Long-Term Endothelial Effects of COVID-19 in Obesity

项目摘要/摘要 冠状病毒2019(新冠肺炎)已在全球感染2900多万人。虽然大多数人 症状轻微，肥胖等因素的存在可确定为特别高危人群 个体对重症新冠肺炎的发生发展有影响。重度新冠肺炎的特点是郁郁 炎症和血管功能障碍，但对心血管的长期影响尚不清楚。我们假设 新冠肺炎感染对血管内皮细胞功能具有广泛和持久的有害影响，包括 肥胖者细胞衰老和炎症的分子途径。我们建议 前瞻性研究100名有新冠肺炎感染史和50岁的肥胖和非肥胖者 性别匹配的对照组。为了进一步了解血管功能障碍的潜在机制，我们将 遵循三条相关调查路线：在目标1中，我们将研究新冠肺炎对血管床位的影响 包括外周和冠状动脉微血管功能。在目标2中，我们将调查 新冠肺炎与血管内皮细胞活化和衰老的循环蛋白质组学研究 对新鲜分离的人内皮细胞进行基因表达分析，并辅之以询问 靶向内皮细胞通路。在目标3中，我们将进行一项前瞻性纵向观察研究，以 观察新冠肺炎对外周和冠脉微血管功能及运动轨迹的影响 6个月病程内皮细胞表型。这项建议利用了一种独特的、经验丰富的 拥有肥胖相关心血管疾病、血管内皮细胞和 衰老生物学、冠状动脉微血管功能障碍和生物信息学。重要的是，我们的调查小组已经 在两个医疗中心成功招募少数族裔参与者的记录。使用一个 严重的新冠肺炎负担在种族和少数民族之间不成比例，我们将是独一无二的 定位于在探索性分析中检查种族/民族差异。这些研究有可能 对驱动内皮细胞炎症和心血管后果的机制提供重要见解 并将为今后着眼于长期的研究奠定基础 心血管并发症及治疗策略。

Project Summary/Abstract Coronavirus 2019 (COVID-19) has infected more than 29 million globally. While the majority of individuals experience mild symptoms, the presence of obesity among other factors identifies a particularly high-risk group of individuals for development of severe COVID-19. Severe COVID-19 is characterized by exuberant inflammation and vascular dysfunction, but long-term cardiovascular effects remain unclear. We hypothesize that COVID-19 infection has widespread and long-lasting deleterious effects on endothelial function, including molecular pathways of cellular senescence and inflammation among obese individuals. We propose to prospectively study 100 obese and non-obese individuals with history of COVID-19 infection and 50 age- and sex-matched controls. To gain further insights into underlying mechanisms of vascular dysfunction, we will pursue three related lines of investigation: In Aim 1, we will study the effect of COVID-19 across vascular beds including peripheral and coronary microvascular function. In Aim 2, we will investigate the association of COVID-19 and molecular pathways of endothelial activation and senescence using circulating proteomic profiling, gene expression profiling of freshly isolated human endothelial cells, complemented by interrogation of targeted endothelial pathways. In Aim 3, we will conduct a prospective longitudinal observational study to examine the effect of COVID-19 on trajectories of peripheral and coronary microvascular function and endothelial phenotype over the course of 6 months. This proposal leverages a unique and highly experienced multidisciplinary team of investigators with expertise in obesity-related cardiovascular disease, endothelial and aging biology, coronary microvascular dysfunction, and bioinformatics. Importantly, our investigative team has a track record of successfully enrolling minority participants across two medical centers. With a disproportionate burden of severe COVID-19 among racial and ethnic minority groups, we will be uniquely positioned to examine race/ethnic differences in exploratory analyses. These studies have the potential to provide important insights into mechanisms driving endothelial inflammation and cardiovascular consequences of COVID-19 among obese individuals and will lay the foundation for future studies focused on long-term cardiovascular complications and therapeutic strategies.