Serum apolipoproteins and apolipoprotein-defined lipoprotein subclasses: a hypothesis-generating prospective study of cardiovascular events in T1D.

APOB, APOC3, and APOE and apolipoprotein-defined lipoprotein subclasses (ADLSs; based on qualitative apolipoprotein complement) have been associated with dyslipidemia and CVD. Our main objective was to define associations of serum apolipoproteins and ADLSs with "any CVD" and "major atherosclerotic cardiovascular events" (MACEs) in a prospective study of T1D. Serum apolipoproteins and ADLSs (14 biomarkers in total) were measured in sera (obtained between 1997 and 2000) from a subset (n = 465) of the Epidemiology of Diabetes Interventions and Complications cohort. Prospective associations of "any CVD" (myocardial infarction, stroke, confirmed angina, silent myocardial infarction, revascularization, or congestive heart failure) and MACEs (fatal or nonfatal myocardial infarction or stroke), over 5,943 and 6,180 patient-years follow-up, respectively, were investigated using Cox proportional hazards models that were unadjusted and adjusted for risk factors. During 15 years of follow-up, 50 "any CVD" events and 24 MACEs occurred. Nominally significant positive univariate associations with "any CVD" were APOB, APOC3 and its subfractions [heparin precipitate, heparin-soluble (HS)], and ADLS-defined Lp-B. In adjusted analyses, APOC3-HS remained nominally significant. Nominally significant positive univariate associations with MACEs were APOC3 and its subfractions and Lp-B:C; those with total APOC3 and APOC3-HS persisted in adjusted analyses. However, these associations did not reach significance after adjusting for multiple testing. There were no significant associations of APOA1, APOA2, APOE, or other ADLSs with either "any CVD" or MACEs. These hypothesis-generating data suggest that total serum APOC3 and APOC3 in HDL are potentially important predictive biomarkers for any CVD and MACEs in adults with T1D.

LpA-II:B:C:D:E: a new immunochemically-defined acute phase lipoprotein in humans.

BACKGROUND: Previous studies of lipoproteins in patients with sepsis have been performed on density fractions isolated by conventional ultracentrifugation that are heterogeneous and provide no information about the cargo of apoproteins present in the immunochemically distinct subclasses that populate the density classes. Since apoproteins are now known to have important roles in host defense, we have separated these subclasses according to their apoprotein content and characterized their changes during experimental endotoxemia in human volunteers. METHODS: We have studied apoB- and apoA containing lipoprotein subclasses in twelve healthy male volunteers before and for 8 h after a single dose of endotoxin (ET; 2 µg/kg) to stimulate inflammation. RESULTS: After endotoxin, TG, TC, apoB and the apoB-containing lipoprotein cholesterol-rich subclass LpB and two of the three triglyceride-rich subclasses (TGRLP: Lp:B:C, LpB:C:E+ LpB:E) all declined. In contrast, the third TGRLP, LpA-II:B:C:D:E ("complex particle"), after reaching a nadir at 4 h rose 49% above baseline, p = .006 at 8 h and became the dominant particle in the TGRLP pool. This increment exceeds the threshold of > 25% change required for designation as an acute phase protein. Simultaneous decreases in LpA-I:A-II and LpB:C:E + LpB:E suggest that these subclasses undergo post-translational modification and contribute to the formation of new LpA-II:B:C:D:E particles. CONCLUSIONS: We have identified a new acute phase lipoprotein whose apoprotein constituents have metabolic and immunoregulatory properties applicable to host defense that make it well constituted to engage in the APR.

Apolipoprotein-defined lipoprotein subclasses, serum apolipoproteins, and carotid intima-media thickness in T1D.

Circulating apolipoprotein-defined lipoprotein subclasses (ADLS) and apolipoproteins predict vascular events in the general and type 2 diabetes populations, but data in T1D are limited. We examined associations of ADLS, serum apolipoproteins, and conventional lipids with carotid intima-media thickness (IMT) measured contemporaneously and 6 years later in 417 T1D participants [men: n = 269, age 42 ± 6 y (mean ± SD); women: n = 148, age 39 ± 8 y] in the Epidemiology of Diabetes Interventions and Complications study, the follow-up of the Diabetes Control and Complications Trial (DCCT). Date were analyzed by multiple linear regression stratified by sex, and adjusted for time-averaged hemoglobin A1C, diabetes duration, hypertension, BMI, albuminuria, DCCT randomization, smoking, statin treatment, and ultrasound devices. In cross-sectional analyses, lipoprotein B (Lp-B), Lp-B:C, Lp-B:E+Lp-B:C:E, Apo-A-II, Apo-B, Apo-C-III-HP (heparin precipitate; i.e., Apo-C-III in Apo-B-containing lipoproteins), and Apo-E were positively associated with common and/or internal carotid IMT in men, but only Apo-C-III (total) was (positively) associated with internal carotid IMT in women. In prospective analyses, Lp-B, Apo-B, and Apo-C-III-HP were positively associated with common and/or internal carotid IMT in men, while Lp-A1:AII and Apo-A1 were inversely associated with internal carotid IMT in women. The only significant prospective association between conventional lipids and IMT was between triacylglycerols and internal carotid IMT in men. ADLS and apolipoprotein concentrations may provide sex-specific biomarkers and suggest mechanisms for IMT in people with T1D.

Dose-response effects of marine omega-3 fatty acids on apolipoproteins, apolipoprotein-defined lipoprotein subclasses, and Lp-PLA2 in individuals with moderate hypertriglyceridemia.

BACKGROUND: Apolipoprotein (apo) distribution and lipoprotein (Lp)-associated markers of inflammation, such as lipoprotein-associated phospholipase A2 (Lp-PLA2), influence the atherogenicity of circulating lipids and lipoproteins. Little evidence exists regarding the dose-response effects of the marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on apos, apo-defined Lps, and Lp-PLA2. OBJECTIVE: The purpose of this study was to compare the effects of 0, 0.85, and 3.4 g/d of EPA + DHA on Lp-PLA2 mass and activity in individuals with moderate hypertriglyceridemia. We also measured effects on concentrations of apoAI, apoAII, apoB, apoC, apoD, and apoE-defined Lp subclasses. METHODS: The study was a randomized, doubleblind, crossover design with 8-week treatment periods and 6-week washout periods. During the 3 treatment periods, subjects (n = 25) received 0 g/d EPA + DHA, 0.85 g/d EPA + DHA (low dose), and 3.4 g/d EPA + DHA (high dose) in random order. RESULTS: apoB and apoC-III were significantly decreased by the high dose relative to placebo and low dose (P < .01), as was very low-density lipoprotein cholesterol (P < .005). The low dose had no effect on Lp outcomes compared with placebo. The high- and low-dose effects differed significantly for heparin-precipitated apoC-III, LpB, LpA-I, and apoB/apoA-I ratio (P < .05). There was a trend for a decreased Lp-PLA2 mass with the high dose (P = .1). CONCLUSION: The effects of 3.4 g/d EPA + DHA on apoB and apoC-III may reduce atherosclerotic plaque progression in individuals with elevated triglycerides.

Apolipoprotein-containing lipoprotein subclasses and subclinical atherosclerosis in systemic lupus erythematosus.

OBJECTIVE: Traditional classification of hyperlipidemia using high-density lipoprotein, low-density lipoprotein (LDL), and very low-density lipoprotein does not provide information on lipoprotein function. Apolipoproteins (Apos), which are protein components of plasma lipoproteins (including A, B, C, D, E) with their different composition, metabolic, and atherogenic properties, provide insight on lipoprotein functioning. In particular, the Apo B/A-I ratio is associated with atherogenic LDL and development of cardiovascular disease. We explored the baseline association between these nontraditional risk factors with subclinical measures of atherosclerosis (coronary artery calcification [CAC] and carotid intima-media thickness [IMT]) in systemic lupus erythematosus (SLE). METHODS: A total of 58 SLE patients (97% women, 58% white, 40% African American, and 2% other, mean ± SD age 44 ± 11 years) had measurement of Apo and lipoproteins by immunoturbidimetric procedures, electroimmunoassays, and immunoprecipitation. CAC was measured by helical computed tomography and carotid IMT by carotid duplex. This study was based on the baseline assessment of subclinical atherosclerosis in the Lupus Atherosclerosis Prevention Study. The measurement of the lipoproteins was made on sera collected at the same time. RESULTS: There was no association between cardioprotective Apos (Apo A-I, LpA-I, LpA-I:A-II) and CAC (P < 0.15, P < 0.41, and P < 0.39, respectively) or carotid IMT (P < 0.97, P < 0.53, and P < 0.76, respectively). CAC and carotid IMT did not associate with atherogenic Apos either, including LpB:E+LpB:C:E, Apo B, LpB, LpB:C, Apo C-III, Apo C-III-HS, Apo C-III-HP, Apo C-III-R, LpA-II:B:C:D:E, and Apo B/Apo A-I. Measures of disease activity, including physician's global assessment and Systemic Lupus Erythematosus Disease Activity Index, were not associated with CAC or carotid IMT. CONCLUSION: Neither cardioprotective nor atherogenic lipoproteins were associated with measures of subclinical atherosclerosis in this series of SLE patients. Further studies with a larger sample size are warranted to confirm our findings.

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.

Apolipoprotein-defined and NMR lipoprotein subclasses in the veterans affairs diabetes trial.

AIMS: The VADT was a randomized clinical trial designed to assess the effect of intensive vs. standard glucose management on cardiovascular events in Type 2 diabetes. At the end of the study, intensive management failed to improve outcomes. We performed plasma lipoprotein subclass analyses to yield new information on the effects of study randomization on cardiovascular risk. METHODS: This is a cross-sectional study of a subset of the VADT (740 men: 368 intensive; 372 standard), conducted at least six months (mean±SD: 2.1±0.8years) post-randomization. Conventional lipids, apolipoprotein-defined (ADLS) lipoprotein subclasses, ApoCIII, ApoE, and Nuclear Magnetic Resonance (NMR) lipoprotein subclasses were determined. RESULTS: In intensive vs. standard groups, conventional lipids and ADLS did not differ significantly. However, with intensive treatment, NMR-determined large and medium VLDL subclasses and VLDL diameter were lower, LDL diameter was higher, medium HDL was higher, and small HDL was lower (all p<0.05). Also, ApoCIII levels were lower (p<0.01). CONCLUSIONS: In a subset of diabetic men from the VADT, intensive glucose management did not affect conventional lipids or ADLS, but had some beneficial effects on particle characteristics as defined by NMR and on ApoCIII.

Apolipoprotein-defined lipoproteins and apolipoproteins: associations with abnormal albuminuria in type 1 diabetes in the diabetes control and complications trial/epidemiology of diabetes interventions and complications cohort.

AIMS: Dyslipoproteinemia has been associated with nephropathy in diabetes, with stronger correlations in men than in women. We aimed to characterize and compare plasma lipoprotein profiles associated with normal and increased albuminuria in men and women using apolipoprotein-defined lipoprotein subclasses and simple apolipoprotein measures. METHODS: This is a cross-sectional study in a subset (154 women and 282 men) of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort, using samples obtained in 1997-9. Immunochemical methods were used to quantify plasma apolipoprotein-based lipoprotein subclasses and individual apolipoprotein levels. RESULTS: In adjusted analyses, elevated Lipoprotein-B (Lp-B) was significantly associated with macroalbuminuria in men [odds ratios (OR) and 95% confidence interval (CI): 2.13 (1.15-3.97)] and women [3.01 (1.11-8.12)], while association with Lp-B:C was observed only in men [1.84 (1.19-2.86)]. For individual apolipoproteins the following significant associations with macroalbuminuria were observed in men only: Apolipoprotein B (ApoB) [1.97 (1.20-3.25)], Apo-AII [0.52 (0.29-0.93)], ApoC-III [1.95 (1.16-3.30)], "ApoC-III in VLDL" (heparin-manganese precipitate) [1.88 (1.16-3.04)], and "ApoCIII in HDL" (heparin-manganese supernatant) [2.03 (1.27-3.26)], all P<0.05). CONCLUSIONS: Atherogenic apolipoprotein-based profiles are associated with nephropathy in Type 1 diabetic men and to a lesser extent in women. The difference could result from the greater prevalence and severity of dyslipoproteinemia, and from the greater prevalence of renal dysfunction, in men vs women.

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 apolipoprotein B (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), low-density lipoprotein (LDL)-cholesterol / high-density lipoprotein (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.

Lipoprotein abnormalities in compound heterozygous lipoprotein lipase deficiency after treatment with a low-fat diet and orlistat.

BACKGROUND: The treatment of familial hyperchylomicronemia presenting in early childhood with episodes of pancreatitis has been ineffective, and affected patients remain at risk for pancreatitis. OBJECTIVE: To report on the effect of orlistat in siblings with severe inherited hyperchylomicronemia and to assess posttreatment lipoprotein concentrations and composition. METHODS: Serial observations of plasma lipid levels and hospitalizations after treatment with orlistat and lipoprotein studies on a single fasting posttreatment sample. RESULTS: The affected siblings inherited a lipoprotein lipase gene mutation from each of their parents: a novel mutation from their father (c.542G > C, p.G181R) and a known missense mutation from their mother (c.644G > A, p.G215E). When the boy presented to us at age 9 years of age and his sister at age 7 years, we found that addition of orlistat, a pancreatic lipase inhibitor, at a dose of 120 mg given before three low-fat meals a day was effective in reducing episodes of pancreatitis in the boy and in maintaining the triglyceride at lower levels in both children. During treatment, the children were observed to have elevations in apolipoprotein (apo)B, low-density lipoprotein particle concentration, abnormal apoB-containing subclasses, and deficiencies in apoA-I and apoA-II-containing lipoproteins, changes consistent with continuing increased cardiovascular risk. CONCLUSION: The data support the need for more effective long-term treatments that not only prevent pancreatitis but also offset cardiovascular risk. Orlistat can be considered effective in augmenting the effect of a low-fat diet and reducing risk for pancreatitis.

Interrelationships between the concentration and size of the largest high-density lipoprotein subfraction and apolipoprotein C-I in infants at birth and follow-up at 2-3 months of age and their parents.

BACKGROUND: Lipoprotein subfractions in infants may predict the risk of cardiovascular disease factors in children. OBJECTIVE: To examine the relationships between lipid and nonlipid factors and lipoprotein subfractions in infants at birth and follow-up (FU) and in their parents. METHODS: Prospective study in a community-based hospital of 103 families ascertained through a pregnant mother at 36 weeks gestation or older. Of 103 infants studied at birth, 85 were sampled at FU at 2-3 months of age, along with 76 fathers. Lipids, lipoproteins, and their subclasses were determined by nuclear magnetic resonance spectroscopy. Correlations of lipid-related parameters were calculated using Spearman rank correlations. RESULTS: Female gender in infants and use of formula only were the only nonlipid variables associated with lipoprotein subfractions. LDL parameters were significantly correlated between infants at birth and FU. The largest high-density lipoprotein subfraction, H5C, was the only lipid variable significantly associated between mothers and infants at birth. Paternal low-density lipoprotein size was significantly correlated with that of infants at FU but not at birth. In each of the four groups, markedly inverse interrelationships were found between H5C and small LDL particles. At birth and at FU, apoC-I was strongly related with H5C but not TG. Conversely, apoC-I in the parents was strongly related with TG but not H5C. CONCLUSION: Significant relationships were found between lipoprotein subfractions within infants at birth and FU and their parents. ApoC-I and H5C levels very early in life may affect the development of dyslipidemia and obesity in childhood.

Apolipoproteins A-I, B, and C-III in young adult Cherokee with metabolic syndrome with or without type 2 diabetes.

BACKGROUND: Because 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 with those with MetS alone. We evaluated apolipoproteins as possible distinguishing markers in the Oklahoma Cherokee. OBJECTIVE: To assess apolipoproteins (apo) 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, ages 18 to 40 years, was conducted to assess differences in the apolipoproteins caused by the presence or absence of T2D among those with MetS, after we adjusted for age and gender. RESULTS: ApoA-I (P = .0222) and high-density lipoprotein cholesterol (HDL-C; P = .0364) were lower, and apoB (P = .0106) and the apoB to A-I ratio (P < .0001) were greater in participants with the MetS and T2D than in those with MetS but without T2D. However, cholesterol, triglyceride, low-density lipoprotein cholesterol, 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 greater 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 MetS may precede T2D.

Human HDL containing a novel apoC-I isoform induces smooth muscle cell apoptosis.

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.

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 ß-cell and contribute to their increased risk for DM2.

Plasma lipoproteins and preeclampsia in women with type 1 diabetes: a prospective study.

CONTEXT: In nondiabetic pregnancy, cross-sectional studies have shown associations between maternal dyslipidemia and preeclampsia (PE). In type 1 diabetes mellitus (T1DM), the prevalence of PE is increased 4-fold, but prospective associations with plasma lipoproteins are unknown. OBJECTIVES: The aim of this study was to define lipoprotein-related markers and potential mechanisms for PE in T1DM. DESIGN AND SETTINGS: We conducted a multicenter prospective study in T1DM pregnancy. PATIENTS: We studied 118 T1DM women (26 developed PE, 92 remained normotensive). Subjects were studied at three visits before PE onset [12.2 ± 1.9, 21.6 ± 1.5, and 31.5 ± 1.7 wk gestation (means ± SD)] and at term (37.6 ± 2.0 wk). Nondiabetic normotensive pregnant women (n = 21) were included for reference. MAIN OUTCOME MEASURES: Conventional lipid profiles, lipoprotein subclasses [defined by size (nuclear magnetic resonance) and by apolipoprotein content], serum apolipoproteins (ApoAI, ApoB, and ApoCIII), and lipolysis (ApoCIII ratio) were measured in T1DM women with and without subsequent PE. RESULTS: In women with vs. without subsequent PE, at the first and/or second study visits: low-density lipoprotein (LDL)-cholesterol, particle concentrations of total LDL and large (but not small) LDL, serum ApoB, and ApoB:ApoAI ratio were all increased (P < 0.05); peripheral lipoprotein lipolysis was decreased (P < 0.01). These early differences remained significant in covariate analysis (glycated hemoglobin, actual prandial status, gravidity, body mass index, and diabetes duration) but were not present at the third study visit. High-density lipoprotein and very low-density lipoprotein subclasses did not differ between groups before PE onset. CONCLUSIONS: Early in pregnancy, increased cholesterol-rich lipoproteins and an index suggesting decreased peripheral lipolysis were associated with subsequent PE in T1DM women. Background maternal lipoprotein characteristics, perhaps masked by effects of late pregnancy, may influence PE risk.

CETP-mediated cholesteryl ester enrichment of apoB subclasses in type 1 diabetes.

OBJECTIVE: Accelerated cholesteryl ester transfer (CET) in patients with types 1 (T1D) and 2 diabetes enhances the atherogenicity of the apoB-containing CE acceptor lipoproteins. The study of lipoprotein density fractions cannot identify which of the five immunologically distinct apoB subclasses function as CE acceptors because they are heterogeneous and present in very low-, intermediate- and low density lipoproteins (VLDL, IDL and LDL, respectively). In order to design lipid-modifying therapies that specifically target these CE-enriched lipoprotein particles, it is necessary to first characterize their CE acceptor function. METHODS AND RESULTS: To identify the CE acceptors, we estimated CE net mass transfer to the apoB subclasses LpB:C, LpB:E + LpB:C:E, LpB and LpAII:B:C:D:E from changes in neutral lipids measured by gas chromatography following their separation by sequential immunoaffinity chromatography in the plasma of 12 patients with T1D and six control subjects. In both groups, CE was distributed equally to LpB:E + LpB:C:E and LpB:C. In the T1D CE acceptors, however, both the magnitude of the increase (18% vs. 10%; P < 0·01) and the per particle mass of CE transferred were significantly greater than in controls (T1D: 2·29 µmol ± 2·1 vs. control 0·43 ± 0·43/mg apoB; P < 0·047). CONCLUSION: While LpB:E + LpB:C:E and LpB:C functioned as CE acceptors in both groups, these subclasses increased their CE content to a greater degree and accrued more CE per particle in the patients with T1D. As this disturbance in lipoprotein remodelling may increase the cholesterol burden and potential atherogenicity of these apoB subclasses, it may be a previously unrecognized factor that increases cardiovascular risk in patients with T1D.

Beef in an Optimal Lean Diet study: effects on lipids, lipoproteins, and apolipoproteins.

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.

Acute effects of interleukin-6 infusion on apo-B-containing lipoprotein subclasses in humans.

IL-6 is believed to mediate the elevation in plasma TG and VLDL lipids in patients with sepsis. Previous studies of lipoprotein density fractions do not reveal the extent to which cytokines change the immunochemically distinct TG-rich (LpB:C, LpB:C:E, LpAII:B:C:D:E) and cholesterol-rich (LpB, LpB:E) apoB-containing subclasses present in VLDL. Therefore, we have directly measured these subclasses following their isolation by sequential immunoprecipitation in seven healthy male subjects during a 3-h infusion with recombinant human (rh) IL-6. Though plasma TG and apoB-containing particle number were unchanged by IL-6, the distribution of TG-rich subclasses was significantly altered. Compared to baseline values, LpB:E + LpB:C:E increased significantly at 0.5 h (p < 0.02) and were higher than saline-infused controls at 0.5 and 1 h (p < 0.05). At 0.5 h LpAII:B:C:D:E reciprocally declined from baseline (p < 0.01). While the pattern of change for total apoB showed an overall decline (p < 0.05), these changes in LpB:E + LpB:C:E and LpAII:B:C:D:E in IL-6 subjects differed from controls (p < 0.05; p < 0.01, respectively). These findings indicate that physiologic concentrations of IL-6 rapidly and selectively regulate the transport of apoB particles that contain apoE. Since apoE has immunomodulatory and host defense functions, these changes may be a previously unrecognized early step in the innate immune response.

Oxidative stress and inflammation in renal patients and healthy subjects.

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.

Lipoprotein abnormalities in patients with atherosclerotic renovascular disease.

BACKGROUND: Patients with atherosclerotic renovascular disease (ARVD) have a high risk of cardiovascular death. The primary aim was to characterize abnormalities in apolipoprotein (Apo)-defined lipoprotein (Lp) subclasses in patients with ARVD. METHODS: Baseline measurements were performed on 42 patients with ARVD 4 weeks after renal angioplasty (PTRA). All patients were on statin treatment. Twenty age-matched healthy subjects without medications served as controls. Subsequently, patients were randomized to treatment with either candesartan (n = 21), or antihypertensive treatment without inhibitors of the renin-angiotensin-aldosterone system (n = 21) and followed for 11 months. RESULTS: At baseline, ApoC-III (12.7 ± 4.6 vs. 8.8 ± 2.6 (SD) mg/dl, p < 0.05), LpB:C:E (13.3 ± 5.4 vs. 8.4 ± 4.3 mg/dl, p < 0.05), and the sum of ApoC-III-containing lipoproteins, i.e. LpB:C + LpB:C:E + LpA-II:B:C:D:E (46 ± 15 vs. 37 ± 8 mg/dl, p < 0.05), were significantly elevated in ARVD patients versus healthy controls. Multiple regression analyses showed that only plasma renin activity was independently associated with ApoC-III levels at baseline (p < 0.05, r = 0.74). Treatment with candesartan did not correct abnormalities. CONCLUSIONS: Patients with ARVD treated with statins have an atherogenic lipoprotein profile characterized by elevated levels of ApoC-III-containing, triglyceride-rich lipoproteins that could accelerate atherosclerotic disease.