Elucidating Pathways of Vascular Dysfunction and Myocardial Injury in ESRD

描述（由申请方提供）：终末期肾病（ESRD）受试者的心血管死亡率非常高。在美国有超过50万名终末期肾病（ESRD）患者，每人在5年内死于脑血管或心血管疾病的几率为25%。他汀类药物等治疗在这一人群中已被证明无效。导致这些患者心血管疾病的生物学机制可能与非ESRD受试者不同，但这些机制尚不清楚。众所周知，血管功能障碍（内皮功能障碍和动脉硬化）是该人群死亡率的独立预测因素。高灵敏度肌钙蛋白T是慢性心肌损伤的一种非常敏感的指标，是该人群死亡率的一个强有力的剂量依赖性预测因子。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ESRD血管功能障碍的潜在可改变途径; 2）确定内皮功能障碍和动脉僵硬度是否与ESRD心肌损伤独立相关。我们将使用标准化的非侵入性测量方法测量大血管内皮功能（肱动脉血流介导的舒张（FMD%））、微血管内皮功能（反应性充血期间肱动脉速度-时间关系的曲线下面积（AUC））和动脉僵硬度（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学标志物与血管功能障碍的这些参数的相关性。我们将检测这些血管参数是否与心肌损伤相关，如高灵敏度肌钙蛋白T所测量的。第二，在一组60例肾移植受者中，我们将比较移植前后内皮功能、动脉硬度和高敏肌钙蛋白T的测量结果。这些研究将阐明哪些心血管疾病机制是ESRD独有的，以及哪些机制最有可能可逆。最终，这些信息将有助于开发更有效的治疗策略，以应对ESRD人群中压倒性的心血管疾病负担。

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.