Transgenic rabbits expressing human apolipoprotein (a).

Elevated plasma levels of lipoprotein (a) [Lp(a)] constitutes an independent risk factor for coronary heart disease, stroke, and restenosis. Over the past years, our understanding of the genetics, metabolism and pathophysiology of Lp(a) have increased considerably. However, the precise mechanism(s) by which this atherogenic lipoprotein mediates the development of atherosclerosis remains unclear. This is partly due to the lack of appropriate animal models since apolipoprotein (a) [apo(a)], a distinct component of Lp(a) is found only in primates and humans. Development of transgenic mice expressing human apo(a) has provided an alternative means to investigate many aspects of Lp(a). However, human apo(a) in transgenic mice can not bind to murine apoB to form Lp(a) particles. In this aspect, we generated transgenic rabbits expressing human apo(a). In the plasma of transgenic rabbits, unlike the plasma of transgenic mice, about 80% of the apo(a) was associated with rabbit apo B and was contained in the fractions with density 1.02-1.10 g/ml, indicating the formation of Lp(a). Our study suggests that transgenic rabbits expressing human apo(a) exhibit efficient assembly of Lp(a) and can be used as an animal model for the study of human Lp(a).     

The role of Lipoprotein(a) in cardiovascular disease: Current concepts and future perspectives

High lipoprotein(a) [Lp(a)] levels are associated with the development of atherosclerotic cardiovascular disease (ASCVD) and with calcific aortic valve stenosis (CAVS) both observationally and causally from human genetic studies. The mechanisms are not well characterized but likely involve its role as a carrier of oxidized phospholipids (OxPLs), which are known to be increased in pro-inflammatory states, to induce pro-inflammatory changes in monocytes leading to plaque instability, and to impair vascular endothelial cell function, a driver of acute and recurrent ischemic events. In addition, Lp(a) itself has prothrombotic activity. Current lipid-lowering strategies do not sufficiently lower Lp(a) serum levels. Lp(a)-specific-lowering drugs, targeting apolipoprotein(a) synthesis, lower Lp(a) by up to 90% and are being evaluated in ongoing clinical outcome trials. This review summarizes the current knowledge on the associations of Lp(a) with ASCVD and CAVS, the current role of Lp(a) assessment in the clinical setting, and emerging Lp(a)-specific-lowering therapies.     

脂蛋白(a)对转基因家族性高脂血症家兔冠状动脉粥样硬化发生的影响

目的应用载脂蛋白(a)转基因家族性高脂血症家兔模型评价脂蛋白(a)在冠状动脉粥样硬化发展过程中的长期作用结果,以进一步探讨脂蛋白(a)在动脉粥样硬化中的作用机制。方法繁殖人类载脂蛋白(a)转基因家族性高脂血症家兔及同窝生非转基因家族性高脂血症家兔,24月龄,标准普通饲料喂养。测量家兔血浆脂蛋白(a)、总胆固醇、甘油三酯、高密度脂蛋白胆固醇及C反应蛋白水平,组织学染色测量病变内膜面积及狭窄率,并采用免疫组织化学染色分析病变的组成。结果24月龄的转基因家族性高脂血症家兔血浆脂蛋白(a)水平为9.1±3.5nmol/L;转基因与非转基因家族性高脂血症家兔的总胆固醇、甘油三酯和高密度脂蛋白胆固醇水平差异无显著性,但转基因家族性高脂血症家兔右冠状动脉病变面积比非转基因家族性高脂血症家兔高3.5倍(P<0.05)。转基因家兔右冠状动脉的病变大小并没有发生相应的管腔狭窄(狭窄率在非转基因组为26.9%±6.6%,转基因组为27.7%±5.0%),转基因家兔右冠状动脉直径由于血管的代偿性重塑而发生了显著的增加(血管面积在非转基因组为1.8±0.6mm2,转基因组为5.3±1.1mm2;P<0.05)。人类载脂蛋白(a)转基因家兔的病变与载脂蛋白B有关,主要分布在细胞外基质的周围。病变富含细胞外基质,病变中细胞成分所占的比例较少,不足10%。发现有33%转基因家兔及9%非转基因家兔发生了明显的心肌梗死。结论增加血浆脂蛋白(a)水平可加重有高脂血症背景家兔的冠状动脉粥样硬化。     

Transgenic rabbits expressing human apolipoprotein(a) develop more extensive atherosclerotic lesions in response to a cholesterol-rich diet

High lipoprotein(a) [Lp(a)] levels constitute an independent risk factor for the development of atherosclerosis. However, the relationship between Lp(a) and atherosclerosis is not fully understood. To examine the effect of Lp(a) on the development of atherosclerosis, we studied transgenic rabbits expressing human apolipoprotein(a) [apo(a)], which was assembled into Lp(a) in the plasma. Human apo(a) transgenic rabbits fed a 0.3% cholesterol diet for 16 weeks had more extensive atherosclerotic lesions than did nontransgenic rabbits, although the cholesterol levels in the plasma of both groups were similarly elevated. Compared with the lesions in control rabbits, the areas of the atherosclerotic lesions in human apo(a) transgenic rabbits were significantly increased in the aorta, the iliac artery, and the carotid artery. Furthermore, human apo(a) transgenic rabbits on a cholesterol-rich diet had a greater degree of coronary atherosclerosis than did control rabbits. Immunohistochemical analysis revealed that human apo(a) was frequently deposited in the atherosclerotic lesions of transgenic rabbits. We conclude that Lp(a) may have proatherogenic effects in the setting of a cholesterol-rich diet in transgenic rabbits.     

Human Genetics and the Causal Role of Lipoprotein(a) for Various Diseases

Lipoprotein(a) [Lp(a)] is a highly atherogenic lipoprotein that is under strong genetic control by the LPA gene locus. Genetic variants including a highly polymorphic copy number variation of the so called kringle IV repeats at this locus have a pronounced influence on Lp(a) concentrations. High concentrations of Lp(a) as well as genetic variants which are associated with high Lp(a) concentrations are both associated with cardiovascular disease which very strongly supports causality between Lp(a) concetrations and cardiovascular disease. This method of using a genetic variant that has a pronounced influence on a biomarker to support causality with an outcome is called Mendelian randomization approach and was applied for the first time two decades ago with data from Lp(a) and cardiovascular disease. This approach was also used to demonstrate a causal association between high Lp(a) concentrations and aortic valve stenosis, between low concentrations and type-2 diabetes mellitus and to exclude a causal association between Lp(a) concentrations and venous thrombosis. Considering the high frequency of these genetic variants in the population makes Lp(a) the strongest genetic risk factor for cardiovascular disease identified so far. Promising drugs that lower Lp(a) are on the horizon but their efficacy in terms of reducing clinical outcomes still has to be shown.     

Emerging Therapeutic Options for Lowering of Lipoprotein(a): Implications for Prevention of Cardiovascular Disease

Purpose of Review

Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are an independent and causal risk factor for cardiovascular diseases including coronary artery disease, ischemic stroke, and calcific aortic valve stenosis. This review summarizes the rationale for Lp(a) lowering and surveys relevant clinical trial data using a variety of agents capable of lowering Lp(a).

Recent Findings

Contemporary guidelines and recommendations outline populations of patients who should be screened for elevated Lp(a) and who might benefit from Lp(a) lowering. Therapies including drugs and apheresis have been described that lower Lp(a) levels modestly (～20 %) to dramatically (～80 %). Existing therapies that lower Lp(a) also have beneficial effects on other aspects of the lipid profile, with the exception of Lp(a)-specific apheresis and an antisense oligonucleotide that targets the mRNA encoding apolipoprotein(a).

Summary

No clinical trials conducted to date have managed to answer the key question of whether Lp(a) lowering confers a benefit in terms of ameliorating cardiovascular risk, although additional outcome trials of therapies that lower Lp(a) are ongoing. It is more likely, however, that Lp(a)-specific agents will provide the most appropriate approach for addressing this question.

     

Cholesterol-fed and transgenic rabbit models for the study of atherosclerosis.

The rabbit has been extensively utilized as an ideal model of atherosclerosis because of its size, easy manipulation, and extraordinary response to dietary cholesterol. The availability of spontaneously hypercholesterolemic model, Watanabe heritable hyperlipidemic rabbits (WHHL) and St. Thomas rabbits, has also provided insights into understanding human familiar hypercholesterolemia and atherosclerosis. With the advent of genetically engineered rabbits, transgenic rabbits have become a novel means to explore a number of proteins that are associated with cardiovascular diseases including atherosclerosis. To date, transgenes for human apo(a), apoA-I, apoB, apoE2, apoE3, hepatic lipase, lecithin: cholesterol acyltransferase (LCAT), lipoprotein lipase, 15-lipoxygenase, as well as for rabbit apolipoprotein B mRNA-editing enzyme catalytic polypeptide 1 (APOBEC-1), have been expressed in rabbits. In addition, human apoA-I, LCAT and apo(a) have been introduced into WHHL rabbits which have deficient LDL receptor function. All of these transgenes have been found to have significant effects on plasma lipoprotein metabolism or/and atherosclerosis. These studies have revealed new insights into the mechanisms responsible for the development of atherosclerosis. In this article, we provide a brief review on the rabbit model for the study of atherosclerosis with emphasis on transgenic rabbit models developed during the past few years.     

Study of ABCA1 function in transgenic mice

The ATP-binding cassette transporter A1 (ABCA1), identified in 1999 as the gene defective in Tangier disease, promotes efflux of cellular cholesterol from macrophages and other peripheral tissues to apolipoprotein acceptors. These ABCA1-mediated processes are anticipated to have antiatherogenic properties, prompting the development of pharmacological agents that increase ABCA1 gene expression as well as the establishment of ABCA1-transgenic mouse lines. Preliminary studies of ABCA1-Tg mice seem to validate the selection of this transporter as a therapeutic target for the treatment of low HDL syndromes and cardiovascular disease but have also raised new questions regarding the function of ABCA1. In particular, the relative contribution of hepatic and peripheral ABCA1 to plasma HDL levels and to reverse cholesterol transport, as well as the potential role of ABCA1 in modulating the plasma concentrations of the apolipoprotein B-containing lipoproteins and protecting against atherosclerosis, seem to be promising areas of investigation. The present review summarizes the most recent studies and discusses insights provided by these transgenic mouse models.     

Lipoprotein(a) and atherosclerosis: New perspectives on the mechanism of action of an enigmatic lipoprotein

Although elevated plasma concentrations of lipoprotein(a) (Lp(a)) have been identified as a risk factor for coronary heart disease, the pathophysiologic and physiologic roles of Lp(a) continue to elude basic researchers and clinicians alike. Lp(a) is a challenging lipoprotein to study because it has a complex structure consisting of a low-density lipoprotein-like moiety to which is covalently attached the unique glycoprotein apolipoprotein(a) (apo(a)). Apo(a) contains multiply repeated kringle domains that are similar to a sequence found in the fibrinolytic proenzyme plasminogen; differing numbers of kringle sequences in apo(a) give rise to Lp(a) isoform size heterogeneity. In addition to elevated plasma concentrations of Lp(a), apo(a) isoform size has been identified as a risk factor for coronary heart disease, although studies addressing this relationship have been limited. The similarity of Lp(a) to low-density lipoprotein and plasminogen provides an enticing link between the processes of atherosclerosis and thrombosis, although a clear demonstration of this association in vivo has not been provided. Clearly, Lp(a) is a risk factor for both atherothrombotic and purely thrombotic events; a plethora of mechanisms to explain these clinical findings has been provided by both in vitro studies as well as animal models for Lp(a).     

Study of lipoprotein(a) and its impact on atherosclerotic cardiovascular disease: Design and rationale of the Mass General Brigham Lp(a) Registry

Lipoprotein(a) [Lp(a)] is independently associated with atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Elevated Lp(a) affects approximately one in five individuals and meaningfully contributes to the residual cardiovascular risk in individuals with otherwise well-controlled risk factors. With targeted therapies in the therapeutic pipeline, there is a need to further characterize the clinical phenotypes and outcomes of individuals with elevated levels of this unique biomarker. The Mass General Brigham Lp(a) Registry will be built from the longitudinal electronic health record of two large academic medical centers in Boston, Massachusetts, to develop a detailed cohort of patients who have had their Lp(a) measured. In combination with structured data sources, clinical documentation will be analyzed using natural language processing techniques to accurately characterize baseline characteristics. Important outcome measures including all-cause mortality, cardiovascular mortality, and cardiovascular events will be available for analysis. Approximately 30 000 patients who have had their Lp(a) tested within the Mass General Brigham system from January 2000 to July 2019 will be included in the registry. This large Lp(a) cohort will provide meaningful observational data regarding the differential risk associated with Lp(a) values and cardiovascular disease. With a new frontier of targeted Lp(a) therapies on the horizon, the Mass General Brigham Lp(a) Registry will help provide a deeper understanding of Lp(a)'s role in long term cardiovascular outcomes.     

Evaluation of dyslipidaemia in patients with rheumatoid arthritis in South Indian population

BackgroundRheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality which is mainly due to accelerated atherosclerosis. The inflammation in rheumatoid arthritis is likely to alter the lipid profile in these patients resulting in dyslipidaemia which is an important cardiovascular disease (CVD) risk factor.Material and methods46 patients diagnosed with RA as per 1987 revised American Rheumatology Association criteria were included in the study. Of the 46 patients, 24 were newly diagnosed RA patients and 22 patients were undergoing treatment with a combination of DMARDs with (n = 14) or without (n = 8) corticosteroids. 46 age and sex matched healthy subjects were included as controls. Total cholesterol (TC), triglycerides, HDL cholesterol, lDL cholesterol, apolipoprotein A-1 (apo A-1), apolipoprotein B (apo B) and lipoprotein(a) (Lp(a)) were measured.ResultsTC, HDL cholesterol and LDL cholesterol levels were similar in all the three study groups. Both groups of patients had significantly elevated triglyceride, apo B and Lp(a) levels compared to controls (p < 0.05). RA patients undergoing treatment had significantly elevated apo A-1 levels when compared to controls (p < 0.05).ConclusionsThe dyslipidaemia pattern in RA patients in the present study is evident in the form of elevated triglycerides, apo B and Lp(a) levels. The beneficial effects of a higher atheroprotective apo A-1 in patients undergoing treatment may be counteracted by the presence of high triglycerides, apo B and Lp(a).     

Lipoprotein(a): Expanding our knowledge of aortic valve narrowing

Elevated levels of lipoprotein(a) [Lp(a)] have been identified as an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and, more recently, calcific aortic valve disease (CAVD). CAVD is a slow, progressive disorder presenting as severe trileaflet calcification known as aortic valve stenosis (AS) that impairs valve motion and restricts ventricular outflow. AS afflicts 2% of the aging population (≥ 65 years) and tends to be quite advanced by the time it presents clinical symptoms of exertional angina, syncope, or heart failure. Currently, the only effective clinical therapy for AS patients is surgical or transcatheter aortic valve replacement. Evidence is accumulating that Lp(a) can exacerbate pathophysiological processes in CAVD, specifically, endothelial dysfunction, formation of foam cells, and promotion of a pro-inflammatory state. In the valve milieu, the pro-inflammatory effects of Lp(a) are manifested in valve thickening and mineralization through pro-osteogenic signaling and changes in gene expression in valve interstitial cells that is primarily facilitated by the oxidized phospholipid content of Lp(a). In AS pathogenesis, an incomplete understanding of the role of Lp(a) at the molecular level and the absence of appropriate animal models are barriers for the development of specific and effective clinical interventions designed to mitigate the role of Lp(a) in AS. However, the advent of effective therapies that dramatically lower Lp(a) provides the possibility of the first medical treatment to halt AS progression.     

Lipids, lipoproteins and apolipoprotein (a) isoforms in type 2 diabetic patients.

BACKGROUND: Patients with type 2 diabetes mellitus have a greater than normal risk of developing atherosclerotic vascular diseases. Higher than normal plasma concentrations of lipoprotein (a) [Lp(a)] have been associated with premature atherosclerosis in several studies. OBJECTIVE: To determine the concentrations of lipids, lipoproteins, and Lp(a) in 107 type 2 diabetic patients, and the distribution of apolipoprotein (a) [apo(a)] phenotypes for this group, and to compare the results found with results for healthy subjects. RESULTS: Plasma concentrations of cholesterol, triglycerides, and apolipoprotein B in the diabetics were significantly higher than those in control subjects. Diabetic patients had slightly lower Lp(a) concentrations than did nondiabetic subjects, but these differences were not statistically significant. Distributions of Lp(a) concentrations both in type 2 diabetic patients and in control subjects were markedly skewed, the highest prevalences being of low values. CONCLUSION: Distributions of apo(a) phenotypes for patients with type 2 diabetes mellitus and controls were remarkably alike. Smaller isoforms were similarly prevalent for the two populations, as were the null, single-band and double-band apo(a) phenotypes.     

Prevalence of atherosclerosis of the coronary and extracranial cerebral arteries in patients undergoing aortic valve replacement for calcified stenosis

BACKGROUND AND AIM OF THE STUDY: The study aim was to investigate the coexistence of various atherosclerotic changes in patients with non-rheumatic calcific aortic valve stenosis (AS), since calcific AS shares various clinical risk factors with atherosclerosis. METHODS: In 282 consecutive patients with severe calcific stenosis of a tricuspid aortic valve scheduled for aortic valve replacement, the prevalence of atherosclerotic changes of the coronary and extracranial cerebral arteries were assessed using coronary angiography and Doppler sonography, respectively. RESULTS: The severities of coronary and extracranial cerebral artery atherosclerosis were significantly associated (p = 0.005). The prevalence and severity of both coronary and extracranial cerebral artery atherosclerosis were age-dependent. Coronary or extracranial cerebral artery stenosis was present in 59% and 16% of patients, respectively, while 91% of the study population and all patients aged > 80 years showed atherosclerosis of the coronary and/or extracranial cerebral arteries. CONCLUSION: The data obtained indicated a very high prevalence of atherosclerotic changes in patients with calcific AS, suggesting pathogenetic similarities of both disorders. Routine screening of the extracranial cerebral arteries is warranted in all patients with calcific AS and scheduled for valve replacement.     

Pathology of calcific aortic stenosis

With the aging of the general population in industrialized nations, calcific aortic stenosis (CAS) is becoming an increasingly important medical problem. The etiology is for the most part, dependent on the age at presentation; the two predominant causes in the western world are calcific aortic valve disease arising in a tricuspid aortic valve and bicuspid aortic valve (BAV). CAS is a progressive disease, exhibiting a spectrum of pathologic findings, ranging from valvular sclerosis to severe nodular calcification. Aortic valve replacement is the recommended treatment for severe disease but tissue valves may also calcify over time. Various atherosclerotic risk factors have been linked to aortic stenosis and there are mechanistic similarities between atherosclerosis and CAS. The precise pathologic mechanisms underlying aortic stenosis are poorly understood.     

Association between calcific aortic stenosis and hypercholesterolemia: Is there a need for a randomized controlled trial of cholesterol‐lowering therapy?

BACKGROUND: Calcific aortic stenosis may have common etiological factors with atherosclerosis. HYPOTHESIS: In this retrospective, case-control study, we aimed to determine whether there is an association between hypercholesterolemia and calcific aortic valve stenosis. METHODS: Consecutive patients undergoing single aortic or mitral valve replacement in a regional cardiothoracic surgical center were reviewed and preoperative patient characteristics were recorded: demographics, comorbidity (including coronary artery disease and associated risk factors), serum total cholesterol, lipid-lowering therapy, and serum creatinine. RESULTS: Serum total cholesterol concentrations were significantly higher in patients with calcific aortic stenosis than in controls (6.2+/-1.1 vs. 5.3+/-1.1 mmol/l; p < 0.001). The significant difference in serum cholesterol concentrations remained following correction for gender and body mass index (p = 0.02) and when patients with coronary artery disease were excluded (6.3+/-1.1 vs. 5.3+/-1.4 mmol/l; p<0.001). Subgroup analysis demonstrated that the association between elevated serum cholesterol concentrations and calcific aortic stenosis was particularly strong in patients with tricuspid aortic valves (6.4+/-1.2 vs. 5.3+/-1.1 mmol/l; p < 0.001) compared with those with bicuspid valves (5.9+/-1.1 vs. 5.3+/-1.1 mmol/l; p = 0.06). CONCLUSIONS: We conclude that hypercholesterolemia is associated with calcific aortic stenosis and may be implicated in its pathogenesis and progression. We believe that there is now a need for a randomized, controlled trial of cholesterol-lowering therapy in patients with calcific aortic stenosis.     

Genetic basis and pathophysiological implications of high plasma Lp(a) levels.

Lipoprotein(a) or Lp(a) is a genetic variant of plasma low density lipoproteins (LDL) containing apoB100 covalently linked to apolipoprotein(a) or apo(a), the specific marker of Lp(a). Lp(a) is heterogeneous in size and density, accounting in part for the marked size polymorphism of apo(a), 300 to 800 kDa. The apo(a) size polymorphism is related to the different number of kringle repeats which are structurally similar although not identical to the kringle 4 of plasminogen. Recent studies on a genomic level have indicated that the apo(a) gene contains at least 19 different alleles varying in length between 48 and 190 kb, partially impacting on the plasma levels of Lp(a). High plasma levels of Lp(a) have been found to be associated with an increased prevalence of premature atherosclerotic cardiovascular disease by mechanism(s) yet to be established. Both atherogenic and thrombogenic potentials have been postulated and have been related to the LDL-like and plasminogen-like properties of Lp(a), respectively.     

Association of elevated lipoprotein(a) levels and coronary heart disease in NIDDM patients. Relationship with apolipoprotein(a) phenotypes

Summary Non-insulin-dependent diabetes mellitus (NIDDM) is a strong and independent risk factor for coronary heart disease. We assessed the potential relationship between plasma Lp(a) levels, apo(a) phenotypes and coronary heart disease in a population of NIDDM patients. Seventy-one patients with coronary heart disease, who previously have had transmural myocardial infarction, or significant stenosis on coronary angiography, or positive myocardial thallium scintigraphy, or in combination, were compared with 67 patients without coronary heart disease, who tested negatively upon either coronary angiography, myocardial thallium scintigraphy or a maximal exercise test. The prevalence of plasma Lp(a) levels elevated above the threshold for increased cardiovascular risk (>0.30 g/l) was significantly higher (p=0.005) in patients with coronary heart disease (33.8%) compared to the control group (13.4%). The relative risk (odds ratio) of coronary heart disease among patients with high Lp(a) concentrations was 3.1 (95% confidence interval, 1.31–7.34;p=0.01). The overall frequency distribution of apo(a) phenotypes differed significantly between the two groups (p=0.043). However, the frequency of apo(a) isoforms of low apparent molecular mass (700 kDa) was of borderline significance (p=0.067) between patients with or without coronary heart disease (29.6% and 16.4%, respectively). In this Caucasian population of NIDDM patients, elevated Lp(a) levels were associated with coronary heart disease, an association which was partially accounted for by the higher frequency of apo(a) isoforms of small size. In multivariate analyses, elevated levels of Lp(a) were independently associated with coronary heart disease (odds ratio 3.48, p=0.0233).Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - IDDM insulin-dependent diabetes mellitus - CHD coronary heart disease - Lp(a) lipoprotein(a) - apo(a) apolipoprotein(a) - apoB apolipoprotein B - HMGCoA reductase hydroxymethylglutaryl coenzyme A reductase     

The role of lipoprotein(a) in the pathogenesis of atherosclerotic cardiovascular disease and its utility as predictor of coronary heart disease events

Lipoprotein(a) [Lp(a)], is a highly heterogeneous lipoprotein, due to variations in the size of apolipoprotein(a) [apo(a)], and the density of the apoB100-containing particles to which apo(a) is linked. Although high plasma levels of Lp(a) have been associated with an increased risk for atherosclerotic cardiovascular disease, the mechanism underlying this association is still largely undetermined, as is the potential role played by the particle’s heterogeneity. Lp(a) pathogenicity may also be influenced by the action of environmental factors and post-translational events relating to oxidative processes, and the action of lipolytic and proteolytic enzymes. Complicating the study of Lp(a) are the competing methods for its quantification due to its complex structure, and the lack of standardized methodologies. The recognition that Lp(a) particles may not all be alike in atherogenic potential should encourage studies to identify genetic and nongenetic factors underlying its heterogeneity, in order to reach a better understanding of its actual impact on atherosclerotic cardiovascular disease.     

Lipid profiles in untreated patients with rheumatoid arthritis.

OBJECTIVE: To investigate lipid profiles in patients with untreated active rheumatoid arthritis (RA) and to assess the relationship of the inflammatory condition of RA with lipid profiles. METHODS: Forty-two patients with RA and 42 age and sex matched healthy controls were studied. Patients with RA had not been treated with corticosteroid or disease modifying antirheumatic drugs prior to the study. Total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, apolipoprotein A1 (apo A1), apolipoprotein B (apo B), lipoprotein(a) [Lp(a)], and C-reactive protein (CRP) were measured in both groups. RESULTS: The levels of apo A1 and HDL-cholesterol were significantly lower in patients than in controls (128.5 vs. 151.8 mg/dl, 41.2 vs. 54.9 mg/dl, respectively). The level of Lp(a) was significantly higher in patients than in controls (27.1 vs. 18.0 mg/dl). The ratios of apo B/apo A1, total cholesterol/HDL-cholesterol, and LDL-cholesterol/HDL-cholesterol were significantly higher in patients than in controls (0.82 vs. 0.67, 4.4 vs. 3.4, 2.8 vs. 1.9, respectively). CRP showed a significant correlation with apo A1 (r = -0.44, p<0.01) and HDL-cholesterol (r = -0.35, p<0.05). CONCLUSION: Our study suggests that patients with untreated active RA have altered lipoprotein and apolipoprotein patterns that may possibly expose them to higher risk of atherosclerosis. The inflammatory condition of RA may affect the metabolism of HDL-cholesterol and apo A1.