The fibrin-derived peptide Bβ_15–42 is cardioprotective in a pig model of myocardial ischemia-reperfusion injury*

Abstract

Objective: 

The fibrin-derived peptide Bβ_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 Bβ_15–42 in pigs, whose coronary anatomy is similar to that of humans. In addition, we evaluated the pharmacokinetics and safety of Bβ_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, Bβ_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 Bβ_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: 

Bβ_15–42 and ischemic preconditioning significantly reduced myocardial infarct size and troponin I levels. Bβ_15–42 also reduces interleukin-6 levels, underlining its anti-inflammatory properties. Furthermore, in humans, the pharmacokinetics of the peptide Bβ_15–42 were comparable to those of animals, and no serious adverse effects were observed.

Conclusions: 

Bβ_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 Bβ_15–42.