High-Density Lipoprotein Subclasses and Noncardiovascular, Noncancer Chronic Inflammatory-Related Events Versus Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis

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Abstract

Background

High-density lipoprotein (HDL) particles have properties beyond reverse cholesterol transport. We hypothesized that their protection extends to inflammation-related disease. The predictive value of HDL particle subclasses and inflammatory markers was studied for noncardiovascular, noncancer chronic inflammation–related death and hospitalization, and for incident cardiovascular disease (CVD).

Methods and Results

A multiethnic, multicenter, prospective observational study was conducted in 6475 men and women (aged 45 to 84 years) free of known CVD at baseline with median follow-up of 10.1 years. Fasting venous samples were analyzed for baseline lipid profile and lipoprotein particles. We focused on the HDL family of variables (small-, medium-, and large-diameter HDL particles and HDL cholesterol). Analyses identified the sum of small- plus medium-diameter HDL particles as important. Small- plus medium-diameter HDL particles were inversely associated with diagnostic code–based noncardiovascular, noncancer chronic inflammation–related death and hospitalization (n=1054) independent of covariates: relative risk per SD 0.85 (95% CI: 0.79 to 0.91, P<0.0001). Small- plus medium-diameter HDL particles were also associated with adjudicated fatal and nonfatal coronary heart disease events (n=423): relative risk per SD 0.88 (95% CI 0.77 to 0.98, P=0.02).

Conclusions

Small- plus medium-diameter HDL particles are an independent predictor for noncardiovascular, noncancer chronic inflammation–related death and hospitalization and for coronary heart disease events in subjects initially free of overt CVD. These findings support the hypothesis that smaller HDL particles of diameter <9.4 nm have anti-inflammatory properties in the general population.

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Most cited references 19

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High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.

D Gordon, J L Probstfield, R Garrison … (1989)

The British Regional Heart Study (BRHS) reported in 1986 that much of the inverse relation of high-density lipoprotein cholesterol (HDLC) and incidence of coronary heart disease was eliminated by covariance adjustment. Using the proportional hazards model and adjusting for age, blood pressure, smoking, body mass index, and low-density lipoprotein cholesterol, we analyzed this relation separately in the Framingham Heart Study (FHS), Lipid Research Clinics Prevalence Mortality Follow-up Study (LRCF) and Coronary Primary Prevention Trial (CPPT), and Multiple Risk Factor Intervention Trial (MRFIT). In CPPT and MRFIT (both randomized trials in middle-age high-risk men), only the control groups were analyzed. A 1-mg/dl (0.026 mM) increment in HDLC was associated with a significant coronary heart disease risk decrement of 2% in men (FHS, CPPT, and MRFIT) and 3% in women (FHS). In LRCF, where only fatal outcomes were documented, a 1-mg/dl increment in HDLC was associated with significant 3.7% (men) and 4.7% (women) decrements in cardiovascular disease mortality rates. The 95% confidence intervals for these decrements in coronary heart and cardiovascular disease risk in the four studies overlapped considerably, and all contained the range 1.9-2.9%. HDLC levels were essentially unrelated to non-cardiovascular disease mortality. When differences in analytic methodology were eliminated, a consistent inverse relation of HDLC levels and coronary heart disease event rates was apparent in BRHS as well as in the four American studies.

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Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy.

Elias Jeyarajah, William C Cromwell, James D. Otvos (2006)

Laboratory measurements of plasma lipids (principally cholesterol and triglycerides) and lipoprotein lipids (principally low-density lipoprotein [LDL] and low-density lipoprotein [HDL] cholesterol) are the cornerstone of the clinical assessment and management of atherosclerotic cardiovascular disease (CVD) risk. LDL particles, and to a lesser extent very-low-density lipoprotein [VLDL] particles, cause atherosclerosis, whereas HDL particles prevent or reverse this process through reverse cholesterol transport. The overall risk for CVD depends on the balance between the "bad" LDL (and VLDL) and "good" HDL particles. Direct assessment of lipoprotein particle numbers us now possible through nuclear magnetic resonance spectroscopic analysis.

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Endothelial and antithrombotic actions of HDL.

Chieko Mineo, Hiroshi Deguchi, John Griffin … (2006)

It is well recognized that high-density lipoprotein (HDL)-cholesterol is antiatherogenic and serves a role in mediating cholesterol efflux from cells. However, HDL has multiple additional endothelial and antithrombotic actions that may also afford cardiovascular protection. HDL promotes the production of the atheroprotective signaling molecule nitric oxide (NO) by upregulating endothelial NO synthase (eNOS) expression, by maintaining the lipid environment in caveolae where eNOS is colocalized with partner signaling molecules, and by stimulating eNOS as a result of kinase cascade activation by the high-affinity HDL receptor scavenger receptor class B type I (SR-BI). HDL also protects endothelial cells from apoptosis and promotes their growth and their migration via SR-BI-initiated signaling. As importantly, there is evidence of a variety of mechanisms by which HDL is antithrombotic and thereby protective against arterial and venous thrombosis, including through the activation of prostacyclin synthesis. The antithrombotic properties may also be related to the abilities of HDL to attenuate the expression of tissue factor and selectins, to downregulate thrombin generation via the protein C pathway, and to directly and indirectly blunt platelet activation. Thus, in addition to its cholesterol-transporting properties, HDL favorably regulates endothelial cell phenotype and reduces the risk of thrombosis. With further investigation and resulting greater depth of understanding, these mechanisms may be harnessed to provide new prophylactic and therapeutic strategies to combat atherosclerosis and thrombotic disorders.

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Author and article information

Journal

Journal ID (nlm-ta): J Am Heart Assoc

Journal ID (iso-abbrev): J Am Heart Assoc

Journal ID (publisher-id): jah3

Title: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Publisher: John Wiley & Sons, Ltd (Chichester, UK )

ISSN (Print): 2047-9980

ISSN (Electronic): 2047-9980

Publication date Collection: September 2015

Publication date (Electronic): 14 September 2015

Volume: 4

Issue: 9

Electronic Location Identifier: e002295

Affiliations

[1 ]Division of Epidemiology and Community Health, School of Public Health, University of Minnesota Minneapolis, MN

[2 ]Department of Medicine, University of Minnesota Minneapolis, MN

[3 ]Department of Laboratory Medicine and Pathology, University of Minnesota Minneapolis, MN

[4 ]Department of Biostatistics, University of Minnesota Minneapolis, MN

[5 ]Laboratory Corporation of America Burlington, NC

[6 ]Department of Pathology, University of Vermont Colchester, VT

[7 ]Department of Medicine, VA Medical Center, University of California San Francisco San Francisco, CA

[8 ]Institute for Public Health and Medicine, Northwestern University Chicago, IL

[9 ]Department of Medicine/Radiology, John Hopkins University Baltimore, MD

[10 ]Department of Epidemiology, University of Pittsburgh PA

Author notes

Correspondence to: Daniel A. Duprez, MD, PhD, Cardiovascular Division, University of Minnesota, 420 Delaware St SE, Minneapolis, MN 55455. E-mail: dupre007@ 123456umn.edu

Accompanying Tables S1 through Tables S5 are available at http://jaha.ahajournals.org/content/4/8/e002295/suppl/DC1

Article

DOI: 10.1161/JAHA.115.002295

PMC ID: 4599511

PubMed ID: 26370448

SO-VID: a482d60a-aaab-4fb6-9667-e4f922b6d3ed

License:

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

High-Density Lipoprotein Subclasses and Noncardiovascular, Noncancer Chronic Inflammatory-Related Events Versus Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis

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Abstract

Background

Methods and Results

Conclusions

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Cardiovascular Innovations and Applications

Most cited references 19

High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.

Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy.

Endothelial and antithrombotic actions of HDL.

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