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

血液透析患者透析中心肌顿抑——一种新的心血管危险因素

• 批准号: 10367558
• 负责人: David M Charytan
• 金额: $ 74.07万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-24 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367558
• 关键词: Acute; Address; American; Arrhythmia; Attention; Autonomic Dysfunction; Autonomic nervous system; Baroreflex; Biological Markers; Black Populations; Blood Pressure; Cardiac; Cardiovascular system; Caring; Catecholamines; Cessation of life; Cities; Collaborations; Complication; Conflict (Psychology); Data; Dialysis patients; Dialysis procedure; Echocardiography; End stage renal failure; Epidemiology; Event; Expenditure; Functional disorder; Funding; Heart; Heart failure; Hemodialysis; Hispanic; Hispanic Populations; Hormones; Impairment; Incidence; Intervention Trial; Investigation; Knowledge; Lead; Left; Left Ventricular Hypertrophy; Life; Link; Maintenance; Measurement; Measures; Medicare; Modality; Monitor; Morbidity - disease rate; Motion; Multicenter Studies; Myocardial; Myocardial Ischemia; Myocardial Stunning; Myocardial dysfunction; Necrosis; Nervous System control; Neurons; Norepinephrine; Osmolar Concentration; Pathogenesis; Pathologic; Patients; Pattern; Phenotype; Physiology; Plasma; Population; Positron-Emission Tomography; Predisposition; Prevalence; Procedures; Publishing; Recurrence; Reflex action; Research Design; Risk Factors; Role; Sampling; Savings; Stress; Stress cardiomyopathy; Subgroup; Sympathetic Nervous System; Syndrome; Testing; Time; Toxic effect; Ultrafiltration; United States; United States National Institutes of Health; Variant; Ventricular; Woman; attributable mortality; autonomic reflex; base; black patient; cardiogenesis; cardiovascular risk factor; cohort; design; heart damage; hemodynamics; high risk; high risk population; improved; innovation; insight; mortality; myocardial damage; neuroimaging; neurophysiology; new therapeutic target; novel; novel therapeutics; patient subsets; prevent; response; sudden cardiac death; targeted treatment; trial design

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.

尽管进行了严格的调查，近6%的医疗保险基金用于他们的护理， 美国511，000名透析患者的死亡率非常高。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，尤其是突发性心血管疾病。 心源性死亡目前的治疗不能有效降低血液透析（HD）患者的CV死亡率，因此 强调解决在理解CV机制方面存在的差距的重要性 HD患者的并发症和确定新的治疗靶点。一过性透析中心肌 HD（美国的主要透析方式）期间的休克（IdMS）越来越多地涉及， 一种这样的机制可能导致进行性心肌损伤和随后的发展 心力衰竭心律失常和心血管死亡然而，目前对这种新的风险因素的理解是可悲的， 不完整先前的研究规模较小，包括少数女性、非白人或偶发性患者， CV死亡的风险最高，估计患病率的变化是极端的（20-100%）。此外，研究 IdMS风险因素的效力不足且相互矛盾，并且仍然不清楚IdMS是否会发生 间歇地或重复地。最后，尽管我们的初步数据和其他小组的研究 暗示自主神经功能障碍在IdMS病理生理学中潜在作用， 对潜在的病理生理学的研究和理解是不完整的。 简而言之，IdMS是HD人群中CV死亡的潜在重要且可治疗的促成因素，但 在了解其流行病学、风险因素和机制方面存在重大差距。我们提出的研究设计 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应旨在降低HD中的CV死亡率：在目标1中，我们建议进行透析中 对400例HD患者的大型、多样化队列进行超声心动图检查，以促进稳定、可推广 IdMS患病率的估计，重要亚组的分析，以及与关键风险相关性的研究 因素在目标2中，我们提出了一个全面的研究假设，即无反对的激增， 交感神经紧张是IdMS易感性的基础。心肌11 C-羟麻黄碱PET扫描和专用 将利用自主神经功能实验室的研究来评估系统性和心肌特异性自主神经功能 功能相反，透析期间将测量透析中自主神经张力和循环激素， 系统地定义自主神经张力的变化模式， IdMS。这些研究将提高对一种潜在的关键疾病的流行病学和生理学的理解。 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，并提供必要的数据，以设计针对性的 降低高风险患者CV死亡的治疗方法。