Study of Platelet Hyperactivity and Vascular Remodeling in Overweight and Obese A

描述（由申请方提供）：心血管疾病（CVD）是美国和整个发达国家发病率和死亡率的主要原因。心血管疾病有一个共同的病理生理学-动脉粥样硬化。动脉粥样硬化是一种受循环细胞（包括血小板）影响的慢性炎症性疾病。血小板不仅在血栓形成过程中起核心作用，而且在动脉粥样硬化形成和动脉粥样硬化病变的进展中起核心作用。血小板过度活跃可能是健康成人亚临床心血管疾病（CVD）进展的重要因素。肥胖和膳食钠是与CVD和血小板功能改变有关的两个因素。肥胖的人有血栓形成的风险增加，这可能部分解释为血小板过度活跃。也有人认为，肥胖的人比正常体重的人对盐更敏感，这可能会增加他们与高盐饮食相关的负面心血管变化的风险。有人提出，生活方式的改变，如减肥和减少饮食中的钠，减少血小板过度活跃的肥胖个体。 拟定项目旨在评估生活方式干预试验中超重和肥胖受试者的体内血小板高活性，评价体重减轻、增加体力活动和限钠对血管重塑的影响（R 01 HL 077525 -04）。尽管肥胖和高钠饮食与体外血小板活化有关，但这些因素和其他CVD危险因素与体内血小板活化的关系仍不清楚，遗传因素在多大程度上影响健康个体体内血小板活化。拟议的项目将使用酶免疫测定法测量体内血小板活化作为血浆2-血栓球蛋白（2-TG）。2-TG仅在血小板活化时由血小板特异性释放。体内血小板活性的血浆标志物，如2-TG，很容易测量，并准确反映血小板活性的基础水平。拟议的项目将确定体内血小板过度活跃（高2-TG）是否与膳食钠，CVD危险因素，血管适应措施，以及血小板受体基因的几种功能多态性是否影响体内活化和血管适应。 该项目的具体目标是在超重/肥胖人群中确定，（1）体内血小板过度活跃是否与膳食钠摄入呈正相关（2）哪些CVD风险因素与血小板过度活跃相关（3）体内血小板过度活跃是否与亚临床CVD的测量或其变化率呈正相关（4）血小板受体基因的功能变异是否影响体内血小板活化和亚临床CVD测量。通过阐明血小板过度活跃的决定因素及其在血管重塑中的作用，该项目将提高我们针对目前健康的超重和肥胖成年人进行适当的生活方式改变以进行一级CVD预防的能力，从而有助于减轻超重和肥胖个体经历的CVD负担。 公共卫生相关性：该项目将确定与健康超重和肥胖成年人血小板活性升高和血管重塑相关的遗传、生理和生活方式因素。特别是，生活方式的改变，如体重减轻和饮食钠减少，将评估他们的能力，以减少在肥胖个体中发现的血小板亢进。由于血小板是心血管疾病的关键罪魁祸首，该项目将有助于我们了解如何减少超重和肥胖个体所经历的过度心血管疾病风险。

DESCRIPTION (provided by applicant): Cardiovascular diseases (CVDs) are the leading causes of morbidity and mortality in the United States and throughout the developed world. CVDs share a common pathophysiology - atherosclerosis. Atherosclerosis is a chronic inflammatory disease influenced by circulating cells, including platelets. Platelets play a central role not only in the process of thrombus formation, but also in atherogenesis and the progression of atherosclerotic lesions. Platelet hyperactivity is likely an important factor in the progression of subclinical cardiovascular disease (CVD) in healthy adults. Obesity and dietary sodium are two factors that have been linked to both CVD and altered platelet function. Obese individuals have an increased risk of thrombosis, which may be partially explained by platelet hyperactivity. It has also been suggested that obese individuals are more salt-sensitive than normal weight individuals, which may place them at an increased risk for negative cardiovascular changes associated with a high salt diet. It is proposed that lifestyle changes, such as weight loss and reduced dietary sodium, reduce platelet hyperactivity in obese individuals. The proposed project aims to assess in vivo platelet hyperactivity in overweight and obese participants in a lifestyle intervention trial evaluating the effects of weight loss, increased physical activity, and sodium restriction on vascular remodeling (R01 HL077525-04). Although both obesity and high dietary sodium have been linked to in vitro platelet hyperactivity, these factors' and other CVD risk factors' associations with in vivo platelet activation remain unclear, as does the extent to which genetics influences in vivo platelet activation in healthy individuals. The proposed project will measure in vivo platelet activation as plasma 2-thromboglobulin (2-TG) using an enzyme immunoassay. 2-TG is released specifically by platelets only upon their activation. Plasma markers of in vivo platelet activity, such as 2-TG, are easily measured and accurately reflect basal levels of platelet activity. The proposed project will identify whether in vivo platelet hyperactivity (high 2-TG) is associated with dietary sodium, CVD risk factors, measures of vascular adaptation, and whether several functional polymorphisms in platelet receptor genes influence in vivo activation and vascular adaptation. The specific aims of this project are to determine, in an overweight/obese population, (1) whether in vivo platelet hyperactivity is positively associated with dietary sodium intake (2) which CVD risk factors are associated with platelet hyperactivity (3) if in vivo platelet hyperactivity is positively associated with measures of subclinical CVD or their rates of change and (4) whether functional variants in platelet receptor genes influence in vivo platelet activation and subclinical CVD measures. By shedding light on the determinants of platelet hyperactivity and its role in vascular remodeling, this project will improve our ability to target currently healthy overweight and obese adults for appropriate lifestyle changes for primary CVD prevention, thereby contributing to reducing the burden of CVD experienced by overweight and obese individuals. PUBLIC HEALTH RELEVANCE: This project will identify genetic, physiologic, and lifestyle factors associated with elevated platelet activity and vascular remodeling in healthy overweight and obese adults. In particular, lifestyle changes such as weight loss and dietary sodium reduction will be evaluated for their abilities to reduce the platelet hyperactivity found in obese individuals. Because platelets are a key culprit in cardiovascular disease, this project will contribute to our understanding of how to reduce the excess cardiovascular disease risk experienced by overweight and obese individuals.