Identifying Vulnerable Plaque in Rheumatoid Arthritis

摘要类风湿性关节炎（RA）与较高的心血管疾病（CVD）风险和死亡率相关，这并不能仅用传统的心血管危险因素来解释。此外，在系统性炎症程度较高的RA患者中，CV死亡风险更高。众所周知，全身炎症也与动脉粥样硬化斑块易感性有关。ra相关的斑块易感性差异尚未得到广泛研究。尽管已知炎症和疾病活动性与类风湿关节炎CVD风险之间存在关联，但传统成像方式无法检测斑块易损特征，并且与类风湿关节炎疾病活动性增加没有相关性。最近，血管新生血管的增加已被确定为炎症和斑块易感性的共同特征，并且已被发现是未来心血管事件的独立预测因子。这表明，RA中CVD风险过高可能是由疾病相关因素引起的，这些因素导致易损的动脉粥样硬化斑块，其特征是血管新生血管增加，而传统的成像方式无法评估这一点。因此，我们假设RA患者比非RA患者更容易形成易损的动脉粥样硬化斑块，这与急性CVD事件相关。微泡对比增强颈动脉超声（CU）是一种新型的成像技术，已被证实可用于检测易损斑块，即血管外血管密度的增加。我们建议的具体目标是：1。在控制CV危险因素后，确定RA患者颈动脉血管外血管密度是否高于无RA的对照组。2. 通过CU评估，确定传统的心血管危险因素和斑块易损性的炎症或ra相关调节剂是否与颈动脉血管外血管密度增加有关。3. 通过CU评估，确定RA患者疾病活动度的增加是否与颈动脉血管外血管密度的增加有关。拟议的研究将从正在进行的nih资助的RA比较有效性研究（RACER）研究中招募RA受试者（pi: Larry Moreland， MD和Marc Levesque， MD, PhD）在匹兹堡大学医学中心（UPMC）。RACER研究是一项RA患者的纵向研究，系统收集疾病活动指数、生活质量测量和储存血清。对照受试者将从最近完成美国国立卫生研究院资助的前瞻性纵向队列研究的低风险受试者中确定，心脏策略集中于风险评估（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）进行CU研究，VCTRC是一个最先进的血管研究单位，其技术人员经过临床和转化科学研究所（CTSI）的培训，在研究方案中对人类受试者进行CU和其他血管研究的综合评估。这个丰富的机构环境和梁博士召集的RA （Moreland博士）和心脏病学/血管成像(dr。Reis， Villanueva和Mulukutla)证明了K23指导患者导向研究职业发展奖的资金适用性。梁博士是开展这项研究的理想人选。她之前在梅奥诊所完成了研究项目，调查类风湿关节炎中心血管疾病的风险。Sherine Gabriel和Eric mattson。她在风湿性疾病和血管炎的过早动脉粥样硬化领域有很强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，作为研究风湿性疾病和血管炎中的易损斑块的手段，为未来的多学科研究发展炎症性血管疾病的纵向队列，并成为一名具有风湿性疾病血管生物学专业知识的独立内科科学家。拟议的工作与她之前在类风湿关节炎的早期CVD研究领域的贡献紧密相关，她提出了一个创新的概念，即类风湿关节炎患者可能比非类风湿关节炎患者更容易出现动脉粥样硬化斑块，这是通过新型CU成像技术实现的。在RA患者中检测亚临床易损斑块具有重要的临床意义，包括可能的早期CVD风险分层和预防策略，以帮助降低这一高危患者群体的临床CVD事件和死亡率的额外负担。

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.