DO HEART FAILURE AND AGING POTENTIATE DIAPHRAGM VASCULAR DYSFUNCTION?
DO HEART FAILURE AND AGING POTENTIATE DIAPHRAGM VASCULAR DYSFUNCTION?
批准号:
10203242
负责人:
Brad J Behnke
金额:
$45.6万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-09-30 至 2024-08-31
关键词:
AddressAgingAmericanAnimal ModelAnimalsArteriesAutomobile DrivingBiological AvailabilityBloodBlood VesselsBlood capillariesBlood flowBreathingCOVID-19COVID-19 pandemicCOVID-19 patientCardiovascular systemCessation of lifeContractsDataDiffuseDiseaseElderlyEndotheliumEquilibriumErythrocytesFailureFemaleFunctional disorderGoalsHeart failureImpairmentIndividualInflammatoryInterventionLifeLimb structureMaintenanceMeasurementMeasuresMechanical ventilationMechanicsMessenger RNAMicrocirculationMicroscopyModelingMorbidity - disease rateMuscleMuscle CellsMuscle functionMyocardial InfarctionNitratesNitric OxideNitric Oxide PathwayOrganOutcomeOxidantsPathway interactionsPatientsPerformancePerfusionPeripheralPopulationPredispositionProductionPropertyQuality of lifeRattusResistanceRespirationRespiratory DiaphragmRespiratory MusclesSavingsSkeletal MuscleSoluble Guanylate CyclaseSupplementationSystemTestingTherapeuticTherapeutic InterventionTimeVascular DiseasesVasoconstrictor AgentsVasodilationVasomotorVentilatorWeaningagedbasecomorbiditycytokineexperiencehemodynamicshuman old age (65+)improvedinsightinterstitialjuvenile animalmalemortalitynovelolder patientoptimal treatmentsphosphorescencepre-clinicalpreservationprotein expressionrespiratorytraditional therapytreatment strategy
中文摘要
项目摘要:心力衰竭(HF)不成比例地影响着老年受损的肌肉氧
英文摘要
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.
期刊论文(5)
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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:
--
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:
--
作者:
[Horn,AndrewG, Kunkel,OliviaN, Schulze,KianaM, Baumfalk,DrydenR, Weber,RamonaE, Poole,DavidC, Behnke,BradleyJ]
通讯作者:
Behnke,BradleyJ
DOI:
10.3389/fphys.2023.1281715
发表时间:
2023
期刊:
Frontiers in physiology
影响因子:
4
作者:
[]
通讯作者:
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
作者:
[]
通讯作者:
Bridges to the Baccalaureate Research Training Program at Kansas State University
-
批准号:10471923
-
项目类别:
-
资助金额:$27.68万
-
财政年份:2021
-
负责人:Brad J Behnke
-
依托单位:
Bridges to the Baccalaureate Research Training Program at Kansas State University
-
批准号:10270653
-
项目类别:
-
资助金额:$27.52万
-
财政年份:2021
-
负责人:Brad J Behnke
-
依托单位:
Bridges to the Baccalaureate Research Training Program at Kansas State University
-
批准号:10671697
-
项目类别:
-
资助金额:$27.73万
-
财政年份:2021
-
负责人:Brad J Behnke
-
依托单位:
Vascular Function with Aging, Viral Gene Therapy and Exercise Training
-
批准号:8123128
-
项目类别:
-
资助金额:$12.13万
-
财政年份:2008
-
负责人:Brad J Behnke
-
依托单位:
Vascular Function with Aging, Viral Gene Therapy and Exercise Training
-
批准号:8318711
-
项目类别:
-
资助金额:$12.13万
-
财政年份:2008
-
负责人:Brad J Behnke
-
依托单位:
Vascular Function with Aging, Viral Gene Therapy and Exercise Training
-
批准号:7916651
-
项目类别:
-
资助金额:$11.84万
-
财政年份:2008
-
负责人:Brad J Behnke
-
依托单位:
Vascular Function with Aging, Viral Gene Therapy and Exercise Training
-
批准号:7530464
-
项目类别:
-
资助金额:$11.28万
-
财政年份:2008
-
负责人:Brad J Behnke
-
依托单位:
Vascular Function with Aging, Viral Gene Therapy and Exercise Training
-
批准号:7682988
-
项目类别:
-
资助金额:$11.55万
-
财政年份:2008
-
负责人:Brad J Behnke
-
依托单位:
Vascular Structure and Function in Aged Skeletal Muscle
-
批准号:7232095
-
项目类别:
-
资助金额:$4.88万
-
财政年份:2006
-
负责人:Brad J Behnke
-
依托单位:
Vascular Structure and Function with Aging
-
批准号:7113456
-
项目类别:
-
资助金额:$4.6万
-
财政年份:2006
-
负责人:Brad J Behnke
-
依托单位:
Vascular Structure and Function with Aging
-
批准号:7385042
-
项目类别:
-
资助金额:$2.51万
-
财政年份:2006
-
负责人:Brad J Behnke
-
依托单位:
Minority Predoctoral Fellowship Program
-
批准号:6545736
-
项目类别:
-
资助金额:$2.41万
-
财政年份:2002
-
负责人:Brad J Behnke
-
依托单位:
Minority Predoctoral Fellowship Program
-
批准号:6608146
-
项目类别:
-
资助金额:$2.59万
-
财政年份:2002
-
负责人:Brad J Behnke
-
依托单位:
海外基金