title: Prolonging hypothermic ischaemic cardiac and vascular storage by inhibiting the activation of the nuclear enzyme poly(adenosine diphosphate-ribose) polymerase.
abstract: OBJECTIVE
  Heart transplantation is the standard treatment in end-stage heart failure and at shortage of cardiac allografts is its major limiting factor. Striving to optimize the use of this limited resource, the aspect that long distance procurement may increase the available donor pool must be taken into consideration. As poly(ADP-ribose)polymerase (PARP)-activation has been identified as a key pathway of reperfusion injury, we assessed the hypothesis that its inhibition would allow an extension of cold preservation time and protect the graft against ischaemia/reperfusion injury.
  
  
  METHODS
  Hearts from donor rats were explanted, stored in a preservation solution (Custodiol) at 4 °C for 4 h or 8 h, and heterotopically transplanted. A vehicle or the PARP-inhibitor, INO-1001 (5 mg/kg), was administered during the reperfusion period. We evaluated post-transplant graft function with a Millar micromanometer at different left-ventricular volumes. Additionally, in organ bath experiments the effect of PARP-inhibition on endothelium-dependent and -independent vasorelaxation was evaluated after long-term cold ischaemic storage/warm reperfusion.
  
  
  RESULTS
  PARP-inhibition resulted in a better systolic functional recovery of grafts submitted to 4 h and 8 h ischaemia. Furthermore, INO-1001 decreased the left-ventricular end-diastolic pressure after 8 h of ischaemia. Coronary blood flow was significantly higher after PARP-inhibition in comparison to controls. Endothelium-dependent vasorelaxation was significantly better in the INO-1001-groups than in the vehicle-treated transplant groups. After 24-h hypothermic storage, treatment of aortic ring with INO-1001 during reoxygenation significantly improved endothelial dysfunction.
  
  
  CONCLUSIONS
  By inhibiting the PARP activation, INO-1001 can protect the graft and endothelium from the injury that is caused by prolonged cold myocardial ischaemia/reperfusion, thereby improving post-transplant graft function.
authors.affiliation: Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Sevil
authors.initials: S
authors.lastname: Korkmaz-Icöz
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Radovits
authors.affiliation: Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany.|Department of Anesthesiology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Sivakkanan
authors.initials: S
authors.lastname: Loganathan
authors.affiliation: Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Shiliang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany.|Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors.forename: Mihály
authors.initials: M
authors.lastname: Ruppert
authors.affiliation: Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
authors.forename: Kálmán
authors.initials: K
authors.lastname: Benke
authors.affiliation: Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Paige
authors.initials: P
authors.lastname: Brlecic
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch Galveston, Galveston, TX, USA.
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
authors.affiliation: Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Karck
authors.affiliation: Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Gábor
authors.initials: G
authors.lastname: Szabó
mesh_terms: D064591:Allografts / Q000187:drug effects*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D016027:Heart Transplantation; D007211:Indoles / Q000494:pharmacology; D008297:Male; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D051381:Rats; D014664:Vasodilation / Q000187:drug effects
chemical_list: C491685:INO 1001; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
keywords: Endothelial dysfunction; Heart transplantation ; Poly(ADP-ribose) polymerase 