Orthopedic surgery increases atherosclerotic lesions and necrotic core area in ApoE-/- mice.
Observational studies show a peak incidence of cardiovascular events after major surgery. For example, the risk of myocardial infarction increases 25-fold early after hip replacement. The acuteness of this increased risk suggests abrupt enhancement in plaque vulnerability, which may be related to intra-plaque inflammation, thinner fibrous cap and/or necrotic core expansion. We hypothesized that acute systemic inflammation following major orthopedic surgery induces such changes.



ApoE-/-mice were fed a western diet for 10 weeks. Thereafter, half the mice underwent mid-shaft femur osteotomy followed by realignment with an intramedullary K-wire, to mimic major orthopedic surgery. Mice were sacrificed 5 or 15 days post-surgery (n = 22) or post-saline injection (n = 13). Serum amyloid A (SAA) was measured as a marker of systemic inflammation. Paraffin embedded slides of the aortic root were stained to measure total plaque area and to quantify fibrosis, calcification, necrotic core, and inflammatory cells.



Surgery mice showed a pronounced elevation of serum amyloid A (SAA) and developed increased plaque and necrotic core area already at 5 days, which reached significance at 15 days (p = 0.019; p = 0.004 for plaque and necrotic core, respectively). Macrophage and lymphocyte density significantly decreased in the surgery group compared to the control group at 15 days (p = 0.037; p = 0.024, respectively). The density of neutrophils and mast cells remained unchanged.



Major orthopedic surgery in ApoE-/- mice triggers a systemic inflammatory response. Atherosclerotic plaque area is enlarged after surgery mainly due to an increase of the necrotic core. The role of intra-plaque inflammation in this response to surgical injury remains to be fully elucidated.
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands; Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: w.fuijkschot@vumc.nl.
Wessel W
WW
Fuijkschot
Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
Martine C
MC
Morrison
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Rianne
R
van der Linden
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.
Paul A J
PAJ
Krijnen
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Ilse P A
IPA
Zethof
Department Clinical Sciences and Services, Royal Veterinary College London, University of London, United Kingdom.
Lars F H
LFH
Theyse
Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands; Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
Robert
R
Kleemann
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands; Department of Cardiac Surgery, VU University Medical Center, Amsterdam, The Netherlands.
Hans W M
HWM
Niessen
Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands; Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
Yvo M
YM
Smulders
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology*; D001018:Aortic Diseases / Q000097:blood / Q000235:genetics / Q000473:pathology*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000473:pathology*; D015415:Biomarkers / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D005269:Femur / Q000601:surgery*; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000473:pathology*; D018836:Inflammation Mediators / Q000097:blood; D018345:Mice, Knockout; D009336:Necrosis; D010027:Osteotomy / Q000009:adverse effects*; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D000685:Serum Amyloid A Protein / Q000378:metabolism; D013997:Time Factors; D061205:Vascular Calcification / Q000097:blood / Q000235:genetics / Q000473:pathology
D001057:Apolipoproteins E; D015415:Biomarkers; D018836:Inflammation Mediators; D000685:Serum Amyloid A Protein
Animal model; Atherosclerosis; Inflammation; Myocardial infarction; Surgery