High-density lipoprotein/apolipoprotein A-I infusion therapy

Strategies to decrease the progression and burden of atherosclerosis by capitalizing on the protective effect of high-density lipoprotein (HDL) and/or apolipoprotein A1 (apoA-I) levels remain active. Although efforts to raise HDL through the administration of oral agents are still being pursued, the disappointing results demonstrated with torcetrapib, an agent that elevated serum HDL and apoA-I levels through the inhibition of cholesterol ester transfer protein, have raised questions regarding this approach. An alternate strategy that consists of short-term infusions of reconstituted HDL or apoA-I is currently under evaluation. Several infusion compounds have been evaluated in clinical trials that utilize cardiovascular imaging technologies and biomarkers to assess potential clinical efficacy. Although these compounds are still in early-stage development, the results of these trials have supported the viability of this line of investigation. This review addresses the potential of HDL and/or apoA-I infusions as a possible therapeutic strategy for the treatment of coronary artery disease.     

Plasma apolipoprotein concentrations in familial apolipoprotein A-I and A-II deficiency (Tangier disease)

Familial apolipoprotein A-I and A-II deficiency (Tangier disease) is characterized by cholesterol ester deposition in histiocytes, decreased plasma cholesterol and low density lipoprotein cholesterol (C-LDL), and a striking deficiency of high density lipoproteins (HDL). We measured plasma lipid, lipoprotein cholesterol, and plasma apolipoprotein (apo) A-I, A-II, B, C-I, C-II, C-III, D, and E concentrations in 7 Tangier homozygotes, 2 obligate heterozygotes, and 50 normal subjects. Heterozygotes had modest reductions in high density lipoprotein cholesterol (C-HDL), plasma apoA-I, and apoA-II levels. Mean concentrations (±SD) of plasma C-HDL and apolipoproteins A-I, A-II, B, C-I, C-II, C-III, D, and E in mg% in normals were: 50 ± 14, 134 ± 24, 68 ± 18, 98 ± 20, 7 ± 2, 3.7 ± 2, 13 ± 5, 10 ± 4, and 10 ± 4, respectively; and in homozygotes were: 1 ± 1, 1.3 ± 0.7, 4.8 ± 2.5, 82.6 ± 18, 4.1 ± 1.7, 2.3 ± 0.9, 6.5 ± 3.8, 2.2 ± 0.5, and 5.4 ± 3.1, respectively. Homozygotes had C-HDL, apoA-I and apoA-II levels which were 2%, 1%, and 7% (p < .001) of normal, respectively, and mean levels of apolipoproteins B, C-I, C-II, C-III, D, and E which were 84%, 59%, 62%, 50%, 22%, and 54% of normal, respectively. There was heterogeneity of these latter apolipoprotein concentrations among homozygotes. Mean apoC-I, apoC-III, apoD, and apoE levels were significantly less than normal (pp < .05) in homozygotes. These data indicate that homozygotes have variable but generally decreased apoC and apoE levels, a deficiency of apoD, and a striking reduction in plasma apoA-I and apoA-II concentrations.     

High-density lipoprotein apolipoprotein A-I kinetics in obese insulin resistant patients. An in vivo stable isotope study

AIMS/HYPOTHESIS: Mechanisms responsible for the decreased high-density lipoprotein (HDL) cholesterol level associated with insulin resistance in obese patients are not clearly understood. To determine the influence of insulin resistance at an early stage on HDL metabolism, we performed a stable isotope kinetic study of apolipoprotein (apo) A-I, in five obese insulin resistant women with normal fasting triglycerides and without impaired glucose tolerance, and in five age-matched control women. METHODS: Each subject received a 16 h constant infusion of L-[1-(13)C]leucine at 0.7 mg/kg/h following a primed bolus of 0.7 mg/kg. RESULTS: ApoA-I fractional catabolic rate (FCR) was significantly increased in insulin-resistant women compared to controls (0.316+/-0.056 vs 0.210+/-0.040 per day, P<0.01), indicating a significant 50% increase of apoA-I catabolism, leading to an important reduction of plasma apoA-I residence time (3.25+/-0.59 vs 4.92+/-1.11, P<0.01). ApoA-I production rate tended to be higher in insulin resistant women than in controls (364+/-77 vs 258+/-60 mg/l/day, P=0.13), but the difference was not statistically significant. ApoA-I FCR was correlated with triglycerides during the fed state (r=0.69; P=0.026) and HDL triglycerides-esterified cholesterol ratio (r=0.73; P=0.016), suggesting that alteration of apoA-I metabolism in insulin resistance may be partly related to HDL enrichment in triglycerides. CONCLUSIONS: Our kinetic study shows that patients, at an early stage of insulin resistance (without impaired glucose tolerance nor fasting hypertriglyceridaemia), already have a significant alteration of apoA-I metabolism (increased apoA-I catabolism), which is consistent with the increased risk of atherosclerosis in this population.     

In vivo metabolism of apolipoprotein E within the HDL subpopulations LpE,LpE:A-I,LpE:A-II and LpE:A-I:A-II

High-density lipoproteins can be separated into distinct particles based on their apolipoprotein content. In the present study, the in vivo metabolism of apoE within the apoE-containing HDL particles LpE, LpE:A-I, LpE:A-II and LpE:A-I:A-II was assessed in control subjects and in patients with abetalipoproteinemia (ABL), in whom HDL are the sole plasma lipoproteins. The metabolism of apoE within these HDL subspecies was investigated in three separate studies which differed by donor or recipient status: (1) particles purified from normolipidemic plasma and reassociated with 125I or 131I-labeled apoE injected into normolipidemic subjects (study 1); (2) particles purified from ABL plasma injected into normolipidemic subjects (study 2); and (3) particles purified from ABL plasma injected into ABL subjects (study 3). The plasma residence times (RT, hours) in study 1 were 14.3+/-2.9, 11.3+/-3.4, and 9.1+/-1.2 for apoE within LpE:A-I:A-II, LpE:A-II and LpE:A-I, respectively, while those in study 2 were 10.1+/-2.2, 9.7+/-2.4, 7.9+/-1.0 and 7.3+/-0.8 for apoE within LpE:A-I:A-II, LpE:A-II, LpE:A-I and LpE, respectively. In study 3, RTs for apoE within LpE:A-I:A-II and LpE were 8.7+/-0.9 and 6.8+/-0.9, respectively. In comparison, RT for apoA-I on LpA-I:A-II has been reported to be 124.1+/-5.5 h and that for apoA-I on LpA-I 105.8+/-6.2 h. Thus, apoE within the different apoE-containing HDL particles was metabolized rapidly and at a similar rate in control and ABL subjects. The plasma RT of apoE was longest when injected on LpE:A-I:A-II particles and shortest when injected on LpE. In summary, our data show that: (1) the plasma RT of apoE within HDL is approximately ten times shorter than that of apoA-I within HDL, and (2) apoE within HDL is metabolized at a slower rate when apoproteins A-I and A-II are present (LpE:A-I:A-II RT>LpE:A-II>LpE:A-I>LpE). These differences were related to the lipid and apolipoprotein composition of the HDL subspecies, and, in control subjects, to the transfer of apoE from HDL subspecies to apoB-containing lipoproteins as well.     

Metabolism of HDL apolipoprotein A-I and A-II in Type 1 (insulin-dependent) diabetes mellitus

Summary Concentrations of HDL cholesterol and apolipoprotein A-I are commonly increased in Type 1 (insul-independent) diabetes mellitus but the mechanisms whereby diabetes influences HDL metabolism have not been studied. We investigated the metabolism of HDL apoproteins A-I and II in normolipidaemic Type 1 diabetic men (n=17, HbA₁ 6.4–11.9%) without microalbuminuria but with a wide range of HDL cholesterol (0.85–2.10 mmol/l) and in nondiabetic men (n=18) matched for body mass index and the range of HDL cholesterol. Input rates and fractional catabolic rates for apolipoproteins A-I and II were determined following injection of ¹²⁵I-apolipoprotein A-I and ¹³¹I-apolipoprotein A-II tracers. Additional multicompartmental analysis was performed using a model to describe the kinetics of HDL particles containing only apolipoprotein A-I (Lp A-I) and apolipoprotein A-I and apolipoprotein A-II (Lp A-I/ A-II). No gross differences from normal subjects were observed in the mean levels of lipids, lipoproteins, apoproteins and the lipolytic enzymes in the diabetic men as a result of the selection process. Furthermore, the relationship between apolipoprotein A kinetics and plasma HDL cholesterol levels appeared to be preserved in the diabetic group. However, some normal interrelationships were disrupted in the diabetic men. Firstly, the rate of apolipoprotein A-II synthesis was 22% lower than in control subjects (p<0.05). Modelling indicated that this was due to decreased input of Lp A-I/A-II particles whereas the input of Lp A-I particles was similar in the two groups. Secondly, there was no correlation between VLDL triglyceride and HDL cholesterol or VLDL triglyceride and the fractional catabolic rate of apolipoproteins A-I and A-II in diabetic men in contrast to that seen in control subjects. We conclude that there is a disruption in the normal association between VLDL and HDL metabolism in Type 1 diabetic men and postulate that the observed differences may be due to the therapeutic use of exogenous insulin.     

High-density lipoprotein cholesterol and apolipoprotein A-I levels at diagnosis in patients with non-insulin dependent diabetes

Summary High-density lipoprotein (HDL) cholesterol levels were decreased in patients with non-insulin dependent diabetes at diagnosis when matched with a control population for sex, age, obesity, alcohol consumption and cigarette smoking. There was no association between serum HDL-cholesterol concentration and the percentage of glycosylated haemoglobin A₁ (HbA₁). Serum HDL-cholesterol levels were lower in diabetics over the whole range of serum triglyceride levels, and particularly in hypertriglyceridaemic diabetics. Serum apolipoprotein A-I levels were not decreased in diabetics with normal serum triglyceride levels, so that the ratio of HDL cholesterol to apolipoprotein A-I was significantly decreased in diabetics (p<0.005). Decreased HDL cholesterol levels in non-insulin dependent diabetes could be relevant to the subsequent development of atherosclerosis.     

Comparison of high-density lipoprotein cholesterol to apolipoprotein A-I and A-II to predict coronary calcium and the effect of insulin resistance

High-density lipoprotein (HDL) cholesterol and its apolipoproteins each capture unique lipid and cardiometabolic information important to risk quantification. It was hypothesized that metabolic factors, including insulin resistance and type 2 diabetes, would confound the association of HDL cholesterol with coronary artery calcification (CAC) and that apolipoprotein A-I (apoA-I) and/or apolipoprotein A-II (apoA-II) would add to HDL cholesterol in predicting CAC. Two community-based cross-sectional studies of white subjects were analyzed: the Penn Diabetes Heart Study (PDHS; n = 611 subjects with type 2 diabetes, 71.4% men) and the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA; n = 803 subjects without diabetes, 52.8% men) using multivariable analysis of apoA-I, apoA-II, and HDL cholesterol stratified by diabetes status. HDL cholesterol was inversely associated with CAC after adjusting for age and gender in whites with type 2 diabetes (tobit ratio for a 1-SD increase in HDL cholesterol 0.58, 95% confidence interval [CI] 0.44 to 0.77, p <0.001) as well as those without diabetes (tobit ratio 0.72, 95% CI 0.59 to 0.88, p = 0.001). In contrast, apoA-I was a weaker predictor in subjects with (tobit ratio 0.64, 95% CI 0.45 to 0.90, p = 0.010) and without (tobit ratio 0.79, 95% CI 0.66 to 0.94, p = 0.010) diabetes, while apoA-II had no association with CAC. Control for metabolic variables, including triglycerides, waist circumference, and homeostasis model assessment of insulin resistance, attenuated these relations, particularly in subjects without diabetes. In likelihood ratio test analyses, HDL cholesterol added to apoA-I, apoA-II, and atherogenic apolipoprotein B lipoproteins but improved CAC prediction over metabolic factors only in subjects with diabetes. In conclusion, HDL cholesterol outperformed apoA-I and apoA-II in CAC prediction, but its association with CAC was attenuated by measures of insulin resistance.     

Serum high density lipoprotein cholesterol, apolipoprotein A-I, A-II and B levels in Singapore ethnic groups

The mortality rate from CAD in Indians is more than 3 times that in the Chinese and Malays in the population of Singapore. The serum total, HDL cholesterol and apolipoprotein levels (Apo A-I, Apo A-II and Apo B) were studied in a group of 344 healthy male adults from the 3 ethnic groups. Indians had a significantly lower level of HDL-cholesterol (38.4 +/- 9.8 mg/dl) than the Chinese (42.7 +/- 8.9 mg/dl) (P less than 0.005). The Apo A-I levels were higher in the Chinese (115.1 +/- 14.8 mg/dl) than in the Indians (108.6 +/- 28.8 mg/dl), but the difference was not statistically significant. The Chinese also had higher levels of Apo A-II (48.1 +/- 7.2 mg/dl) compared to those in the Indians (38.6 +/- 6.4 mg/dl) and Malays (38.0 +/- 4.9 mg/dl) (P less than 0.001). The ratio of Apo A-I/Apo B level was also higher in the Chinese (1.28) than in the Indians and Malays (1.09). Higher levels of Apo B and lower levels of HDL-cholesterol, Apo A-I and Apo A-II in Indians may partly explain the higher incidence of CAD in Indians.     

Human high-density lipoprotein associated amyloid A protein. Structural characteristics, relation to apo A-I and A-II concentrations, and plasma clearance kinetics in the rat

Five amyloid related low-molecular-weight apoproteins were isolated and characterized from the plasma high-density lipoprotein fraction of a patient with glomerulonephritis caused by basement membrane antibodies. Amino acid and carbohydrate analyses of apoSAA subfractions showed that they were non-glycosylated polypeptides rich in aspartic acid, glycine, glutamic acid, glutamine, and arginine. The apo SAA subtype pattern was similar to that described in some other pathological conditions. Following injections of the isolated SAA-rich high density lipoprotein fraction into rat circulation, similar disappearance curves were obtained for apoSAA and apo A-I.     

High-density lipoprotein cholesterol efflux, nitration of apolipoprotein A-I, and endothelial function in obese women

Subjects at risk of atherosclerosis might have dysfunctional high-density lipoprotein (HDL) despite normal cholesterol content in the plasma. We considered whether the efflux of excess cellular cholesterol to HDL from obese subjects is associated with impaired arterial endothelial function, a biomarker of cardiovascular risk. A total of 54 overweight (body mass index [BMI] 25 to 29.9 kg/m(2)) or obese (BMI ≥30 kg/m(2)) women, aged 46 ± 11 years, were enrolled in a worksite wellness program. The HDL cholesterol averaged 57 ± 17 mg/dl and was inversely associated with the BMI (r = -0.419, p = 0.002). Endothelial function was assessed using brachial artery flow-mediated dilation. Cholesterol efflux from (3)H-cholesterol-labeled baby hamster kidney cells transfected with the adenosine triphosphate-binding cassette transporter 1 showed 8.2% to 22.5% cholesterol efflux within 18 hours when incubated with 1% serum and was positively correlated with brachial artery flow-mediated dilation (p <0.05), especially in the 34 subjects with BMI ≥30 kg/m(2) (r = 0.482, p = 0.004). This relation was independent of age, HDL or low-density lipoprotein cholesterol concentrations in plasma, blood pressure, or insulin resistance on stepwise multiple regression analysis (β = 0.31, R(2) = 0.21, p = 0.007). Nitration of apolipoprotein A-I tyrosine residues (using sandwich enzyme-linked immunosorbent assay) was significantly greater in women with a BMI ≥30 kg/m(2) and the lowest cholesterol efflux than in women with a BMI of 25 to 29.9 kg/m(2) and the greatest cholesterol efflux (p = 0.01). In conclusion, we have shown that decreased cholesterol efflux by way of the adenosine triphosphate-binding cassette transporter 1 is associated with increased nitration of apolipoprotein A-I in HDL and is an independent predictor of impaired endothelial function in women with a BMI of ≥30 kg/m(2). This finding suggests that the functional measures of HDL might be better markers for cardiovascular risk than the HDL cholesterol levels in this population.     

Evidence for linkage of the apolipoprotein A-II locus to plasma apolipoprotein A-II and free fatty acid levels in mice and humans.

Although it has been hypothesized that the synteny between mouse and human genes provides an approach to the localization of genes that determine quantitative traits in humans, this has yet to be demonstrated. We tested this approach with two quantitative traits, plasma apolipoprotein A-II (apoAII) and free fatty acid (FFA) levels. ApoAII is the second most abundant protein of high density lipoprotein particles, but its function remains largely unknown. We now show that, in a backcross between strains Mus spretus and C57BL/6J, apoAII levels correlate with plasma FFA concentrations on both chow (P < 0.0001) and high-fat (P < 0.0003) diets and that apoAII levels are linked to the apoAII gene (P < 0.0002). To test whether variations of the apoAII gene influence plasma lipid metabolism in humans, we studied 306 individuals in 25 families enriched for coronary artery disease. The segregation of the apoAII gene was followed by using an informative simple sequence repeat in the second intron of the gene and two nearby genetic markers. Robust sib-pair linkage analysis was performed on members of these families using the SAGE linkage programs. The results suggest linkage between the human apoAII gene and a gene controlling plasma apoAII levels (P = 0.03). Plasma apoAII levels were also significantly correlated with plasma FFA levels (P = 0.007). Moreover, the apoAII gene exhibited linkage with a gene controlling FFA levels (P = 0.003). Evidence for nonrandom segregation was seen with markers as far as 6-12 centimorgans from the apoAII structural locus. These data provide evidence, in two species, that the apoAII gene is linked to a gene that controls plasma apoAII levels and that apoAII influences, by an unknown mechanism, plasma FFA levels. The results illustrate the utility of animal studies for analysis of complex traits.     

C-terminal sequence of amyloid-resistant type F apolipoprotein A-II inhibits amyloid fibril formation of apolipoprotein A-II in mice

In murine senile amyloidosis, misfolded serum apolipoprotein (apo) A-II deposits as amyloid fibrils (AApoAII) in a process associated with aging. Mouse strains carrying type C apoA-II (APOA2C) protein exhibit a high incidence of severe systemic amyloidosis. Previously, we showed that N- and C-terminal sequences of apoA-II protein are critical for polymerization into amyloid fibrils in vitro. Here, we demonstrate that congenic mouse strains carrying type F apoA-II (APOA2F) protein, which contains four amino acid substitutions in the amyloidogenic regions of APOA2C, were absolutely resistant to amyloidosis, even after induction of amyloidosis by injection of AApoAII. In vitro fibril formation tests showed that N- and C-terminal APOA2F peptides did not polymerize into amyloid fibrils. Moreover, a C-terminal APOA2F peptide was a strong inhibitor of nucleation and extension of amyloid fibrils during polymerization. Importantly, after the induction of amyloidosis, we succeeded in suppressing amyloid deposition in senile amyloidosis-susceptible mice by treatment with the C-terminal APOA2F peptide. We suggest that the C-terminal APOA2F peptide might inhibit further extension of amyloid fibrils by blocking the active ends of nuclei (seeds). We present a previously unidentified model system for investigating inhibitory mechanisms against amyloidosis in vivo and in vitro and believe that this system will be useful for the development of novel therapies.Amyloidosis refers to a group of protein structural disorders characterized by the extracellular deposits of insoluble amyloid fibrils resulting from abnormal conformational changes (1–5). Amyloid fibrils have a characteristic ultrastructural appearance and a β-pleated sheet core structure that consists of full-length proteins and/or fragments of either WT or mutant proteins found in familial diseases (2, 6–8). In humans, 28 amyloidogenic proteins have been identified. They are associated with prominent diseases such as Alzheimer’s disease, hemodialysis-associated amyloidosis, and familial amyloid polyneuropathy (2, 9, 10). To develop a therapeutic strategy for these disorders, it is essential to understand the mechanisms of amyloid fibril formation. Currently, the molecular and biological mechanisms that convert proteins into amyloid fibrils in vivo and in vitro remain largely unknown.Apolipoprotein (apo) A-II is the second most abundant apolipoprotein in human and mouse plasma high-density lipoproteins (HDLs) (11) and the most important protein associated with murine senile amyloidosis because it is the precursor of amyloid fibrils (AApoAII) (12–15). Seven alleles of the apoA-II gene have been found among inbred strains of mice, with polymorphisms in 15 nucleotide positions comprising eight amino acid positions (16). Each inbred laboratory mouse strain has a single type apoA-II protein, and the pathological findings of senile amyloidosis in strains with type A, B, or C apoA-II (APOA2A, APOA2B, or APOA2C, respectively) have been investigated (13, 17, 18). C57BL/6J, ICR, and DBA/2 strains have APOA2A and exhibit a moderate incidence of mild amyloid deposits with aging (19, 20). BALB/c, C3H/He, N2B, 129/SV, and SAMR1 strains have APOA2B and exhibit a low incidence of slight amyloid deposits with aging. In contrast, the SAMP1 strain has APOA2C and spontaneously exhibits a high incidence of severe systemic amyloid deposits with aging (20–22). We previously reported a unique mechanism in which N- and C-terminal peptides of apoA-II protein associated into amyloid fibrils in vitro (23) according to the nucleation-dependent polymerization model, which can explain the general mechanisms of amyloid fibril formation (24–28). The 11-residue amino acid sequence from positions 6–16 in the N terminus of apoA-II protein is critical for polymerization into amyloid fibrils. The 18-residue amino acid sequence from positions 48–65 in the C terminus of apoA-II is also necessary for nucleation, but not for the extension phase. Both sequences are common, and there is no substitution among APOA2A, APOA2B, and APOA2C (Fig. 1).Open in a separate windowFig. 1.Amino acid sequences of mouse apoA-II and synthetic partial peptides. For types A, B, and C apoA-II proteins (APOA2A, APOA2B, and APOA2C, respectively), the two amino acid sequences indicated in the red-colored boxes at positions 6–16 at the N terminus and 48–65 at the C terminus are the essential and common sequences required for amyloid fibril formation (23). Synthetic partial peptides were used to evaluate polymerization into amyloid fibrils in vitro and suppression against amyloid deposition in mice. The bold and blue-colored letters at positions 9, 16, 54, and 62 indicate the four variant amino acids in the core sequences for types A/B/C and F apoA-II proteins. Peptides containing orange letters represent substitutions of the a48/65(N62K) peptide.We hypothesized that some amino acid substitutions in these N- and C-terminal amyloidogenic sequences of apoA-II might inhibit the polymerization of apoA-II into amyloid fibrils. In that regard, type F apoA-II (APOA2F) contains four substitutions in the N- and C-terminal peptides relative to APOA2C (16) (Fig. 1). In this study, we evaluated the in vivo incidence of amyloidosis in mice having APOA2F and compared it with those in mice having APOA2A or APOA2C. We also analyzed the ability of APOA2F peptides to polymerize into amyloid fibrils in vitro. In previous studies, we found that injection of a very small amount of AApoAII amyloid fibrils markedly accelerated amyloid deposition (13–15). We demonstrated that mice with APOA2F were absolutely resistant against senile amyloidosis, even after induction of amyloidosis by injection with type C AApoAII fibrils. Thus, we have succeeded in suppressing amyloid deposits in amyloidosis-susceptible mice by treatment with the C-terminal APOA2F peptide. We thus demonstrate that the C-terminal sequence of APOA2F is an important inhibitor of polymerization into amyloid fibrils in vitro and in vivo. These findings provide a previously unidentified model system for investigating inhibitory mechanisms against amyloidosis in vivo and in vitro.     

Influence of cholesteryl ester transfer protein, peroxisome proliferator-activated receptor α, apolipoprotein E, and apolipoprotein A-I polymorphisms on high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein A-I, and lipoprotein A-I:A-II concentrations: the Prospective Epidemiological Study of Myocardial Infarction study

The plasma level of high-density lipoprotein cholesterol (HDL-C) is known to be inversely associated with cardiovascular risk. However, besides lifestyle, gene polymorphism may influence the HDL-C concentration. The aim of this study was to investigate the possibility of interactions between CETP, PPARA, APOE, and APOAI polymorphisms and HDL-C, apolipoprotein (apo) A-I, lipoprotein (Lp) A-I, and Lp A-I:A-II in a sample selected from the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study population who remained free of cardiovascular events over 5 years of follow-up. Healthy individuals (857) were randomly selected for genotyping the PRIME study subjects. The population was selected so as to provide 25% of subjects in the lowest tertile of HDL-C (≤28 mg/dL) in the whole PRIME study sample, 25% of subjects in the highest tertile of HDL-C (≥73 mg/dL), and 50% of subjects in the medium tertile of HDL-C (28-73 mg/dL). Genotyping was performed by using a polymerase chain reaction system with predeveloped TaqMan allelic discrimination assay. The CETP A373P rare allele c was less frequent in the group of subjects with high HDL-C, apo A-I, Lp A-I, and Lp A-I:A-II concentrations. Apolipoprotein A-I and Lp A-I were also found to be higher in the presence of the ?2 allele coding for APOE. The effect of the CETP A373P rare allele c on HDL-C was independent of all tested parameters except triglycerides. The respective effect of these polymorphisms and triglycerides on cardiovascular risk should be evaluated prospectively.     

Plasma apolipoprotein A-I, A-II, B, E and C-III containing particles in men with premature coronary artery disease

Lipoprotein (Lp) cholesterol and apolipoproteins (apo) A-I and B levels have been shown to be better markers for the presence of coronary artery disease than total cholesterol. In this study, we determined the plasma levels of lipoprotein particles containing apo A-I only (LpA-1), apo A-I and A-IL (LpA-I:A-1I), apo B and C-III (LpB:C-III) and apo B and E (LpB:E) in 145 patients with coronary artery disease (mean age ± SD, 51 ± 7 years) and 135 healthy control men (mean age 49 ± 11 years). Patients with CAD had lower high density lipoprotein (HDL) cholesterol and apo A-I levels and higher triglycerides and apo B levels than controls. In patients with CAD, LpA-I (0.341 ± 0.093 vs. 0.461 ± 148 g/1) and LpA-1:A-II (0.694 ± 0.171 vs. 0.899 ± 0.148 g/1) were lower, whereas LpB:E (0.372 ± 0.204 vs. 0.235 ± 0.184 g/1) were higher than in controls (cases vs. controls, all P < 0.005). No significant differences were observed for LpB:C-III (0.098 ± 0.057 vs. 0.107 ± 0.061 g/1, p = 0.235) particles. Discriminant analysis indicates that LpA-II:A-I, LpE:B, LpA-I, and triglycerides best differentiate between cases and controls. Plasma apo C-III (0.027 ± 0.008 vs. 0.036 ± 0.020 g/1) and E (0.040 ± 0.015 vs. 0. 055 ± 0.029 g/1) were lower in the CAD group (P < 0.001). The finding that apo C-III and E levels are lower in the CAD patients relate to the fact that in our patients, HDL particles are the main carriers of apo E and C-III and that in addition to HDL-cholesterol, the protein component of HDL particles are reduced in CAD. We conclude that apo B, LpB:E but not LpB:C-III containing particles are increased in patients with CAD and that apo A-I containing particles, with or without apo A-II are reduced in patients with CAD. In addition, HDL-cholesterol and associated apolipoproteins (A-I, A-11, C-III and E) are reduced in CAD.     

Effect of body mass index on apolipoprotein A-I kinetics in middle-aged men and postmenopausal women

The effect of body mass index (BMI) and obesity on apolipoprotein (apo) A-I levels and kinetics was examined by gender. Apo A-I kinetics were determined with a primed, constant infusion of deuterated leucine in the fed state in 19 men and 13 postmenopausal women. Compared with nonobese men, nonobese women had a higher level of high-density lipoprotein cholesterol (HDL-C) and apo A-I due to a 48% higher apo A-I production rate (PR) (P = .05). Obesity had no significant effects on apo A-I kinetics in women. In contrast, compared with nonobese men, obese men had a 9% lower apo A-I level due to a 64% higher fractional catabolic rate (FCR) partially offset by a 47% higher PR. Obese women had a 52% higher HDL-C than obese men (50 vs 33 mg/dL, respectively; P = .012), a finding related to the faster apo A-I FCR in obese men. BMI was directly correlated with apo A-I FCR (r = 0.84, P < .001) and PR (r = 0.79, P < .001) in men but not in women. Sixty-two percent of the variability in PR and 71% of the variability in FCR were due to BMI in men and only 3% and 23%, respectively, in women. In conclusion, BMI has a significant effect on apo A-I PR and FCR in men but not in women.     

Clinical significance of measurements of serum apolipoprotein A-I, A-II and B in hypertriglyceridemic male patients with and without coronary artery disease

To examine the relationship of hypertriglyceridemia to coronary artery disease (CAD), we measured serum cholesterol, triglyceride, high density lipoprotein cholesterol (HDL-C) and apolipoproteins (apo) A-I, A-II and B in 82 male patients with angiographically defined CAD and 140 age-matched healthy controls. The CAD patients had significantly lower apo A-I and A-II and HDL-C levels, but had higher apo B and triglyceride levels than the controls. After adjustments of apolipoproteins for serum triglyceride, CAD patients had significantly higher apo B and lower apo A-I and A-II levels than the controls. Discriminant analysis showed that apo B was the best discriminator and that apo A-I was next. In the normotriglyceridemic subgroup HDL-C also had a sufficient power for discrimination between CAD patients and the controls, but in the hypertriglyceridemic subgroup HDL-C had no discriminative power. Both apo A-I and B had significant discriminative power between CAD patients and the controls, independently of the serum triglyceride level. These results indicate that measurements of serum apo A-I and apo B are useful for the study of coronary risk factor in hypertriglyceridemic subjects. Finally, it is necessary to sub-classify dyslipoproteinemia by serum apolipoprotein levels for predicting the future occurrence of CAD in the general population.