Elucidating Pathways of Vascular Dysfunction and Myocardial Injury in ESRD

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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. PUBLIC HEALTH RELEVANCE: In 2007 there were over 500,000 patients with end stage renal disease (ESRD) in the United States, each with a 25% chance of dying of cerebrovascular or cardiovascular disease within 5 years. We currently lack effective therapies for the overwhelming burden of cardiovascular disease in this population. By investigating the mechanisms underlying cardiovascular disease in subjects with ESRD, I hope to design effective therapies to ameliorate their high rate of hospitalizations and death due to cardiovascular disease.