Aprotinin Exerts Differential and Dose-Dependent Effects on Myocardial Contractility, Oxidative Stress, and Cytokine Release After Ischemia-Reperfusion

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Presentation transcript:

Aprotinin Exerts Differential and Dose-Dependent Effects on Myocardial Contractility, Oxidative Stress, and Cytokine Release After Ischemia-Reperfusion Matthew D. McEvoy, MD, Anna-Greta Taylor, MD, Juozas A. Zavadzkas, MD, Ira M. Mains, BS, Rachael L. Ford, BS, Robert E. Stroud, MS, Laura B. Jeffords, Christy U. Beck, BS/BT, Scott T. Reeves, MD, Francis G. Spinale, MD, PhD The Annals of Thoracic Surgery Volume 86, Issue 2, Pages 568-575 (August 2008) DOI: 10.1016/j.athoracsur.2008.04.025 Copyright © 2008 The Society of Thoracic Surgeons Terms and Conditions

Fig 1 Relative plasma concentrations of aprotinin were computed using a fluorogenic assay in which a specific peptide, cleaved by plasmin was utilized. Using fixed concentrations of the plasmin peptide and plasmin, a standardized curve could be generated with increasing concentrations of aprotinin. The specific reagents and incubation conditions are detailed in the text. An exponential aprotinin inhibition curve was generated and was then fit to an exponential regression equation. An excellent regression fit was obtained, as shown by the dashed lines (y = 4,071 ± 7,643 e−0.003x; r2 = 0.98, p < 0.0001), and the 95% confidence interval for the aprotinin assay is shown by the solid lines. The relative fluorescence and computed plasma aprotinin concentrations for the 2 × 104 KIU/kg dose (triangles) and the 4 × 104 KIU/kg dose (diamonds) have been superimposed on the standard curve (circles [error bars are the standard deviation from the estimate]). The Annals of Thoracic Surgery 2008 86, 568-575DOI: (10.1016/j.athoracsur.2008.04.025) Copyright © 2008 The Society of Thoracic Surgeons Terms and Conditions

Fig 2 (Top) The relative change in maximal left ventricle (LV) elastance (Emax), an index of LV contractility, was computed as a percent of baseline values after ischemia/reperfusion (I/R). A significant reduction in Emax occurred in the vehicle (n = 10) and 4 × 104 KIU/kg aprotinin group (n = 10). However, this depression in LV contractile function was ameliorated in the 2 × 104 KIU/kg aprotinin group (n = 11). (Middle) Plasma levels for the cytokine tumor necrosis factor-alpha (TNF-α) were increased after I/R in both the vehicle and 2 × 104 KIU/kg aprotinin groups when computed as a percent change to reference control values. This I/R-induced TNF release was abrogated in the 4 × 104 KIU/kg aprotinin group. (Bottom) Myeloperoxidase (MPO) content, as assessed by immunohistochemistry, was increased significantly from control values in all I/R groups when compared with reference control values. However, MPO levels were reduced from vehicle values in the 2 × 104 KIU/kg aprotinin group. Absolute values for these indices are provided in the Results. (*p < 0.05 versus respective baseline/referent control; +p < 0.05 versus vehicle; #p < 0.05 versus 2 × 104 KIU/kg aprotinin). (Black bars = vehicle; striped bars = 2 × 104 KIU/kg aprotinin; diagonal striped bars = 4 × 104 KIU/kg aprotinin.) The Annals of Thoracic Surgery 2008 86, 568-575DOI: (10.1016/j.athoracsur.2008.04.025) Copyright © 2008 The Society of Thoracic Surgeons Terms and Conditions

Fig 3 Representative photomicrographs of left ventricle sections stained for myeloperoxidase (MPO) taken from (a) reference control; (b) after ischemia/reperfusion in the vehicle only group; (c) in the 2 × 104 KIU/kg aprotinin group; and (d) in the 4 × 104 KIU/kg aprotinin group. A significant and robust increase in MPO staining was observed in the vehicle group, and while evident in the aprotinin groups, appeared reduced. Quantitative results are presented in Figure 2. Higher power images of a left ventricle section taken from the vehicle group revealed (e) an egress of MPO staining from interstitial cells, whereas in the 2 × 104 KIU/kg aprotinin group (f), MPO staining appeared to be confined to the intracellular compartment of these interstitial cells. (Original magnification: a, b, c, d, ×20; e and f, ×63.) The Annals of Thoracic Surgery 2008 86, 568-575DOI: (10.1016/j.athoracsur.2008.04.025) Copyright © 2008 The Society of Thoracic Surgeons Terms and Conditions