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1.  Human HDL containing a novel apoC-I isoform induces smooth muscle cell apoptosis 
Cardiovascular Research  2013;98(1):83-93.
Aims
We discovered that some adults with coronary heart disease (CHD) have a high density lipoprotein (HDL) subclass which induces human aortic smooth muscle cell (ASMC) apoptosis in vitro. The purpose of this investigation was to determine what properties differentiate apoptotic and non-apoptotic HDL subclasses in adults with and without CHD.
Methods and results
Density gradient ultracentrifugation was used to measure the particle density distribution and to isolate two HDL subclass fractions, HDL2 and HDL3, from 21 individuals, including 12 without CHD. The HDL fractions were incubated with ASMCs for 24 h; apoptosis was quantitated relative to C2-ceramide and tumour necrosis factor-alpha (TNF-α). The observed effect of some HDL subclasses on apoptosis was ∼6-fold greater than TNF-α and ∼16-fold greater than the cell medium. We observed that apoptotic HDL was (i) predominately associated with the HDL2 subclass; (ii) almost exclusively found in individuals with a higher apoC-I serum level and a novel, higher molecular weight isoform of apoC-I; and (iii) more common in adults with CHD, the majority of whom had high (>60 mg/dL) HDL-C levels.
Conclusions
Some HDL subclasses enriched in a novel isoform of apoC-I induce extensive ASMC apoptosis in vitro. Individuals with this apoptotic HDL phenotype generally have higher apoC-I and HDL-C levels consistent with an inhibitory effect of apoC-I on cholesteryl ester transfer protein activity. The association of this phenotype with processes that can promote plaque rupture may explain a source of CHD risk not accounted for by the classical risk factors.
doi:10.1093/cvr/cvt014
PMCID: PMC3598419  PMID: 23354389
High density lipoprotein; Atherosclerosis; Smooth muscle cell; Apoptosis; Apolipoprotein C-I
2.  Apolipoproteins A-I, B and C-III in Young Adult Cherokee with The Metabolic Syndrome; with or without Type 2 Diabetes 
BACKGROUND
Since type 2 diabetes (T2D) is a coronary artery disease risk equivalent, it is important to identify difference in risk markers between cases with T2D and the metabolic syndrome (MetS) compared to those with MetS alone. We evaluated apolipoproteins as possible distinguishing markers in the Oklahoma Cherokee.
OBJECTIVE
To assess apolipoproteins A-I, B and C-III in young adult Cherokee who have the metabolic syndrome (MetS), as defined by the National Cholesterol Education Program (NCEP), either with or without T2D.
METHODS
A cross-sectional comparison of young adult Oklahoma Cherokee, aged 18 to 40 years, was conducted to assess differences in the apolipoproteins due to the presence or absence of T2D among those with the MetS, after adjusting for age and gender.
RESULTS
ApoA-I (p=0.0222) and HDL-C (p=0.0364) were lower, and apoB (p=0.0106) and the apoB to A-I ratio (p<0.0001) were higher in participants with the MetS and T2D than in those with MetS but without T2D. However, cholesterol, triglyceride, LDL-C, non-HDL-C, total apoC-III, non-HDL apoC-III and the bimodal lipoprotein distribution of apoC-III (apoC-III ratio) were not significantly different between the two groups.
CONCLUSION
ApoA-I and HDL-C are lower and apoB and the apoB:A-I ratio are higher in those with MetS and T2D than in those who have the MetS but without T2D, suggesting that the presence of diabetes adversely influences plasma apoA-I and apoB levels. However, apoC-III and non-HDL apoC-III are unchanged by the addition of diabetes suggesting that the increased levels associated with the metabolic syndrome may precede T2D.
doi:10.1016/j.jacl.2012.06.007
PMCID: PMC3558999  PMID: 23351581
ApoA-I; apoB; apoC-III; diabetes; risk factors
3.  Influence of Peripheral Artery Disease and Statin Therapy on Apolipoprotein Profiles 
Apolipoprotein B is a stronger predictor of myocardial infarction than LDL cholesterol, and it is inversely related to physical activity and modifiable with exercise training. As such, apolipoprotein measures may be of particular relevance for subjects with PAD and claudication. We compared plasma apolipoprotein profiles in 29 subjects with peripheral artery disease (PAD) and intermittent claudication and in 39 control subjects. Furthermore, we compared the plasma apolipoprotein profiles of subjects with PAD either treated (n = 17) or untreated (n = 12) with statin medications. For the apolipoprotein subparticle analyses, subjects with PAD had higher age-adjusted Lp-B:C (P < 0.05) and lower values of Lp-A-I:A-II (P < 0.05) than controls. The PAD group taking statins had lower age-adjusted values for apoB (P < 0.05), Lp-A-II:B:C:D:E (P < 0.05), Lp-B:E + Lp-B:C:E (P < 0.05), Lp-B:C (P < 0.05), and Lp-A-I (P < 0.05) than the untreated PAD group. Subjects with PAD have impaired apolipoprotein profiles than controls, characterized by Lp-B:C and Lp-A-I:A-II. Furthermore, subjects with PAD on statin medications have a more favorable risk profile, particularly noted in multiple apolipoprotein subparticles. The efficacy of statin therapy to improve cardiovascular risk appears more evident in the apolipoprotein sub-particle profile than in the more traditional lipid profile of subjects with PAD and claudication. This trial is registered with ClinicalTrials.gov NCT00618670.
doi:10.1155/2013/548764
PMCID: PMC3786464  PMID: 24102029
4.  APOLIPOPROTEIN PROFILES IN SUBJECTS WITH AND WITHOUT PERIPHERAL ARTERY DISEASE 
We compared plasma apolipoprotein profiles in subjects with peripheral artery disease (PAD) treated with statin medications (n = 21), subjects with PAD who are untreated with statins (n = 18), and control subjects (n = 70). Subjects were assessed on plasma apolipoproteins, medical history, physical examination, ankle/brachial index, and exercise performance using a treadmill test. The percentage of subjects with an abnormal value of ApoB (≥ 95 mg/dL) was 53% in the PAD group untreated with statins, 29% in the treated PAD group, and 13% in the controls (p<0.001). The PAD group untreated with statins had higher values for ApoB (p<0.001), triglycerides (p<0.01), LDL-cholesterol/HDL-cholesterol ratio (p<0.05), and glucose (p<0.01) than the control group. In contrast, when the statin treated PAD group was compared with controls, none of the variables were different except that the treated PAD group had lower LDL-cholesterol (p<0.01) and higher glucose (p<0.01). Furthermore, the PAD group treated with statins had lower ApoB (p<0.01), triglycerides (p<0.001), LDL-cholesterol (p<0.05), LDL-cholesterol/HDL-cholesterol ratio (p<0.05), and non-HDL-cholesterol (p<0.05) than the untreated PAD group. In conclusion, subjects with PAD who are untreated with statin medications have higher levels of ApoB than controls, whereas subjects treated with statins have a more favorable risk profile, characterized by lower ApoB, LDL-C, LDL-C/HDL-C ratio, and non-HDL-C concentrations. Statin therapy may be efficacious for improving apolipoprotein profiles in subjects with PAD and intermittent claudication.
doi:10.1177/1358863X13489768
PMCID: PMC3753187  PMID: 23720036
Apolipoproteins; Intermittent Claudication; Lipids; Peripheral Artery Disease; Statins
5.  Sex differences in HDL ApoC-III in American Indian youth 
Background
Since American Indians are predisposed to type 2 diabetes (DM2) and associated cardiovascular risk, Cherokee boys and girls (n = 917) were studied to determine whether BMI Z (body mass index Z score) is associated with the apoC-III (apolipoprotein C-III) content of HDL (high density lipoprotein), a previously reported predictor of DM2.
Methods
An ad hoc cross-sectional analysis was conducted on a previously studied cohort. Participants were grouped by gender-specific age groups (5 to 9, 10 to 14 and 15 to 19 years). ApoA-I (apolipoprotein A-I) and HDL apoC-III were assayed by electroimmunoassay. ApoC-III was measured in whole plasma, and in HDL to determine the molar proportion to apoA-I. General linear models were used to assess association.
Results
The HDL apoC-III to apoA-I molar ratio increased by BMI Z quartile in girls aged 10–14 years (p < 0.05 for linear trend, p < 0.05 for difference in BMI Z quartile IV vs. I to III) and aged 15–19 years (p < 0.05 for trend). In boys the increase by BMI Z occurred only at ages 15–19 years (p < 0.01 for trend and for quartile difference).
Conclusions
ApoC-III showed an obesity-related increase relative to apoA-I during adolescence beginning in girls aged 10 to 14 years and in boys aged 15 to 19 years. The earlier changes in girls may alter HDL’s protective properties on the β-cell and contribute to their increased risk for DM2.
doi:10.1186/2042-6410-3-18
PMCID: PMC3526514  PMID: 22898077
Gender; HDL; ApoC-III; Children; Adolescents
6.  Beef in an Optimal Lean Diet study: effects on lipids, lipoproteins, and apolipoproteins123 
Background: A Step I diet with lean beef compared with lean white meat both decrease LDL cholesterol. To our knowledge, no studies have evaluated a low–saturated fatty acid (SFA) (<7% calories) diet that contains lean beef.
Objective: We studied the effect on LDL cholesterol of cholesterol-lowering diets with varying amounts of lean beef [ie, Dietary Approaches to Stop Hypertension (DASH): 28 g beef/d; Beef in an Optimal Lean Diet (BOLD): 113 g beef/d; and Beef in an Optimal Lean Diet plus additional protein (BOLD+): 153 g beef/d] compared with that of a healthy American diet (HAD).
Design: Thirty-six hypercholesterolemic participants (with LDL-cholesterol concentrations >2.8 mmol/L) were randomly assigned to consume each of the 4 diets (HAD: 33% total fat, 12% SFA, 17% protein, and 20 g beef/d), DASH (27% total fat, 6% SFA, 18% protein, and 28 g beef/d), BOLD (28% total fat, 6% SFA, 19% protein, and 113 g beef/d), and BOLD+ (28% total fat, 6% SFA, 27% protein, and 153 g beef/d) for 5 wk.
Results: There was a decrease in total cholesterol (TC) and LDL-cholesterol concentrations (P < 0.05) after consumption of the DASH (−0.49 ± 0.11 and −0.37 ± 0.09 mmol/L, respectively), BOLD (−0.48 ± 0.10 and −0.35 ± 0.9 mmol/L, respectively), and BOLD+ (−0.50 ± 0.10 and −0.345 ± 0.09 mmol/L, respectively) diets compared with after consumption of the HAD (−0.22 ± 0.10 and −0.14 ± 0.10 mmol/L, respectively). Apolipoprotein A-I, C-III, and C-III bound to apolipoprotein A1 particles decreased after BOLD and BOLD+ diets compared with after the HAD, and there was a greater decrease in apolipoprotein B after consumption of the BOLD+ diet than after consumption of the HAD (P < 0.05 for both). LDL cholesterol and TC decreased after consumption of the DASH, BOLD, and BOLD+ diets when the baseline C-reactive protein (CRP) concentration was <1 mg/L; LDL cholesterol and TC decreased when baseline CRP concentration was >1 mg/L with the BOLD and BOLD+ diets.
Conclusions: Low-SFA, heart-healthy dietary patterns that contain lean beef elicit favorable effects on cardiovascular disease (CVD) lipid and lipoprotein risk factors that are comparable to those elicited by a DASH dietary pattern. These results, in conjunction with the beneficial effects on apolipoprotein CVD risk factors after consumption of the BOLD and BOLD+ diets, which were greater with the BOLD+ diet, provide support for including lean beef in a heart-healthy dietary pattern. This trial was registered at clinicaltrials.gov as NCT00937898.
doi:10.3945/ajcn.111.016261
PMCID: PMC3238465  PMID: 22170364
7.  Oxidative Stress and Inflammation in Renal Patients and Healthy Subjects 
PLoS ONE  2011;6(7):e22360.
The first goal of this study was to measure the oxidative stress (OS) and relate it to lipoprotein variables in 35 renal patients before dialysis (CKD), 37 on hemodialysis (HD) and 63 healthy subjects. The method for OS was based on the ratio of cholesteryl esters (CE) containing C18/C16 fatty acids (R2) measured by gas chromatography (GC) which is a simple, direct, rapid and reliable procedure. The second goal was to investigate and identify a triacylglycerol peak on GC, referred to as TG48 (48 represents the sum of the three fatty acids carbon chain lengths) which was markedly increased in renal patients compared to healthy controls. We measured TG48 in patients and controls. Mass spectrometry (MS) and MS twice in tandem were used to analyze the fatty acid composition of TG48. MS showed that TG48 was abundant in saturated fatty acids (SFAs) that were known for their pro-inflammatory property. TG48 was significantly and inversely correlated with OS. Renal patients were characterized by higher OS and inflammation than healthy subjects. Inflammation correlated strongly with TG, VLDL-cholesterol, apolipoprotein (apo) C-III and apoC-III bound to apoB-containing lipoproteins, but not with either total cholesterol or LDL-cholesterol.
In conclusion, we have discovered a new inflammatory factor, TG48. It is characterized with TG rich in saturated fatty acids. Renal patients have increased TG48 than healthy controls.
doi:10.1371/journal.pone.0022360
PMCID: PMC3145638  PMID: 21829457
8.  High-Dose B-Vitamin Supplementation and Progression of Subclinical Atherosclerosis: A Randomized Controlled Trial 
Background and Purpose
Although plasma total homocysteine (tHcy) levels are associated with cardiovascular disease (CVD), it remains unclear whether homocysteine is a cause or a marker of atherosclerotic vascular disease. We determined whether reduction of tHcy levels with B-vitamin supplementation reduces subclinical atherosclerosis progression.
Methods
In this double-blind clinical trial, 506 participants 40–89 years of age with an initial tHcy >8.5 μmol/L without diabetes and CVD were randomized to high-dose B-vitamin supplementation (folic acid 5 mg + vitamin B12 0.4 mg + vitamin B6 50 mg) or matching placebo for 3.1 years. Subclinical atherosclerosis progression across 3 vascular beds was assessed using high-resolution B-mode ultrasonography to measure carotid artery intima-media thickness (primary outcome) and multidetector spiral computed tomography to measure aortic and coronary artery calcium (secondary outcome).
Results
Although the overall carotid artery intima-media thickness progression rate was lower with B-vitamin supplementation than with placebo, statistically significant between-group differences were not found (p=0.31). However, among subjects with baseline tHcy≥9.1 μmol/L, those randomized to B-vitamin supplementation had a statistically significant lower average rate of carotid artery intima-media thickness progression compared with placebo (p=0.02); among subjects with a baseline tHcy <9.1 μmol/L there was no significant treatment effect (p-value for treatment interaction=0.02). B-vitamin supplementation had no effect on progression of aortic or coronary artery calcification overall or within subgroups.
Conclusion
High-dose B-vitamin supplementation significantly reduces progression of early stage subclinical atherosclerosis (carotid artery intima-media thickness) in well-nourished healthy B-vitamin “replete” individuals at low-risk for CVD with a fasting tHcy >9.1 μmol/L.
doi:10.1161/STROKEAHA.108.526798
PMCID: PMC2701290  PMID: 19118243
Atherosclerosis; Computed tomography; Folate; Homocysteine; Intima-media thickness; Randomized controlled trials; Vitamin B12

Results 1-8 (8)