The Journal of Thoracic and Cardiovascular Surgery
Volume 128, Issue 4 , Pages 602-608, October 2004

Reduction of myocardial reperfusion injury by aprotinin after regional ischemia and cardioplegic arrest☆

  • Tanveer A. Khan, MD

      Affiliations

    • Department of Surgery, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass, USA
    • ,
  • Cesario Bianchi, MD, PhD

      Affiliations

    • Department of Surgery, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass, USA
    • ,
  • Pierre Voisine, MD

      Affiliations

    • Department of Surgery, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass, USA
    • ,
  • Jun Feng, MD, PhD

      Affiliations

    • Department of Surgery, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass, USA
    • ,
  • Jeralyn Baker, CCP

      Affiliations

    • Department of Surgery, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass, USA
    • ,
  • Melanie Hart, PhD

      Affiliations

    • Department of Anesthesiology, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass, USA
    • ,
  • Minoru Takahashi, PhD

      Affiliations

    • Department of Anesthesiology, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass, USA
    • ,
  • Greg Stahl, PhD

      Affiliations

    • Department of Anesthesiology, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass, USA
    • ,
  • Frank W. Sellke, MD

      Affiliations

    • Department of Surgery, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass, USA
    • Corresponding Author InformationAddress for reprints: Frank W. Sellke, MD, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, 110 Francis St, LMOB 2A, Boston, MA 02215, USA

Received 21 October 2003; received in revised form 9 February 2004; accepted 17 March 2004.

Abstract 

Background

Surgical coronary revascularization with cardiopulmonary bypass and cardioplegia has been associated with reperfusion injury. The serine protease inhibitor aprotinin has been suggested to reduce reperfusion injury, yet a clinically relevant study examining regional ischemia under conditions of cardiopulmonary bypass and cardioplegia has not been performed.

Methods

Pigs were subjected to 30 minutes of regional myocardial ischemia by distal left anterior descending coronary artery occlusion, followed by 60 minutes of cardiopulmonary bypass with 45 minutes of cardioplegic arrest and 90 minutes of post–cardiopulmonary bypass reperfusion. The treatment group (n = 6) was administered aprotinin systemically (40,000 kallikrein-inhibiting units [KIU]/kg intravenous loading dose, 40,000 KIU/kg pump prime, and 10,000 KIU · kg−1 · h−1 intravenous continuous infusion). Control animals (n = 6) received crystalloid solution. Global and regional myocardial functions were analyzed by the left ventricular+dP/dt and the percentage segment shortening, respectively. Left ventricular infarct size was measured by tetrazolium staining. Tissue myeloperoxidase activity was measured. Myocardial sections were immunohistochemically stained for nitrotyrosine. Coronary microvessel function was studied by videomicroscopy.

Results

Myocardial infarct size was decreased with aprotinin treatment (27.0% ± 3.5% vs 45.3% ± 3.0%, aprotinin vs control; P < .05). Myocardium from the ischemic territory showed diminished nitrotyrosine staining in aprotinin-treated animals versus controls, and this was significant by grade (1.3 ± 0.2 vs 3.2 ± 0.2, aprotinin vs control; P < .01). In the aprotinin group, coronary microvessel relaxation improved most in response to the endothelium-dependent agonist adenosine diphosphate (44.7% ± 3.2% vs 19.7% ± 1.7%, aprotinin vs control; P < .01). No significant improvements in myocardial function were observed with aprotinin treatment.

Conclusions

Aprotinin reduces reperfusion injury after regional ischemia and cardioplegic arrest. Protease inhibition may represent a molecular strategy to prevent postoperative myocardial injury after surgical revascularization with cardiopulmonary bypass.

Keywords:  17, 25, 31

 

☆ Funding was provided by National Institutes of Health grants R01 HL46716 (F.W.S.) and NRSA 1F32 HL69651 (T.A.K.) and by the Bayer Corporation.

PII: S0022-5223(04)00433-7

doi:10.1016/j.jtcvs.2004.02.037

The Journal of Thoracic and Cardiovascular Surgery
Volume 128, Issue 4 , Pages 602-608, October 2004

Article Tools

* Image Usage & Resolution