Elucidating Pathways of Vascular Dysfunction and Myocardial Injury in ESRD

描述(由申请人提供)：患有终末期肾病(ESRD)的受试者心血管死亡率非常高。美国有50多万终末期肾病(ESRD)患者，每个人都有25%的机会在5年内死于脑血管或心血管疾病。他汀类药物等治疗已被证明在这一人群中无效。这些患者导致心血管疾病的生物学机制可能与非ESRD患者不同，但这些机制尚不清楚。已知血管功能障碍(内皮功能障碍和动脉僵硬)是该人群死亡率的独立预测因子。高敏感性肌钙蛋白T是慢性心肌损伤的一个极其敏感的指标，是该人群死亡率的一个强有力的、剂量依赖的预测因子。血管功能障碍在多大程度上导致慢性心肌损伤尚不清楚。我们的总体目标是：1)确定导致终末期肾病血管功能障碍的潜在的可改变的途径；2)确定内皮功能障碍和动脉僵硬是否与终末期肾病的心肌损伤独立相关。我们将使用标准化的非侵入性测量大血管内皮功能(肱动脉血流介导的扩张(FMD%))、微血管内皮功能(反应性充血时臂动脉血流速度-时间关系的曲线下面积(AUC))和动脉僵硬(评估为脉搏波速度(PWV))。首先，在120名ESRD研究参与者的队列中，我们将评估骨代谢、炎症、营养不良和一氧化氮产生的血清标志物与这些血管功能障碍参数的相关性。我们将测试这些血管参数是否与高敏肌钙蛋白T测量的心肌损伤有关。其次，在60名肾移植受者的队列中，我们将比较移植前后内皮功能、动脉僵硬和高敏肌钙蛋白T的测量。这些研究将阐明哪些心血管疾病机制是ESRD独有的，哪些机制最有可逆性。最终，这些信息将有助于开发更有效的治疗策略，以应对ESRD人群中不堪重负的心血管疾病。

DESCRIPTION (provided by applicant): Subjects with end stage renal disease (ESRD) suffer a very high rate of cardiovascular mortality. There are more than 500,000 patients with end stage renal disease (ESRD) in the United States, and each has a 25% chance of dying of cerebrovascular or cardiovascular disease within 5 years. Treatments such as statins have proven ineffective in this population. It is likely that biological mechanisms leading to cardiovascular disease in these patients are different from those in subjects without ESRD, yet these mechanisms are poorly understood. It is known that vascular dysfunction (endothelial dysfunction and arterial stiffness) is an independent predictor for mortality in this population. High-sensitivity Troponin T, an extremely sensitive measure of chronic myocardial injury, is a strong, dose-dependent predictor for mortality in this population. The extent to which vascular dysfunction contributes to chronic myocardial injury is unknown. Our overall objectives are 1) to identify potentially modifiable pathways that lead to vascular dysfunction in ESRD and 2) to determine whether endothelial dysfunction and arterial stiffness are independently associated with myocardial injury in ESRD. We will use standardized, non-invasive measures for macrovascular endothelial function (brachial artery flow mediated dilation (FMD%)), microvascular endothelial function (area under the curve (AUC) of the brachial artery velocity-time relationship during reactive hyperemia), and arterial stiffness (assessed as pulse wave velocity (PWV)). First, in a cohort of 120 ESRD study participants, we will evaluate the associations of serological markers of bone metabolism, inflammation, malnutrition, and nitric oxide production with these parameters of vascular dysfunction. We will test whether these vascular parameters are associated with myocardial injury, as measured by high-sensitivity troponin T. Second, in a cohort of 60 kidney transplant recipients, we will compare pre- and post-transplant measures of endothelial function, arterial stiffness and high sensitivity troponin T. These investigations will elucidate which mechanisms of cardiovascular disease are unique to ESRD, and which of these have the most potential for reversibility. Ultimately, such information will facilitate the development of more effective therapeutic strategies for the overwhelming burden of cardiovascular disease in the ESRD population.