The Study For Metabolism Of Lipid In Patients With Rheumatoid Arthritis

Background:Rheumatoid arthritis(RA) is a systemic immune and inflammatory disease,damaging the function of many systemic joints;its basic pathological change is arthrosynovitis.RA may also reduce life expectancy.It has been reported that the mortality in RA patients increases by approximate 70%over in normal subjects.The cardiovascular diseases are the leading cause of death and result in 50%of mortality in RA.RA is considered to be an independent risk factor for coronary heart disease(CHD).Studies have shown that patients with RA,especially in young patients,have a particularly excess risk of CHD.Traditional cardiovascular risk factors,including hyperlipidaemia,hypertension,obesity and diabetes mellitus,do not fully explain the excessive cardiovascular events observed in patients with RA. Some studies demonstrated that the morbility of atherosclerosis(As) is higher in RA patients than in the general population.Most patients did not exhibit evident clinical symptoms at the early phase of the disease,but obvious pathological changes in coronary arteries have developed,which were a threat against lives of the RA patients. It has been considered that high morbility of cardiovascular event in RA patients is due to the process of accelerated atherosclerosis.Close attention has been paid to the relationship of RA and atherosclerosis in the past few years,which has become the focus to be studied in this field.Inflammation,abnormal lipoprotein profile and pro-thrombotic factor have been considered to be the main risk factors.The reports published about the change of lipid concentrations in RA patients are different.Some studies demonstrated that the lipids profile in RA was characterized by low levels of total cholesterol(TC),high density lipoprotein cholesterol (HDL-C)and high levels of triglyceride(TG),while some reports showed that the levels of TC,TG and low density lipoprotein cholesterol(LDL-C),and the ratio of LDL/HDL increased.Inflammation markers,including C-reactive protein(CRP) and erythrocyte sedimentation rate(ESR),have been found negatively related with the level of HDL-C or Apolipoprotein AI.Oxidized low density lipoprotein(Ox-LDL) play an important role in the initiation and progression of atherosclerosis.High level of Ox-LDL is a powerful index of atherosclerotic cardiovascular disease.Small dense low-density lipoproteins (sd-LDL) has been reported to be more susceptible to oxidation,resulting in plasma high level of Ox-LDL.Ox-LDL is a ligand for scavenger receptors and might reasonably be expected to contribute to foam cell formation.Ox-LDL in vivo also have reported to trigger an immune response leading to the production of autoantibodies and subsequently to the formation of immune complex(IC),which induces foam cell formation by theγ-receptor pathway more efficiently than any other known mechanisms and secretes many cytokines,destroying vascular endothelium and inducing proliferation of smooth muscle cell and subsequently accelerating the development of atherosclerosis.Lipoprotein(a)[Lp(a)]has been established to be a independent risk factor for atherosclerosis.Oxidized Lp(a) [Ox-Lp(a)]and its autoantibody have been reported to be present in human blood circulation.Similarly,Lp(a) -IC might play a pathogenic role in atherosclerosis. Increased levels of Ox-Lp(a) and Lp(a)-IC have also found in patients with CHD.Therefore,it is useful to approach the mechanism of high morbility of CHD in RA that to detect lipids,Ox-LDL,Lp(a) and IC levels,as well as to explore the reasons that high Ox-LDL level is present in vivo.Aim:1.To explore the abnormal characters of lipids,including plasma lipids, apolipoproteins(apo),Ox-LDL level,and their associations with inflammation markers.2.To analyze level of native,oxidized Lp(a) and Lp(a)-IC in RA patients and their possible relation with inflammation markers.3.To investigate malondialdehyde-modified LDL(MDA-LDL),LDL-IC levels and their relation with inflammation markers in patients with RA.4.To explore relationship between Ox-LDL level and susceptibility of LDL to in vitro oxidation in patients with RA. Methods 1.Fifty-five patients with RA and 60 healthy controls were randomly chosen.TC,TG,HDL-C,LDL-C,apoAI,apoB and Ox-LDL levels,as well as inflammation markers,including ESR,CRP and rheumatoid factor(RF) level were studied in patients with RA.2.Fifty-five patients with RA(24 were activity,31 were inactivity),and 60 healthy controls were randomly chosen.Plasma native,oxidized Lp(a) and its IC levels were all studied by ELISAs.3.Fifty-five patients with RA(13 of which with CHD,42 without CHD) and 60 healthy controls were randomly chosen. Plasma MDA-LDL and LDL-IC levels were both determined by ELISAs.4.LDL was isolated using preparative ultra-centrifugation from 23 patients with RA and 25 control subjects.The susceptibility of LDL to Cu²⁺-mediated oxidation was analyzed by absorbance measurements at 234 nm.Ox-LDL was also detected by ELISA.Results 1.Compared to control,TC,TG,LDL-C,apoB and Ox-LDL levels were all found increased in patients with RA(P＜0.01);apoAI and HDL-C levels had the tendency to increase,while the changes didn't reach statistical significance.ESR was found negatively related with LDL-C(r=-0.316,P=0.019) and apo AI(r=-0.335, P=0.012),respectively;CRP was found negatively related with HDL-C(r=-0.396, P=0.003) and apoAI(r=-0.374,P=0.005),respectively;while no relationship was found between RF and above plasma lipid parameters.2.Native and oxidized Lp(a) and Lp(a)-IC levels in active RA patients were higher than those in inactive RA patients(P＜0.01;P＜0.05;P＜0.05,respectively) and control(P＜0.01;P＜0.01; P＜0.01,respectively),while no difference was found in the above indexes between inactive RA patients and control.ESR were found positively related with native Lp(a) (r=0.315,P=0.019),oxidized Lp(a)(r=0.371,P=0.005) and Lp(a)-IC(r=0.419, P=0.001),respectively.Mealwhile,CRP were found positively related with native Lp(a)(r=0.324,P=0.016),oxidized Lp(a)(r=0.459,P=0.000) and Lp(a)-IC(r=0.529, P=0.000),respectively.3.Compared to the control,plasma lipids and apolipoproteins levels in RA patients with CHD had the tendency to increase,while of which,only apoB levels reached statistical significance.Meanwhile,TC,TG,LDL-C and apoB level in simple RA patients were found significantly increased.No difference in lipids and apoprotein levels was found between RA patients with CHD and simple RA; MDA-LDL level in RA with CHD,simple RA and control were 187.81±90.89 mg/L, 102.01±57.73 mg/L and 32.65±27.00 mg/L,respectively.LDL-IC level in the three groups were 2.58±1.69 AU,1.87±0.74 AU and 1.21±0.38 AU,respectively. Compared to the control,MDA-LDL and LDL-IC levels increased in both simple RA patients and RA patients with CAD(P＜0.01;P＜0.01,respectively),furthermore, MDA-LDL and LDL-IC levels in RA patients with CHD were both found significantly higher than those in simple RA(P＜0.01;P＜0.05,respectively).LDL-IC level was found positively related with CRP(R=0.282,P=0.037),and MDA-LDL level was found positively related with ESR(R=0.268,P=0.048).4.Lag time, maximal rate and total amount of conjugated dienes in the test for LDL oxidizability in RA patients were significantly different from that in control group.Ox-LDL levels were significantly higher in the active RA than in controls(101.78±53.53 vs. 74.16±17.36μg/mL,P＜0.01).The lag time of LDL became short(P＜0.05),maximal rate and total amount of conjugated dienes increased(P＜0.05;P＜0.01,respectively). Ox-LDL level was found related with the lag time of LDL in the RA patients (r=-0.618,P=0.002).Conclusions 1.Plasma lipids,apolipoproteins and Ox-LDL levels were significantly changed in RA patients.Inflammation may induce the abnormal metabolism of lipoproteins.Ox-LDL may play a linking role in inflammation,lipids and endothelium dysfunction,resulting in development of atherosclerosis in RA patients.2.Native,oxidized Lp(a) levels were changed in RA patients.Inflammation may induce the abnormal metabolism of Lp(a) and result in Lp(a) to be highly oxidized and to form its IC,which accelerated the process of atherosclerosis.3. MDA-LDL and LDL-IC levels were both increased in RA patients;especially MDA-LDL level in RA patients with CHD was significantly higher than in simple RA patients,which suggested that high level of MDA-LDL and LDL-IC play an important role in the progress of atherosclerosis.4.LDL from patients with RA is more susceptible to oxidative modification,resulting in the increased plasma Ox-LDL level,which may play a role in the development of atherosclerosis.