Red Blood Cell Fatty Acid Biomarkers and Cardiovascular Disease Risk

描述(申请人提供)：omega-3脂肪酸(n-3FA)被认为可以降低心血管疾病(CVD)，特别是心脏性猝死和充血性心力衰竭(CHF)的风险。然而，流行病学仍然相互矛盾，饮食中n-3脂肪酸的作用机制仍然是推测的。心率减慢、心率变异性增加、内皮功能改善都与较高水平的n-3FA生物标志物相关。这可能是通过膜结构/功能的改变和/或二十烷类化合物或细胞因子诱导的炎性蛋白的改变来调节的。红细胞(RBC)n-3FA含量是反映人体心肌n-3FA水平的有效生物标志物。除了更客观(相对于基于饮食问卷的衡量标准)，RBC n-3FA可能比血浆FA水平更可取，因为它们反映了几周内组织FA水平，且变异性较小(在评估平均血糖水平时类似于血红蛋白A1C)。先前没有研究评估RBC n-3FA(或FA模式)对心血管结局和血管危险标记物的关系。为了解决这些知识上的差距，我们建议在两个Framingham心脏研究队列(子孙研究和少数，OMNI研究)中测量RBC FA的组成。RBC n-3FA含量将结合已收集的关于这些对象的丰富数据集进行分析，这些数据集包括经典和新兴危险因素、亚临床左心室(LV)重构、血管僵硬和内皮功能。这些受试者也在持续监测心血管疾病和充血性心力衰竭的发展。我们提出以下三个目标：目的1.RBC n-3FAs与临床的相关性。为了确定横断面临床相关性，以社区为基础的样本中RBC n-3FA含量的遗传度和稳定性。目的2.红细胞n-3FAs与血管和心室重构。研究RBC n-3FA与a)微循环功能和管道动脉硬度的横断面关系(使用眼压计)，b)内皮功能(使用基于超声的肱动脉血流介导的扩张)，以及c)左室重构的指标(使用超声心动图)。目的3.RBC n-3FAs与心血管疾病危险因素及发病机制的研究进展。前瞻性探讨RBC n-3FA含量与心血管危险因素演变及心血管事件发生率的纵向追踪关系。这些数据不仅将为未来评估红细胞脂肪酸对心血管疾病的预测价值的研究提供信息，还将为其他疾病(如痴呆症、关节炎、黄斑变性等)提供信息。可能受到这些FA的调制。与公众健康相关：人们对鱼油对心脏健康的影响越来越感兴趣，特别是它们所含的omega-3脂肪酸(EPA和DHA)。虽然我们现在知道，给心脏病高危人群补充鱼油似乎可以降低他们患心脏病的风险，但我们不知道这些天然油是如何帮助心脏的，也不知道血液水平的正常变化与心脏病风险因素的关系。这项研究将试图揭示血中omega-3水平与高血压的发展速度、血管的柔韧性(即健康程度)、心脏泵血的强劲程度或动脉炎症程度之间迄今未知的联系。所有这些因素对确定心脏病发作和中风的风险都很重要，因此了解它们是如何受到omega-3脂肪酸的影响将有助于我们设计新的治疗策略，以降低美国这些主要疾病的风险。

DESCRIPTION (provided by applicant): Omega-3 fatty acids (n-3 FAs) are believed to reduce risk for cardiovascular disease (CVD), especially sudden cardiac death, and for congestive heart failure (CHF). The epidemiology, however, remains conflicted, and the mechanisms by which dietary n-3 FAs operate remain speculative. A decrease in heart rate, an increase in heart rate variability, and improved endothelial function have all been associated with higher levels of n-3 FA biomarkers. These may be mediated by changes in membrane structure/function and/or eicosanoids or cytokine- induced inflammatory proteins. Red blood cell (RBC) n-3 FA content has recently been shown to be a valid surrogate biomarker of human myocardial n-3 FA levels. In addition to being more objective (relative to dietary questionnaire-based measures), RBC n-3 FAs may be preferable to plasma levels of FAs because they reflect tissue FA levels over several weeks and are less variable (analogous to hemoglobin A1C in the assessment of average blood glucose levels). No prior studies have evaluated the relationships between RBC n-3 FAs (or FA patterns) on cardiovascular outcomes and vascular risk markers. To address these gaps in knowledge, we propose to measure RBC FA composition in two Framingham Heart Study cohorts (the Offspring Study and the minority, Omni Study). The RBC n-3 FA content will be analyzed in conjunction with the rich dataset already collected on these subjects which includes classical and emerging risk factors, subclinical left ventricular (LV) remodeling, vascular stiffness, and endothelial function. These subjects are also under continuous surveillance for the development of CVD and CHF. We propose the following 3 aims: Aim 1. RBC n-3FAs and clinical correlates. To define the cross-sectional clinical correlates, the heritability and the stability of RBC n-3 FA content in a community-based sample. Aim 2. RBC n-3 FAs and vascular & ventricular remodeling. To examine the cross-sectional relations of RBC n-3 FAs to a) microcirculatory function and conduit artery stiffness (using tonometry), b) endothelial function (using ultrasound-based brachial artery flow-mediated dilation), and c) indexes of LV remodeling (using echocardiography). Aim 3. RBC n-3 FAs and the development of CVD risk factors & incident CVD. To investigate prospectively the relations of RBC n-3 FA content to longitudinal tracking of the evolution of CVD risk factors and of the incidence of CVD events. These data will not only inform future studies assessing the predictive value of RBC FAs for CVD, but also for other diseases (e.g., dementia, arthritis, macular degeneration, etc.) potentially modulated by these FAs. PUBLIC HEALTH RELEVANCE: There has been increasing interest in the heart-healthy effects of fish oils, especially the omega-3 fatty acids (EPA and DHA) that they contain. While we now know that giving fish oil supplements to people who are at high risk for heart attacks seems to reduce their risk for heart disease, we don't know how these natural oils work to help the heart, nor do we know the degree to which normal variations in blood levels are related to heart disease risk factors. This study will attempt to uncover heretofore unknown links between blood omega-3 levels and such things as how fast people develop high blood pressure, how flexible (i.e., healthy) the blood vessels are, how vigorously the heart pumps blood, or how inflamed the arteries are. All of these factors are important in determining risk for heart attacks and strokes, and so learning how they are affected by omega-3 fatty acids will help us devise new treatment strategies to reduce risk for these major diseases in the US.