DO HEART FAILURE AND AGING POTENTIATE DIAPHRAGM VASCULAR DYSFUNCTION?

项目总结：心力衰竭（HF）严重影响老年人受损的肌肉O2 运输，削弱生活质量和诱发隔膜故障。这种情况下， 随着COVID-19大流行显示HF是主要的合并症和老年人， 在死亡人数中有代表性的病人。已建立的HF动物模型绝大多数 利用年轻的动物而不是年老的动物。从病理生理学上讲，老年人的HF（HF+Aged）是一种 与年轻动物的疾病有着深刻的不同。因此， 功能障碍和治疗对策必须特别针对这一人群。HF 损害多种O2运输系统（特别是呼吸系统、心血管系统和肌肉系统）， 这些作用合并在骨骼肌微循环血-肌细胞O2通量降低中。这 一项提案从一种新的角度阐述了HF+老年诱导的膈肌功能障碍的机制基础。 垂直整合的角度，并评估是否硝酸盐治疗和/或sGC激活剂（BAY 60-2770）可保护、保存或恢复HF+老龄动物的膈肌血管扩张控制 特别是在机械通气（MV）期间。初步数据支持HF+老年肌肉 O2输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 也就是说，硝酸盐补充和目标sGC。我们将讨论全球假设，即在HF+老年人中， 在大鼠中，膈肌血管功能障碍减少了膈肌O2的输送，并通过 降低NO生物利用度。针对中枢神经系统和 外周O2转运系统控制将恢复隔膜毛细血管功能的缺陷， O2输送/利用平衡。 我们的方法的优势包括：1.对灌注性和扩散性进行分解和分区 在HF+老年人和MV中损害隔膜O2输送的机制。2.我们独特的活体 隔膜显微镜模型有利于直接观察微循环， 在收缩期间使用磷光猝灭的血-肌细胞O2通量的保真度测定。 3.避免在技术上无法进行精确的微米级空间[NO]测量 通过直接测定内源性NO对毛细血管的贡献， 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 有和无MV的HF患者。5.首次测试最新型号的毛细血管功能， 收缩期间血-肌细胞O2流量。拟议的研究将提供新的和重要的数据 解决HF+老年人的膈肌功能障碍，定义其机制基础，并评估 老年HF患者，尤其是接受MV的患者的可行治疗策略的有效性。

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.