ROLE OF ANGIOTENSIN-(1-7) AND DIAPHRAGM VASCULAR FUNCTION IN HEART FAILURE AND PROLONGED MECHANICAL VENTILATION

血管紧张素-(1-7) 和隔膜血管功能在心力衰竭和长时间机械通气中的作用

基本信息

批准号：
10607545
负责人：
Andrew Horn
金额：
$ 3.55万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-04 至 2025-01-03
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607545
关键词：
Acetylcholine Anatomy Angiotensin II Animal Disease Models Artificial Heart Atrophic Blood Vessels Blood flow Breathing COVID-19 Cardiovascular system Cause of Death Cholinergic Agonists Clinical Critical Thinking Data Development Disease Educational process of instructing Elements Endothelium Environment Exhibits Failure Fatigue Functional disorder Goals Health Heart Diseases Heart failure Human Hyperemia Impairment Infusion procedures Intervention Kansas Kinesiology Knowledge Laboratories Measurement Measures Mechanical ventilation Medial Mediator Messenger RNA Microspheres Muscle Muscle Fatigue Muscle function Myocardial Infarction NG-Nitroarginine Methyl Ester Outcome Oxygen Pathology Pathway interactions Patients Perfusion Peripheral Pharmaceutical Preparations Pharmacological Treatment Physiology Predisposition Preparation Quality of life Rattus Receptor Activation Regulation Relaxation Renin-Angiotensin System Research Resistance Respiratory Diaphragm Respiratory Muscles Role Skeletal Muscle Techniques Testing Time Training United States Universities Vascular Diseases Vascular resistance Vasodilation Vasodilator Agents Vasomotor Ventilator Weaning angiotensin I (1-7)arteriole career endothelial dysfunction exercise intolerance experimental study frontier improved in vivo insight mortality neglect novel patient population pharmacologic preservation prevent protein expression response skills

项目摘要

PROJECT SUMMARY Heart disease is the leading cause of death in the United States. Diaphragm dysfunction is prevalent in heart failure (HF) patients and both precedes and surpasses that seen in other locomotory skeletal muscles; increasing susceptibility to respiratory muscle failure and exercise intolerance as well as predisposing these patients to ventilator-induced diaphragmatic dysfunction (VIDD). Impaired vascular function is regularly present in peripheral skeletal muscles with HF, compromising the blood flow and oxygen delivery required to support contractile function. However, the role of diaphragm vascular dysfunction in HF-induced diaphragm fatigue, and whether these changes in diaphragm vasomotor control are exacerbated with prolonged mechanical ventilation (MV), often employed in this patient population, is not known. Further, cardiovascular dysfunction is an important contributor to problematic weaning and increased mortality with MV. Prolonged MV in-and-of itself elicits diaphragm vascular dysfunction, which contributes to weaning failure with MV. HF and MV patients consistently exhibit increased renin-angiotensin system (RAS) activation and elevated levels of circulating Angiotensin-II (Ang-II), which largely contributes to skeletal muscle vascular dysfunction as well as diaphragm atrophy in both HF and prolonged MV. These findings suggest that HF patients are predisposed to more pronounced MV-induced diaphragm vascular dysfunction. Preliminary data supports that HF impairs endothelial-dependent vasorelaxation in diaphragm arterioles, and the added insult of prolonged MV nearly abolishes endothelial-dependent vasorelaxation. However, the impact of HF combined with prolonged MV on diaphragm blood flow and vasomotor control has never been determined. Therefore, our global hypothesis is that diaphragm resistance vessel (i.e. arterioles) function (e.g. endothelial-dependent vasorelaxation) is significantly diminished in HF and exacerbated with MV. As such, pharmacologically counteracting the vascular effects of Ang-II will improve diaphragm perfusion and preserve vascular function with prolonged MV and HF + prolonged MV. This project will be completed at Kansas State University (KSU) under the guidance of Drs. Bradley J. Behnke and David C. Poole. The training plan has been formulated to facilitate the development of technical proficiencies and critical thinking skills needed to execute the proposed experiments and incorporates the elements essential for the applicant to transition into an independent scientific career. The Behnke and Poole Laboratories, and the Departments of Kinesiology and Anatomy and Physiology at KSU represent a rich scientific environment that will provide outstanding graduate training and a research opportunity to gain new insights into diaphragm blood flow regulation and vasomotor control in healthy and diseased animal models.

项目概要心脏病是美国的首要死因。膈肌功能障碍常见于心力衰竭（HF）患者的情况均优于并超过其他运动骨骼肌；增加对呼吸肌衰竭和运动不耐受的易感性以及诱发这些呼吸机引起的膈肌功能障碍（VIDD）患者。血管功能受损是经常存在的在心力衰竭的周围骨骼肌中，会损害支持所需的血流和氧气输送收缩功能。然而，膈肌血管功能障碍在高频引起的膈肌疲劳中的作用，以及膈肌血管舒缩控制的这些变化是否会随着长时间的机械运动而加剧该患者群体中经常使用的通气 (MV) 尚不清楚。此外，心血管功能障碍 MV 导致断奶困难和死亡率增加的一个重要因素。延长 MV 进出时间本身会引起膈肌血管功能障碍，从而导致 MV 撤机失败。心力衰竭和MV患者始终表现出肾素-血管紧张素系统 (RAS) 激活增加和循环水平升高血管紧张素-II (Ang-II)，主要导致骨骼肌血管功能障碍以及膈肌功能障碍 HF 和延长 MV 时均出现萎缩。这些研究结果表明，心力衰竭患者更容易发生明显的 MV 引起的膈肌血管功能障碍。初步数据支持心力衰竭损害膈肌内皮依赖性血管舒张作用微动脉，以及延长 MV 的额外损伤几乎消除了内皮依赖性血管舒张作用。然而，HF 联合延长 MV 对膈肌血流和血管舒缩控制的影响已从来没有确定过。因此，我们的总体假设是隔膜阻力容器（即心力衰竭和小动脉）功能（例如内皮依赖性血管舒张）显着减弱 MV 加剧。因此，从药理学上抵消 Ang-II 的血管效应将通过延长 MV 和 HF + 延长时间来改善膈肌灌注并保护血管功能 MV。该项目将在堪萨斯州立大学（KSU）博士的指导下完成。布拉德利·J。本克和大卫·C·普尔。制定培训计划，促进技术发展执行所提议的实验所需的熟练程度和批判性思维技能，并将申请人过渡到独立科学职业所必需的要素。本克和普尔肯塔基州立大学的实验室以及运动机能学、解剖学和生理学系代表了丰富的科学环境将提供出色的研究生培训和获得新知识的研究机会深入了解健康和患病动物模型中的隔膜血流调节和血管舒缩控制。