Cited by 255Lipoproteins and Cardiovascular HealthParaoxonase enzyme and polymorphismsCholesterol and Lipid Metabolism

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Association Between High-Density Lipoprotein Cholesterol Levels and Adverse Cardiovascular Outcomes in High-risk Populations

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Liu, Chang, Dhindsa, Devinder, Almuwaqqat, Zakaria, Ko, Yi-An, Mehta, Anurag, Alkhoder, Ayman A., Alras, Zahran, Desai, Shivang Rajan, Patel, Krishan Jignesh, Hooda, Ananya, Wehbe, Mohamad, Sperling, Laurence S., Sun, Yan V., Quyyumi, Arshed A.·2022·JAMA Cardiology

DOI 10.1001/jamacardio.2022.0912PMC PMC9118072

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Abstract

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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Authors: Liu, C., Dhindsa, D., Almuwaqqat, Z., Ko, Y.-A., Mehta, A., Alkhoder, A. A., Alras, Z., Desai, S. R., Patel, K. J., Hooda, A., Wehbe, M., Sperling, L. S., Sun, Y. V., & Quyyumi, A. A.
Affiliations: Emory University (US)
ORCID: Liu, Chang
Dhindsa, Devinder
Almuwaqqat, Zakaria
Ko, Yi-An
Mehta, Anurag
Alkhoder, Ayman A.
Desai, Shivang Rajan
Patel, Krishan Jignesh
Sperling, Laurence S.
Sun, Yan V.
Quyyumi, Arshed A.
Venue: JAMA Cardiology
Publisher: American Medical Association (AMA)
Published: 2022-07-01
Volume: 7
Issue: 7
Pages: 672
ISSN: 2380-6583 (ISSN-L)
DOI: 10.1001/jamacardio.2022.0912
PMC: PMC9118072
OpenAlex: W4280530834
Semantic Scholar: 6d4ebe822cf6955b795923be8dc61ee482ea2dae
Cited by: 250
References: 27
Citations by year: 2026: 48 · 2025: 75 · 2024: 80 · 2023: 35 · 2022: 12
FWCI: 49.42
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: JAMA Cardiology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Medical Research Council (MC_PC_17228)
National Institute on Aging (U54AG062334)
National Heart, Lung, and Blood Institute (P01HL101398, P20HL113451, P01HL086773, R61HL138657, R01HL141205, T32HL130025)
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK111024)
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Keywords: cholesterol, coronary artery disease, all-cause mortality, cardiovascular mortality, U-shaped relationship, genetic variants, cardiovascular risk, vulnerable populations, cardiovascular outcomes, UK Biobank
MeSH terms: Aged, Cholesterol, Coronary Artery Disease, Female, Humans, Cholesterol, HDL, Male, Middle Aged, Prospective Studies, Risk Factors, Cohort Studies

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Association Between High-Density Lipoprotein Cholesterol Levels and Adverse Cardiovascular Outcomes in High-risk Populations

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