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？

• 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
• 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

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)不成比例地困扰着老年人受损的肌肉氧气 运输，削弱了生活质量，使隔膜容易出现故障。这个场景有 随着新冠肺炎大流行的流行，心力衰竭变得非常常见，显示出心力衰竭是一种主要的老年共病 患者在死亡人数中所占比例不成比例。建立压倒性的心力衰竭动物模型 利用年轻的动物，而不是年老的动物。从病理生理学上讲，老年人心力衰竭(HF+AGE)是一种 这种疾病与年轻动物的疾病截然不同。因此，其产生的机制基础 功能障碍和治疗对策必须在这一人群中得到专门的解决。高频 损害多种氧气运输系统(特别是呼吸、心血管和肌肉) 这些作用汇聚成骨骼肌微循环血液-心肌细胞氧流量降低。这 建议从一个新的角度解决HF+老年性隔膜功能障碍的机制基础 垂直整合的观点和评估硝酸盐疗法和/或sGC激活剂(BAY) 60-2770)可保护、保存或恢复心力衰竭+老年动物的膈肌血管运动控制 特别是在机械通气(MV)期间。初步数据支持HF+衰老肌肉 氧输送失调可以通过提高一氧化氮(NO)生物利用度的策略来改善 即硝酸盐补充剂和靶向sGC。我们将解决全球假设，即在HF+AGE中 大鼠，隔膜血管功能障碍减少了隔膜O2的输送，并通过MV加重 降低了无生物利用度。针对中央和中枢神经的多靶点治疗干预 外周O2转运系统的控制会恢复隔膜毛细血管功能的缺陷 氧气输送/利用平衡。 我们的方法的优点包括：1.分解和划分泛滥和扩散的 心力衰竭+老年组和MV组膈肌氧输送功能受损的机制。2.我们独一无二的生命中 横隔膜显微镜模型便于直接观察高时相微循环 用磷光猝灭测定收缩过程中血液-心肌细胞氧流量的保真度。 3.避免在技术上不可能进行精确的微米级空间[否]测量 通过直接测定内源性NO对毛细血管的贡献来收缩肌肉 血流动力学。4.提供新的经验证据，支持老年人的最佳治疗策略 有无机械通气的心衰患者。5.首次测试最新型号的毛细管功能和 收缩过程中的血液-心肌细胞氧流量。拟议的研究将提供新的和重要的数据 治疗心力衰竭+老年患者的隔膜功能障碍明确其机制基础并评估 可行的治疗策略对老年心衰患者，尤其是接受机械通气的患者的疗效。

项目成果

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。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 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)
• 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.

• DOI: 10.3389/fphys.2023.1281715
• 发表时间: 2023
• 期刊: Frontiers in physiology
• 影响因子: 4

Post-occlusive reactive hyperemia and skeletal muscle capillary hemodynamics.

卵巢后反应性充血和骨骼肌毛细血管血液动力学。

• DOI: 10.1016/j.mvr.2021.104283
• 发表时间: 2022-03
• 期刊: Microvascular research
• 影响因子: 3.1
• 作者: Horn AG;Schulze KM;Weber RE;Barstow TJ;Musch TI;Poole DC;Behnke BJ
• 通讯作者: Behnke BJ

Head-up tilt does not enhance prostate tumor perfusion or oxygenation in young rats.

头部倾斜不会增强年轻大鼠的前列腺肿瘤灌注或氧合。

• DOI: 10.14814/phy2.15548
• 发表时间: 2022-12
• 期刊: Physiological reports
• 影响因子: 2.5