Cardiovascular health assessment & outcomes of systemic lupus erythematosus: bridging pediatric and adult- onset disease

项目总结/摘要 儿童型系统性红斑狼疮（pSLE）具有高风险的心血管疾病介导 慢性炎症和过早的动脉粥样硬化，但响应替代结果的措施， 心血管（CV）风险目前缺乏。夜间血压（NBP）下降的丧失 血压监测（ABPM）在pSLE儿童中很常见，并有可能作为一种早期的，可改变的， 非侵入性测量血管健康。NBP下降的丧失预测成人的CV事件，并且可能是 内皮功能障碍的标志物，其先于动脉粥样硬化的结构变化。更重要的是， 与NBP下降相关的心血管风险可能通过肾素-血管紧张素系统（RAS）逆转 封锁为了确定NBP下降作为pSLE结局指标的作用，本建议寻求 首先了解哪些心血管风险增加的机制导致NBP下降的损失， NBP下降如何与内皮功能或亚临床动脉粥样硬化的其他指标相关。响应 结果测量将使干预研究能够改善血管健康。潜在药理学 干预措施包括RAS阻断，其靶向内皮功能而不增加感染， 免疫抑制然而，缺乏数据来指导pSLE中RAS阻断剂的使用。 本建议的目标是：1）确定导致净BP下降的主要因素 在pSLE中; 2）确定NBP下降的丧失是否与内皮功能障碍相关， 作为CV风险标志物或潜在治疗靶点;和3）确定RAS阻断是否与心血管疾病相关。 降低青少年或年轻成人SLE患者的CV事件风险。我们将进行前瞻性的 入选接受系列ABPM、外周内皮功能检测的SLE儿童的纵向研究 和全面的血管概况我们还将使用先进的 评估RAS阻断对心血管事件风险影响的药物流行病学方法 在青少年和成年人中的一个大型电子健康记录数据库中。 K23候选人Chang博士完成了美国大学临床流行病学硕士学位， 宾夕法尼亚大学（宾夕法尼亚大学），并已被任命为助理教授在儿童医院的 费城（CHOP）。拟议的研究和培训计划将为她提供必要的经验 进行前瞻性的以患者为导向的研究，扩展她在无创血管评估方面的专业知识 和心血管结局研究，并提供药物流行病学方法的高级培训， 成为早期识别和预防儿童心血管并发症的专家 风湿病她建立了一个强大的多学科指导团队， 在CHOP和宾夕法尼亚大学的资源，将促进拟议的工作，并促进她的发展， 心脏病学和儿科风湿病学的独立研究者和领导者。

PROJECT SUMMARY/ABSTRACT Pediatric-onset systemic lupus erythematosus (pSLE) carries a high risk of cardiovascular disease mediated by chronic inflammation and premature atherosclerosis, but responsive surrogate outcome measures of cardiovascular (CV) risk are currently lacking. Loss of nocturnal blood pressure (NBP) decline by ambulatory blood pressure monitoring (ABPM) is common in children with pSLE, and has potential as an early, modifiable, non-invasive measure of vascular health. Loss of NBP decline predicts CV events in adults and may be a marker of endothelial dysfunction, which precedes structural changes in atherosclerosis. More importantly, cardiovascular risk associated with NBP decline is potentially reversible with renin-angiotensin-system (RAS) blockade. In order to determine the role of NBP decline as an outcome measure in pSLE, this proposal seeks to first understand which mechanisms of increased cardiovascular risk contribute to loss of NBP decline, and how NBP decline relates to endothelial function or other measures of subclinical atherosclerosis. Responsive outcome measures would enable studies of interventions to improve vascular health. Potential pharmacologic interventions include RAS blockade, which targets endothelial function without increasing infections from immune suppression. There is, however, a paucity of data to guide the use of RAS blockade in pSLE. The objectives of this proposal are to: 1) identify the major factors that contribute to loss of NBP decline in pSLE; 2) determine whether loss of NBP decline is associated with endothelial dysfunction and could serve as a CV risk marker or potential treatment target; and 3) determine whether RAS blockade is associated with a decreased risk of CV events in adolescents or young adults with SLE. We will perform a prospective longitudinal study of children with SLE recruited to undergo serial ABPM, peripheral endothelial function testing and comprehensive vascular profiles. We will also perform a retrospective analysis using advanced pharmacoepidemiologic methods to estimate the effect of RAS blockade on the risk of cardiovascular events among adolescents and adults in a large electronic health record database. K23 Candidate Dr. Chang completed a Master of Science in Clinical Epidemiology at the University of Pennsylvania (UPenn) and has been appointed as an Assistant Professor at the Children’s Hospital of Philadelphia (CHOP). The proposed research and training plan will provide her with the necessary experience conducting prospective patient-oriented research, expand her expertise in non-invasive vascular assessment and cardiovascular outcomes research, and provide advanced training in pharmacoepidemiologic methods, to become an expert in early identification and prevention of cardiovascular complications of child-onset rheumatic disease. She has established a strong multidisciplinary mentoring team that, together with the vast resources at CHOP and UPenn, will facilitate the proposed work and foster her development as an independent investigator and leader at the cross-section of cardiology and pediatric rheumatology.