title: Cold ischemia contributes to the development of chronic rejection and mitochondrial injury after cardiac transplantation.
abstract: Chronic rejection (CR) remains an unsolved hurdle for long-term heart transplant survival. The effect of cold ischemia (CI) on progression of CR and the mechanisms resulting in functional deficit were investigated by studying gene expression, mitochondrial function, and enzymatic activity. Allogeneic (Lew→F344) and syngeneic (Lew→Lew) heart transplantations were performed with or without 10 h of CI. After evaluation of myocardial contraction, hearts were excised at 2, 10, 40, and 60 days for investigation of vasculopathy, gene expression, enzymatic activities, and mitochondrial respiration. Gene expression studies identified a gene cluster coding for subunits of the mitochondrial electron transport chain regulated in response to CI and CR. Myocardial performance, mitochondrial function, and mitochondrial marker enzyme activities declined in all allografts with time after transplantation. These declines were more rapid and severe in CI allografts (CR-CI) and correlated well with progression of vasculopathy and fibrosis. Mitochondria related gene expression and mitochondrial function are substantially compromised with the progression of CR and show that CI impacts on progression, gene profile, and mitochondrial function of CR. Monitoring mitochondrial function and enzyme activity might allow for earlier detection of CR and cardiac allograft dysfunction.
authors.affiliation: Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Innsbruck Medical University, Anichstrasse 35, Innsbruck, Austria. stefan.schneeberger@i-med.ac.at
authors.forename: Stefan
authors.initials: S
authors.lastname: Schneeberger
authors.forename: Albert
authors.initials: A
authors.lastname: Amberger
authors.forename: Julia
authors.initials: J
authors.lastname: Mandl
authors.forename: Theresa
authors.initials: T
authors.lastname: Hautz
authors.forename: Oliver
authors.initials: O
authors.lastname: Renz
authors.forename: Peter
authors.initials: P
authors.lastname: Obrist
authors.forename: Hugo
authors.initials: H
authors.lastname: Meusburger
authors.forename: Gerald
authors.initials: G
authors.lastname: Brandacher
authors.forename: Walter
authors.initials: W
authors.lastname: Mark
authors.forename: Daniela
authors.initials: D
authors.lastname: Strobl
authors.forename: Jakob
authors.initials: J
authors.lastname: Troppmair
authors.forename: Johann
authors.initials: J
authors.lastname: Pratschke
authors.forename: Raimund
authors.initials: R
authors.lastname: Margreiter
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Kuznetsov
mesh_terms: D000818:Animals; D050377:Cold Ischemia; D020869:Gene Expression Profiling; D006084:Graft Rejection; D016027:Heart Transplantation / Q000009:adverse effects / Q000502:physiology*; D008297:Male; D008929:Mitochondria, Heart / Q000502:physiology*; D009200:Myocardial Contraction; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous