With the K24 Mid-Career Investigator Award I would build a new patient-oriented research and training program in rheumatic disease outcomes research and specifically study molecular, inflammatory, and modifiable risk factors associated with early atherosclerotic vascular disease (ASVD) in Systemic Lupus Erythematosus (SLE). SLE is associated with 50-fold greater risk of early onset cardiovascular morbidity and mortality that is not explained by traditional risk factors. Systemic inflammation is a central feature of both ASVD and SLE disease expression. Impaired endothelium-dependent vasodilatation, the earliest manifestation of ASVD, occurs earlier than detectable structural changes. Traditional cardiac risk factors and inflammation are hypothesized to confer risk by augmenting oxidative stress in the endothelium, which leads to endothelial dysfunction, decreased nitrous oxide (NO) bioavailability and the development of ASVD. Early ASVD in this study will be defined by vascular phenotype according to impaired flow-mediated vasodilatation (FMD) of the brachial artery and pulse wave amplitude-reactive hyperemia (PWA-RH) measures of endothelial dysfunction, and by increased carotid intima-media thickness (IMT). We hypothesize that specific endothelial nitric oxide synthase (eNOS;NOS3), inducible nitric oxide synthase (iNOS;NOS2), angiotensin converting enzyme (ACE), interleukin-6 (IL-6), E-Selectin, P-Selectin, and PECAM alleles are surrogate markers that modulate predisposition of the endothelium to oxidative stress and increase the risk of endothelial dysfunction.
Specific Aims are to: 1) to establish a clinical research and training program in patient-oriented rheumatic diseases outcomes research. 2) To develop a comprehensive research program to study risk factors for early arteriosclerosis in SLE;a) To determine the prevalence of a high-risk vascular phenotype using FMD, PWA-RH, and carotid IMT in a cohort of 200 SLE patients;b) To establish a repository of biologic samples of serum, plasma, and DMA from 200 well-characterized SLE patients with vascular phenotype determined by FMD, PWA-RH and IMT;and c) To identify the most predictive markers of a high-risk vascular phenotype in SLE evaluating an array of genetic markers, inflammatory markers, traditional risk factors, disease activity measures, and environmental factors. The proposed study leverages an existing SLE registry with >1100 validated SLE cases to recruit 200 female, premenopausal SLE patients for vascular studies, cardiovascular risk factor and disease activity assessment, and blood draw to collect plasma, serum, and buffy coat for storage for future analyses. Accelerated ASVD has been recognized as a serious complication. Of SLE for at least three decades. Improved understanding of genetic factors and the mechanism of inflammation and ASVD in SLE will facilitate the development of disease-specific strategies for the prevention and/or amelioration of accelerated ASVD risk in SLE and could provide insights into the mechanisms of inflammation and ASVD in the general population.
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