The fibrin-derived peptide Bbeta(15-42) significantly attenuates ischemia-reperfusion injury in a cardiac transplant model.
BACKGROUND
The inflammatory response after prolonged ischemia and subsequent reperfusion leads to increased risk of primary organ dysfunction after cardiac transplantation. It has been demonstrated that the fibrin-derived peptide Bbeta(15-42) (also called FX06) reduces infarct size in coronary artery occlusion/reperfusion models by inhibition of leukocyte migration. Further, Bbeta(15-42) preserves endothelial barrier function. The purpose of this study was to investigate whether Bbeta(15-42) has a protective effect in cardiac allografts exposed to prolonged global ischemia and subsequent in vivo reperfusion.


METHODS
Hearts of male Lewis rats were flushed and stored in cold Bretschneider preservation solution for 4 or 8 hr. Bbeta(15-42) was administered before being transplanted into syngeneic recipients. Serum samples were collected for troponin-T measurements. Hemodynamic performance was evaluated after a reperfusion period of 24 hr. Morphologic quantification of myocardial necrosis was performed in hearts exposed to 24 hr or 10 days of reperfusion.


RESULTS
Allografts from Bbeta(15-42) treated animals showed less myocardial necrosis (2.5% +/- 2.5% vs. 18.4% +/- 9.2%, P=0.0019) and decreased values of cardiac troponin-T (1.1 +/- 0.6 ng/mL vs. 2.7+/-2.3 ng/mL, P=0.0045), reduced number of infiltrating leukocytes (7.2 +/- 13.6 vs. 49.2 +/- 34.9 per high powerfield, P=0.0045), and superior cardiac output (78.1 +/- 1.8 mL/min vs. 21.7 +/- 4 mL/min, P = 0.0034). Hearts exposed to 0 and 4 hr of ischemia showed no severe signs of myocardial damage.


CONCLUSIONS
Bbeta(15-42) ameliorates the ischemia-reperfusion injury in transplanted hearts during extended cold ischemia by reduction of infiltrating leukocytes. This experimental protocol provides evidence that Bbeta(15-42) may play a useful role in organ preservation, but clinical evaluation is warranted.
Wiedemann
Dominik
D
Department of Cardiac Surgery, Innsbruck Medical University, Innsbruck, Austria.
Schneeberger
Stefan
S
Friedl
Peter
P
Zacharowski
Kai
K
Wick
Nikolaus
N
Boesch
Florian
F
Margreiter
Raimund
R
Laufer
Guenther
G
Petzelbauer
Peter
P
Semsroth
Severin
S
D000818:Animals; D015415:Biomarkers / Q000097:blood; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D050377:Cold Ischemia / Q000009:adverse effects*; D005338:Fibrin Fibrinogen Degradation Products / Q000494:pharmacology*; D016027:Heart Transplantation / Q000009:adverse effects*; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D008297:Male; D023421:Models, Animal; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D019188:Organ Preservation Solutions / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors; D014184:Transplantation, Homologous; D020107:Troponin T / Q000097:blood; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
D015415:Biomarkers; D002316:Cardiotonic Agents; D005338:Fibrin Fibrinogen Degradation Products; D019188:Organ Preservation Solutions; D010446:Peptide Fragments; D020107:Troponin T; C033786:fibrinogen Bbeta (15-42)