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.

项目摘要心脏病是美国死亡的主要原因。 diaphragm功能障碍在心力衰竭（HF）患者以及在其他机骨骨骼肌中看到的前期和超越；增加对呼吸肌肉衰竭和运动不耐受的敏感性以及使这些呼吸机诱导的隔膜功能障碍（VIDD）的患者。血管功能受损定期存在在带有HF的外周骨骼肌中，损害了支持的血流和氧气递送收缩功能。但是，隔膜血管功能障碍在HF诱导的隔膜疲劳中的作用，隔膜血管舒缩控制中的这些变化是否通过延长的机械性加剧尚不清楚通常在该患者人群中使用的通风（MV）。此外，心血管功能障碍是有问题的断奶和MV死亡率增加的重要原因。长时间的MV及以上本身会引起diaphragm血管功能障碍，这导致MV的断奶失败。 HF和MV患者一贯表现出增加的肾素 - 血管紧张素系统（RAS）激活和循环水平升高血管紧张素-II（ANG-II），很大程度上有助于骨骼肌肉血管功能障碍以及隔膜 HF和延长MV的萎缩。这些发现表明，HF患者易受更多明显的MV诱导的隔膜血管功能障碍。初步数据支持HF会损害隔膜中内皮依赖性血管延缓小动脉，以及延长的MV的侮辱几乎消除了内皮依赖性的血管长期化。然而，HF与长时间MV对隔膜血流和血管舒适控制的影响具有从未确定。因此，我们的全球假设是隔膜抗性容器（即小动脉）功能（例如内皮依赖性血管汇总）在HF和用MV加剧。因此，在药理上抵消Ang-II的血管作用将改善diaphragm灌注并保留长时间的MV和HF +长时间的血管功能 MV。该项目将在DRS的指导下在堪萨斯州立大学（KSU）完成。布拉德利J. Behnke和David C. Poole。已经制定了培训计划，以促进技术的发展执行拟议的实验所需的熟练和批判性思维技能并结合了申请人过渡到独立科学生涯所必需的要素。 Behnke和Poole 实验室以及KSU的运动学和解剖学和生理学的部门代表了丰富的科学环境将提供出色的研究生培训和研究机会，以获得新的在健康和患病的动物模型中，深入了解隔膜血流调节和血管舒缩控制。