Identifying Vulnerable Plaque in Rheumatoid Arthritis

描述(申请人提供)：在类风湿性关节炎中识别易损斑块摘要众所周知，类风湿性关节炎(RA)与心血管疾病(CVD)和死亡率的高风险相关，这不能仅用传统的心血管危险因素来解释。此外，在全身炎症程度较高的RA患者中，这种心血管死亡风险更高。已知全身性炎症也与动脉粥样硬化斑块易损性有关。斑块易损性与RA相关的差异还没有得到广泛的研究。传统的成像方法无法发现斑块易损性的特征，也没有与RA疾病活动增加相关，尽管炎症和疾病活动与RA的心血管疾病风险之间存在已知的关联。最近，血管新生血管增多被认为是炎症和斑块易损性的共同特征，并被发现是未来心血管事件的独立预测因子。这提示类风湿性关节炎患者过度的心血管风险可能是由疾病相关因素引起的，这些因素导致了脆弱的动脉粥样硬化斑块，其特征是血管新生血管的增加，这是传统的成像方法所不能评估的。因此，我们假设类风湿性关节炎患者比非类风湿性关节炎患者更有可能出现与急性心血管事件相关的易损性动脉粥样硬化斑块。微泡增强颈动脉超声(CU)是一种新的成像技术，已被用于检测易损斑块的测量，即外膜血管密度增加。我们建议的具体目的是：1.在控制心血管危险因素后，确定类风湿性关节炎患者的颈动脉外膜血管密度是否高于非类风湿性关节炎对照组。2.探讨CU评价颈动脉外膜血管密度增加是否与传统的心血管危险因素和斑块易损性的炎性或RA相关的调节因子有关。3.根据CU评估，确定RA疾病活动性措施增加是否与颈动脉外膜血管密度增加相关。这项拟议的研究将从匹兹堡大学医学中心(UPMC)正在进行的NIH资助的RA比较有效性研究(RACER)研究(PI：Larry Moland，MD和Marc Levesque，MD，PhD)中招募RA受试者。RACER研究是对RA患者的纵向研究，系统地收集疾病活动指数、生活质量测量和储存的血清。对照受试者将从最近在NIH资助的前瞻性纵向队列研究中完成CU研究的低风险受试者中确定，该研究名为UPMC的心脏策略专注于风险评估(心脏评分)(PI：Steven Reis，MD)。受试者将在血管临床和转化研究中心(VCTRC)接受CU研究，VCTRC是一个最先进的血管研究单位，技术人员接受过通过临床和转化科学研究所(CTSI)在研究方案中对CU和人类受试者的其他血管研究进行全面评估的培训。这种丰富的机构环境和梁博士集结的RA(摩兰博士)和心脏病学/血管成像(Reis、Villanueva和Mulukutla博士)专家导师团队证明了资助K23导师以患者为导向的研究职业发展奖是合适的。梁博士是开展这项拟议调查的理想人选。她之前在梅奥诊所完成了研究项目，在Sherine Gabriel博士和Eric Matteson博士的指导下调查RA的心血管疾病风险。她在风湿性疾病和脉管炎的过早动脉粥样硬化领域有很好的发表和发表工作的记录。她的短期和长期职业目标包括精通新型CU成像技术，以此作为研究风湿性疾病和脉管炎中脆弱斑块的一种手段，为未来的多学科研究开发炎症性血管疾病的纵向队列，以及成为一名在风湿性疾病中拥有血管生物学专业知识的独立内科科学家。这项拟议的工作顺应了她之前在RA早产CVD研究领域的贡献，提出了创新的概念，即通过新的CU成像技术显示，患有RA的人可能比没有RA的人发展出更脆弱的动脉粥样硬化斑块。检测RA患者亚临床易损斑块的重要临床意义包括可能的早期心血管风险分层和预防策略，以帮助降低这一高危患者群体中临床心血管事件的额外负担和死亡率。

DESCRIPTION (provided by applicant): Identifying Vulnerable Plaque in Rheumatoid Arthritis Abstract It is well established that rheumatoid arthritis (RA) is associated with a higher risk of cardiovascular disease (CVD) and mortality, which is not explained by traditional CV risk factors alone. Furthermore, this CV mortality risk is higher among RA patients with higher degrees of systemic inflammation. It is known that systemic inflammation is also associated with atherosclerotic plaque vulnerability. RA-related differences in plaque vulnerability have not been extensively studied. Traditional imaging modalities fail to detect features of plaque vulnerability and have not been correlated with increased disease activity in RA, despite the known association between inflammation and disease activity on CVD risk in RA. Recently, increased neovascularization in vasa vasorum has been identified as a common feature of inflammation and plaque vulnerability, and has been found to be an independent predictor of future CV events. This suggests that excess CVD risk in RA may be caused by disease-related factors that lead to vulnerable atherosclerotic plaque characterized by increased neovascularization of vasa vasorum, which is not assessed by traditional imaging modalities. Accordingly, we hypothesize that RA patients are more likely than non-RA patients to develop vulnerable atherosclerotic plaques that are associated with acute CVD events. Microbubble contrast-enhanced carotid ultrasound (CU) is a novel imaging technique that has been validated in detecting measures of vulnerable plaque, namely increased adventitial vasa vasorum density. The Specific Aims of our proposal are: 1. To determine whether patients with RA have an increased density of carotid artery adventitial vasa vasorum compared to control subjects without RA, after controlling for CV risk factors. 2. To determine whether both traditional CV risk factors and inflammatory or RA-related modulators of plaque vulnerability are associated with increased density of carotid artery adventitial vasa vasorum, as assessed by CU. 3. To determine whether increased disease activity measures in RA are associated with increased density of carotid artery adventitial vasa vasorum, as assessed by CU. The proposed study will recruit RA subjects from the ongoing NIH-funded RA Comparative Effectiveness Research (RACER) study (PIs: Larry Moreland, MD and Marc Levesque, MD, PhD) at the University of Pittsburgh Medical Center (UPMC). The RACER study is a longitudinal study of RA patients, with systematic collection of disease activity indices, quality-of-life measures, and stored serum. Control subjects will be identified from low-risk subjects who have recently completed CU studies in the NIH-funded prospective longitudinal cohort study, Heart Strategies Concentrating On Risk Evaluation (Heart SCORE) (PI: Steven Reis, MD) at UPMC. Subjects will undergo the CU studies at the Vascular Clinical and Translational Research Center (VCTRC), which is a state-of-the-art vascular studies unit with technicians trained in comprehensive assessments of CU and other vascular studies in human subjects in research protocols through the Clinical and Translational Science Institute (CTSI). This rich institutional environment and Dr. Liang's assembled mentoring team of experts in RA (Dr. Moreland) and cardiology/vascular imaging (Drs. Reis, Villanueva, and Mulukutla) demonstrate the suitability of funding for this K23 Mentored Patient-Oriented Research Career Development Award. Dr. Liang is an ideal candidate to carry out the proposed investigation. She has previously completed research projects at the Mayo Clinic investigating the risk of CVD in RA under the mentorship of Drs. Sherine Gabriel and Eric Matteson. She has a strong track record of presenting and publishing work in the areas of premature atherosclerosis in the rheumatic diseases as well as in vasculitis. Her short- and long-term career goals include becoming proficient in the novel CU imaging technique as a means to study vulnerable plaque in the rheumatic diseases and in vasculitis, developing a longitudinal cohort of inflammatory vascular diseases for future multidisciplinary studies, and becoming an independent physician-scientist with expertise in vascular biology within the rheumatic diseases. The proposed work follows seamlessly along her prior contributions to the field of study in premature CVD in RA, with the innovative concept that persons with RA may develop more vulnerable atherosclerotic plaque, as visualized by the novel CU imaging technique, than persons without RA. The significant clinical implications of detecting subclinical vulnerable plaque in patients with RA include possible early CVD risk stratification and prevention strategies, to help lower the excess burden of clinical CVD events and mortality in this high-risk patient population.