title: Molecular Mechanisms Linking Autonomic Dysfunction and Impaired Cardiac Contractility in Critical Illness.
abstract: Molecular mechanisms linking autonomic dysfunction with poorer clinical outcomes in critical illness remain unclear. We hypothesized that baroreflex dysfunction alone is sufficient to cause cardiac impairment through neurohormonal activation of (nicotinamide adenine dinucleotide phosphate oxidase dependent) oxidative stress resulting in increased expression of G-protein-coupled receptor kinase 2, a key negative regulator of cardiac function.
  
  
  
  Laboratory/clinical investigations.
  
  
  
  University laboratory/medical centers.
  
  
  
  Adult rats; wild-type/nicotinamide adenine dinucleotide phosphate oxidase subunit-2-deficient mice; elective surgical patients.
  
  
  
  Cardiac performance was assessed by transthoracic echocardiography following experimental baroreflex dysfunction (sino-aortic denervation) in rats and mice. Immunoblots assessed G-protein-coupled receptor recycling proteins expression in rodent cardiomyocytes and patient mononuclear leukocytes. In surgical patients, heart rate recovery after cardiopulmonary exercise testing, time/frequency measures of parasympathetic variables were related to the presence/absence of baroreflex dysfunction (defined by spontaneous baroreflex sensitivity of <6 ms mm Hg). The associations of baroreflex dysfunction with intraoperative cardiac function and outcomes were assessed.
  
  
  
  Experimental baroreflex dysfunction in rats and mice resulted in impaired cardiac contractility and upregulation of G-protein-coupled receptor kinase 2 expression. In mice, genetic deficiency of gp91 nicotinamide adenine dinucleotide phosphate oxidase subunit-2 prevented upregulation of G-protein-coupled receptor kinase 2 expression in conditions of baroreflex dysfunction and preserved cardiac function. Baroreflex dysfunction was present in 81 of 249 patients (32.5%) and was characterized by lower parasympathetic tone and increased G-protein-coupled receptor kinase 2 expression in mononuclear leukocytes. Baroreflex dysfunction in patients was also associated with impaired intraoperative cardiac contractility. Critical illness and mortality were more frequent in surgical patients with baroreflex dysfunction (relative risk, 1.66 [95% CI, 1.16-2.39]; p = 0.006).
  
  
  
  Reduced baroreflex sensitivity is associated with nicotinamide adenine dinucleotide phosphate oxidase subunit-2-mediated upregulation of G-protein-coupled receptor kinase 2 expression in cardiomyocytes and impaired cardiac contractility. Autonomic dysfunction predisposes patients to the development of critical illness and increases mortality.
authors.affiliation: 1Clinical Physiology, Division of Medicine, University College London, London, United Kingdom. 2University College London/University College London Hospitals NIHR Biomedical Research Centre, London, United Kingdom. 3Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom. 4William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. 5Peninsula Medical School, Plymouth, United Kingdom. 6British Heart Foundation Centre for Excellence, Kings College, London, United Kingdom.
authors.forename: Gareth L
authors.initials: GL
authors.lastname: Ackland
authors.forename: John
authors.initials: J
authors.lastname: Whittle
authors.forename: Andrew
authors.initials: A
authors.lastname: Toner
authors.forename: Asif
authors.initials: A
authors.lastname: Machhada
authors.forename: Ana Gutierrez
authors.initials: AG
authors.lastname: Del Arroyo
authors.forename: Alberto
authors.initials: A
authors.lastname: Sciuso
authors.forename: Nicholas
authors.initials: N
authors.lastname: Jenkins
authors.forename: Alex
authors.initials: A
authors.lastname: Dyson
authors.forename: Richard
authors.initials: R
authors.lastname: Struthers
authors.forename: J Robert
authors.initials: JR
authors.lastname: Sneyd
authors.forename: Gary
authors.initials: G
authors.lastname: Minto
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Gourine
mesh_terms: D000818:Animals; D017704:Baroreflex / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology; D016638:Critical Illness; D004452:Echocardiography; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D006321:Heart / Q000503:physiopathology*; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D011183:Postoperative Complications / Q000453:epidemiology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013514:Surgical Procedures, Operative / Q000379:methods; D015854:Up-Regulation
chemical_list: D019255:NADPH Oxidases; D054769:G-Protein-Coupled Receptor Kinase 2