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Eur J Cardiothorac Surg 2002;22:733-737
© 2002 Elsevier Science NL

Donor heart contractile dysfunction following prolonged ex vivo preservation can be prevented by gene-mediated ß-adrenergic signaling modulation

^a Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
^b Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
^c Department of Cardiovascular Surgery, University Hospital, (CHUV), rue du Bugnon 46, CH-1011 Lausanne, Switzerland

Received 13 March 2002; received in revised form 24 July 2002; accepted 26 July 2002.

* Corresponding author. Tel.: +41-21-314-2280; fax: +41-21-314-2278
e-mail: hendrik.tevaearai{at}chuv.hospvd.ch

Objectives: Reperfusion after myocardial ischemia goes together with alteration of the ß-adrenergic (ßAR) signaling. Especially the level and catalytic activity of ß AR kinase (ßARK1) are increased. We hypothesized that myocardial expression of a ßARK1 inhibitor (ßARKct) may protect from post-reperfusion dysfunction. Methods: Two groups of rabbits were treated by intracoronary delivery of either phosphate-buffered saline (PBS) or a solution of adenovirus carrying the ßARKct transgene (Adeno-ßARKct). At day 5, the hearts were explanted after cold cardioplegic arrest, and preserved at 4 °C for 4 h. Reperfusion was hemodynamically standardized on a Langendorff apparatus with oxygenated Krebs solution for 30 min before left ventricular (LV) pressure was recorded using an LV latex balloon connected to a pressure transducer. Non-arrested hearts immediately perfused on the Langendorff apparatus served as controls. Results: LV contractility (LV dP/dt_max, P<0.05) and relaxation (LV dP/dt_min, P<0.05) were reduced, and end diastolic pressure (LV EDP) was increased after prolonged exposure to cold preservation solution as compared to normal control hearts, both under basal conditions and when stimulated with the ßAR agonist isoproterenol. However, these parameters remained within a normal range in Adeno-ßARKct-expressing hearts arrested and preserved for 4 h. Biochemical analysis shows a reduced ßAR density and an impaired signaling after reperfusion of hearts arrested for 4 h whereas it is normalized in Adeno-ßARKct-expressing hearts. Conclusion: Myocardial gene-mediated inhibition of ßARK1 via ßARKct expression avoids ventricular dysfunction after prolonged preservation. Therefore, this may represent a way of improving early results of cardiac transplantation and perioperative function.

Key Words: Transplantation • Myocardial preservation • ß-Adrenergic receptor • Gene therapy • Heart failure

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