Phosphorus and Vitamin D Metabolism and Cardiovascular Outcomes: The multi-ethni

描述(由申请人提供)：不断发展的证据表明，磷过量和维生素D不足会导致心血管疾病(CVD)和过早死亡。磷过量直接将血管平滑肌组织转化为成骨样细胞，成骨细胞样细胞使内侧血管壁钙化。维生素D缺乏激活肾素-血管紧张素-醛固酮系统，刺激致动脉粥样硬化的细胞因子的表达，并直接促进心肌细胞的生长。现有知识中的重要空白限制了对人类矿物质代谢-心血管关系的充分理解。首先，目前对磷和维生素D代谢轴的确定是粗糙的，模糊了与心血管疾病预后的关系，并阻碍了转化为临床应用。第二，人类体内矿物质代谢紊乱可能促进CVD的CVD途径未得到完全评估。第三，磷和维生素D的代谢因种族/民族的不同而有很大差异，但有关矿物质代谢紊乱对心血管的影响的知识来自多样性有限的人群。这项建议的总体目标是确定在以社区为基础的多种族人口中，磷过量和维生素D缺乏与病理生理学相关的临床和亚临床心血管疾病结局的关系。我们将使用多个血清和尿液生物标记物来确定磷和维生素D代谢轴的特征，这些生物标记物来自之前从多种族动脉粥样硬化研究(MESA)的6736名参与者那里收集的基线样本。MESA提供了一个全面评估新的心血管风险因素的独特机会，因为其多种族抽样策略、在基线时排除临床心血管疾病、最先进的亚临床心血管测量以及可判定的心血管事件。我们假设，磷过量(血清磷、血清成纤维细胞生长因子-23和尿磷浓度较高)和维生素D缺乏(25-羟基维生素D浓度较低和甲状旁腺激素浓度较高)的生物标志物将与心血管事件、高血压和慢性肾脏疾病相关。我们进一步假设，磷过量和维生素D缺乏的生物标志物将与与矿物质代谢直接相关的亚临床心血管疾病测量相关：冠状动脉钙化、胸主动脉钙化、动脉僵硬和左心室质量。 公共卫生相关性：在工业化世界，心血管疾病(CVD)是导致男女死亡的主要原因。磷和维生素D代谢紊乱可能是CVD的新危险因素，并可能为预防或治疗干预提供新的机会。拟议的研究将确定在种族和民族多样化的人群中，磷过量和维生素D缺乏是否与临床相关的心血管疾病有关。研究结果将有助于阐明与心血管健康有关的磷和维生素D生物标志物的最佳血清浓度，并为针对矿物质代谢以预防和减少心血管疾病的临床试验提供信息。

DESCRIPTION (provided by applicant): Evolving evidence suggests that phosphorous excess and vitamin D insufficiency contribute to cardiovascular disease (CVD) and premature death. Phosphorous excess directly transforms vascular smooth muscle tissue into osteoblast-like cells, which calcify the medial vessel wall. Vitamin D insufficiency activates the renin-angiotensin-aldosterone system, stimulates atherogenic cytokine expression, and directly promotes cardiomyocyte growth. Important gaps in existing knowledge constrain full understanding of mineral metabolism-CVD relationships in humans. First, current ascertainment of the phosphorous and vitamin D metabolic axes is crude, obscuring relationships with CVD outcomes and impeding translation to clinical application. Second, CVD pathways through which disturbed mineral metabolism may promote CVD are incompletely evaluated in humans. Third, phosphorous and vitamin D metabolism vary strongly by race/ethnicity, but knowledge of cardiovascular consequences of mineral metabolism disorders derive from populations with limited diversity. The overall goal of this proposal is to define relationships of phosphorous excess and vitamin D insufficiency with pathophysiologically relevant clinical and subclinical CVD outcomes in a community based, multi-ethnic population. We will characterize the phosphorous and vitamin D metabolic axes using multiple serum and urine biomarkers measured from previously collected baseline samples obtained from 6,736 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). MESA offers a unique opportunity to comprehensively evaluate novel CVD risk factors because of its multi-ethnic sampling strategy, exclusion of clinical CVD at baseline, state-of-the-art subclinical CVD measurements, and adjudicated cardiovascular events. We hypothesize that biomarkers of phosphorous excess (higher concentrations of serum phosphorous, serum fibroblast growth factor-23, and urine phosphorous) and vitamin D deficiency (lower 25- hydroxyvitamin D and higher parathyroid hormone concentrations) will be associated with incident cardiovascular events, incident hypertension, and incident chronic kidney disease. We further hypothesize that biomarkers of phosphorous excess and vitamin D deficiency will be associated with subclinical cardiovascular disease measurements that are directly relevant to mineral metabolism: coronary artery calcification, thoracic aorta calcification, arterial stiffness, and left ventricular mass. PUBLIC HEALTH RELEVANCE: Cardiovascular diseases (CVD) are the major cause of eath in the industrialized world for both men and women. Disturbances in phosphorous and vitamin D metabolism may be novel risk factors for CVD and may offer new opportunities for preventive or therapeutic intervention. The proposed studies will determine whether phosphorus excess and vitamin D deficiency are linked with clinically relevant CVD in a racially and ethnically diverse population. Findings will help clarify optimal serum concentrations of phosphorous and vitamin D biomarkers with respect to cardiovascular health and inform clinical trials which target mineral metabolism to prevent and reduce CVD.