Intradialytic Myocardial Stunning in Hemodialysis Patients - a Novel Cardiovascular Risk Factor

尽管进行了严格的调查，并花费了近6%的医疗保险基金用于他们的护理，但每年 在美国，511,000名透析患者的死亡率非常高。大约17% 的患者每年死亡，其中一半的死亡可归因于心血管(CV)原因，特别是突发 心源性死亡。目前的治疗方法并不能有效降低血液透析(HD)患者的心血管死亡率 强调在了解个人简历背后的机制方面弥补现有差距的重要性 HD患者的并发症和寻找新的治疗靶点。一过性透析内心肌 HD期间的眩晕(IDMS)--在美国占主导地位的透析方式--越来越多地被认为是 一种这样的机制可能导致进行性心肌损害和随后的发展 心力衰竭、心律失常和心血管死亡的风险。然而，目前对这种新的风险因素的理解是可悲的。 不完整。以前的研究规模很小，包括很少的女性、非白人或偶发患者-那些患有 心血管死亡的风险最高--估计患病率的差异是极端的(20%-100%)。此外，还研究了 IDMS风险因素力量不足且相互冲突，目前尚不清楚是否会发生IDMS 断断续续地或反复地。最后，尽管我们自己的初步数据和其他组织的研究 暗示自主神经功能障碍在IDMS病理生理学中的潜在作用，但几乎没有机制 对潜在的病理生理学的调查和理解是不完整的。 简而言之，IDMS是HD人群心血管死亡的潜在重要和可治疗的贡献者，但 在了解其流行病学、风险因素和机制方面存在重大差距。我们建议设计研究 解决这些关键的知识差距，并提供必要的信息，以确定是否以及如何 IDMS应以降低HD的心血管死亡率为目标：在目标1中，我们建议进行传统透析 超声心动图对400例突发HD患者进行超声心动图检查以利于稳定性和通用性 IDMS流行率的估计、重要亚组的分析以及与关键风险的关联研究 各种因素。在目标2中，我们提出了一个全面的研究假设，即无反对的涌入 交感神经的语调是IDMS易感性的基础。心肌~(11)C-羟麻黄碱正电子发射计算机断层扫描及专用 自主功能实验室的研究将被用来评估系统性和心肌特异性的自主神经。 功能。相反，在透析过程中将测量透析中的自主神经张力和循环激素 系统地定义自主神经语调在发作前和易患上的变化模式 IDMS。这些研究将提高对潜在危重病的流行病学和生理学的了解。 透析人群心血管发病率和死亡率的贡献者，提高对 HD对心脏的病理生理影响，并为有针对性的设计提供必要的数据 减少高危患者心血管死亡的治疗方法。

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 pathophysiologic impact of HD on the heart, and provide the necessary data to design targeted therapeutics to reduce CV death for high-risk patients.