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

项目摘要/摘要 儿童起病的系统性红斑狼疮(PSLE)具有心血管疾病的高风险 通过慢性炎症和过早的动脉粥样硬化，但反应灵敏的替代结果指标 目前缺乏心血管(CV)风险。夜间血压(NBP)下降的消失 血压监测(ABPM)在pSLE儿童中很常见，作为一种早期的、可修改的、 血管健康的非侵入性测量。NBP下降的消失可以预测成年人的心血管事件，可能是一种 内皮功能障碍的标志，这是动脉粥样硬化结构变化的先兆。更重要的是， 与NBP下降相关的心血管风险在肾素-血管紧张素系统(RAS)中可能是可逆的 封锁。为了确定NBP下降在pSLE中作为结局指标的作用，本提案寻求 首先了解心血管风险增加的哪些机制有助于减少NBP下降，以及 NBP下降如何与内皮功能或其他亚临床动脉粥样硬化指标相关。反应灵敏 结果措施将使改善血管健康的干预措施的研究成为可能。潜在药理作用 干预措施包括RAS阻断，它以内皮功能为目标，而不会增加来自 免疫抑制。然而，缺乏数据来指导在pSLE中使用RAS阻滞剂。 该提案的目标是：1)确定造成NBP递减损失的主要因素 在pSLE中；2)确定NBP下降的消失是否与内皮功能障碍有关 作为心血管风险标记或潜在的治疗目标；以及3)确定RAS阻断是否与 降低青少年或青壮年SLE患者发生心血管事件的风险。我们将表演一场前瞻性的 系统性红斑狼疮儿童接受系列ABPM、外周血管内皮细胞功能测试的纵向研究 和全面的血管特征。我们还将使用高级 药物流行病学方法评估RAS受体阻滞剂对心血管事件风险的影响 在一个大型电子健康记录数据库中对青少年和成年人进行了调查。 K23候选人张博士在加州大学获得临床流行病学理学硕士学位 宾夕法尼亚州(UPenn)，并已被任命为儿童医院的助理教授 费城(CHOP)。拟议的研究和培训计划将为她提供必要的经验 开展以患者为中心的前瞻性研究，扩展她在非侵入性血管评估方面的专业知识 和心血管结果研究，并提供药物流行病学方法方面的高级培训，以 成为早期识别和预防儿童期心血管并发症的专家 风湿病。她建立了一支强大的多学科指导团队，与广大的 在CHOP和UPenn的资源，将促进拟议的工作，并促进她作为 心脏病和儿科风湿病领域的独立研究员和领导者。

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.