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Molecular mechanisms of vascular effects of High-density lipoprotein: alterations in cardiovascular disease.

ABSTRACT: Low high-density lipoprotein (HDL)-cholesterol levels are associated with an increased risk of coronary artery disease (CAD) and myocardial infarction, which has triggered the hypothesis that HDL, in contrast to low-density lipoprotein (LDL), acts as an anti-atherogenic lipoprotein. Moreover, experimental studies have identified potential anti-atherogenic properties of HDL, including promotion of macrophage cholesterol efflux and direct endothelial-protective effects of HDL, such as stimulation of endothelial nitric oxide production and repair, anti-apoptotic, anti-inflammatory and anti-thrombotic properties. Studies in gene-targeted mice, however, have also indicated that increasing HDL-cholesterol plasma levels can either limit (e.g. apolipoprotein A-I) or accelerate (e.g. Scavenger receptor class B type I) atherosclerosis. Moreover, vascular effects of HDL have been observed to be heterogenous and are altered in patients with CAD or diabetes, a condition that has been termed 'HDL dysfunction'. These alterations in biological functions of HDL may need to be taken into account for HDL-targeted therapies and considering raising of HDL-cholesterol levels alone is likely not sufficient in this respect. It will therefore be important to further determine, which biological functions of HDL are critical for its anti-atherosclerotic properties, as well as how these can be measured and targeted.

SUBMITTER: Besler C

PROVIDER: S-EPMC3376856 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Molecular mechanisms of vascular effects of High-density lipoprotein: alterations in cardiovascular disease.

Besler Christian C Lüscher Thomas F TF Landmesser Ulf U

EMBO molecular medicine 20120316 4

Low high-density lipoprotein (HDL)-cholesterol levels are associated with an increased risk of coronary artery disease (CAD) and myocardial infarction, which has triggered the hypothesis that HDL, in contrast to low-density lipoprotein (LDL), acts as an anti-atherogenic lipoprotein. Moreover, experimental studies have identified potential anti-atherogenic properties of HDL, including promotion of macrophage cholesterol efflux and direct endothelial-protective effects of HDL, such as stimulation ...[more]

PMID: 22431312

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Project description:BackgroundThe effects of increasing high-density lipoprotein cholesterol on cardiovascular outcomes remain uncertain.DesignWe conducted a meta-analysis to investigate the effects of high-density lipoprotein cholesterol modifiers (niacin, fibrates and cholesteryl ester transfer protein inhibitors) on cardiovascular outcomes.MethodsThirty-one randomized controlled trials (154,601 patients) with a follow-up of 6 months or more and a sample size of 100 or more patients were selected using MEDLINE, EMBASE and CENTRAL database (inception January 2018).ResultsHigh-density lipoprotein cholesterol modifiers had no statistically significant effect on cardiovascular mortality in terms of relative risk (RR) (RR 0.94, 95% confidence interval (CI) 0.89-1.00, P = 0.05, I2 = 13%) or absolute risk (risk difference -0.0001, 95% CI -0.0014, 0.0011, P = 0.84, I2 = 28%). High-density lipoprotein cholesterol modifiers reduced the RR of myocardial infarction (RR 0.87, 95% CI 0.82-0.93, P < 0.001, I2 = 37%). This significant effect was derived by the use of fibrates (RR 0.80, 95% CI 0.73-0.87, P < 0.001, I2 = 22%) and meta-regression analysis showed that this benefit was consistent with an absolute reduction in low-density lipoprotein cholesterol. High-density lipoprotein cholesterol modifiers had no effect on stroke (RR 1.00, 95% CI 0.93-1.09, P = 0.94, I2 = 25%) or all-cause mortality (RR 1.02, 95% CI 0.97-1.08, P = 0.48, I2 = 49%). Meta-regression analyses failed to demonstrate a significant association of pharmacologically increased high-density lipoprotein cholesterol with key endpoints. In studies with background statin therapy, high-density lipoprotein cholesterol modifiers had no statistically significant impact on cardiovascular mortality, myocardial infarction, stroke or all-cause mortality ( P > 0.05).ConclusionThe use of high-density lipoprotein cholesterol modifying treatments had no significant effect on cardiovascular mortality, stroke or all-cause mortality. The beneficial effect on myocardial infarction was lost when drugs were used with statin therapy.

Project description:Background High-density lipoprotein (HDL) particle concentration likely outperforms HDL cholesterol in predicting atherosclerotic cardiovascular events. Whether size-based HDL subspecies explain the atheroprotective associations of HDL particle concentration remains unknown. Our objective was to assess whether levels of specific size-based HDL subspecies associate with atherosclerotic cardiovascular disease in a multiethnic pooled cohort and improve risk prediction beyond traditional atherosclerotic cardiovascular disease risk factors. Methods and Results Seven HDL size-based subspecies were quantified by nuclear magnetic resonance (LP4 algorithm; H1=smallest; H7=largest) among participants without prior atherosclerotic cardiovascular disease in ARIC (Atherosclerosis Risk in Communities), MESA (Multi-Ethnic Study of Atherosclerosis), PREVEND (Prevention of Renal and Vascular Endstage Disease), and DHS (Dallas Heart Study) cohorts (n=15 371 people). Multivariable Cox proportional hazards models were used to evaluate the association between HDL subspecies and incident myocardial infarction (MI) or ischemic stroke at follow-up (average 8-10 years) adjusting for HDL cholesterol and risk factors. Improvement in risk prediction was assessed via discrimination and reclassification analysis. Within the pooled cohort (median age 57 years; female 54%; Black 22%) higher H1 (small) and H4 (medium) concentrations were inversely associated with incident MI (hazard ratio [HR]/SD, H1 0.88 [95% CI, 0.81-0.94]; H4 0.89 [95% CI, 0.82-0.97]). H4 but not H1 improved risk prediction indices for incident MI. Increasing H2 and H4 were inversely associated with improved risk prediction indices for composite end point of stroke, MI, and cardiovascular death (HR/SD, H2 0.94 [95% CI, 0.88-0.99]; H4 0.91 [95% CI, 0.85-0.98]). Levels of the large subspecies (H6 and H7) were not associated with any vascular end point. Conclusions Two of 7 HDL size-based subspecies modestly improved risk prediction for MI and composite vascular end points in a large multiethnic pooled cohort. These findings support assessment of precise HDL subspecies for future studies regarding clinical utility.

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Molecular mechanisms of vascular effects of High-density lipoprotein: alterations in cardiovascular disease.

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Molecular mechanisms of vascular effects of High-density lipoprotein: alterations in cardiovascular disease.

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