The fibrin-derived peptide Bβ15-42 is cardioprotective in a pig model of myocardial ischemia-reperfusion injury

Objective: The fibrin-derived peptide B beta(15-42) has been shown to reduce infarct size in rodent models of ischemia-reperfusion injury. To increase its potential for translation into the clinic, we studied the effects of B beta(15-42) in pigs, whose coronary anatomy is similar to that of humans. In addition, we evaluated the pharmacokinetics and safety of B beta(15-42) in several species, including humans. Design: Animal study and phase I trial. Setting: University hospital and contract research laboratories. Subjects: Pigs/healthy volunteers. Interventions: Male farm-bred Landrace pigs were subjected to 1 hr of left anterior descending coronary artery occlusion followed by 3 hrs of reperfusion. At the time of reperfusion, B beta(15-42) (2.4 mg/kg, n = 6) or random peptide (control; 2.4 mg/kg, n = 6) was administered as an intravenous bolus. As a positive control, pigs were subjected to ischemic preconditioning (n = 6). Cardiac damage and hemodynamics were recorded. Biodistribution and pharmacokinetics of B beta(15-42) were determined in rats and dogs. In a phase I trial involving 30 male healthy volunteers, pharmacokinetics and safety were tested in a randomized, double-blinded, placebo-controlled, parallel-group, single ascending dose study. Measurements and Main Results: B beta(15-42) and ischemic preconditioning significantly reduced myocardial infarct size and troponin I levels. B beta(15-42) also reduces interleukin-6 levels, underlining its anti-inflammatory properties. Furthermore, in humans, the pharmacokinetics of the peptide B beta(15-42) were comparable to those of animals, and no serious adverse effects were observed. Conclusions: B beta(15-42) elicits cardioprotection in pigs and is clinically safe in phase I testing of humans. This study confirms the new concept of a pathogenic role of fibrin derivatives in myocardial reperfusion injury, which can be inhibited by peptide B beta(15-42).