title: Acute perioperative-stress-induced increase of atherosclerotic plaque volume and vulnerability to rupture in apolipoprotein-E-deficient mice is amenable to statin treatment and IL-6 inhibition.
abstract: Myocardial infarction and stroke are frequent after surgical procedures and consume a considerable amount of benefit of surgical therapy. Perioperative stress, induced by surgery, is composed of hemodynamic and inflammatory reactions. The effects of perioperative stress on atherosclerotic plaques are ill-defined. Murine models to investigate the influence of perioperative stress on plaque stability and rupture are not available. We developed a model to investigate the influence of perioperative stress on plaque growth and stability by exposing apolipoprotein-E-deficient mice, fed a high cholesterol diet for 7 weeks, to a double hit consisting of 30 min of laparotomy combined with a substantial blood loss (approximately 20% of total blood volume; 400 µl). The innominate artery was harvested 72 h after the intervention. Control groups were sham and baseline controls. Interleukin-6 (IL-6) and serum amyloid A (SAA) plasma levels were determined. Plaque load, vascular smooth muscle cell (VSMC) and macrophage content were quantified. Plaque stability was assessed using the Stary score and frequency of signs of plaque rupture were assessed. High-dose atorvastatin (80 mg/kg body weight/day) was administered for 6 days starting 3 days prior to the double hit. A single dose of an IL-6-neutralizing antibody or the fusion protein gp130-Fc selectively targeting IL-6 trans-signaling was subcutaneously injected. IL-6 plasma levels increased, peaking at 6 h after the intervention. SAA levels peaked at 24 h (n=4, P<0.01). Plaque volume increased significantly with the double hit compared to sham (n=8, P<0.01). More plaques were scored as complex or bearing signs of rupture after the double hit compared to sham (n=5-8, P<0.05). Relative VSMC and macrophage content remained unchanged. IL-6-inhibition or atorvastatin, but not blocking of IL-6 trans-signaling, significantly decreased plaque volume and complexity (n=8, P<0.01). Using this model, researchers will be able to further investigate the pathophysiology of perioperative plaque stability, which can result in myocardial infarction, and, additionally, to test potential protective strategies.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany Department of Anesthesiology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Henrike
authors.initials: H
authors.lastname: Janssen
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Christian S
authors.initials: CS
authors.lastname: Wagner
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Demmer
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Callies
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Gesine
authors.initials: G
authors.lastname: Sölter
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Houra
authors.initials: H
authors.lastname: Loghmani-khouzani
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Niandan
authors.initials: N
authors.lastname: Hu
authors.affiliation: Department of Cardiology, University Hospital Marburg, 35043 Marburg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Schuett
authors.affiliation: Department of Pediatrics, University of Groningen, UMCG, NL-9700 Groningen, The Netherlands.
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
authors.affiliation: Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany German Centre for Lung Research (DZL), 30625 Hannover, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Warnecke
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany Department of Anesthesiology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Larmann
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany Faculty VI - Medicine and Health Sciences, Dept of Health Services Sciences, University of Oldenburg, 26129 Germany Gregor.Theilmeier@uni-oldenburg.de.
authors.forename: Gregor
authors.initials: G
authors.lastname: Theilmeier
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D000069059:Atorvastatin / Q000627:therapeutic use; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007249:Inflammation; D007813:Laparotomy; D008074:Lipoproteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D059035:Perioperative Period; D058226:Plaque, Atherosclerotic / Q000503:physiopathology*; D012421:Rupture; D000685:Serum Amyloid A Protein / Q000378:metabolism; D015398:Signal Transduction; D000093242:Interleukin-6 Inhibitors; D015850:Interleukin-6
chemical_list: D001057:Apolipoproteins E; D000069059:Atorvastatin; D002784:Cholesterol; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D000685:Serum Amyloid A Protein; D000093242:Interleukin-6 Inhibitors; C577686:interleukin-6, mouse; D015850:Interleukin-6
keywords: Atherosclerosis; Mouse model; Perioperative stress