Phosphorus and Vitamin D Metabolism and Cardiovascular Outcomes: The MESA Study

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细胞样细胞，使内侧血管壁钙化。维生素D不足激活肾素-血管紧张素-醛固酮系统，刺激致动脉粥样硬化细胞因子表达，直接促进心肌细胞生长。现有知识的重要差距限制了对人类矿物质代谢与心血管疾病关系的充分理解。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CVD结果的关系，阻碍了转化为临床应用。其次，在人类中，矿物质代谢紊乱可能促进心血管疾病的CVD途径尚未完全评估。第三，磷和维生素D的代谢因种族而有很大差异，但对矿物质代谢紊乱的心血管后果的了解来自于多样性有限的人群。该建议的总体目标是确定磷过量和维生素D不足与病理生理学相关的临床和亚临床CVD结果在社区为基础的多民族人群中的关系。我们将使用多种血清和尿液生物标志物来表征磷和维生素D代谢轴，这些生物标志物来自先前收集的来自多种族动脉粥样硬化研究（MESA）中6,736名参与者的基线样本。MESA提供了一个独特的机会来全面评估新的心血管疾病危险因素，因为它采用了多民族抽样策略，在基线时排除临床心血管疾病，最先进的亚临床心血管疾病测量，以及确定的心血管事件。我们假设磷过量的生物标志物（较高浓度的血清磷、血清成纤维细胞生长因子-23和尿磷）和维生素D缺乏（较低的25-羟基维生素D和较高的甲状旁腺激素浓度）将与心血管事件、高血压事件和慢性肾病事件有关。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。

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.