title: Understanding the structural features of symptomatic calcific aortic valve stenosis: A broad-spectrum clinico-pathologic study in 236 consecutive surgical cases.
abstract: BACKGROUND
  With age, aortic valve cusps undergo varying degrees of sclerosis which, sometimes, can progress to calcific aortic valve stenosis (AVS). To perform a retrospective clinico-pathologic investigation in patients with calcific AVS.
  
  
  METHODS
  We characterized and graded the structural remodeling in 236 aortic valves (200 tricuspid and 36 bicuspid) from patients with calcific AVS (148 males; average 72years); possible relationships between general/clinical/echocardiographic characteristics and the histopathologic changes were explored. Twenty autopsy aortic valves served as controls. In 40 cases, we also tested the immunohistochemical expression of metalloproteinases and cytokines, and characterized the inflammatory infiltrate. In 5 cases, we cultured cusp stem cells and explored their potential to differentiate into osteoblasts/adipocytes.
  
  
  RESULTS
  AVS cusps showed structural remodeling as severe fibrosis (100%), calcific nodules (100%), neoangiogenesis (81%), inflammation (71%), bone metaplasia with or without hematopoiesis (6% and 53%, respectively), adipose metaplasia (16%), and cartilaginous metaplasia (7%). At multivariate analysis, AVS degree and interventricular septum thickness were the only predictors of remodeling (barring inflammation). All the tested metalloproteinases (except MMP-13) and cytokines were expressed in AVS cusps. Inflammation mainly consisted of B and T lymphocytes (CD4+/CD8+ cell ratio 3:1) and plasma cells. AVS changes were mostly different from typical atherosclerosis. Cultured mesenchymal cusp stem cells could differentiate into osteoblasts/adipocytes.
  
  
  CONCLUSIONS
  Structural remodeling in AVS is peculiar and considerable, and is related to the severity of the disease. However, the different newly formed tissues-where "valvular interstitial cells" play a key role-and their well-known slow turnover suggest a reverse structural remodeling improbable.
authors.affiliation: Department of Biomedical, Biotechnological, and Translational Sciences (S. Bi. Bi. T.), Anatomy and Histology Unit, University of Parma, Parma, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Galli
authors.affiliation: Department of Biomedical, Biotechnological, and Translational Sciences (S. Bi. Bi. T.), Unit of Pathology, University of Parma, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Manuguerra
authors.affiliation: Department of Biomedical, Biotechnological, and Translational Sciences (S. Bi. Bi. T.), Unit of Pathology, University of Parma, Italy.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Monaco
authors.affiliation: Department of Biomedical, Biotechnological, and Translational Sciences (S. Bi. Bi. T.), Unit of Pathology, University of Parma, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Manotti
authors.affiliation: Department of Clinical and Experimental Medicine, Unit of Occupational and Environmental Medicine, University of Parma, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Goldoni
authors.affiliation: Department of Biomedical, Biotechnological, and Translational Sciences (S. Bi. Bi. T.), Unit of Pathology, University of Parma, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Becchi
authors.affiliation: Department of Biomedical, Biotechnological, and Translational Sciences (S. Bi. Bi. T.), Anatomy and Histology Unit, University of Parma, Parma, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Carubbi
authors.affiliation: Department of Biomedical, Biotechnological, and Translational Sciences (S. Bi. Bi. T.), Unit of Forensic Medicine, University of Parma, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Vignali
authors.affiliation: Department of Biomedical, Biotechnological, and Translational Sciences (S. Bi. Bi. T.), Unit of Forensic Medicine, University of Parma, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Cucurachi
authors.affiliation: Department of Clinical and Experimental Medicine, Cardiac Surgery Unit, University of Parma, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Gherli
authors.affiliation: Department of Clinical and Experimental Medicine, Cardiac Surgery Unit, University of Parma, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Nicolini
authors.affiliation: Cardio-Thoracic Surgery Department, Heart and Vascular Centre, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Roberto
authors.initials: R
authors.lastname: Lorusso
authors.affiliation: Department of Biomedical, Biotechnological, and Translational Sciences (S. Bi. Bi. T.), Anatomy and Histology Unit, University of Parma, Parma, Italy; CoreLab Scientific Director, University Hospital, Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Vitale
authors.affiliation: Department of Biomedical, Biotechnological, and Translational Sciences (S. Bi. Bi. T.), Unit of Pathology, University of Parma, Italy. Electronic address: domenico.corradi@unipr.it.
authors.forename: Domenico
authors.initials: D
authors.lastname: Corradi
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001021:Aortic Valve / Q000000981:diagnostic imaging / Q000473:pathology* / Q000601:surgery; D001024:Aortic Valve Stenosis / Q000000981:diagnostic imaging / Q000401:mortality* / Q000473:pathology / Q000601:surgery*; D001344:Autopsy; D001707:Biopsy, Needle; D002114:Calcinosis / Q000000981:diagnostic imaging / Q000401:mortality* / Q000473:pathology / Q000601:surgery*; D016022:Case-Control Studies; D002423:Cause of Death; D015331:Cohort Studies; D004452:Echocardiography / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D019918:Heart Valve Prosthesis Implantation / Q000379:methods / Q000401:mortality; D006801:Humans; D007150:Immunohistochemistry; D007558:Italy; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012189:Retrospective Studies; D018570:Risk Assessment; D012737:Sex Factors; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D016896:Treatment Outcome
keywords: Aortic valve stenosis; Histopathology; Osseous metaplasia; Structural remodeling; Valvular interstitial cells