Inflammation and Cardiovascular Disease in Rheumatoid Arthritis

摘要 患有类风湿性关节炎（RA）的个体发生心力衰竭（HF）和HF的风险增加50%。 相关的发病率和死亡率比非RA对照组。即使在调整冠状动脉粥样硬化后，这种风险仍然存在。 动脉疾病，这意味着RA固有的免疫和炎症因子有助于增加 HF的风险。我们的总体假设是，心肌炎症和微血管缺血是普遍存在的， 类风湿性关节炎患者，是通过抗体介导的心肌瓜氨酸化蛋白，促进左心室功能受损， 心室（LV）结构/功能，并与RA治疗减弱。事实上，在128例RA患者中， 接受[18氟脱氧葡萄糖]正电子发射计算机断层扫描（FDG PET-CT）的临床CVD患者 (the RHYTHM研究），我们观察到35%的FDG摄取（炎症）和受损的心肌血流 储备（MFR）为29%。心肌炎症和MFR受损均与临床 和RA疾病活动的实验室测量;受损的MFR也与较高的LV质量相关， 已知的HF前体。这些数据表明，心肌炎症和受损的MFR部分介导， 早于临床HF的LV结构/功能的早期变化;但在以下方面确认这些关系至关重要： 纵向研究。RA中介导心肌病理的近端事件尚不清楚。我们假设 抗瓜氨酸化心肌蛋白（APCA）的抗体在一定程度上介导了这种异常的心肌 表型（炎症和MFR受损），导致心肌重塑，并最终导致功能性 下降我们的初步数据表明，在一种新的心肌梗死患者中，30%的RHYTHM血清具有血清反应性。 蛋白质阵列支持这一假设。一个相关的问题是肿瘤坏死抑制剂（TNFi）是否影响 心肌炎症这不是一个无关紧要的问题，因为TNFi与HF增加有关 非RA HF患者的住院率和死亡率以及RA患者的HF风险仍不清楚， 使用.在下一个资助期内，我们寻求延长RHYTHM队列目标1和3的研究期， 并利用独立资助的研究（目标2），以调查以下目标： 1)确定基线时心肌病理学的成像指标（炎症、受损 MFR）预测LV结构和功能测量的纵向（不利）变化超过4-6 在基线时无临床心血管疾病（CVD）的RA患者中， 2)为了确定，在目前正在招募的NIH-NIAMS资助的随机临床试验（TARGET）中， 研究），如果RA治疗减少心肌炎症。 3)确定RHYTHM参与者对瓜氨酸化心肌抗原的血清反应性是否 与基线心肌炎症和MFR受损和/或与 LV结构/功能参数。这些研究将促进对机制的理解， 有助于并减轻RA心肌功能障碍的风险增加。

ABSTRACT Individuals with rheumatoid arthritis (RA) are at 50% greater risk for developing heart failure (HF) and HF- associated morbidity and mortality than non-RA controls. This risk persists even after adjustment for coronary artery disease, implying that immunologic and inflammatory factors intrinsic to RA contribute to the increased risk of HF. Our overall hypothesis is that myocardial inflammation and microvascular ischemia are prevalent in RA patients, are mediated by antibodies to myocardial citrullinated proteins, promote impairment of left ventricular (LV) structure/function, and are attenuated with RA therapies. Indeed, in 128 RA patients without clinical CVD who underwent [18fluoro-deoxyglucose] positron emission-computed tomography (FDG PET-CT) (the RHYTHM study), we observed FDG uptake (inflammation) in 35% and impaired myocardial blood flow reserve (MFR) in 29%. Both myocardial inflammation and impaired MFR were strongly associated with clinical and laboratory measures of RA disease activity; impaired MFR was also associated with higher LV mass, a known precursor of HF. These data suggest that myocardial inflammation and impaired MFR mediate, in part, early changes in LV structure/function that predate clinical HF; but it is critical to confirm these relationships in longitudinal studies. Proximal events that mediate myocardial pathology in RA are unknown. We hypothesize that antibodies against citrullinated myocardial proteins (APCAs) mediate, in part, this abnormal myocardial phenotype (inflammation and impaired MFR), leading to myocardial remodeling and ultimately to functional decline. Our preliminary data demonstrating seroreactivity in 30% of RHYTHM sera in a novel myocardial protein array support this hypothesis. A related question is whether tumor necrosis inhibitors (TNFi’s) affect myocardial inflammation. This is a far from insignificant question as TNFi’s were associated with increased HF hospitalizations and death in non-RA HF patients and their risk for HF in RA is still unclear despite widespread use. In the next funding period, we seek to extend the study period for the RHYTHM cohort for aims 1 and 3, and to utilize an independently funded study (TARGET) for aim 2, in order to investigate the following aims: 1) To determine if imaging indicators of myocardial pathology at baseline (inflammation, impaired MFR) are predictive of longitudinal (adverse) change in measures of LV structure and function over 4-6 years in RA patients without clinical cardiovascular disease (CVD) at baseline. 2) To determine, in a currently enrolling NIH-NIAMS funded randomized clinical trial (the TARGET study), if RA therapies reduce myocardial inflammation. 3) To determine if seroreactivity to citrullinated myocardial antigens in RHYTHM participants is associated with baseline myocardial inflammation and impaired MFR and/or with change over time in parameters of LV structure/function. These investigations will advance understanding of mechanisms that contribute to and mitigate increased risk of myocardial dysfunction in RA.