The fibrin-derived peptide Bbeta(15-42) significantly attenuates ischemia-reperfusion injury in a cardiac transplant model.

Contains fulltext : 87825.pdf (publisher's version ) (Closed access)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. CONCLUSION: 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

Nitric oxide homeostasis as a target for drug additives to cardioplegia

The vascular endothelium of the coronary arteries has been identified as the important organ that locally regulates coronary perfusion and cardiac function by paracrine secretion of nitric oxide (NO) and vasoactive peptides. NO is constitutively produced in endothelial cells by endothelial nitric oxide synthase (eNOS). NO derived from this enzyme exerts important biological functions including vasodilatation, scavenging of superoxide and inhibition of platelet aggregation. Routine cardiac surgery or cardiologic interventions lead to a serious temporary or persistent disturbance in NO homeostasis. The clinical consequences are “endothelial dysfunction”, leading to “myocardial dysfunction”: no- or low-reflow phenomenon and temporary reduction of myocardial pump function. Uncoupling of eNOS (one electron transfer to molecular oxygen, the second substrate of eNOS) during ischemia-reperfusion due to diminished availability of L-arginine and/or tetrahydrobiopterin is even discussed as one major source of superoxide formation. Therefore maintenance of normal NO homeostasis seems to be an important factor protecting from ischemia/reperfusion (I/R) injury. Both, the clinical situations of cardioplegic arrest as well as hypothermic cardioplegic storage are followed by reperfusion. However, the presently used cardioplegic solutions to arrest and/or store the heart, thereby reducing myocardial oxygen consumption and metabolism, are designed to preserve myocytes mainly and not endothelial cells. This review will focus on possible drug additives to cardioplegia, which may help to maintain normal NO homeostasis after I/R