increased risk of adverse outcomes at very high HDL-C concentrations in the general population.
Purpose of the Study:
- To investigate the association between very high HDL-C levels (>80 mg/dL) and mortality in patients with coronary artery disease (CAD).
- To examine the relationship between known HDL-C genotypes and outcomes associated with high HDL-C levels.
Main Methods:
- Prospective, multicenter cohort study including patients with confirmed CAD from the UK Biobank and Emory Cardiovascular Biobank.
- Data analysis involved assessing all-cause and cardiovascular death over a median follow-up of 6.7 to 8.9 years.
- Adjustments were made for confounding factors and HDL-C genetic risk scores.
Main Results:
- A U-shaped association was observed, with increased mortality risk at both low and very high HDL-C levels compared to midrange values.
- Very high HDL-C levels (>80 mg/dL) were significantly associated with increased all-cause death (HR, 1.96) and cardiovascular death (HR, 1.71).
- These associations were consistent across both cohorts and persisted after adjusting for HDL-C genetic risk score; higher risk was noted in men.
Conclusions:
- Very high HDL-C levels (>80 mg/dL) are paradoxically linked to increased mortality risk in individuals with CAD.
- This association is independent of common genetic polymorphisms influencing HDL-C levels.
- Findings suggest that extremely high HDL-C may not be protective and could indicate underlying risks in CAD patients.
Importance:
Previous studies have shown lower cardiovascular risk with higher high-density lipoprotein cholesterol (HDL-C) levels. However, recent data in the general population have shown increased risk of adverse outcomes at very high HDL-C concentrations.
Objective:
To study the association between very high HDL-C levels (>80 mg/dL) and mortality in patients with coronary artery disease (CAD) and to investigate the association of known HDL-C genotypes with high HDL-C level outcomes.
Design, Setting, And Participants:
This prospective, multicenter, cohort study, conducted from 2006 to present in the UK and from 2003 to present in Atlanta, Georgia, recruited patients with CAD from the UK Biobank (UKB) and the Emory Cardiovascular Biobank (EmCAB), respectively. Patients without confirmed CAD were excluded from the study. Data analyses were conducted from May 10, 2020, to April 28, 2021.
Exposure:
High HDL-C levels (>80 mg/dL).
Main Outcomes And Measures:
The primary outcome was all-cause death. The secondary outcome was cardiovascular death.
Results:
A total of 14 478 participants (mean [SD] age, 62.1 [5.8] years; 11 034 men [76.2%]) from the UKB and 5467 participants (mean [SD] age, 63.8 [12.3] years; 3632 men [66.4%]) from the EmCAB were included in the study. Over a median follow-up of 8.9 (IQR, 8.0-9.7) years in the UKB and 6.7 (IQR, 4.0-10.8) years in the EmCAB, a U-shaped association with outcomes was observed with higher risk in those with both low and very high HDL-C levels compared with those with midrange values. Very high HDL-C levels (>80 mg/dL) were associated with increased risk of all-cause death (hazard ratio [HR], 1.96; 95% CI, 1.42-2.71; P < .001) and cardiovascular death (HR, 1.71; 95% CI, 1.09-2.68; P = .02) compared with those with HDL-C levels in the range of 40 to 60 mg/dL in the UKB after adjustment for confounding factors. These results were replicated in the EmCAB. These associations persisted after adjustment for the HDL-C genetic risk score within the UKB. Sensitivity analyses demonstrated that the risk of all-cause mortality in the very high HDL-C group was higher among men than women in the UKB (HR, 2.63; 95% CI, 1.75-3.95; P < .001 vs HR, 1.39; 95% CI, 0.82-2.35; P = .23).
Conclusions And Relevance:
Results of this cohort study suggest that very high HDL-C levels are paradoxically associated with higher mortality risk in individuals with CAD. This association was independent of the common polymorphisms associated with high HDL-C levels.
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