Mediterranean diet, Metabolites, and cardiovascular Disease

描述（由申请人提供）：在美国，每三个死亡中就有一个可归因于心血管疾病（CVD）。健康的饮食和生活方式对预防心血管疾病至关重要。传统的地中海饮食模式因其对心血管疾病风险的潜在有益影响而受到越来越多的关注。最近，具有里程碑意义的PREDIMED随机试验（n=7,447名基线时未诊断出心血管疾病的参与者）表明，在中位随访4.8年后，与对照饮食相比，地中海饮食模式补充初橄榄油或树坚果可显着降低主要临床心血管事件的风险约30%。该项目的目的是研究随机PREDIMED饮食干预对血浆代谢物水平的影响，并确定这些代谢谱是否介导了干预对心血管疾病风险的益处。将采用嵌套病例队列设计，纳入所有288例CVD事件病例和基线随机选择的745例（10%）试验参与者。在基线和试验第一年收集的空腹血液样本将使用麻省理工学院和哈佛大学Broad研究所开发的最先进的LC-MS技术，对约300种代谢产物进行有效的测量。我们将重点关注与心脏代谢风险有关的代谢物类别。我们的项目包括三个具体目标：1)检查随机饮食干预对745名随机选择的试验参与者从基线到第1年血浆代谢物水平变化的影响；2)采用有效的病例队列设计，研究1年内血浆代谢物水平的变化是否介导了随机饮食干预对随后2 - 5年CVD临床结局的影响；3)采用病例队列设计，研究基线代谢物水平是否会改变随机饮食干预对心血管疾病风险的影响。作为次要目的，我们将在745名随机选择的试验参与者中研究1年内代谢物的变化是否介导饮食干预对随后代谢综合征发生的益处。PREDIMED是首个评估地中海式饮食干预对硬心血管终点影响的随机一级预防试验。目前的提案概述了一项极其高效和创新的研究，该研究将最先进的代谢组学技术应用于一项严格实施的饮食干预试验。这项研究为发现饮食影响心血管疾病风险的新途径提供了一个理想的机会，可以获得基线和随访时存档的血浆样本，记录良好的心血管疾病终点，以及具有良好依从性的长期随机干预措施。2010年美国膳食指南已经认识到地中海饮食模式，以及停止高血压的饮食方法（DASH）饮食，是预防心血管疾病的健康饮食。这项研究的结果将为支持饮食预防心血管疾病的公共卫生建议提供进一步的证据。

DESCRIPTION (provided by applicant): In the U.S., one in every three deaths is attributable to cardiovascular disease (CVD). Healthy diet and lifestyle are crucial for CVD prevention. The traditional Mediterranean dietary pattern has received increasing attention because of its potential beneficial effects on CVD risk. Recently, the landmark PREDIMED randomized trial (n=7,447 participants free of diagnosed CVD at baseline) demonstrated that a Mediterranean dietary pattern, supplemented with either virgin olive oil or tree nuts, significantly reduced the risk of major clinical CVD events by ~30%, compared to a control diet, after a median follow-up of 4.8 years. The goal of this project is to examine the effects of the randomized PREDIMED dietary interventions on plasma levels of metabolites, and to determine whether these resulting metabolic profiles mediate the interventions' benefits on CVD risk. A nested case-cohort design will be used, incorporating all 288 incident cases of CVD and 745 (10%) randomly selected trial participants at baseline. Stored fasting blood specimens collected at baseline and at year 1 of the trial will be measured for a well-validated panel of ~300 metabolites, using the state-of-the-art LC-MS technology developed by the Broad Institute of MIT and Harvard. We will focus on classes of metabolites that have been implicated in cardio-metabolic risk. Our project includes three specific aims: 1) To examine the effects of the randomized dietary interventions on changes in plasma levels of metabolites from baseline to year 1 in 745 randomly selected trial participants; 2) To examine whether 1-year changes in plasma levels of metabolites mediate the effect of the randomized dietary interventions on subsequent clinical CVD outcomes from years 2 to 5, using the efficient case-cohort design; and 3) To examine whether baseline metabolite levels modify the effects of the randomized dietary interventions on CVD risk, using a case-cohort design. As a secondary aim, we will examine whether 1-year changes in metabolites mediate the benefits of dietary interventions on subsequent occurrence of the metabolic syndrome, among 745 randomly selected trial participants. The PREDIMED is the first randomized primary prevention trial to evaluate the effects of Mediterranean-style dietary interventions on hard CVD endpoints. The current proposal outlines an extremely efficient and innovative study that applies the state-of-the-art metabolomics technology to a rigorously conducted dietary intervention trial. This study provides an ideal opportunity to discover novel pathways through which diet influences CVD risk, with access to archived plasma samples at baseline and follow-up, well-documented CVD endpoints, and long-term, randomized interventions with excellent compliance. The 2010 Dietary Guidelines for Americans has recognized the Mediterranean dietary pattern, along with the Dietary Approaches to Stop Hypertension (DASH) diet, as a healthy diet for CVD prevention. Results from this study will provide further evidence to support public health recommendations for dietary prevention of CVD.