title: Histopathological assessment of calcification and inflammation of calcific aortic valves from patients with and without diabetes mellitus.
abstract: BACKGROUND
  Calcific aortic valve disease (CAVD) is the most common valvular heart disease and likely evolves from inflammatory pre-conditions in the valve. Type II diabetes mellitus (DMII) has been associated with pathogenesis of CAVD, however, the mechanism initiating CAVD in DMII is not well understood and the human valve pathology in DMII has not been described. We therefore performed quantitative histological analyses of aortic valves of CAVD patients with and without DMII.
  
  
  METHODS
  CAVD human aortic valves (n=45) obtained after surgical valve replacement were examined macroscopically with gross measurements of calcified areas. Inflammation and calcification were assessed by immunohistochemistry and immunofluorescence staining.
  
  
  RESULTS
  Calcification was increased in diabetic patients according to gross measurements (p<0.01) and alizarin red staining (p=0.05). Early calcification markers, including Runx2 (p=0.02) and alkaline phosphatase (ALP, p=0.03) were significantly elevated in diabetic patients. Furthermore, in diabetic patients we found significantly increased expression of annexin II (p=0.04) and annexin V (p=0.04), both of which are thought to play a role in microcalcification formation via apoptosis or extracellular vesicle release. Macrophage numbers were comparable in both groups (p=0.41), while the expression of the pro-inflammatory protein S100A9 (p<0.01) was significantly decreased in diabetic individuals. Evaluation of lymphocytes revealed similar CD8 (p=0.45) and CD4 (p=0.92) T cell counts in diabetic and non-diabetic aortic valves.
  
  
  CONCLUSIONS
  Aortic valves from diabetic patients show more calcification, while inflammation is similar in both patient populations. Considering the generally accepted theory of an inflammation-dependent mechanism of calcification, these data suggest that in patients with CAVD requiring valve replacement, diabetic patients could be molecularly in a more advanced disease stage with a higher grade of mineralization than non-diabetic patients.
authors.affiliation: Center of Excellence in Vascular Biology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.|Department of Cardiology, University Hospital, Heidelberg, Germany.
authors.forename: Josephin
authors.initials: J
authors.lastname: Mosch
authors.affiliation: Department of Cardiology, University Hospital, Heidelberg, Germany.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Gleissner
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Body
authors.affiliation: Center of Excellence in Vascular Biology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.|Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, USA. eaikawa@partners.org.
authors.forename: Elena
authors.initials: E
authors.lastname: Aikawa
mesh_terms: D000368:Aged; D001021:Aortic Valve / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000150:complications* / Q000473:pathology*; D002114:Calcinosis / Q000150:complications* / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008297:Male; D008875:Middle Aged