Time-dependent efficacy of initial reperfusion with 2,3 butanedione monoxime (BDM) on release of cytosolic enzymes and ultrastructural damage in isolated hearts.
BACKGROUND
Reperfusion injury after cardioplegia may not be sufficiently addressed by conventional cardioplegic techniques in open heart surgery. 2,3-butanedione monoxime (BDM) has the potential to reduce myocardial reperfusion injury by uncoupling myocyte contraction from the intracellular calcium concentration, thus reducing reperfusion contracture. The aim of this study was to investigate the effects of different application periods of BDM during initial reperfusion on myocardial tissue injury after cardioplegia.


METHODS
Isolated guinea-pig hearts underwent 50 min of cardioplegic arrest in St. Thomas' Hospital II solution at 37 C. Control hearts (n = 8) were immediately reperfused with normal Krebs-Henseleit solution for 30 min. In the therapy groups BDM-5, BDM-20, and BDM-40 (n = 8, each), hearts were initially reperfused with BDM (20mmol/L) for either 5, 20, or 40 min, respectively, followed by 30 min of reperfusion with normal Krebs-Henseleit solution. Coronary venous effluent was collected to estimate myocardial tissue damage through release of cytosolic enzymes (LDH and CK) and cardiac troponin 1. Ultrastructural alterations were qualitatively assessed by electron microscopy.


RESULTS
Initial reperfusion with BDM markedly reduced LDH and CK release, as long as BDM was present. After washout of the protective agent a rebound of enzyme release occurred in BDM-5 hearts which was effectively reduced in BDM-20 and BDM-40 hearts. Troponin I release was similarly increased in all groups at the onset of reperfusion and rapidly decreased thereafter. Myocardial ultrastructural damage was most pronounced in control hearts, intermediate in BDM-5 and BDM-40 hearts, but markedly attenuated in BDM-20 hearts.


CONCLUSIONS
Both 20 and 40 min of initial reperfusion effectively protected the hearts from reperfusion damage as indicated by cytosolic enzyme release, while 5 min of treatment were clearly insufficient. Toxic effects of BDM during the longer treatment period of 40 min or induction of edema by the long-term perfusion of non-beating hearts in this group may account for the worse preservation of myocardial ultrastructure in BDM-40 hearts. Thus, contraction uncoupling during initial reperfusion by BDM or similarly acting drugs may prove a viable principle for reduction of myocardial reperfusion injury. However, the ideal duration of treatment for the best therapeutic effect must be carefully evaluated.
Voigtländer
J
J
Institute for Surgical Research, Klinikum Grosshadern, University of Munich, Germany.
Leiderer
R
R
Mühlbayer
D
D
Habazettl
H
H
D000818:Animals; D015415:Biomarkers / Q000097:blood; D003402:Creatine Kinase / Q000097:blood; D003931:Diacetyl / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000097:blood; D015425:Myocardial Reperfusion / Q000379:methods*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D019188:Organ Preservation Solutions / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D019210:Troponin I / Q000097:blood
D015415:Biomarkers; D019188:Organ Preservation Solutions; D019210:Troponin I; C004717:diacetylmonoxime; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D003931:Diacetyl