title: Inhibition of cusp and aortic wall calcification in ethanol- and aluminum-treated bioprosthetic heart valves in sheep: background, mechanisms, and synergism.
abstract: OBJECTIVE
  Calcification of bioprosthetic heart valves fabricated from glutaraldehyde (GA)-pretreated heterograft tissue is frequently responsible for the clinical failure of these devices. Stentless bioprostheses fabricated from GA-fixed porcine aortic valves pose an important challenge in this regard, as pathologic calcification can affect not only the bioprosthetic cusps, but also the aortic wall segment.
  
  
  METHODS
  A synergistic approach was used to prevent bioprosthetic cusp and aortic wall calcification. Ethanol pretreatment of bioprosthetic heart valves was shown to inhibit cuspal calcification due to multiple mechanisms, including alterations of collagen structure and lipid extraction. AlCl3 pretreatment of bioprostheses to prevent calcification was also investigated; this alters elastin structure, inhibits alkaline phosphatase, and complexes with phosphoesters, thereby inhibiting aortic wall mineralization.
  
  
  RESULTS
  Experimental data from rat subdermal implants and sheep mitral replacements showed successful synergism with co-pretreatment of porcine aortic valve bioprostheses with ethanol and AlCl3. Significant inhibition of both cusp and aortic wall calcification was achieved by differential pretreatments that restrict AlCl3 to only the aortic wall, and not the cusp, accompanied by ethanol cuspal exposure. Sequential exposure of bioprostheses, first to AlCl3 and then to ethanol, led to unexpectedly severe cuspal calcification.
  
  
  CONCLUSIONS
  Differential pretreatment of stentless bioprostheses with ethanol and AlCl3 can effectively inhibit both cuspal and aortic wall calcification.
authors.affiliation: Children's Hospital of Philadelphia, Abramson Pediatric Research Center, Philadelphia, PA 19104, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Levy
authors.forename: Narendra
authors.initials: N
authors.lastname: Vyavahare
authors.forename: Matthew
authors.initials: M
authors.lastname: Ogle
authors.forename: Paul
authors.initials: P
authors.lastname: Ashworth
authors.forename: Richard
authors.initials: R
authors.lastname: Bianco
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Schoen
mesh_terms: D000535:Aluminum / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000818:Animals; D001021:Aortic Valve / Q000187:drug effects* / Q000473:pathology*; D001705:Bioprosthesis; D002114:Calcinosis / Q000188:drug therapy*; D020099:Coated Materials, Biocompatible / Q000494:pharmacology*; D024042:Collagen Type I / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004549:Elastin / Q000187:drug effects; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D006349:Heart Valve Diseases / Q000188:drug therapy*; D006350:Heart Valve Prosthesis; D050356:Lipid Metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008955:Models, Cardiovascular; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep; D012997:Solvents / Q000494:pharmacology*
chemical_list: D020099:Coated Materials, Biocompatible; D024042:Collagen Type I; D012997:Solvents; D000431:Ethanol; D004549:Elastin; D000535:Aluminum