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Molecular Mechanisms Linking Autonomic Dysfunction and Impaired Cardiac Contractility in Critical Illness

Ackland, GL; Whittle, J; Toner, A; Machhada, A; Del Arroyo, AG; Sciuso, A; Jenkins, N; ... Gourine, AV; + view all (2016) Molecular Mechanisms Linking Autonomic Dysfunction and Impaired Cardiac Contractility in Critical Illness. Critical Care Medicine , 44 (8) e614-e624. 10.1097/CCM.0000000000001606. Green open access

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Abstract

OBJECTIVES: 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. DESIGN: Laboratory/clinical investigations. SETTING: University laboratory/medical centers. SUBJECTS: Adult rats; wild-type/nicotinamide adenine dinucleotide phosphate oxidase subunit-2–deficient mice; elective surgical patients. INTERVENTIONS: 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–1). The associations of baroreflex dysfunction with intraoperative cardiac function and outcomes were assessed. MEASUREMENTS AND MAIN RESULTS: 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). CONCLUSIONS: 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.

Type: Article
Title: Molecular Mechanisms Linking Autonomic Dysfunction and Impaired Cardiac Contractility in Critical Illness
Open access status: An open access version is available from UCL Discovery
DOI: 10.1097/CCM.0000000000001606
Publisher version: http://dx.doi.org/10.1097/CCM.0000000000001606
Language: English
Additional information: Copyright © by 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. This is a non-final version of an article published in final form in Critical Care Medicine.
Keywords: Science & Technology, Life Sciences & Biomedicine, Critical Care Medicine, General & Internal Medicine, autonomic dysfunction, cardiac contractility, G-protein-coupled receptor, G-protein-coupled receptor kinase, multiple organ dysfunction syndrome, sepsis, Randomized Controlled-trial, Coupled Receptor Kinases, Blood Mononuclear-cells, Heart-rate-variability, Beta-arrestins, Sinoaortic Denervation, Nervous-system, Severe Sepsis, Rate Recovery, Septic Shock
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Internal Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Targeted Intervention
URI: http://discovery.ucl.ac.uk/id/eprint/1489590
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