系统性红斑狼疮早发动脉粥样硬化的研究进展

系统性红斑狼疮(systemic lupus erythematosus,SLE)是累及多系统多器官的自身免疫病,近年来的流行病学研究发现SLE患者已成为心血管痰病(cardiovascular disease,CVD)的高危人群,早发动脉粥样硬化(atherosclerosis,AS)是SLE患者最常见的CVD之一.传统心血管危险因素如高血压、高脂血症、肥胖等不能完全解释SLE早发AS,非传统危险因素如自身抗体、免疫复舍物、内皮功能障碍、系统性炎症反应等在SLE早发AS的发病机制中的作用越来越受到关注,深入研究这些非传统危险因素在SLE早发AS的致病作用,将有助于防治SLE患者的CVD,提高SLE患者生存率.     

细胞焦亡与糖尿病及其并发症的关系研究进展

细胞焦亡(pyroptosis)是近年来新发现的一种程序性细胞死亡方式,其主要是由不同类型的半胱氨酸蛋白酶和促炎细胞因子的释放所触发的炎症反应。2型糖尿病(type 2 diabetes mellitus, T2DM)是以慢性高血糖为主要特征的代谢性疾病,在长期高血糖的刺激下,患者处于慢性低度炎症状态,常造成如心血管、肾脏、眼睛,以及神经等组织器官发生慢性进行性病变。近年来研究发现细胞焦亡在T2DM及其并发症中发挥重要作用,该文就细胞焦亡与糖尿病及其并发症的关系和机制进行综述。     

糖尿病与肺功能的关系及相互影响机制

糖尿病是一种影响多器官的疾病,其并发症包括糖尿病肾病、糖尿病神经病变、糖尿病视网膜病变以及心血管病变等.由于吸入性胰岛素的使用,越来越多的人开始关注糖尿病和肺功能之间的关系以及糖尿病与肺功能损害相互影响的机制.糖尿病患者普遍存在肺功能降低,肺功能降低或可导致易患糖尿病,其相互影响机制可能与低氧血症、系统性炎症反应、胰岛素抵抗相关.长期有效的血糖控制、低氧运动和高压氧疗对改善糖尿病患者胰岛素抵抗和肺功能均有良好的作用,但更多的机制和干预方法尚待进一步研究.本文拟对糖尿病与肺功能的关系及相互影响的机制做一综述.     

急性心肌梗死行PCI患者炎症因子的检测及其与预后的关系

目的:探讨急性心肌梗死行经皮冠状动脉介入治疗(PCI)血清炎症因子的改变及其与预后的关系。方法:选择126例拟行PCI治疗的急性心肌梗死患者为研究对象,比较PCI手术前后血清超敏C反应蛋白(hs-CRP)及肿瘤坏死因子α(TNF-α)的改变。同时比较PCI术后3月发生心血管事件患者与未发生心血管事件患者术后12h血清hs-CRP及TNF-α的差别。结果:患者PCI术后血清hs-CRP及TNF-α水平均显著升高,与术前相比差别具有统计学意义(P<0.05);PCI术后3月发生心血管事件患者PCI术后12h血清hs-CRP及TNF-α水平显著高于未发生心血管事件患者(P<0.05);Logistic回归结果显示:hs-CRP及TNF-α与心血管事件发生率显著相关。结论:急性心肌梗死行PCI患者术后发生急性炎症反应,hs-CRP及TNF-α水平升高与患者心血管事件发生密切相关,可作为评估预后的血清学指标。     

DNA甲基化与2型糖尿病血管并发症的研究进展

2型糖尿病(type 2 diabetes mellitus, T2DM)是一种复杂的以慢性高血糖为特征的代谢性疾病。近年来,越来越多的研究发现T2DM患者体内的高糖环境可以改变DNA甲基化程度,影响相关基因功能,从而导致糖代谢、脂肪代谢和能量代谢紊乱或炎症反应,进而造成血管病变。T2DM常见的血管并发症有大血管病变引起的心脑血管疾病,以及微血管病变引起的糖尿病肾病、糖尿病视网膜病变、糖尿病周围神经病变等。DNA甲基化标记在T2DM血管并发症的早期诊断与治疗中可能有重要意义,已成为相关领域的研究热点。现主要对近期DNA甲基化在T2DM血管并发症方面的研究及其研究策略加以综述,以期深入了解T2DM血管并发症发生发展的表观遗传机制和可能的防治途径。     

糖尿病肾病致凝血异常的研究

糖尿病(DM)已成为世界性的常见病,其发病率高,并且随着生活水平的改善,其发病率必然还会进一步加剧。血管病变是DM的重要并发症之一,糖尿病肾病(DN)是糖尿病常见且严重的微血管并发症,与血栓形成密切相关。糖尿病肾病的进展伴随着体内凝血活性和抗凝活性的失调,同时激活自身免疫系统,发生炎症反应。炎症应答过程中释放的炎症因子损伤肾小球内皮细胞,导致抗凝活性减弱。DN患者体内血细胞激活,微粒形成增多会加强凝血活性。此外,纤溶酶抑制剂(PAI-1)与纤溶酶激活剂(t PA)的失衡会引起纤溶系统紊乱。这三个方面引起DN患者体内的高凝状态加重,并因此加速肾功能恶化,导致肾小球率过滤降低,系膜基质增多,最终引起肾小球硬化及终末期肾脏疾病。本文就糖尿病肾病致凝血异常的发生机制做一综述。     

高血压免疫机制的研究进展

高血压可引发多种心脑血管并发症,严重威胁人类健康。目前研究发现,高血压患者免疫调节功能异常,可导致持续性的炎症。而炎症可损伤血管内皮功能,激活肾素-血管紧张素系统,引起血管重构、血管硬化、血管舒缩功能异常等,加重高血压的发展。高血压患者免疫调节功能异常主要涉及非特异性免疫中的吞噬细胞对组织的浸润、树突细胞的抗原递呈、自然杀伤细胞的活化以及特异性免疫中T细胞的活化等。Toll样受体识别抗原启动免疫系统,从而引发炎症是高血压免疫机制的关键。自主神经系统也与高血压发生发展密切相关,自主神经对免疫具有调节作用,高血压患者自主神经失衡,导致免疫调节异常,引发心血管损伤,造成血管舒缩功能异常,从而加剧高血压的发展。因此,对神经免疫调节的研究有望为高血压的治疗提供新的策略。本文就高血压中免疫机制以及自主神经系统对免疫系统调节作用的研究进展作一综述。     

细胞因子对类风湿性关节炎骨平衡的调节作用

类风湿性关节炎(rheumatoid arthritis, RA)是一种以滑膜持续炎症和关节软骨及骨质破坏为特征的自身免疫性疾病。RA的发展伴随着滑膜细胞增生、新生血管、局部大量炎性细胞浸润及细胞因子水平的失调。异常炎症反应贯穿RA始终,细胞因子失调引起的骨破坏和骨建之间的失衡导致RA关节炎症和骨质破坏。RA致残率极高,且没有根治方法对其进行早期诊断和治疗,延缓骨损伤尤为重要。目前临床常用的诊断指标缺乏特异性。现以细胞因子为切入点,概述其在RA不同时期的不同存在及对RA骨平衡的调控作用机制,为寻找RA更加精准的早期诊断指标和治疗靶点提供线索。     

维持性血液透析患者心血管并发症的防治进展

目前,维持性血液透析仍是晚期肾功能衰竭患者的主要治疗手段,尿毒症的诸多症状在透析治疗中可得到明显改善.但维持性血液透析的患者长期处于一种由氧化应激导致的慢性炎症状态[1],而引起诸多并发症.其中高血压、心力衰竭、冠心病、心包炎、心律失常等心血管并发症是最常见和最严重的并发症,是导致维持性血液透析患者死亡的主要原因.因此,积极防治心血管并发症,对降低透析患者的病死率、改善生活质量和延长寿命具有重要意义.现就近年来血液透析患者心血管并发症的防治进展概述如下.     

2 型糖尿病患者凝血功能水平与血管病变发生的相关性

目的:探讨2型糖尿病患者凝血功能及血清肿瘤坏死因子α(TNF-α)及白细胞介素18(IL-18)水平与糖尿病血管病变的关系。方法:选择2014年6月-2015年10月在我院接受治疗的2型糖尿病患者83例作为研究对象,根据患者疾病进展情况将其分为血管病变组(45例)和无血管病变组(38例)。测定两组患者凝血酶时间(TT)、活化部分凝血酶原时间(APTT)、凝血酶原时间(PT)、纤维蛋白原(Fg)、血糖(Glu)、糖化血红蛋白(Hb A1c)、肿瘤坏死因子α(TNF-α)及白细胞介素18(IL-18)水平;采用logistics回归分析2型糖尿病患者发生血管病变的危险因素。结果:血管病变组患者Glu,Hb A1c及Fg水平均显著高于无血管病变组,而APTT及PT水平均显著低于无血管病变组,差异均具有统计学意义(P0.05);两组间TT水平比较,差异无统计学意义(P0.05)。血管病变组患者血清中TNF-α及IL-18水平均高于无血管病变组患者,差异具有统计学意义(P0.05)。Hb A1c,Fg,TNF-α以及IL-18水平异常是2型糖尿病患者发生血管病变的独立危险因素(OR=1.23,1.45,2.632,3.884,P0.05)。结论:凝血功能紊乱及炎症反应是2型糖尿病患者发生血管病变的重要因素,临床应给予重视。     

High-density lipoprotein cholesterol subfractions HDL2 and HDL3 are reduced in women with rheumatoid arthritis and may augment the cardiovascular risk of women with RA: a cross-sectional study

IntroductionHigher levels of high density lipoprotein (HDL) subfractions HDL3-chol and particularly HDL2-chol protect against cardiovascular disease (CVD), but inflammation reduces the HDL level and may impair its anti-atherogenic effect. Changed HDL composition through the impact of inflammation on HDL subfractions may contribute to the excess risk of CVD in rheumatoid arthritis (RA). In this study, we investigated whether HDL2-chol and HDL3-chol concentrations differ between RA patients and healthy controls, and whether these levels are related to the level of RA disease activity.MethodsNon-fasting blood samples were collected from 45 RA patients and 45 healthy controls. None of the participants had a history of CVD, diabetes, or used lipid-lowering drugs. HDL2-chol and HDL3-chol concentrations were obtained by ultracentrifugation. Regression modeling was used to compare HDL subfraction levels between RA patients and healthy controls, and to analyze the effect of disease activity on HDL2-chol and HDL3-chol.ResultsHDL2-chol and HDL3-chol were significantly lower in RA patients compared to healthy controls (P = 0.01, P = 0.005, respectively). The HDL2:HDL3 ratio was significantly lower in patients compared to controls (P = 0.04). Reduced HDL2-chol and HDL3-chol levels were primarily present in female RA patients and not in male RA patients. A modest effect of the disease activity score in 28 joins ( DAS28) on HDL2-chol concentrations was found, after correction for disease duration, glucocorticosteroid use and body mass index (BMI), with a 0.06 mmol/L decrease with every point increase in DAS28 (P = 0.05). DAS28 did not significantly affect HDL3-chol concentrations (P = 0.186).ConclusionsBoth HDL subfractions but particularly HDL2-chol concentrations were decreased in RA, primarily in women. This seems to be associated with disease activity and is of clinical relevance. The reduction of the HDL subfraction concentrations, particularly the supposedly beneficial HDL2-chol, may negatively impact the cardiovascular risk profile of women with RA.     

Classical cardiovascular disease risk factors associate with vascular function and morphology in rheumatoid arthritis: a six-year prospective study

Introduction

Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD). An early manifestation of CVD is endothelial dysfunction which can lead to functional and morphological vascular abnormalities. Classical CVD risk factors and inflammation are both implicated in causing endothelial dysfunction in RA. The objective of the present study was to examine the effect of baseline inflammation, cumulative inflammation, and classical CVD risk factors on the vasculature following a six-year follow-up period.

Methods

A total of 201 RA patients (155 females, median age (25th to 75th percentile): 61 years (53 to 67)) were examined at baseline (2006) for presence of classical CVD risk factors and determination of inflammation using C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). At follow-up (2012) patients underwent assessments of microvascular and macrovascular endothelium-dependent and endothelium-independent function, along with assessment of carotid atherosclerosis. The CRP and ESR were recorded from the baseline study visit to the follow-up visit for each patient to calculate cumulative inflammatory burden.

Results

Classical CVD risk factors, but not RA disease-related inflammation, predicted microvascular endothelium-dependent and endothelium-independent function, macrovascular endothelium-independent function and carotid atherosclerosis. These findings were similar in a sub-group of patients free from CVD, and not receiving non-steroidal anti-inflammatory drugs, cyclooxygenase 2 inhibitors or biologics. Cumulative inflammation was not associated with microvascular and macrovascular endothelial function, but a weak association was apparent between area under the curve for CRP and carotid atherosclerosis.

Conclusions

Classical CVD risk factors may be better long-term predictors of vascular function and morphology than systemic disease-related inflammation in patients with RA. Further studies are needed to confirm if assessments of vascular function and morphology are predictive of long-term CV outcomes in RA.     

The role of inflammation and cardiovascular disease risk on microvascular and macrovascular endothelial function in patients with rheumatoid arthritis: a cross-sectional and longitudinal study

Introduction

Rheumatoid arthritis (RA) is associated with an increased risk for cardiovascular disease (CVD), and it has been postulated that RA disease-related inflammation contributes to endothelial dysfunction. The aim of the present work was to examine predictors (RA-related and CVD risk factors) and anti-tumor necrosis factor-alpha (anti-TNF-α) treatment effects on endothelial function in different vascular beds.

Methods

Microvascular endothelial function (laser Doppler imaging with iontophoresis of acetylcholine and sodium-nitroprusside), and macrovascular endothelial function (flow-mediated dilatation and glyceryl-trinitrate-mediated dilatation) were analyzed in parallel with disease activity. Individual CVD risk factors and global CVD risk were assessed cross-sectionally in 99 unselected RA patients and longitudinally (baseline, 2 weeks, and 3 months) in 23 RA patients commencing anti-TNF-α therapy.

Results

In this cross-sectional study, regression analyses revealed that markers of RA disease-related inflammation were not associated with microvascular or macrovascular endothelium-dependent function (P > 0.05); global CVD risk inversely correlated with microvascular endothelium-dependent function (P < 0.01) and with macrovascular endothelium-independent function (P < 0.01). In the longitudinal study, only microvascular endothelium-dependent function showed an improvement after 2 weeks of anti-TNF-α treatment when compared with baseline (437% ± 247% versus 319% ± 217%; P = 0.001), but no association was evident between change in endothelial function and change in inflammatory markers.

Conclusions

Classical CVD risk may influence endothelial function more than disease-related markers of inflammation in RA. Classical CVD risk factors and anti-TNF-α medication have different effects on microvascular and macrovascular endothelial function, suggesting that combined CVD-prevention approaches may be necessary. Prospective studies examining whether assessments of vascular function are predictive of long-term CV outcomes in RA are required.     

Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study

Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease (CVD). This study investigates possible associations between CVD and the use of conventional disease-modifying antirheumatic drugs (DMARDs) in RA. Using a case control design, 613 RA patients (5,649 patient-years) were studied, 72 with CVD and 541 without CVD. Data on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first cardiovascular event or the end of the follow-up period. The dataset was categorized according to DMARD use: sulfasalazine (SSZ), hydroxychloroquine (HCQ) or methotrexate (MTX). Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD group. Patients who never used SSZ, HCQ or MTX were used as a reference group. MTX treatment was associated with a significant CVD risk reduction, with ORs (95% CI): 'MTX only', 0.16 (0.04 to 0.66); 'MTX and SSZ ever', 0.20 (0.08 to 0.51); and 'MTX, SSZ and HCQ ever', 0.20 (0.08 to 0.54). The risk reductions remained significant after additional correction for the presence of rheumatoid factor and erosions. After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever' and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. Rheumatoid factor positivity and erosions both increased CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively. MTX and, to a lesser extent, SSZ were associated with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX. We hypothesize that DMARD use, in particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and subsequently clinically overt CVD.     

Rheumatoid arthritis–associated autoantibodies in non–rheumatoid arthritis patients with mucosal inflammation: a case–control study

IntroductionRheumatoid arthritis–associated autoantibodies (RA-AAB) can be present in serum years before clinical onset of rheumatoid arthritis (RA). It has been hypothesized that initiation of RA-AAB generation occurs at inflamed mucosal surfaces, such as in the oral cavity or lungs. The aim of this study was to assess systemic presence of RA-AAB in patients without RA who had oral or lung mucosal inflammation.MethodsThe presence of RA-AAB (immunoglobulin A [IgA] and IgG anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), IgM and IgA rheumatoid factor (RF), IgG anti-carbamylated protein antibodies and IgG and IgA anti-citrullinated peptide antibodies against fibrinogen, vimentin and enolase) were determined in sera of non-RA patients with periodontitis (PD, n = 114), bronchiectasis (BR, n = 80) or cystic fibrosis (CF, n = 41). Serum RA-AAB levels were compared with those of periodontally healthy controls (n = 36). Patients with established RA (n = 86) served as a reference group. Association of the diseases with RA-AAB seropositivity was assessed with a logistic regression model, adjusted for age, sex and smoking.ResultsLogistic regression analysis revealed that IgG anti-CCP seropositivity was associated with BR and RA, whereas the association with PD was borderline significant. IgA anti-CCP seropositivity was associated with CF and RA. IgM RF seropositivity was associated with RA, whereas the association with BR was borderline significant. IgA RF seropositivity was associated with CF and RA. Apart from an influence of smoking on IgA RF in patients with RA, there was no influence of age, sex or smoking on the association of RA-AAB seropositivity with the diseases. Anti-CarP levels were increased only in patients with RA. The same held for IgG reactivity against all investigated citrullinated peptides.ConclusionAlthough overall levels were low, RA-AAB seropositivity was associated with lung mucosal inflammation (BR and CF) and may be associated with oral mucosal inflammation (PD). To further determine whether mucosal inflammation functions as a site for induction of RA-AAB and precedes RA, longitudinal studies are necessary in which RA-AAB of specifically the IgA isotype should be assessed in inflamed mucosal tissues and/or in their inflammatory exudates.     

Knowledge-based analysis of genetic associations of rheumatoid arthritis to inform studies searching for pleiotropic genes: a literature review and network analysis

IntroductionPleiotropy describes the genetic effect of a single gene on multiple phenotypic traits. Gene variants directly affect the normal processes of a series of physiological and biochemical reactions, and therefore cause a variety of diseases traits to be changed accordingly. Moreover, a shared genetic susceptibility mechanism may exist between different diseases. Therefore, shared genes, with pleiotropic effects, are important to understand the sharing pathogenesis and hence the mechanisms underlying comorbidity.MethodsIn this study, we proposed combining genome-wide association studies (GWAS) and public knowledge databases to search for potential pleiotropic genes associated with rheumatoid arthritis (RA) and eight other related diseases. Here, a GWAS-based network analysis is used to recognize risk genes significantly associated with RA. These RA risk genes are re-extracted as potential pleiotropic genes if they have been proved to be susceptible genes for at least one of eight other diseases in the OMIM or PubMed databases.ResultsIn total, we extracted 116 potential functional pleiotropic genes for RA and eight other diseases, including five hub pleiotropic genes, BTNL2, HLA-DRA, NOTCH4, TNXB, and C6orf10, where BTNL2, NOTCH4, and C6orf10 are novel pleiotropic genes identified by our analysis.ConclusionsThis study demonstrates that pleiotropy is a common property of genes associated with disease traits. Our results ascertained the shared genetic risk profiles that predisposed individuals to RA and other diseases, which could have implications for identification of molecular targets for drug development, and classification of diseases.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0715-1) contains supplementary material, which is available to authorized users.     

Carotid artery plaque in women with rheumatoid arthritis and low estimated cardiovascular disease risk: a cross-sectional study

IntroductionWe previously reported that most patients with rheumatoid arthritis (RA) and moderate cardiovascular disease (CVD) risk according to the Systematic COronary Evaluation score (SCORE) experience carotid artery plaque. In this study, we aimed to identify patient characteristics that can potentially predict carotid plaque presence in women with RA and a concurrent low CVD risk according to the SCORE.MethodsA cohort of 144 women with an evaluated low risk of CVD (SCORE value of zero) was assembled amongst 550 consecutive patients with RA that underwent CVD risk factor recording and carotid artery ultrasound. Participants had no established CVD, moderate or severe chronic kidney disease, or diabetes. We assessed carotid plaque(s) presence and its associated patient characteristics.ResultsCarotid artery plaque was present in 35 (24.3%) of women with RA. Age, the number of synthetic disease-modifying agents (DMARDs) and total cholesterol concentrations were independently associated with plaque in multivariable stepwise backward regression analysis (odds ratio (95% confidence interval) = 1.15 (1.07 to 1.24), P <0.0001, 1.51 (1.05 to 2.17), P = 0.03 and 1.66 (1.00 to 2.73) P = 0.04), respectively). The area under the curve (AUC) of the receiver operating curve (ROC) for the association with plaque was 0.807 (P <0.0001), 0.679 (P = 0.001) and 0.599 (P = 0.08) for age, total cholesterol concentrations and number of synthetic DMARDs used, respectively. The optimal cutoff value in predicting plaque presence for age was 49.5 years with a sensitivity and specificity of 74% and 75%, respectively, and for total cholesterol concentration, it was 5.4 mmol/l with a sensitivity and specificity of 63% and 70%, respectively. The plaque prevalence was 37.5% in patients (n = 80; 55.6%) with age >49.5 years or/and total cholesterol concentration of >5.4 mmol/l, respectively, compared to only 7.8% in those (n = 64; 44.4%) with age ≤49.5 years or/and total cholesterol concentration of ≤5.4 mmol/l, respectively.ConclusionsApproximately one-third of women with RA who experience a low SCORE value and are aged >49.5 years or/and have a total cholesterol concentration of >5.4 mmol/l, experience high-risk atherosclerosis, which requires intensive CVD risk management.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0576-7) contains supplementary material, which is available to authorized users.     

A Genetic Variant in Proline and Serine Rich Coiled-Coil 1 Gene Is Associated with the Risk of Cardiovascular Disease

Background:Cardiovascular disease is one of the most common causes of morbidity and mortality worldwide. The Proline and Serine Rich Coiled-Coil 1 gene in 1p13.3 locus has been reported to be associated with low density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD). The objective of this study was to investigate the association between the rs599839 polymorphism of the Proline and Serine Rich Coiled-Coil 1 (PSRC1) gene with CVD outcomes in a population sample recruited as part of the Mashhad-Stroke and Heart-Atherosclerotic-Disorders (MASHAD) cohort.Methods:Five hundred and nine individuals who had an average follow-up period of 10 years were enrolled as part of the MASHAD cohort. DNA was extracted and genotyped using the TaqMan-real-time-PCR based method.Results:The study found individuals with GA/GG genotypes were at a higher risk of CVDs (OR= 4.7; 95% CI, 2.5-8.7; p< 0.001) in comparison to those with AA genotype; however, the result was not significant for GG genotype data.Conclusion:The results suggest that the GA/GG genotypes of the PSRC1gene locus were at increased risk of CVD in a representative population-based cohort, demonstrating further functional analysis to discover the value of emerging marker as a risk stratification biomarker to recognize high risk cases.Key Words: Cardiovascular diseases, Cohort studies, Genetic Polymorphism, PSRC1 Gene