DO HEART FAILURE AND AGING POTENTIATE DIAPHRAGM VASCULAR DYSFUNCTION?

心力衰竭和衰老会加剧膈肌血管功能障碍吗？

基本信息

批准号：
10203242
负责人：
Brad J Behnke
金额：
$ 45.6万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10203242
关键词：
Address Aging American Animal Model Animals Arteries Automobile Driving Biological Availability Blood Blood Vessels Blood capillaries Blood flow Breathing COVID-19 COVID-19 pandemic COVID-19 patient Cardiovascular system Cessation of life Contracts Data Diffuse Disease Elderly Endothelium Equilibrium Erythrocytes Failure Female Functional disorder Goals Heart failure Impairment Individual Inflammatory Intervention Life Limb structure Maintenance Measurement Measures Mechanical ventilation Mechanics Messenger RNA Microcirculation Microscopy Modeling Morbidity - disease rate Muscle Muscle Cells Muscle function Myocardial Infarction Nitrates Nitric Oxide Nitric Oxide Pathway Organ Outcome Oxidants Pathway interactions Patients Performance Perfusion Peripheral Population Predisposition Production Property Quality of life Rattus Resistance Respiration Respiratory Diaphragm Respiratory Muscles Savings Skeletal Muscle Soluble Guanylate Cyclase Supplementation System Testing Therapeutic Therapeutic Intervention Time Vascular Diseases Vasoconstrictor Agents Vasodilation Vasomotor Ventilator Weaning aged base comorbidity cytokine experience hemodynamics human old age (65+)improved insight interstitial juvenile animal male mortality novel older patient optimal treatments phosphorescence pre-clinical preservation protein expression respiratory traditional therapy treatment strategy

项目摘要

PROJECT SUMMARY: Heart failure (HF) disproportionally afflicts the aged impairing muscle O2 transport, crippling the quality of life and predisposing the diaphragm to failure. This scenario has become all-too-common with the COVID-19 pandemic revealing HF as a major comorbidity and elderly patients disproportionally represented in the death toll. Established HF animal models overwhelmingly utilize young rather than old animals. Pathophysiologically, HF in aged individuals (HF+Aged) is a profoundly different disease from that in younger animals. Therefore, the mechanistic bases for dysfunction and therapeutic countermeasures must be addressed specifically in this population. HF compromises multiple O2 transport systems (especially respiratory, cardiovascular and muscular) with these effects coalescing in decreased skeletal muscle microcirculatory blood-myocyte O2 flux. This proposal address the mechanistic bases for HF+old-age-induced diaphragm dysfunction from a novel vertically-integrated perspective and assesses whether nitrate therapy and/or the sGC activator (BAY 60-2770) can protect, preserve or recover diaphragm vasomotor control in HF+Aged animals specifically during mechanical ventilation (MV). Preliminary data support that both HF+Aged muscle O2 delivery dysregulation can be ameliorated by strategies that increase nitric oxide (NO) bioavailability i.e., nitrate supplementation and target sGC. We will address the global hypothesis that, in HF+Aged rats, diaphragm vascular dysfunction reduces diaphragm O2 delivery and is exacerbated by MV via decreased NO bioavailability. Multi-targeted therapeutic interventions directed towards central and peripheral O2 transport system control will restore deficits in diaphragm capillary function and restore the O2 delivery/utilization balance. Strengths of our approach include: 1. Resolving and partitioning the perfusive and diffusive mechanisms impairing diaphragm O2 delivery in HF+Aged and with MV. 2. Our unique intravital diaphragm microscopy model facilitates direct observation of the microcirculation with high temporal fidelity determination of blood-myocyte O2 flux using phosphorescence quenching during contractions. 3. Circumventing the technical impossibility of making precise micron-level spatial [NO] measurements in contracting muscle by determining directly the endogenous NO contribution to capillary hemodynamics. 4. Providing novel empirical evidence supporting optimal treatment strategies for older HF patients with and without MV. 5. Testing, for the first time, the latest model of capillary function and blood-myocyte O2 flux during contractions. The proposed studies will provide novel and important data addressing diaphragm dysfunction in HF+Aged defining their mechanistic bases and assess the efficacy of feasible treatment strategies for older HF patients and especially those undergoing MV.

项目摘要：心力衰竭（HF）不成比例地折磨老年肌肉O2 运输，削弱生活质量，使隔膜失败。这种情况有与共同的19大流行有关HF作为主要合并症和老年人，变得非常普遍在死亡人数中代表的患者不成比例。建立的HF动物模型绝大多数利用年轻动物而不是老动物。从病理生理上，老年个体的HF（HF+老年）是一个与年轻动物中的疾病完全不同。因此，机械基础必须在该人群中专门解决功能障碍和治疗对策。 HF 妥协多个O2传输系统（尤其是呼吸系统，心血管和肌肉）这些影响在减少骨骼肌微循环血神经细胞O2通量中融合在一起。这提案解决了新颖的HF+老年诱导的diaphragm功能障碍的机械基础垂直综合的透视图，并评估硝酸盐治疗和/或SGC激活剂是否（BAY） 60-2770）可以在HF+老年动物中保护，保存或恢复diaphragm diaphragm diaphragm the 特别是在机械通气期间（MV）。 HF+老年肌肉的初步数据支持 O2递送失调可以通过增加一氧化氮（NO）生物利用度的策略来改善即，补充硝酸盐和靶标SGC。我们将解决全球假设，即HF+老年大鼠，diaphragm血管功能障碍可减少diaphragm o2递送，并被MV通过没有生物利用度降低。针对中央的多目标治疗干预措施外围O2运输系统控制将恢复diaphragm毛细管功能的缺陷并恢复 O2交付/利用余额。我们方法的优势包括：1。解决和划分普及和扩散 HF+年龄和MV中diaphragm o2递送的机制会损害diaphragm o2的递送。 2。我们独特的插入隔膜显微镜模型促进了高时间直接观察微循环在收缩过程中，使用磷光淬灭来确定血细胞O2通量。 3。避免进行精确的微米级空间[no]测量的技术不可能的可能性通过直接确定内源性对毛细管的无贡献来收缩肌肉血液动力学。 4。提供新颖的经验证据，为老年人提供最佳治疗策略 HF患者有或没有MV。 5。首次测试毛细管功能的最新模型和收缩期间血细胞O2通量。拟议的研究将提供新颖而重要的数据解决HF+老年diaphragm功能障碍，以定义其机械基础并评估可行治疗策略对老年HF患者，尤其是患有MV的疗效。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Monocrotaline-induced Pulmonary Hypertension Impairs Diaphragm Vasomotor Function.

野百合碱引起的肺动脉高压会损害膈肌血管舒缩功能。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Horn,AndrewG;Schulze,KianaM;Baumfalk,DrydenR;Weber,RamonaE;Kunkel,OliviaN;Musch,TimothyI;Poole,DavidC;Behnke,BradleyJ
通讯作者：
Behnke,BradleyJ

Supplemental oxygen administration during mechanical ventilation reduces diaphragm blood flow and oxygen delivery.

机械通气期间补充氧气会减少膈肌血流量和氧气输送。

DOI：
10.1152/japplphysiol.00021.2022
发表时间：
2022
期刊：
Journal of applied physiology (Bethesda, Md. : 1985)
影响因子：
0
作者：
Horn,AndrewG;Kunkel,OliviaN;Schulze,KianaM;Baumfalk,DrydenR;Weber,RamonaE;Poole,DavidC;Behnke,BradleyJ
通讯作者：
Behnke,BradleyJ

Pulmonary hypertension alters blood flow distribution and impairs the hyperemic response in the rat diaphragm.