Despite rigorous investigations and the expenditure of nearly 6% of Medicare funds on their care, annual mortality among the 511,000 dialysis patients in the United States is extraordinarily high. Approximately, 17% of patients die annually with half of deaths attributable to cardiovascular (CV) causes, particularly sudden cardiac death. Current therapies do not effectively lower CV mortality in hemodialysis (HD) patients thus highlighting the importance of addressing existing gaps in understanding of the mechanisms underlying CV complications in HD patients and identifying novel therapeutic targets. Transient intra-dialytic myocardial stunning (IdMS) during HD—the dominant dialysis modality in the US—has been increasingly implicated as one such mechanism potentially responsible for progressive myocardial damage and subsequent development of heart failure, arrhythmia, and CV death. However, current understanding of this novel risk factor is woefully incomplete. Prior studies were small, included few women, non-white, or incident patients—those with the highest risk of CV death—and variation in estimated prevalence was extreme (20-100%). In addition, studies of IdMS risk factors were underpowered and conflicting, and it is remains unknown whether IdMS occurs intermittently or repetitively. Finally, although our both our own preliminary data and studies by other groups implicate a potential role for autonomic dysfunction in IdMS pathophysiology, there have been few mechanistic investigations and understanding of the underlying pathophysiology is incomplete. In short, IdMS is a potentially important and treatable contributor to CV death in the HD population, but there are major gaps in understanding its epidemiology, risk factors, and mechanisms. We propose studies designed to address these critical knowledge gaps and provide the necessary information to determine whether and how IdMS should be targeted to reduce CV mortality in HD: In Aim 1, we propose performing intradialytic echocardiography on a large, diverse cohort of 400 incident HD patients to facilitate stable, generalizable estimates of IdMS prevalence, the analysis of important subgroups, and the study of associations with key risk factors. In Aim 2, we propose a comprehensive investigation of the hypothesis that unopposed surges in sympathetic tone underlie susceptibility to IdMS. Myocardial 11C-hydroxephderine PET scanning and dedicated studies in an autonomic function lab will be utilized to assess systematic and myocardial-specific autonomic function. Conversely, intradialytic autonomic tone and circulating hormones will be measured during dialysis to systematically define the patterns of change in autonomic tone preceding and predisposing to episodes of IdMS. These studies will improve understanding of the epidemiology and physiology of a potentially critical contributor to cardiovascular morbidity and mortality in the dialysis population, improve basic understanding of the pathophys...