Cholesterol Content Of Particles Research Articles

Apolipoprotein B compared with low-density lipoprotein cholesterol in the atherosclerotic cardiovascular diseases risk assessment

The subendothelial retention of apolipoprotein B (apoB)-containing lipoproteins is a critical step in the initiation of pro-atherosclerotic processes. Recent genetic and clinical evidence strongly supports the concept that the lipid content of the particles is secondary to the number of circulating atherogenic particles that are trapped within the arterial lumen. Since each low-density lipoproteins (LDL) particle contains one apoB molecule, as do intermediate density lipoprotein (IDL) and very low-density lipoprotein (VLDL) particles, apoB level represents the total number of atherogenic lipoproteins, which is independent of particle density, and not affected by the heterogeneity of particle cholesterol content (clinically evaluated by LDL-cholesterol level). From this perspective, apoB is proposed as a better proxy to LDL-cholesterol for assessing atherosclerotic cardiovascular disease risk, especially in specific subgroups of patients, including subjects with diabetes mellitus, with multiple cardiometabolic risk factors (obesity, metabolic syndrome, insulin resistance, and hypertension) and with high triglyceride levels and very low LDL-cholesterol levels. Therefore, given the causal role of LDL-cholesterol in atherosclerotic cardiovascular disease (ASCVD) development, routine measurement of both LDL-cholesterol and apoB is of utmost importance to properly estimate global cardiovascular risk and to determine the 'residual' risk of ASCVD in patients receiving therapy, as well as to monitor therapeutic effectiveness.

Apolipoprotein B and Cardiovascular Disease: Biomarker and Potential Therapeutic Target.

Apolipoprotein (apo) B, the critical structural protein of the atherogenic lipoproteins, has two major isoforms: apoB48 and apoB100. ApoB48 is found in chylomicrons and chylomicron remnants with one apoB48 molecule per chylomicron particle. Similarly, a single apoB100 molecule is contained per particle of very-low-density lipoprotein (VLDL), intermediate density lipoprotein, LDL and lipoprotein(a). This unique one apoB per particle ratio makes plasma apoB concentration a direct measure of the number of circulating atherogenic lipoproteins. ApoB levels indicate the atherogenic particle concentration independent of the particle cholesterol content, which is variable. While LDL, the major cholesterol-carrying serum lipoprotein, is the primary therapeutic target for management and prevention of atherosclerotic cardiovascular disease, there is strong evidence that apoB is a more accurate indicator of cardiovascular risk than either total cholesterol or LDL cholesterol. This review examines multiple aspects of apoB structure and function, with a focus on the controversy over use of apoB as a therapeutic target in clinical practice. Ongoing coronary artery disease residual risk, despite lipid-lowering treatment, has left patients and clinicians with unsatisfactory options for monitoring cardiovascular health. At the present time, the substitution of apoB for LDL-C in cardiovascular disease prevention guidelines has been deemed unjustified, but discussions continue.

Discordance between lipoprotein particle number and cholesterol content: an update

The cholesterol content within atherogenic apolipoprotein-B (apoB) containing lipid particles is the center of consensus guidelines and clinicians' focus whenever evaluating a patient's risk for atherosclerotic cardiovascular disease. The pathobiology of atherosclerosis requires the retention of lipoprotein particles within the vascular intima over time followed by maladaptive inflammation resulting in plaque formation and rupture in some. The cholesterol content is widely variable within each particle creating either cholesterol-deplete or cholesterol-enriched particles. This variance in particle cholesterol content varies within and between individuals. Discordance analysis exploits this difference in cholesterol content of particles to demonstrate the differential significance of LDL-cholesterol (LDL-C) and non-HDL-C from measures of lipoprotein particle number in terms of assessing atherosclerotic cardiovascular disease risks. Three studies have added to the growing body of literature of discordance analysis. Despite wide variability of discordance cutoffs, baseline risk of atherosclerotic disease, and populations sampled, the conclusion remains the same: risk of atherosclerotic disease follows apoB lipid particle concentration rather than cholesterol content of lipid particles. In addition to traditional lipid fractions, assessments of atherogenic particle number should be strongly considered whenever assessing CVD risk in nontreated and treated individuals. There is a need for clinical trials that focus not only on the reduction in LDL-C but apoB, as well.

Association of Comprehensive Lipoprotein Profiling with Coronary Artery Disease in Allogeneic Stem Cell Transplant (Allo-SCT) Survivors

INTRODUCTION:Premature vascular disease is a leading cause of late mortality in allogeneic stem cell transplantation (SCT) survivors but the underlying mechanism is not understood. Dyslipidemia is a strong and targetable risk factor for coronary artery disease (CAD) in the general population and its relevance (higher prevalence and high attributable risk in epidemiologic studies of arterial disease) has also been recognized in SCT survivors over the last decade. However, we have previously shown that Framingham risk scores, which rely upon traditional lipid cholesterol measures, are insensitive in determining the presence of CAD. Here, we present the first comprehensive lipoprotein analysis in well-annotated asymptomatic SCT survivors, simultaneously assessed for vascular health using cardiac CT to identify CAD.PATIENTS & METHODS:We performed a cross-sectional analysis of 67 survivors who underwent allo-SCT between 1993 and 2012 for hematologic malignancies and survived for at least three years. All subjects received total body irradiation (TBI) based conditioning followed by a 3-4 log ex vivo T cell depleted graft. The median age at transplant was 39 years (range 17-69). The median duration of follow up was 11 years (range 3-22). Sixty percent were male. Seventy percent had some chronic GVHD, but only 23% required immunosuppression at 3 years post transplant. All subjects had a cardiac CT performed and CAD was defined by the presence of either luminal stenosis by angiography or coronary calcification. Cardiovascular clinical data (hypertension, diabetes, dyslipidemia, smoking, CRP, body mass index) and 10- year Framingham risk scores were also collected. Comprehensive lipoprotein analysis was performed on fasting plasma samples using nuclear magnetic resonance (NMR) with the Vantera clinical analyzer (LipoScience Inc., Raleigh, NC). Digitized spectral data signals undergo algorithmic processing to identify and quantify concentrations of lipoproteins and, potentially, small molecule metabolites from a single sample. 13 subjects with history of lipid lowering therapy or absence of plasma sample were excluded. 24 lipoprotein metabolites were measured including particle cholesterol content (_C), particle count (_P), size [small (S_), medium (M_), large (L_), large + medium (LM_)] and average size (_Z). Due to natural variability in the amount of cholesterol per particle, HDL_C/LDL_C and HDL_P/LDL_P levels often are discordant. HDL_P/LDL_P provides a more clinically reliable measure of HDL/LDL quantity than HDL_C/LDL_C.RESULTS:CAD was confirmed in 45% of survivors; 89% of lesions were non-obstructive and 28% of plaques were non-calcified. Lipoprotein analysis on 54 subjects showed no significant association between HDL or LDL particle cholesterol content, particle count or size distribution. Interestingly, measures of Triglyceride and VLDL were significantly higher in survivors with CAD vs no CAD [VLDL_P median 90.4 vs 54.0 nmol/L (p= 0.009), M_VLDL_P 40.2 vs 23.1 nmol/L (p= 0.03), LM_VLDL_P 44.5 vs 26.1 nmol/L (p= 0.04), and total triglycerides (TG) 172 vs 133 mg/dL (p= 0.03)] (Figure 1).CONCLUSION:In allo-SCT long term survivors, elevated triglyceride and VLDL counts were associated with early CAD even when traditional targetable measures of dyslipidemia (HDL and LDL) were normal. Future efforts will integrate traditional cardiac risk factors with metabolic markers (lipoproteins, insulin resistance and growth hormone deficiency) to better understand premature coronary artery disease in SCT recipients. [Display omitted] DisclosuresBattiwalla:NIH/NHLBI: Employment.

Abstract P193: Increased High Density Lipoprotein Cholesterol:ApolipoproteinA1 Ratio is Associated with Less Progression of Coronary Atherosclerosis in Statin-Treated Patients

Background HDL cholesterol (HDL-C) and apolipoprotein AI (apoAI) levels are inversely related to adverse cardiovascular outcome. Associations between these HDL related measures and their ratio with coronary plaque progression have not been studied. It has been proposed that increasing HDL particle cholesterol content impairs HDL function, but impact on disease progression is unknown. We hypothesize that all HDL related measures are inversely associated with coronary plaque progression. Methods Retrospective analysis was performed of 1528 statin treated patients with angiographic CAD who had serial evaluation of atheroma burden with intravascular ultrasound. Relationships between achieved levels of HDL related measures with clinical characteristics and changes in plaque burden were determined. Results Strong correlation between HDL-C and apoAI (r=0.73, p<0.0001) was noted. Patients with highest levels of HDL-C:apoAI were more likely to be female, black, and have lower BMI and less likely to be smokers or have previous revascularization (all p<0.001) or acute coronary syndrome (p=0.013). HDL-C, apoAI, and HDL-C:apoAI demonstrated negative correlation with change in total atheroma volume (p<0.01). For HDL-C:apoAI and HDL-C, increasing tertiles of achieved levels were associated with a linear benefit in slowing progression. For apoAI, a nonlinear association was seen, with similar benefit on progression in the middle and upper tertiles ( Table ). There was no statistical interaction for heterogeneity between HDL-C:apoAI and atheroma burden based on achieved levels of HDL-C (p=0.581). Change in IVUS Measures By Tertiles of Achieved HDL-related Parameters Percent Atheroma Volume Parameter T1 T2 T3 P Value HDL-C 0.58±0.27 0.26±0.27 0.11±0.27 0.012 ApoAI 0.28±0.26 −0.04±0.26 −0.08±0.26 0.10 HDL-C:ApoAI 0.22±0.27 0.13±0.27 −0.27±0.27 0.021 Total Atheroma Volume Parameter T1 T2 T3 P Value HDL-C −2.46±2.21 −4.18±2.20 −5.31±2.20 0.035 ApoAI −4.94±2.13 −6.30±2.13 −7.40±2.13 0.135 HDL-C:ApoAI −4.59±2.25 −6.38±2.24 −8.07±2.26 0.022 Conclusions Increase in all HDL related measures was associated with less progression of coronary atherosclerosis. Association of higher HDL-C:ApoAI with favorable effect on plaque progression at all levels of HDL-C suggests intact HDL functionality of larger cholesterol rich particles. Interventions that increase HDL particle cholesterol content, such as CETP inhibitors, may thus have beneficial effect at the artery wall.

High-density lipoprotein associations with coronary heart disease: Does measurement of cholesterol content give the best result?

The protective role played by high-density lipoprotein (HDL) in atherogenesis is well-accepted, as is the significant inverse association of HDL cholesterol (HDL-C) with coronary heart disease (CHD) risk. What remains controversial is whether we are using the best measure(s) of HDL to identify and manage HDL-related cardiovascular risk. Measuring particle number has been postulated to offer additional and possibly more specific information regarding risk. Although HDL-C is thought to indicate the quantity of circulating HDL particles, it is underappreciated that the amount of cholesterol carried inside lipoprotein particles is highly variable among individuals with the same HDL-C. Numerous trials have investigated the relations of CHD with various measures of HDL other than those based on cholesterol content of the particles present. Studies regarding the association of alternate measures of HDL with CHD risk have been mixed, possibly due to diversity in clinical characteristics accompanying low HDL-C states, variability in cholesterol content of HDL particles, and substantial inter-correlations of HDL with other lipoprotein particles. Additional research is needed to assess the clinical settings in which individual HDL tests, after multivariate adjustment for confounding factors, provide superior independent prediction of CHD events beyond HDL-C. Such studies show promise in defining measures of particle number that will prove useful in future strategies to enhance management of CHD risk and assess response to therapy at an individual patient level.

Effects of Bezafibrate on HDL2/HDL3 Ratio in Postmenopausal Hypertriglyceridemic Women

The short-term effects of bezafibrate on high-density lipoprotein cholesterol quality and triglyceride-rich lipoprotein metabolism in 186 postmenopausal hypertriglyceridemic women were investigated. Patients were randomized to an untreated group and to bezafibrate (400 mg/d) for 6 months. Fasting lipid concentrations, high-density lipoprotein 2, and high-density lipoprotein 3 levels were measured at baseline and after 3 and 6 months. At 3 months, bezafibrate had significantly decreased mean serum triglycerides and remnant-like particle cholesterol levels (105.7 +/- 43.4 mg/dL and 5.33 +/- 2.1 mg/dL, P < .001, respectively) from baseline values (232.5 +/- 63.9 mg/dL and 9.69 +/- 3.8 mg/dL, respectively). It also maintained lower total cholesterol, low-density lipoprotein cholesterol, triglycerides, and remnant-like particle cholesterol concentrations to 6 months. After 3 months, it significantly increased mean serum high-density lipoprotein cholesterol (55.1 +/- 14.7 vs 64.8 +/- 12.1 mg/dL; P < .0001) and maintained higher high-density lipoprotein cholesterol at 6 months. The high-density lipoprotein 2-high-density lipoprotein 3 ratio was decreased after 3 months of therapy with bezafibrate (2.13 +/- 0.68) from the baseline (2.42 +/- 0.71) (P < .01).

Interaction of apoA-1 and ApoE-3 with triglyceride-phospholipid emulsions containing increasing cholesterol concentrations. Model of triglyceride-rich nascent and remnant lipoproteins

The cholesterol content of triglyceride-rich lipoproteins increases during their catabolism in circulation. We therefore studied the binding of the exchangeable apoprotein apoA-1 and apoE-3 to triolein-rich emulsions with increasing cholesterol content. Five emulsion systems containing 83.1-88.8% (w/w) triolein, 9.3-10.1% egg yolk phosphatidylcholine, and 1.1-7.3% cholesterol were isolated from sonicated lipid mixtures by flotation. Negative stain EM of emulsions containing 1.1 and 7.3% cholesterol showed polydisperse populations of large spherical particles with diameters of 106 +/- 39 and 108 +/- 57 nm. These values are similar to particle diameters calculated from the lipid composition data. No lamellar structures were observed by EM, even after addition of apoA-1 at a molar ratio to lecithin of 10(-2). Apolipoproteins apoA-1 and apoE-3 bound to the particles in a saturable manner without altering particle morphology. We found a dissociation constant Kd = 7.4 x 10(-7) M and a binding capacity N = 3.9 x 10(-3) proteins/lecithin for apoA-1 with particles containing 1.1% cholesterol; the Kd and N values for apoE-3 were very similar. When the emulsion particles were saturated with cholesterol at 7.3%, the protein binding capacity N sharply decreased to 0.6 x 10(-3) (apoA-1) and 0.7 x 10(-3) proteins/lecithin (apoE-3), but the Kd values were virtually unchanged. No change in N occurred when the particle cholesterol content was increased from 1.1 to 3.7%, which spans the normal physiological range. These results suggest that increases in lipoprotein cholesterol content above 3.7% may be responsible for impaired apoprotein redistribution and altered metabolism of remnants such as beta-VLDL.