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

描述(申请人提供)：心血管疾病(心血管疾病)是美国和整个发达国家发病率和死亡率的主要原因。心血管疾病有着共同的病理生理学--动脉粥样硬化。动脉粥样硬化是一种慢性炎症性疾病，受到包括血小板在内的循环细胞的影响。血小板不仅在血栓形成过程中起着中心作用，而且在动脉粥样硬化的形成和病变的进展中也起着核心作用。在健康成年人中，血小板过度活跃可能是亚临床心血管疾病进展的一个重要因素。肥胖和饮食中的钠是导致心血管疾病和血小板功能改变的两个因素。肥胖的人血栓形成的风险增加，这可能部分是因为血小板过度活跃。也有研究表明，肥胖的人比正常体重的人对盐更敏感，这可能会使他们面临与高盐饮食相关的心血管负面变化的风险增加。有人提出，改变生活方式，如减肥和减少饮食中的钠，可以减少肥胖者的血小板过度活动。这项拟议的项目旨在评估生活方式干预试验中超重和肥胖参与者体内的血小板过度活性，评估体重减轻、体力活动增加和钠限制对血管重构的影响(R01 HL077525-04)。虽然肥胖和高钠饮食都与体外血小板过度活跃有关，但这些因素和其他心血管危险因素与体内血小板激活的关系尚不清楚，遗传学对健康个体体内血小板激活的影响程度也不清楚。拟议的项目将使用酶免疫分析法在体内测量血浆2-血栓球蛋白(2-TG)的血小板激活。2-甘油三酯只有在被激活时才能被血小板特异性释放。体内血小板活性的血浆标志物，如2-甘油三酯，很容易测量，并准确地反映血小板活性的基础水平。这项拟议的项目将确定体内血小板高活性(高2-甘油三酯)是否与饮食钠、心血管危险因素、血管适应措施有关，以及血小板受体基因的几个功能多态性是否影响体内激活和血管适应。该项目的具体目的是在超重/肥胖人群中确定(1)体内血小板过度活跃是否与饮食中的钠摄入量呈正相关；(2)哪些心血管危险因素与血小板过度活跃有关；(3)体内血小板过度活跃是否与亚临床心血管疾病的指标或其变化率呈正相关；以及(4)血小板受体基因的功能变异是否会影响体内的血小板活化和亚临床心血管指标。通过揭示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生活方式改变的能力，从而初步预防心血管疾病，从而有助于减轻超重和肥胖个人经历的心血管疾病负担。 公共卫生相关性：该项目将确定与健康超重和肥胖成年人的血小板活性升高和血管重构相关的遗传、生理和生活方式因素。特别是，生活方式的改变，如减肥和饮食钠的减少，将被评估它们降低肥胖者发现的血小板过度活动的能力。由于血小板是心血管疾病的主要罪魁祸首，这个项目将有助于我们理解如何降低超重和肥胖个人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.