Concentration of Smaller High-Density Lipoprotein Particle (HDL-P) Is Inversely Correlated With Carotid Intima Media Thickening After Confounder Adjustment: The Multi Ethnic Study of Atherosclerosis (MESA).

Recent studies have failed to establish a causal relationship between high-density lipoprotein cholesterol levels (HDL-C) and cardiovascular disease (CVD), shifting focus to other HDL measures. We previously reported that smaller/denser HDL levels are protective against cerebrovascular disease. This study sought to determine which of small+medium HDL particle concentration (HDL-P) or large HDL-P was more strongly associated with carotid intima-media thickening (cIMT) in an ethnically diverse cohort. In cross-sectional analyses of participants from the Multi Ethnic Study of Atherosclerosis (MESA), we evaluated the associations of nuclear magnetic resonance spectroscopy-measured small+medium versus large HDL-P with cIMT measured in the common and internal carotid arteries, through linear regression. After adjustment for CVD confounders, low-density lipoprotein cholesterol (LDL-C), HDL-C, and small+medium HDL-P remained significantly and inversely associated with common (coefficient=-1.46 μm; P=0.00037; n=6512) and internal cIMT (coefficient=-3.82 μm; P=0.0051; n=6418) after Bonferroni correction for 4 independent tests (threshold for significance=0.0125; α=0.05/4). Large HDL-P was significantly and inversely associated with both cIMT outcomes before HDL-C adjustment; however, after adjustment for HDL-C, the association of large HDL-P with both common (coefficient=1.55 μm; P=0.30; n=6512) and internal cIMT (coefficient=4.84 μm; P=0.33; n=6418) was attenuated. In a separate sample of 126 men, small/medium HDL-P was more strongly correlated with paraoxonase 1 activity (rp=0.32; P=0.00023) as compared to both total HDL-P (rp=0.27; P=0.0024) and large HDL-P (rp=0.02; P=0.41) measures. Small+medium HDL-P is significantly and inversely correlated with cIMT measurements. Correlation of small+medium HDL-P with cardioprotective paraoxonase 1 activity may reflect a functional aspect of HDL responsible for this finding.

Kim DS ，Li YK ，Bell GA ，Burt AA ，Vaisar T ，Hutchins PM ，Furlong CE ，Otvos JD ，Polak JF ，Arnan MK ，Kaufman JD ，McClelland RL ，Longstreth WT Jr ，Jarvik GP ... -  《Journal of the American Heart Association》

High-density lipoprotein particle concentration and subclinical atherosclerosis of the carotid arteries in Japanese men.

The association of high-density lipoprotein particle (HDL-P) with atherosclerosis may be stronger than that of HDL-cholesterol (HDL-C) and independent of conventional cardiovascular risk factors. Whether associations persist in populations at low risk of coronary heart disease (CHD) remains unclear. This study examines the associations of HDL-P and HDL-C with carotid intima-media thickness (cIMT) and plaque counts among Japanese men, who characteristically have higher HDL-C levels and a lower CHD burden than those in men of Western populations. We cross-sectionally examined a community-based sample of 870 Japanese men aged 40-79 years, free of known clinical cardiovascular disease (CVD) and not on lipid-lowering medication. Participants were randomly selected among Japanese living in Kusatsu City in Shiga, Japan. Both HDL-P and HDL-C were inversely and independently associated with cIMT in models adjusted for conventional CHD risk factors, including low-density lipoprotein cholesterol (LDL-C) and diabetes. HDL-P maintained an association with cIMT after further adjustment for HDL-C (P < 0.01), whereas the association of HDL-C with cIMT was noticeably absent after inclusion of HDL-P in the model. In plaque counts of the carotid arteries, HDL-P was significantly associated with a reduction in plaque count, whereas HDL-C was not. HDL-P, in comparison to HDL-C, is more strongly associated with measures of carotid atherosclerosis in a cross-sectional study of Japanese men. Findings demonstrate that, HDL-P is a strong correlate of subclinical atherosclerosis even in a population at low risk for CHD.

Zaid M ，Fujiyoshi A ，Miura K ，Abbott RD ，Okamura T ，Takashima N ，Torii S ，Saito Y ，Hisamatsu T ，Miyagawa N ，Ohkubo T ，Kadota A ，Sekikawa A ，Maegawa H ，Nakamura Y ，Mitsunami K ，Ueshima H ，SESSA Research group ... -  《-》

High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis).

The purpose of this study was to evaluate independent associations of high-density lipoprotein cholesterol (HDL-C) and particle (HDL-P) concentrations with carotid intima-media thickness (cIMT) and incident coronary heart disease (CHD). HDL-C is inversely related to CHD, and also to triglycerides, low-density lipoprotein particles (LDL-P), and related metabolic risk. HDL-P associations with CHD may be partially independent of these factors. In a multiethnic study of 5,598 men and women ages 45 to 84 years old, without baseline CHD, excluding subjects on lipid-lowering medications, triglycerides >400 mg/dl, or missing values, we evaluated associations of HDL-C and nuclear magnetic resonance spectroscopy-measured HDL-P with cIMT and incident CHD (myocardial infarction, CHD death, and angina, n = 227 events; mean 6.0 years follow-up). All models were adjusted for age, sex, ethnicity, hypertension, and smoking. HDL-C and HDL-P correlated with each other (ρ = 0.69) and LDL-P (ρ = -0.38, -0.25, respectively, p < 0.05 for all). For (1 SD) higher HDL-C (15 mg/dl) or HDL-P (6.64 μmol/l), cIMT differences were - 26.1 (95% confidence interval [CI]: -34.7 to -17.4) μm and -30.1 (95% CI: -38.8 to - 21.4) μm, and CHD hazard ratios were 0.74 (95% CI: 0.63 to 0.88) and 0.70 (95% CI: 0.59 to 0.82), respectively. Adjusted for each other and LDL-P, HDL-C was no longer associated with cIMT (2.3; 95% CI: - 9.5 to 14.2 μm) or CHD (0.97; 95% CI: 0.77 to 1.22), but HDL-P remained independently associated with cIMT (-22.2; 95% CI: - 33.8 to -10.6 μm) and CHD (0.75; 95% CI: 0.61 to 0.93). Interactions by sex, ethnicity, diabetes, and high-sensitivity C-reactive protein were not significant. Adjusting for each other and LDL-P substantially attenuated associations of HDL-C, but not HDL-P, with cIMT and CHD. Potential confounding by related lipids or lipoproteins should be carefully considered when evaluating HDL-related risk.

Mackey RH ，Greenland P ，Goff DC Jr ，Lloyd-Jones D ，Sibley CT ，Mora S ... -  《-》

Apolipoprotein B is associated with carotid atherosclerosis progression independent of individual cholesterol measures in a 9-year prospective study of Multi-Ethnic Study of Atherosclerosis participants.

High blood cholesterol contributes to atherosclerosis, yet reliance on the lipid panel alone may mischaracterize individuals with elevated lipoprotein particle numbers. The aim of the article was to determine whether elevated lipoprotein or apolipoprotein measures are associated with carotid atherosclerosis and plaque progression independent of cardiovascular (CV) risk factors including standard lipids in a subcohort of 2228 Multi-Ethnic Study of Atherosclerosis participants. Ultrasonography assessed carotid artery plaque and common carotid intima-media thickness (cIMT) at baseline and after a median period of 9.4 years. Nuclear magnetic resonance spectroscopy estimated lipoprotein particle concentrations. Apolipoprotein B (ApoB) and apolipoprotein A-I were measured using an automated immunoassay. Regression analysis determined associations of apolipoprotein and lipoprotein measurements with cIMT and relative risk regression determined associations with carotid plaque progression. After adjustment for typical CV risk factors, individuals in top quartiles of ApoB, ApoB/apolipoprotein A-I, low-density lipoprotein particles (LDL-P), small LDL-P, and total LDL-P/high-density lipoprotein (HDL) particles showed similar risks of carotid plaque and cIMT progression as LDL-C, non-HDL cholesterol (HDL-C), total cholesterol (TC), and TC/HDL-C. A significant association with plaque progression remained in the top ApoB quartile after further adjustment for LDL-C (P = .02) or TC + HDL-C (P = .04), but was nonsignificant when adjusted for all lipid covariates (P = .086). Those in the top quartile of small LDL-P concentrations showed greater cIMT progression than those in the referent after adjustment for LDL-C, but this was nonsignificant after adjustment for TC + HDL-C. When coupled with evidence that apolipoprotein testing identifies lipid-lipoprotein discordance, these findings suggest that ApoB and small LDL-P provide atherosclerosis risk information that is not revealed by typical CV risk factors.

Steffen BT ，Guan W ，Remaley AT ，Stein JH ，Tattersall MC ，Kaufman J ，Tsai MY ... -  《-》

High density lipoprotein with apolipoprotein C-III is associated with carotid intima-media thickness among generally healthy individuals.

About 6-7% of high density lipoprotein (HDL) has a protein called apolipoprotein (apo) C-III that regulates lipoprotein metabolism and can provoke an inflammatory response. HDL without apoC-III is inversely associated with coronary heart disease (CHD), whereas HDL with apoC-III is directly associated with CHD. We investigated how the presence of apoC-III affects the association between HDL and early stages of atherosclerosis measured as carotid intima-media thickness (cIMT). We examined the cross-sectional associations between the apoA-I concentrations of HDL subspecies with and without apoC-III and cIMT measured by high resolution B-mode carotid ultrasonography among 847 participants from the European multi-center Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. HDL with and without apoC-III demonstrated significantly opposite associations with both cIMT indexes (p-heterogeneity of associations comparing the two subspecies was 0.002 for cIMT at common carotid artery (cIMT at CCA) and 0.006 for the maximum cIMT in any carotid segment (cIMT max)). Compared to the lowest quintile, the highest quintile of apoA-I in HDL without apoC-III was associated with 3.7% lower cIMT at CCA (p-trend = 0.01) or 7.3% lower cIMT max (p-trend = 0.003), while the highest quintile of apoA-I in HDL with apoC-III was associated with 4.4% higher cIMT at CCA (p-trend = 0.001) or 7.9% higher cIMT max (p-trend = 0.002). Total apoA-I as well as total HDL cholesterol was not associated with cIMT whereas higher levels of total apoC-III and apoC-III contained in HDL were significantly associated with higher cIMT (p-trend<0.01). HDL apoC-III is a promising target for atherosclerosis prevention and treatment.

Yamamoto R ，Sacks FM ，Hu FB ，Rosner B ，Furtado JD ，Aroner SA ，Ferrannini E ，Baldi S ，Kozakova M ，Balkau B ，Natali A ，Jensen MK ，RISC Investigators ... -  《-》