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

Abstract

OBJECTIVES:

Reperfusion after myocardial ischemia goes together with alteration of the beta-adrenergic (betaAR) signaling. Especially the level and catalytic activity of beta AR kinase (betaARK1) are increased. We hypothesized that myocardial expression of a betaARK1 inhibitor (betaARKct) 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 betaARKct transgene (Adeno-betaARKct). At day 5, the hearts were explanted after cold cardioplegic arrest, and preserved at 4 degrees 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 betaAR agonist isoproterenol. However, these parameters remained within a normal range in Adeno-betaARKct-expressing hearts arrested and preserved for 4 h. Biochemical analysis shows a reduced betaAR density and an impaired signaling after reperfusion of hearts arrested for 4 h whereas it is normalized in Adeno-betaARKct-expressing hearts.

CONCLUSION:

Myocardial gene-mediated inhibition of betaARK1 via betaARKct expression avoids ventricular dysfunction after prolonged preservation. Therefore, this may represent a way of improving early results of cardiac transplantation and perioperative function.

• Authors: Hendrik T Tevaearai, G Brant Walton, Andrea D Eckhart, Janelle R Keys, Walter J Koch
• Journal: European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery (Eur J Cardiothorac Surg) Vol. 22 Issue 5 Pg. 733-7 (Nov 2002) ISSN: 1010-7940 [Print] Germany
• PMID: 12414039 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2002 Elsevier Science B.V.

Chemical References

• Cyclic AMP-Dependent Protein Kinases
• beta-Adrenergic Receptor Kinases

Topics

• Adenoviridae (genetics)
• Animals
• Cyclic AMP-Dependent Protein Kinases (genetics, metabolism)
• Genetic Therapy (methods)
• Genetic Vectors (administration & dosage)
• Heart Arrest, Induced (adverse effects)
• Heart Transplantation (adverse effects)
• Myocardial Contraction
• Myocardial Reperfusion Injury (complications, enzymology, prevention & control)
• Preservation, Biological
• Rabbits
• Transgenes
• Ventricular Dysfunction, Left (etiology, prevention & control)
• beta-Adrenergic Receptor Kinases