Document text
Principal Investigator: Andrew Horn
Organization: KANSAS STATE UNIVERSITY
Fiscal Year: 2024
Award: $36,760
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Acetylcholine><Acetylcholine Agonists><Anatomic Sites><Anatomic structures><Anatomy><Ang I (1-7)><AngII><Angiotensin II><Animal Disease Models><Artificial Heart><Atrophic><Atrophy><Blood Vessels><Blood flow><Breathing><COVID-19><CV-19><Cardiac Diseases><Cardiac Disorders><Cardiac infarction><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cause of Death><Cholinergic Agonists><Clinical><Common Rat Strains><Complex thinking><Coronavirus Infectious Disease 2019><Critical Thinking><Data><Development><Diaphragm><Disease><Disorder><Drugs><Dysfunction><Educational process of instructing><Elements><Endothelium><Environment><Evaluative Thinking><Exhibits><Failure><Fatigue><Functional disorder><Goals><Health><Heart Diseases><Heart Vascular><Heart failure><Human><Hyperemia><Impairment><Infusion><Infusion procedures><Intervention><Intervention Strategies><Kansas><Kinesiology><Knowledge><L-NAME><Laboratories><Lack of Energy><Measurement><Measures><Mechanical ventilation><Medial><Mediator><Medication><Messenger RNA><Microbeads><Microspheres><Modern Man><Movement science><Muscle><Muscle Fatigue><Muscle Tissue><Muscle function><Muscular Fatigue><Myocardial Infarct><Myocardial Infarction><N omega-Nitro-L-arginine Methyl Ester><N(G)-Nitro-L-arginine Methyl Ester><N(G)-Nitroarginine Methyl Ester><NG-Nitro-L-Arginine Methyl Ester><NG-Nitroarginine Methyl Ester><O element><O2 element><Outcome><Oxygen><Pathology><Pathway interactions><Patients><Perfusion><Peripheral><Pharmaceutical Preparations><Pharmacological Treatment><Physiology><Physiopathology><Predisposition><Preparation><QOL><Quality of life><Rat><Rats Mammals><Rattus><Receptor Activation><Regulation><Relaxation><Renin-Angiotensin System><Research><Resistance><Respiratory Aspiration><Respiratory Diaphragm><Respiratory Inspiration><Respiratory Muscles><Role><Skeletal Muscle><Susceptibility><Teaching><Techniques><Testing><Time><Training><United States><Universities><Vascular Diseases><Vascular Disorder><Vascular resistance><Vasodilatation><Vasodilating Agent><Vasodilation><Vasodilator Agents><Vasodilator Drugs><Vasodilators><Vasomotor><Vasorelaxation><Ventilator><Ventilatory Muscles><Voluntary Muscle><Weaning><angiotensin I (1-7)><angiotensin-(1-7)><arteriole><blood vessel disorder><cardiac failure><cardiac infarct><cardiac prosthesis><career><circulatory system><coronary attack><coronary infarct><coronary infarction><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><developmental><drug/agent><endothelial dysfunction><exercise intolerance><experiment><experimental research><experimental study><experiments><frontier><heart attack><heart disorder><heart infarct><heart infarction><heart prosthesis><improved><in vivo><infusions><insight><inspiration><interventional strategy><mRNA><mechanical heart><mechanical respiratory assist><mechanically ventilated><mortality><muscular><neglect><novel><pathophysiology><pathway><patient population><pharmacologic><preparations><preservation><prevent><preventing><prosthetic heart><protein expression><resistant><response><skills><social role><vascular><vascular dysfunction><vasculopathy>