High density lipoproteins, genetic polymorphism for apo A-I and coronary artery disease

HDL cholesterol and apolipoprotein A-I are associated with the development of coronary artery-disease (CAD). The presence of a PstI site polymorphism adjacent to the gene encoding apo A-I (known as P₂) has also been shown to be associated with CAD but this relationship is controversial. A case control study was conducted in an Australian population to re-examine whether the rare P₂ allele is associated with CAD. Data were derived from 159 cases of angiographically confirmed CAD and 99 healthy controls. The proportion of CAD cases carrying the P₂ allele did not differ significantly from controls (11% versus 9%). In a multiple logistic regression model controlling for the effects of age, country of birth, hypertension and hypotensive drugs, body mass index and lipid variables, the P₂ allele failed to predict significantly the presence of CAD (odds ratio 1.83; 95% confidence interval 0.65–5.19).     

Apolipoprotein A-I in liver disease

Apolipoprotein A-I and high-density lipoprotein concentrations in the plasma of patients with liver disease have been found to be either normal or lower than normal. In this study the apolipoprotein A-I concentration was measured in the plasma of 19 patients with cholestatic liver disease and 21 patients with noncholestatic liver disease. To evaluate the severity of liver disease, serum albumin, prealbumin, bilirubin, and bile salts were also measured. Apolipoprotein A-I concentrations in plasma correlated positively with serum albumin (r = 0.55, p less than 0.001) and prealbumin (r = 0.57, p less than 0.001) and negatively with serum bilirubin (r = -0.47, p less than 0.01) and bile salts (r = -0.54, p less than 0.001). The apolipoprotein A-I level thus seems to reflect the severity of liver disease. This is presumably due to a decreased liver synthesis of apolipoprotein A-I in liver disease.     

Apolipoprotein A-I gene polymorphisms: frequency in patients with coronary artery disease and healthy controls and association with serum apo A-I and HDL-cholesterol concentration

We have investigated the association between serum high density lipoprotein-cholesterol (HDL-C) and apo A-I concentration and the PstI and XmnI restriction fragment length polymorphisms of the apolipoprotein AI-CIII-AIV multigene complex. Two groups of subjects were examined. The first comprised 174 unrelated male patients under 60 years of age with angiographic evidence of coronary artery disease (CAD). Of this group 34 were non-North European. The second group consisted of 104 unrelated healthy male North European subjects aged under 60 and free from demonstrable CAD, who attended a health screening clinic in London. For the PstI polymorphism, the frequency of the rarer P2 allele was 0.12 in both the North European and non-North European patients and this was higher than in the control group (P2 frequency 0.06, P less than 0.05). Healthy individuals with the genotype P1P2 had higher levels of apo A-I but similar levels of HDL-C compared to those with the genotype P1P1. However, CAD patients with the genotype P1P2 had lower serum levels of apo A-I and significantly lower serum levels of HDL-C compared to those with the genotype P1P1 (0.85 mmol/l vs. 1.0 mmol/l, P less than 0.05). The allele frequencies of the XmnI polymorphisms were not significantly different in the control group and the group of North European patients, although within the sample of non-North European patients, the frequency of the X2 allele was significantly higher than that found in the North European controls (0.26 vs. 0.09). Patients with the genotype X1X2 had a higher mean serum concentration of HDL-C and apo A-I compared with patients with the genotype X1X1 (1.14 and 0.93 mmol/l for HDL-C, P less than 0.05; 147 and 123 mg/dl for apo A-I, P less than 0.05). Associations between HDL-C and apo A-I levels and PstI and XmnI genotype were similar in patients taking and not taking beta-blockers. The data show that genetic variation in the apo AI-CIII-AIV gene cluster is associated with coronary artery disease although only weakly, and suggest that the mechanism of this association may operate through an effect in determining the serum concentration of apo A-I and HDL-cholesterol.     

Autoantibodies against modified low-density lipoproteins in coronary artery disease

OBJECTIVES: To evaluate the importance of different autoantibodies against modified low-density lipoprotein (LDL) in patients with coronary artery disease (CAD). BACKGROUND: Previous studies of autoantibodies against LDL have shown that patients with CAD have increased titers of autoantibodies against LDL modified by copper and malondialdehyde (MDA), whereas there is a lack of information about autoantibody titers against LDL modified by hypochlorite (HOCl). Studies of autoantibodies in relation to severity of atherosclerosis are few and have reached divergent results. Furthermore, no data exist on the relationship between autoantibody titers and prognosis. METHODS: Titers of autoantibodies against copper-, MDA- and HOCl-modified LDL were determined in serum by ELISA. Autoantibody titers in young male survivors of a first myocardial infarction were compared with those of healthy controls and related to coronary angiographic findings and to prognosis during 11 years of follow-up. RESULTS: Patients had higher titers of autoantibodies against LDL modified by copper and MDA than controls. In contrast, no consistent associations were found between autoantibody titers and global severity of coronary atherosclerosis or number and severity of coronary stenoses and prognosis. CONCLUSIONS: The prognostic value of autoantibodies against modified LDL is limited in young postinfarction patients despite the fact that autoantibody titers against copper- and MDA-modified LDL are raised compared with healthy controls. Furthermore, the results indicate that autoantibodies against modified LDL are not protective in later stages of coronary atherosclerosis.     

Relation of high-density lipoproteins to coronary artery disease

Low mean concentrations of high-density lipoprotein (HDL) cholesterol have long been recognized as a characteristic of patients with coronary heart disease, and the measurement of this fraction is a relatively strong discriminator between patients with coronary heart disease and those without. When subjects are ranked by the severity of coronary atherosclerosis determined angiographically, levels of HDL cholesterol, particularly of its HDL₂ subclass, are consistently lower in subjects with extensive disease than in those with minimal atheroma. HDL cholesterol is derived from a number of sources, mobilization from peripheral tissues being but one. Generally, longitudinal studies have confirmed that a low HDL cholesterol level is potently and independently predictive of a high risk of coronary heart disease, one exception being a study of subjects with hypercholesterolemia. Despite the strength of these epidemiologic associations, there is no evidence from experimental studies or clinical trials to establish that low HDL levels are causally important in atherogenesis.     

Apolipoprotein concentrations during treatment and recurrent coronary artery disease events

The effect of untreated total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) as cardiovascular risk factors in both primary and secondary prevention has been extensively investigated. The predictive value of on-treatment lipid and apolipoprotein levels on subsequent cardiovascular events is as yet uncertain. Eight hundred forty-eight patients (675 men and 173 women) with angiographically proven coronary artery disease (CAD) who received effective statin therapy (>/=30% decrease of baseline TC) were studied. We analyzed the predictive value of on-treatment levels of TC, LDL-C, triglycerides (TG), apolipoprotein A-I (apoA-I) and apolipoprotein B (apoB) on subsequent myocardial infarction (MI) and all cause mortality. On-treatment LDL-C levels were 2.55+/-0.55 mmol/L and 2.58+/-0.62 mmol/L for men and women respectively. Age-adjusted Cox regression analysis showed that only on-treatment apoA-I was predictive for future CAD events in both men and women, whereas on-treatment HDL-C was exclusively predictive in women. On-treatment apoB levels were predictive for recurrent CAD events in the total population but not after separate analysis for men and women. On-treatment levels of TC, LDL-C, and TG did not predict subsequent events. Multivariate analysis showed that on-treatment apoA-I and apoB were the only significant predictors for future cardiovascular events. On-treatment levels of TC, LDL-C, and TG were no longer associated with increased risk of recurrent cardiovascular events in CAD patients treated to target levels, which justifies the current guidelines. However, on-treatment levels of apoB and in particular apoA-I (and HDL-C in women) were significantly predictive for MI and all-cause mortality and may therefore be more suitable for cardiovascular risk assessment in this population.     

Accumulation of apoE-enriched triglyceride-rich lipoproteins in patients with coronary artery disease

Triglycerides (TGs) are vehicled by multiple particles with different abilities to promote atherosclerosis. Among plasma TG-rich lipoproteins (TRLs), subspecies may or may not contain apolipoprotein E (apoE) molecules: in this study, we evaluated the relative contribution of apoE-rich and apoE-poor TRLs to coronary atherosclerosis. We selected a group of males with premature coronary artery disease (CAD) without any of the classical nonlipid risk factors and/or high plasma lipid levels and evaluated the plasma concentration of TRL subspecies in comparison with healthy controls. Patients with CAD and controls had total cholesterol and TG levels within the normal range (despite slightly, even if significantly, higher TG levels in patients with CAD) and low-density lipoprotein cholesterol levels near optimal values. Nevertheless, patients with CAD had significantly lower high-density lipoprotein cholesterol, smaller low-density lipoprotein peak particle size, and a reduced HDL2b subfraction than controls. In addition, we observed higher concentrations of total TRL in patients with CAD together with a selective increase in apoE-rich particles. All these data were confirmed after correction for TG levels. We also investigated which parameters were associated with the spread of coronary atherosclerosis. Subjects with a single-vessel disease had selectively lower levels of apoE-rich fractions than patients with a multivessel disease. This was confirmed by multivariate analysis. Patients with a premature CAD free of nonlipid conventional risk factors, despite not having elevated lipid levels, show several lipoprotein abnormalities. Besides known atherogenic alterations, the accumulation of apoE-rich TRL subfractions may represent an additive factor that can potentially promote and initiate the atherosclerotic process.     

Apolipoprotein E polymorphism in northern Chinese elderly patients with coronary artery disease

Background and objective Apolipoprotein E is a constituent of lipoproteins with considerable variation due to cysteine-argin-ine exchanges. We investigated the relationship between apo E gene polymorphism and the occurrence of coronary artery disease (CAD) in the older population of northern China. Methods The distribution of the HhaI polymorphisms of the apolipoprotein E gene was determined among 55 patients with CAD (CAD group), which was compared with that of 36 elderly subjects without CAD (control group). Results Genotype distributions at both sites (apo E gene 112-bp and 158-bp sites ) were different between the CAD and control groups. The CAD group had lower apolipoprotein E"ε2"frequencies than the control group (P<0.05). Conclusion Individuals with apolipoprotein E"ε2"are likely to have a reduced risk of developing coronary artery disease as demonstrated by elderly subjects in Northern China.     

Apolipoprotein A-I mimetic peptides

Recent publications reveal the mechanism of action of apolipoprotein A-I (apoA-I) mimetic peptides to be the remarkable binding affinity that oxidized lipids have for these peptides compared with apoA-I. There was no difference in the binding affinity of oxidized lipids or in peptide efficacy in reducing inflammation and atherosclerosis in rabbits injected with peptides synthesized from all D- or all L-amino acids. The apoA-I mimetic peptide 4F increased the formation of pre-β high-density lipoprotein, increased cholesterol efflux, and reduced lipoprotein oxidation in vitro; it increased antioxidants and vascular repair in type 1 diabetic rats; it improved vasodilation, oxidative stress, myocardial inflammation, and angiogenic potential in a mouse model of scleroderma; it reduced renal inflammation in low-density lipoprotein receptor-null mice fed a Western diet; it reduced arthritis in a rat model; it reduced adiposity, increased adiponectin levels, and improved insulin sensitivity in obese mice; and it improved high-density lipoprotein inflammatory properties in humans with coronary heart disease.     

Apolipoprotein A-I mimetic peptides

Despite identical amino acid composition, differences in class A amphipathic helical peptides caused by differences in the order of amino acids on the hydrophobic face results in substantial differences in antiinflammatory properties. One of these peptides is an apolipoprotein A-I (apoA-I) mimetic, D-4F. When given orally to mice and monkeys, D-4F caused the formation of pre-beta high-density lipoprotein (HDL), improved HDL-mediated cholesterol efflux, reduced lipoprotein lipid hydroperoxides, increased paraoxonase activity, and converted HDL from pro-inflammatory to antiinflammatory. In apolipoprotein E (apoE)-null mice, D-4F increased reverse cholesterol transport from macrophages. Oral D-4F reduced atherosclerosis in apoE-null and low-density lipoprotein (LDL) receptor-null mice. In vitro when added to human plasma at nanomolar concentrations, D-4F caused the formation of pre-beta HDL, reduced lipoprotein lipid hydroperoxides, increased paraoxonase activity, and converted HDL from pro-inflammatory to antiinflammatory. Physical-chemical properties and the ability of various class A amphipathic helical peptides to activate lecithin cholesterol acyltransferase (LCAT) in vitro did not predict biologic activity in vivo. In contrast, the use of cultured human artery wall cells in evaluating these peptides was more predictive of their efficacy in vivo. We conclude that the antiinflammatory properties of different class A amphipathic helical peptides depends on subtle differences in the configuration of the hydrophobic face of the peptides, which determines the ability of the peptides to sequester inflammatory lipids. These differences appear to be too subtle to predict efficacy based on physical-chemical properties alone. However, understanding these physical-chemical properties provides an explanation for the mechanism of action of the active peptides.     

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.     

Apolipoproteins A-I and B as predictors of angiographically defined coronary artery disease

Apolipoprotein A-I and B concentrations were measured in 502 patients undergoing diagnostic cardiac catheterization to assess the predictive power of apolipoproteins B and A-I to discriminate between patients with coronary artery disease and those with normal coronary arteries as defined by coronary arteriography. The strength of the associations was compared with that of the associations between traditional risk factors (eg, smoking status, cholesterol levels) and coronary artery disease. The study population consisted of 154 women (mean age, 62.9 years) and 348 men (mean age, 59.6 years). The apolipoprotein A-I concentration averaged (+/- SD) 124 +/- 25 mg/dL and the apolipoprotein B concentration, 98 +/- 24 mg/dL. In all cases, the apolipoprotein measures showed a larger univariate difference between the "normal" (no coronary artery disease) group (66 patients) and the group with coronary artery disease (436 patients) than did the corresponding standard lipoprotein measures. The variable with the strongest association with coronary artery disease was the ratio of apolipoprotein A-I to apolipoprotein B, followed by apolipoprotein B level. These findings were confirmed using logistic regression, adjusting for other coronary artery disease risk factors. Fasting status did not affect apolipoprotein A-I or B concentrations. We conclude that the use of apolipoprotein A-I and B concentrations gives additional information to that supplied by lipoprotein measures to help predict the presence of coronary artery disease. Since traditional lipid measures may be changed by a meal, apolipoproteins A-I and B might be more useful measures when the fasting status of a patient is in question.     

High-density lipoproteins: Epidemiologic profile and risks of coronary artery disease

The lipid-atherogenesis connection has undergone an evolutionary metamorphosis from a focus initially on serum total cholesterol, subsequently on other lipids, then on the lipoproteins that transport them, and now on the distribution of cholesterol in the low-density lipoproteins (LDL), high-density lipoproteins (HDL) and very low density lipoproteins. it is now established that the relation of serum total cholesterol to coronary heart disease (CHD) derives chiefly from the atherogenic LDL component, and that level of HDL cholesterol is inversely related to risk. The protective effect of HDL is at least as strong as the atherogenic effect of LDL and is independent of lipids and other risk factors. Every change of 10 mg/dl in the HDL cholesterol level is associated with a 50 % change in risk. At any level of serum total cholesterol, risk varies widely, depending on the $\text{LDL}\text{HDL}$ ratio. A serum total $\text{cholesterol}\text{HDL}$ ratio of 5.0 is associated with average risk; optimal ratios, around 3.5, correspond to half the standard risk. Further refinements in the lipid profile may be possible because there are several HDL and LDL subfractions with different atherogenic potential probably related to their apoprotein makeup. Only weak and inconsistent relationships of stroke and peripheral arterial disease to serum cholesterol and its lipoprotein fractions have been found, although there is the expected inverse relation to HDL cholesterol. An inverse relation of LDL level to stroke in women, and in men a possible excess mortality at very low serum cholesterol values attributed to colon cancer, have been reported.     

Apolipoprotein B and apolipoprotein A-I: risk indicators of coronary heart disease and targets for lipid-modifying therapy

Although LDL cholesterol (LDL-C) is associated with an increased risk of coronary heart disease, other lipoproteins and their constituents, apolipoproteins, may play an important role in atherosclerosis. Elevated levels of apolipoprotein (apo) B, a constituent of atherogenic lipoproteins, and reduced levels of apo A-I, a component of anti-atherogenic HDL, are associated with increased cardiac events. Apo B, apo A-I and the apo B/apo A-I ratio have been reported as better predictors of cardiovascular events than LDL-C and they even retain their predictive power in patients receiving lipid-modifying therapy. Measurement of these apolipoproteins could improve cardiovascular risk prediction.     

Apolipoprotein E and coronary artery disease: the debate is still on

Apolipoprotein E (Apo E) is quite a fascinating lipoprotein. As reported by Zou et al. 1 in this issue of the Journal of Geriatric Cardiology, Apo E has three isoforms,ε2, ε3, and ε4, differing from each other by the polymorphisms found in the amino acid residues at sites 112 and 158. Apo E and its three isoforms, with ε3 being the most common, is like a Pandora‘s box of sorts, where upon investigation, interesting correlations to some very prominent modem diseases have been found. For example, there was evidence that the presence of one ε4 allele in their Apo E gene increased the risk for type-2Alzheimer‘s disease and two ε4 alleles would increase further this risk. Also intriguing is the subject of this paper by Zou et al.: the relationship between Apo E isoform ε2 and the presence of coronary artery disease (CAD).……     

Metabolic basis of high density lipoproteins and apolipoprotein A-I increase by HMG-CoA reductase inhibition in healthy subjects and a patient with coronary artery disease.

HMG-CoA reductase inhibitors, such as pravastatin, are widely used as lipid lowering drugs in hypercholesterolemia. Pravastatin does not only reduce the atherogenic low density lipoprotein (LDL)-cholesterol, but is also increasing high density lipoprotein (HDL)-cholesterol. However, the mechanism leading to an increase of HDL are unclear. Therefore, the effects of pravastatin on the in vivo kinetics of apolipoprotein (apo) A-I were studied in six normolipidemic subjects and in a patient with coronary artery disease (CAD) utilizing stable isotope tracer techniques. Two turnover studies were performed. The first turnover study was carried out before any drug treatment, the second study after 6 weeks of 40 mg pravastatin/day. Three times deuterium labeled L-leucine (3D-leucine) was given as a primed bolus constant infusion (bolus: 1340 microg/kg; infusion: 22 microg/kg per h), and tracer uptake into HDL apoA-I was determined by gas chromatography (GC)-mass-spectrometry (MS). In the healthy subjects HDL-cholesterol increased by 13% and apoA-I increased by 12% under pravastatin treatment. The HDL in the CAD patient decreased by 3% and apoA-I increased by 2%. Prior to drug treatment the mean apoA-I fractional synthetic rate (FSR) was 0.194 per day (S.D. +/- 0.02) and apoA-I production rate (PR) was 10.8 mg/kg per day (S.D. +/- 2.1). The CAD patient had a FSR of 0.219 per day and a PR of 10.6 mg/kg per day. After treatment with pravastatin the mean apoA-I FSR was 0.204 per day (S.D. +/- 0.02) and apoA-I PR was 12.5 mg/kg per day (S.D. +/- 1.5) in the healthy subjects. Despite only minor changes of HDL and apoA-I in the CAD patient, there were significant changes of FSR (0.267 per day) and PR (13.1 mg/kg per day) with pravastatin treatment. The in vivo kinetic data demonstrate an increased FSR of apoA-I. The increase in apoA-I is due to an increased PR of apoA-I. This study demonstrates increased production of HDL apoA-I as the metabolic cause of the increase in HDL and apoA-I levels under inhibition of HMG-CoA reductase in man.