Treatment with apo B peptide vaccines inhibits atherosclerosis in human apo B-100 transgenic mice without inducing an increase in peptide-specific antibodies

Objectives. Autoantibodies to apolipoprotein (apo) B‐100 peptides are present in human plasma and have been shown to be associated with decreased cardiovascular risk. The present study aimed to determine if apo B‐100 peptide vaccines are atheroprotective in mice expressing human apo B‐100 and if the effectiveness of the vaccines is influenced by the level of pre‐existing peptide‐specific autoantibodies. Design. LDL receptor^?/?/human apo B‐100 transgenic mice were immunized with native human apo B‐100 peptides p45 or p210 at 6, 9 and 11 weeks and the extent of atherosclerosis determined by en face Oil Red O staining of the aorta at 25 weeks. Autoantibody levels were determined by enzyme‐linked immunosorbent assay, and RNA expression in the spleen was assessed by real time PCR. Results. Control mice had high levels of autoantibodies against p210 but only low levels against p45. Immunization with native p45 and p210 reduced atherosclerosis by 66% (P < 0.02) and 59% (P = 0.06), respectively. The atheroprotective effect of apo B peptide immunization occurred in the absence of an increase in peptide‐specific IgG, but was associated with an increase in IgM recognizing native and copper‐oxidized LDL. Conclusions. Immunization with apo B peptide‐based vaccines inhibits atherosclerosis in mice expressing human apo B‐100 suggesting that they can interact with their target as expressed in humans. The protective effect is independent of the pre‐existing level of apo B peptide autoantibodies and can occur without activating an increase in peptide‐specific antibodies suggesting that atheroprotection can be mediated by cellular immune responses.     

Lesion development and response to immunization reveal a complex role for CD4 in atherosclerosis

Atherosclerosis is a complex disease, bearing many of the characteristics of a chronic inflammatory process. Both cellular and humoral immune responses may be involved in the disease development. Oxidized low-density lipoprotein (oxLDL) is suggested to be an autoantigen in atherosclerosis. A protective effect against atherosclerosis has been demonstrated in animals immunized with oxLDL. Such a protection is associated with elevation of T cell-dependent IgG antibodies against oxLDL. In addition, it has been shown that immunization with Freund adjuvant alone also confers protection against development of atherosclerosis. We therefore hypothesized that CD4+ T cells are critical in the development of atherosclerosis and that they are involved in protective immune reactions after immunization. The development of atherosclerosis was studied in apolipoprotein E knockout (apoE KO) mice and CD4/apoE double knockout (dKO) mice that were immunized with either oxLDL in Freund adjuvant or adjuvant alone, or left untreated. Our results show that (1) the absence of CD4+ cells in apoE KO mice leads to reduced atherosclerosis, indicating that CD4+ cells constitute a major proatherogenic cell population, and (2) the atheroprotective effect of LDL immunization does not depend on CD4+ cells, whereas (3) the atheroprotective effect of adjuvant injection is CD4-dependent. These findings demonstrate complex roles of immune cell-cell interactions in the regulation of the atherosclerotic process and point to several possible targets in the treatment and prevention of atherosclerosis.     

Atheroprotective effect of adjuvants in apolipoprotein E knockout mice

Strategies aimed at treating atherosclerosis by immunization protocols are emerging. Such protocols commonly use adjuvants as non-specific stimulators of immune responses. However, adjuvants are known to modify various disease processes. The aim of this study was to determine whether adjuvants alter the development of atherosclerosis. We performed immunization protocols in apolipoprotein E knockout mice (E degrees ) following chronic administration schedules commonly employed in experimental atherosclerosis. Our results point out a dramatic effect of several adjuvants on the development of atherosclerosis; three of the four adjuvants tested reduced lesion size. The Alum adjuvant, which is the adjuvant currently used in most vaccination protocols in humans, displayed a strong atheroprotective effect. Mechanisms accounting for atheroprotective effect of Freund's adjuvants included their capacity to increase both Th2 responses and anti-MDA-LDL IgM titers, and/or to impose atheroprotective lipoprotein profiles. The present study indicates that adjuvants have potent atheromodulating capabilities, and thus, implies that the choice of adjuvant is crucial in long-term immunization protocols in experimental atherosclerosis.     

Predictive and protective autoimmunity in cardiovascular diseases: is vaccination therapy a reality?

The role of the immune system in modulating atherosclerosis has recently been well documented. Studies have revealed that cellular and humoral immunity plays crucial roles in atherogenic plaque formation. This includes macrophages, CD4+ T cells and dendritic cells as well as autoantigens such as oxidized low density lipoprotein (oxLDL), heat shock proteins and beta2-glycoprotein I. Given these recent advances, various modifications of the immune system in experimental models have been proposed as therapeutic strategies, with the potential of inhibiting atherosclerosis progression. These modifications are switching the immune system (CD4+ T cells) from Th1 towards a Th2 anti-inflammatory cytokine secretion, and the induction of protective antibodies both of which may be induced by specific vaccination. Recent identification of specific immunoreactive antigenic epitopes on modified LDL, their successful implementation for immunization and the induction of atheroprotection, supports the idea that active vaccination may emerge as a novel immuno-modulating atheroprotective strategy.     

LDL immunization induces T-cell-dependent antibody formation and protection against atherosclerosis

Atherosclerosis is an inflammatory disease, and the involvement of immune mechanisms in disease progression is increasingly recognized. Immunization with oxidized low density lipoprotein (LDL) decreases atherosclerosis in several animal models. To explore humoral and cellular immune reactions involved in this protection, we immunized apolipoprotein E knockout mice with either homologous plaque homogenates or homologous malondialdehyde (MDA)-LDL. Immunization with both these antigen preparations reduced lesion development. The plaques contained immunogen(s) sharing epitopes on MDA-LDL, MDA-very low density lipoprotein, and oxidized cardiolipin. This shows that a T-cell-dependent antibody response was associated with protection against atherosclerosis. The protection was associated with specific T-cell-dependent elevation of IgG antibodies against MDA-LDL and oxidized phospholipids, and the increased titers of IgG antibodies were correlated with decreased lesion formation and lower serum cholesterol levels.     

Maternal immunization programs postnatal immune responses and reduces atherosclerosis in offspring

Maternal hypercholesterolemia during pregnancy increases offspring susceptibility to atherosclerosis by an oxidation-dependent mechanism. The present studies investigated whether maternal immunization with oxidized LDL (OxLDL) before pregnancy protects the fetus from atherogenic in utero programming by maternal hypercholesterolemia. Maternal immunization of NZW rabbits and LDL receptor-deficient mice indeed reduced atherosclerosis in adult offspring by up to 56%, but the protective effect could not be attributed to a reduction of fetal exposure to hypercholesterolemia alone, and even nonspecific immune stimulation with adjuvant only provided some protection. Unexpectedly, offspring of immunized mothers developed increased IgM antibodies to selective OxLDL epitopes and increased IgM-LDL immune complexes, compared with offspring of nonimmunized controls. Even na?ve offspring of OxLDL-immunized mothers never exposed to postnatal hypercholesterolemia responded to a one-time OxLDL and KLH challenge with greater OxLDL-specific IgM responses, increased OxLDL-specific IgM-secreting B cells, and more IgM-LDL immune complexes. In contrast, maternal immunization with KLH, a T cell-dependent nonmammalian antigen, did not influence postnatal immune responses. Effects of maternal OxLDL-immunization on offspring B cells and selective antibodies were independent of transplacental passage of maternal immunoglobulins. Results show that maternal immunization with antigens prevalent in atherosclerotic lesions reduces atherogenesis in their offspring by mechanisms that include, but are not limited to, reduced fetal exposure to maternal hypercholesterolemia and lipid peroxidation. More importantly, they demonstrate in principle that maternal adaptive immunity to selective antigens influences postnatal B cell and antibody responses in offspring, and that modulation of in utero immune programming may influence immune-modulated diseases later in life.     

Relations between the levels of lipoprotein-containing immune complexes and lipids in the blood of patients with ischemic heart disease

The sera from most patients with coronary heart disease concurrent with angiographically documented coronary atherosclerosis were found to contain apolipoprotein B (Apo B), neither apolipoprotein E (Apo E) nor apolipoprotein AI (Apo AI) in the circulating immune complexes precipitated by polyethylene glycol-6000 (PEG). Low density lipoproteins are the major components of cholesterol-containing immune complexes precipitated by PEG. A correlation was established between the serum levels of total cholesterol (r = 0,74; p less than 0.01), and low density lipoprotein (LDL) cholesterol (r = 0.77; p less than 0.01) in patients with coronary heart disease and cholesterol in LDL-containing No relationship was found in healthy individuals. The in vitro increase in LDL levels in most patients with coronary heart disease concurrent with coronary atherosclerosis was not followed by an elevation in LDL-containing immune complexes.     

Antibodies to oxidized low density lipoprotein: epidemiological studies and potential clinical applications in cardiovascular disease

The pathogenesis of atherosclerosis is mediated by genetic susceptibility along with a variety of cardiovascular risk factors and environment influences. As atherosclerotic lesions progress, they manifest several features typical of chronic inflammation, such as the presence of monocyte/macrophages, T-cells and inflammatory cytokines. This inflammatory response is fueled and enhanced by oxidative stress, which may be the link between lipid disorders and inflammation. Oxidation of lipoproteins is intimately involved in all stages of atherosclerosis and oxidative byproducts co-localize with inflammatory cells. When low density lipoprotein enters the subintimal space, it is oxidized by several mechanisms, including both enzymatic and non-enzymatic pathways and becomes a ligand for scavenger receptors on macrophages leading to generation of foam cells. Oxidized LDL is not only pro-inflammatory and pro-atherogenic, but several of the neoepitopes generated during oxidation are highly immunogenic and result in the generation of autoantibodies. Autoantibodies to OxLDL are found within atherosclerotic lesions and in apparently healthy subjects, as well as patients with various manifestations of cardiovascular disease. In this article, the role of circulating autoantibodies to OxLDL in cardiovascular disease will be reviewed. Although controversy still exists, the overall evidence supports the notion that IgG autoantibodies to OxLDL are associated with pro-atherogenic properties and IgM autoantibodies to OxLDL with atheroprotective properties. Whether such antibodies have a modulating role or are merely reflectors of atherogenesis has not been fully determined. Data is also emerging on the role of natural antibodies, which are primarily of the IgM class, that recognize oxidation-specific epitopes. Among other properties, these antibodies may be involved in housekeeping functions in binding and clearing pro-inflammatory oxidized lipids and therefore may be atheroprotective. Several studies have also recently evaluated the potential therapeutic role of antibodies to OxLDL either through active immunization using OxLDL or model oxidation-specific epitopes as immunogens or through passive immunization with human antibodies directed to oxidation-specific epitopes. Although these investigation are at an early stage, they show promise that immune modulation may lead to novel approaches to treat atherosclerosis and cardiovascular disease.     

Immunization for atherosclerosis

This review summarizes experimental findings that highlight the complex roles of the immune system in atherogenesis. Immune activation can have either proatherogenic or atheroprotective effects. Immune-modulation therapy via an active or passive immunization strategy aims to exploit the atheroprotective aspects of the immune system to modulate atherosclerosis. Several experimental studies have demonstrated that such an approach is feasible and effective, raising the tantalizing possibility that an atheroprotective vaccine can be developed for clinical testing. Several potential immunogens have been identified and tested for their atheroprotective efficacy with variable results. Although several questions such as choice of optimal antigens, choice of most effective adjuvants, the optimal route of administration, durability of effects, and safety remain to be answered, we believe that a vaccine-based approach to manage atherosclerotic cardiovascular disease is a potentially viable paradigm.     

Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine

Abstract. Wigren M, Kolbus D, Dunér P, Ljungcrantz I, Söderberg I, Björkbacka H, Fredrikson GN, Nilsson J. (Malmö University Hospital, Lund University; Malmö University, Malmo; Sweden) Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine. J Intern Med 2011; 269 : 546–556. Objectives. Autoimmune responses against oxidized low‐density lipoprotein are considered to play an important pro‐inflammatory role in atherosclerosis and to promote disease progression. T‐regulatory cells (Tregs) are immunosuppressive cells that have an important part in maintaining self‐tolerance and protection against autoimmunity. We investigated whether aBp210, a prototype atherosclerosis vaccine based on a peptide sequence derived from apolipoprotein B, inhibits atherosclerosis through the activation of Tregs. Design. Six‐week‐old Apoe^?/? mice were immunized with aBp210 and received booster immunizations 3 and 5 weeks later, as well as 1 week before being killed at 25 weeks of age. Results. At 12 weeks, immunized mice had increased expression of the Treg marker CD25 on circulating CD4 cells, and concanavalin A (Con A)‐induced interferon‐γ, interleukin (IL)‐4, and IL‐10 release from splenocytes was markedly depressed. At 25 weeks, there was a fivefold expansion of splenic CD4+ CD25+ Foxp3 Tregs, a 65% decrease in Con A‐induced splenic T‐cell proliferation and a 37% reduction in the development of atherosclerosis in immunized mice. Administration of blocking antibodies against CD25 neutralized aBp210‐induced Treg activation as well as the reduction of atherosclerosis. Conclusions. The present findings demonstrate that immunization of Apoe^?/? mice with the apolipoprotein B peptide vaccine aBp210 is associated with activation of Tregs. Administration of antibodies against CD25 results in depletion of Tregs and blocking of the atheroprotective effect of the vaccine. Modulation in atherosclerosis‐related autoimmunity by antigen‐specific activation of Tregs represents a novel approach for treatment of atherosclerosis.     

Thyroid disease and lipids.

The composition and the transport of lipoproteins are seriously disturbed in thyroid diseases. Overt hypothyroidism is characterized by hypercholesterolaemia and a marked increase in low-density lipoproteins (LDL) and apolipoprotein B (apo A) because of a decreased fractional clearance of LDL by a reduced number of LDL receptors in the liver. The high-density lipoprotein (HDL) levels are normal or even elevated in severe hypothyroidism because of decreased activity of cholesteryl-ester transfer protein (CETP) and hepatic lipase (HL), which are enzymes regulated by thyroid hormones. The low activity of CETP, and more specifically of HL, results in reduced transport of cholesteryl esters from HDL(2) to very low-density lipoproteins (VLDL) and intermediate low-density lipoprotein (IDL), and reduced transport of HDL(2) to HDL(3). Moreover, hypothyroidism increases the oxidation of plasma cholesterol mainly because of an altered pattern of binding and to the increased levels of cholesterol, which presents a substrate for the oxidative stress. Cardiac oxygen consumption is reduced in hypothyroidism. This reduction is associated with increased peripheral resistance and reduced contractility. Hypothyroidism is often accompanied by diastolic hypertension that, in conjunction with the dyslipidemia, may promote atherosclerosis. However, thyroxine therapy, in a thyrotropin (TSH)-suppressive dose, usually leads to a considerable improvement of the lipid profile. The changes in lipoproteins are correlated with changes in free thyroxine (FT(4)) levels. Hyperthyroidism exhibits an enhanced excretion of cholesterol and an increased turnover of LDL resulting in a decrease of total and LDL cholesterol, whereas HDL are decreased or not affected. The action of thyroid hormone on Lp(a) lipoprotein is still debated, because both decrease or no changes have been reported. The discrepancies are mostly because of genetic polymorphism of apo(a) and to the differences between the various study groups. Subclinical hypothyroidism (SH) is associated with lipid disorders that are characterized by normal or slightly elevated total cholesterol levels, increased LDL, and lower HDL. Moreover, SH has been associated with endothelium dysfunction, aortic atherosclerosis, and myocardial infarction. Lipid disorders exhibit great individual variability. Nevertheless, they might be a link, although it has not been proved, between SH and atherosclerosis.     

Increased LDL cholesterol and atherosclerosis in LDL receptor-deficient mice with attenuated expression of scavenger receptor B1

Scavenger receptor BI (SR-BI) is a multiligand cell-surface receptor that plays a central role in high density lipoprotein homeostasis in rodents. To investigate a role for SR-BI in atherosclerosis, mice with attenuated SR-BI expression were crossed with low density lipoprotein (LDL) receptor-deficient mice. Compound-homozygous mutants showed increased plasma cholesterol, surprisingly due primarily to increased LDL cholesterol and apolipoprotein B levels. LDL turnover studies showed that this resulted from increased LDL cholesterol production rather than decreased LDL catabolism. Atherosclerotic lesion size was significantly increased in male compound-mutant mice relative to LDL receptor-deficient controls (93 427+/-16 079 versus 34 448+/-5 331 microm(2), respectively; P=0.003). The proatherogenic effect of attenuated SR-BI expression may in part be due to increased LDL cholesterol levels. These findings suggest that upregulation of the receptor could have therapeutic potential for the treatment of atherosclerosis.     

Proportion of oxidized LDL relative to plasma apolipoprotein B does not change during statin therapy in patients with heterozygous familial hypercholesterolemia

OBJECTIVE: Circulating oxidized low-density lipoprotein (LDL) has been shown to be a useful marker for identifying patients with coronary heart disease (CHD) and persons at high cardiovascular risk. The effect of cholesterol-lowering therapy on plasma level of oxidized LDL is not clear. METHODS AND RESULTS: We investigated effects of cholesterol lowering by therapeutic intervention (2 years) with atorvastatin (80 mg daily) and simvastatin (40 mg daily) on circulating oxidized LDL (absolute level and in proportion to plasma apolipoprotein B) in relation to atherosclerosis progression (carotid intima-media thickness, carotid IMT) and to inflammation (high-sensitivity C-reactive protein, hsCRP) in 115 stable patients with heterozygous familial hypercholesterolemia (FH). Atorvastatin and simvastatin reduced plasma-oxidized LDL (-43 and -35%, respectively) in proportion to the decrease in plasma apolipoprotein B. Neither absolute nor relative level of oxidized LDL correlated with carotid IMT or hsCRP at baseline. Also changes in levels of circulating oxidized LDL were not related to changes in carotid IMT and hsCRP. CONCLUSIONS: In familial hypercholesterolemia-oxidized LDL carried in plasma is strongly associated with apolipoprotein B but not with inflammation nor with carotid IMT, and statin treatment does not reduce oxidized LDL relative to apolipoprotein B.     

Relationships of low density lipoprotein subfractions to angiographically defined coronary artery disease in young survivors of myocardial infarction.

Low density lipoprotein (LDL) from 36 young post-infarction patients was separated by isopycnic density gradient ultracentrifugation to determine the relationships of plasma levels and chemical composition of different LDL subfractions to the global severity and rate of progression of coronary atherosclerosis assessed by angiography. There were marked elevations of the cholesterol and triglyceride concentrations in the very low density lipoprotein (VLDL) fraction, whereas the high density lipoprotein (HDL) cholesterol level was reduced in the patients compared with 70 healthy population-based controls. Plasma total LDL cholesterol and triglyceride concentrations were similar. The distribution of apolipoprotein B along the LDL density range, viz. the LDL particle distribution, was displaced towards the dense LDL region among the patients compared with 14 healthy normolipidaemic controls. A preponderance of dense LDL particles was associated with elevated plasma VLDL triglyceride concentration. The patients had significantly higher plasma concentrations of lipid and protein in dense LDL (d greater than 1.040 kg/l), while no group differences were found in the light LDL (d less than 1.040 kg/l). However, there were no percentage compositional differences in the light or dense LDL between patients and controls. Among all constituents of lipoprotein fractions and subfractions determined, only the plasma level of triglycerides in both light and dense LDL correlated significantly with the angiographic estimates of global severity and rate of progression of coronary atherosclerosis, respectively. On a percentage composition basis, both light and dense LDL tended to be richer in triglycerides in the subjects with a more severe coronary artery disease. Neither VLDL or HDL, nor LDL cholesterol were associated with the angiographic scores, the plasma LDL triglyceride concentration or the triglyceride enrichment of LDL. Although there is ample experimental evidence that triglyceride-enriched LDL predisposes to atherosclerosis, the LDL associations with coronary lesion severity and progression observed in the present study might not reflect a causal mechanism, but merely mirror the atherogenicity of disturbances affecting the metabolism of triglyceride-rich lipoproteins. Prospective studies of larger groups of unselected patients are needed to corroborate these findings.     

Increased plasma glycated low-density lipoprotein concentrations in diabetes: a marker of atherogenic risk

Nonenzymatic glycation of apolipoprotein B in the low-density lipoprotein (LDL) complex has been considered a proatherogenic modification contributory to the increased susceptibility of patients with diabetes to atherosclerosis. We postulated that glycated LDL concentrations might be associated with other markers of cardiovascular disease. To explore this hypothesis, we measured glycated LDL concentrations by a monospecific immunoassay in 50 patients with type 1 and 100 patients with type 2 diabetes and examined relationships with the amount of albumin excretion and the serum cholesterol and triglyercide concentrations. Plasma glycated LDL showed a significant positive correlation (r = 0.325; P < 0.001) with urinary albumin excretion that was higher in type 1 (r = 0.463) than in type 2 (r = 0.245) patients. The mean glycated LDL concentration progressively increased with increasing albumin excretion when patients were subcategorized into groups of normoalbuminuria, low (相似文献   

Passive immunization with monoclonal IgM antibodies against phosphorylcholine reduces accelerated vein graft atherosclerosis in apolipoprotein E-null mice

Phosphorylcholine (PC) headgroup is one of the neoantigens exposed by LDL oxidation that can elicit an immune response. Active immunization with Streptococcus pneumoniae, which bears PC on its cell wall, reduced atherosclerosis in hypercholesterolemic mice and this effect was attributed to an immune response to PC. In this study we tested the hypothesis that passive immunization with a monoclonal anti-PC IgM antibody can be athero-protective in a murine model of native aortic and vein graft atherosclerosis. Inferior vena cava from 16-week-old donor male apoE-null mice was grafted into right carotid artery of age-matched male recipient apoE-null mice. Anti-PC IgM titers were evaluated before and 4 weeks after surgery. For the immunization protocol, a separate group of mice received weekly intraperitoneal injection of monoclonal anti-PC IgM (400 microg) for 4 weeks, starting the day of surgery. Controls received PBS or pooled polyclonal IgM. Anti-PC IgM titres significantly increased at 4 weeks following surgery. Passive immunization with anti-PC IgM reduced vein graft plaque size and neointimal thickness resulting in a larger luminal area; in addition immunization reduced the inflammatory cell content of the plaques. There was no significant effect on the established native aortic atherosclerotic lesions. Immunization did not affect circulating cholesterol levels. Taken together our data suggest that passive immunization with anti-PC IgM significantly reduces vein graft lesion size with less inflammatory phenotype without affecting cholesterol levels, indicating an athero-protective immune response to PC. Lack of effect on established native aortic lesions may have been due to short duration of therapy and/or reduced efficacy in established lesions as compared to evolving lesions of vein graft atherosclerosis.     

Gemfibrozil therapy in primary type II hyperlipoproteinemia: effects on lipids, lipoproteins and apolipoproteins

Gemfibrozil lowers triglycerides, low density lipoprotein (LDL) and very low density lipoprotein (VLDL) cholesterol. It also promotes a significant increase of high density lipoprotein (HDL) cholesterol. It has been established that normalization of apolipoproteins is an important protective factor against atherosclerosis. The present report examines the effectiveness of 12 months of gemfibrozil treatment on plasma lipids and apolipoproteins in types IIa (VLDL 18 +/- 2 mg cholesterol/dL) and IIb (VLDL 58 +/- 7 mg cholesterol/dL) hypercholesterolemic patients. Gemfibrozil lowered plasma triglycerides, VLDL cholesterol and apolipoprotein B (apoB), increased HDL cholesterol and apoAI levels in both groups, and induced a very substantial reduction in LDL cholesterol in type IIa patients only. Even though HDL particles were enriched in cholesterol, indicating improvement in the reverse cholesterol transport and lower risk of atherosclerosis in both groups, it is important to note that production of cholesterol-poor LDL particles and reduction in LDL cholesterol and the LDL/HDL cholesterol ratio were observed only in the normotriglyceride group (type IIa). Due to the initially elevated concentration of plasma triglycerides and VLDL in type IIb patients and the increased catabolism of VLDL to LDL during gemfibrozil therapy, this drug has a more efficient regulating effect on LDL particles in type IIa compared with type IIb hyperlipidemia.     

Lipoprotein predictors of the severity of coronary artery disease in men and women

In this study we examined the relationships between levels of several components of plasma lipoproteins and severity of coronary artery disease in 65 men and 42 women who underwent coronary arteriography for suspected coronary disease. Severity of coronary atherosclerosis was scored as the extent of disease seen at arteriography. Univariate analyses of the relationships between the plasma lipoprotein parameters and score for severity of atherosclerosis revealed a marked difference between men and women. In men, the score for severity of atherosclerosis was strongly related to the low-density lipoprotein (LDL) cholesterol and apolipoprotein B concentrations, whereas in women it was related to the triglyceride concentrations in plasma intermediate-density lipoprotein (IDL) and LDL and to the cholesterol and apolipoprotein B concentrations in IDL. The significance of these correlations was not negated by possible confounding factors such as alcohol intake, diabetes, and treatment with thiazides and beta-adrenergic blockers. Stepwise regression analyses of data adjusted for weight and age indicated that 22% of the variation in the score for severity of atherosclerosis could be accounted for by levels of LDL cholesterol in men. No other lipoprotein parameter could account for any further variation. In contrast, cholesterol did not account for any variation in the score for severity of atherosclerosis in women, whereas plasma triglyceride accounted for 16% of the observed variation in this group. No relationships were found between score for severity of atherosclerosis and high-density lipoprotein cholesterol or plasma apolipoprotein A-I concentrations in either group.(ABSTRACT TRUNCATED AT 250 WORDS)     

HDL-Spiegel oder HDL-Funktion als prim?res Target der pr?ventiven Kardiologie

The risk for myocardial infarction can be reduced by almost 50% solely by lowering LDL cholesterol. Despite success reducing LDL and cholesterol, atherosclerosis and myocardial infarction remain significant challenges. However, mechanisms of the reverse cholesterol transport system might be used more effectively in the foreseeable future. Although the benefit of high HDL cholesterol appears to be obvious, most clinical trials aimed at increasing HDL cholesterol failed to generate convincing results. Therefore, the question arises as to whether indeed only HDL level or perhaps rather more HDL function is of considerable therapeutic relevance. If function is the crucial issue drugs such as CETP (cholesteryl ester transfer protein) activators or SR-B1 (scavenger receptor type B-1) upregulators could be beneficial. These types of drugs could improve HDL metabolism and might have beneficial effects despite the fact that they lower HDL levels. Ongoing studies on next generation CETP inhibitors and nicotinic acid will clarify this question and might help in our struggle against atherosclerosis.     

Familial aggregation of non-insulin dependent diabetes and coronary heart disease are accompanied by different effects on serum lipids, lipoproteins and apolipoproteins

This study was designed to investigate whether the presence of non-insulin-dependent diabetes mellitus (NIDDM) or coronary heart disease (CHD) in probands have different effects on serum lipid, lipoprotein and apolipoprotein concentrations in the first-degree relatives. Altogether 161 probands (114 men, 47 women) and 788 first-degree relatives of these probands (174 brothers, 246 sisters, 180 sons, 188 daughters) were included in the analyses. The presence of NIDDM in the proband was associated with lowered total, LDL and HDL cholesterol and apolipoprotein A1 and elevated total triglyceride levels in the brothers (P less than 0.05) and elevated total and LDL cholesterol levels in the sisters (P less than 0.05). Total LDL and VLDL cholesterol and apolipoprotein B were higher (P less than 0.05) and HDL/total cholesterol ratio and apolipoprotein A1/B ratio lower (P less than 0.05) in the daughters of the nondiabetic and diabetic probands were pooled, CHD in the proband was associated particularly with low apolipoprotein A1/B ratio. In conclusion, (1) the presence of NIDDM in the proband appears to be associated in siblings with more profound lipid and lipoprotein changes (especially low HDL cholesterol and high total triglycerides) than a history of CHD in the proband, (2) a history of CHD in the proband is associated in children with apolipoprotein changes favouring atherosclerosis (low apolipoprotein A1, high apolipoprotein B, low apolipoprotein A1/B ratio). Different effects of a history of NIDDM and CHD in the proband on lipid, lipoprotein and apolipoprotein levels in the first-degree relatives warrants more population-based studies.