Identifying Vulnerable Plaque in Rheumatoid Arthritis

识别类风湿关节炎中的易损斑块

• 批准号: 8164542
• 负责人: Kimberly P Liang
• 金额: $ 12.57万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8164542
• 关键词: Acute; Area; Arterial Fatty Streak; Autoantibodies; Biology; Blood Vessels; C-reactive protein; CD40 Ligand; Cardiology; Cardiovascular Diseases; Carotid Arteries; Carotid Artery Plaques; Cell Adhesion Molecules; Center for Translational Science Activities; Clinic; Clinical; Clinical Research; Clinical Sciences; Cohort Studies; Collection; Contrast Media; Coronary; Detection; Disease; Doctor of Philosophy; Endothelial Cells; Endothelium; Environment; Evaluation; Event; Funding; Future; Goals; Heart; Image; Imaging Techniques; Inflammation; Inflammatory; Institutes; Investigation; Lead; Leukocyte Adhesion Molecules; Leukocyte-Adhesion Receptors; Leukocytes; Longitudinal Studies; Matrix Metalloproteinases; Measures; Medical center; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Microbubbles; Patients; Persons; Physicians; Prevention strategy; Protocols documentation; Publishing; Quality of life; Recruitment Activity; Research; Research Project Grants; Rheumatism; Rheumatoid Arthritis; Risk; Risk Factors; Rupture; Scientist; Serum; Stratification; Surface; Techniques; Thick; Training; Translational Research; Ultrasonography; United States National Institutes of Health; Universities; Vascular Diseases; Vasculitis; Work; abstracting; atherogenesis; cardiovascular disorder risk; career; cohort; comparative effectiveness; density; effectiveness research; field study; high risk; human subject; imaging modality; indexing; innovation; intima media; mortality; multidisciplinary; neovascularization; novel; patient population; premature; premature atherosclerosis; prospective; research study; vasa vasorum

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. PUBLIC HEALTH RELEVANCE: Identifying Vulnerable Plaque in Rheumatoid Arthritis Project Narrative 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 CVD risk factors alone. It is also known that widespread inflammation, like that experienced by RA patients, is also associated with a more vulnerable atherosclerotic plaque, which is more prone to rupture and result in CVD events like heart attacks. Moreover, RA-related differences in plaque vulnerability have not been extensively studied. Traditional imaging techniques, like carotid ultrasound without contrast, fail to detect plaque vulnerability. We will test a novel, innovative microbubble-enhanced contrast agent in detecting vulnerable plaque and understanding its role in CVD risk in the RA patient.

描述（由申请人提供）：识别风湿性关节炎中的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）和死亡率的较高风险相关，这不能仅用传统的CV风险因素来解释。此外，在全身炎症程度较高的RA患者中，CV死亡风险较高。已知全身性炎症也与动脉粥样硬化斑块易损性相关。RA相关的斑块易损性差异尚未得到广泛研究。传统的成像方式无法检测斑块易损性的特征，并且与RA中疾病活动增加无关，尽管已知RA中炎症和疾病活动与CVD风险之间存在相关性。最近，血管中的新血管形成增加已被确定为炎症和斑块易损性的共同特征，并且已被发现是未来CV事件的独立预测因子。这表明，RA中过多的CVD风险可能是由疾病相关因素引起的，这些因素导致以血管新生血管增加为特征的易损动脉粥样硬化斑块，而传统的成像方式无法评估。因此，我们假设RA患者比非RA患者更可能发展与急性CVD事件相关的易损动脉粥样硬化斑块。微泡造影剂增强颈动脉超声（CU）是一种新的成像技术，已被验证在检测易损斑块的措施，即增加外膜血管密度。我们建议的具体目标是：1。确定在控制CV风险因素后，与非RA对照受试者相比，RA患者的颈动脉外膜血管密度是否增加。2.通过CU评估，确定传统CV风险因素和炎症或RA相关斑块易损性调节剂是否与颈动脉外膜血管密度增加相关。3.通过CU评估，确定RA中疾病活动度指标增加是否与颈动脉外膜血管密度增加相关。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莫兰，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，系统收集疾病活动指数、生活质量指标和储存血清。对照受试者将从最近在UPMC完成NIH资助的前瞻性纵向队列研究（心脏策略集中于风险评估（心脏评分）（PI：Steven Reis，MD））中的CU研究的低风险受试者中确定。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，其技术人员接受过临床和转化科学研究所（CTSI）研究方案中CU和其他人类受试者血管研究综合评估的培训。丰富的机构环境和梁博士组建的RA（莫兰博士）和心脏病学/血管成像（Reis，Villanueva和Mulukutla博士）专家指导团队证明了K23指导的以患者为导向的研究职业发展奖的资金适用性。梁博士是进行拟议调查的理想人选。她以前曾在马约诊所完成研究项目，在Sherine Gabriel和Eric Matteson博士的指导下调查RA中CVD的风险。她在风湿性疾病和血管炎中的过早动脉粥样硬化领域的报告和出版工作方面有着良好的记录。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易损斑块的一种手段，为未来的多学科研究开发炎性血管疾病的纵向队列，并成为风湿性疾病中血管生物学专业知识的独立医生科学家。拟议的工作遵循无缝沿着她以前的贡献，在RA过早心血管疾病的研究领域，与创新的概念，RA的人可能会发展更脆弱的动脉粥样硬化斑块，如可视化的新CU成像技术，比没有RA的人。在RA患者中检测亚临床易损斑块的重要临床意义包括可能的早期CVD风险分层和预防策略，以帮助降低该高危患者人群中临床CVD事件和死亡率的过度负担。 公共卫生关系：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CVD风险因素来解释。还已知广泛的炎症，如RA患者所经历的，也与更脆弱的动脉粥样硬化斑块相关，其更容易破裂并导致CVD事件，如心脏病发作。此外，RA相关的斑块易损性差异尚未得到广泛研究。传统的成像技术，如无造影剂的颈动脉超声，无法检测斑块的脆弱性。我们将测试一种新的，创新的微泡增强造影剂在检测易损斑块和了解其在RA患者CVD风险中的作用。