The fibrin-derived peptide Bbeta15-42 is cardioprotective in a pig model of myocardial ischemia-reperfusion injury

JP Roesner, P Petzelbauer, A Koch, J Mersmann, PA Zacharowski, O Boehm, S Reingruber, W Pasteiner, D Mascher, M Wolzt, C Barthuber, GE Noldge-Schomburg, TW Scheeren, KD Zacharowski

    Research output: Contribution to journalArticle (Academic Journal)peer-review

    41 Citations (Scopus)

    Abstract

    : OBJECTIVE: The fibrin-derived peptide Bbeta15-42 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 Bbeta15-42 in pigs, whose coronary anatomy is similar to that of humans. In addition, we evaluated the pharmacokinetics and safety of Bbeta15-42 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, Bbeta15-42 (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 Bbeta15-42 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: Bbeta15-42 and ischemic preconditioning significantly reduced myocardial infarct size and troponin I levels. Bbeta15-42 also reduces interleukin-6 levels, underlining its anti-inflammatory properties. Furthermore, in humans, the pharmacokinetics of the peptide Bbeta15-42 were comparable to those of animals, and no serious adverse effects were observed. CONCLUSIONS: Bbeta15-42 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 Bbeta15-42.
    Translated title of the contributionThe fibrin-derived peptide Bbeta15-42 is cardioprotective in a pig model of myocardial ischemia-reperfusion injury
    Original languageEnglish
    Pages (from-to)1730 - 1735
    Number of pages6
    JournalCritical Care Medicine
    Volume35 (7)
    DOIs
    Publication statusPublished - Jul 2007

    Bibliographical note

    Publisher: Lippincott, Williams & Wilkins

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