Horm Metab Res 2023; 55(01): 65-74
DOI: 10.1055/a-1984-0255
Original Article: Endocrine Research

Aprotinin does not Impair Vascular Function in Patients Undergoing Coronary Artery Bypass Graft Surgery

Josephine Tolkmitt
1   Department of Medicine III, Division of Vascular Endothelium and Microcirculation, Technische Universität Dresden, Dresden, Germany
,
Heike Brendel
1   Department of Medicine III, Division of Vascular Endothelium and Microcirculation, Technische Universität Dresden, Dresden, Germany
,
Birgit Zatschler
2   Institute of Physiology, Technische Universität Dresden, Dresden, Germany
,
Stefan Brose
3   Department of Cardiac Surgery, University Heart Center Dresden, Technische Universität Dresden, Dresden, Germany
,
Coy Brunssen
4   Division of Vascular Endothelium and Microcirculation, Technische Universität Dresden, Dresden, Germany
,
Irakli Kopaliani
2   Institute of Physiology, Technische Universität Dresden, Dresden, Germany
,
Andreas Deussen
2   Institute of Physiology, Technische Universität Dresden, Dresden, Germany
,
Klaus Matschke
3   Department of Cardiac Surgery, University Heart Center Dresden, Technische Universität Dresden, Dresden, Germany
,
Henning Morawietz
1   Department of Medicine III, Division of Vascular Endothelium and Microcirculation, Technische Universität Dresden, Dresden, Germany
› Author Affiliations
Funding Information Else Kröner-Fresenius-Stiftung — http://dx.doi.org/10.13039/ 501100003042; 2010_A105; Deutsches Zentrum für Herz-Kreislaufforschung — http://dx.doi.org/10.13039/100010447; 81 × 2800207; Excellence Initiative by the German Federal and State Governments (Institutional Strategy, measure ‘support the best’) — 3–25 2, Grant F-03661–553–41B-1250000; Deutsche Forschungsgemeinschaft — http://dx.doi.org/10.13039/501100001659; 47081312

Abstract

Bleeding is a major complication in coronary artery bypass graft surgery. Antifibrinolytic agents like serine protease inhibitor aprotinin can decrease postoperative bleeding and complications of cardiac surgery. However, the effects of aprotinin on vascular function are not completely elucidated. We compared the ex vivo vascular function of left internal mammary arteries from patients undergoing coronary artery bypass graft surgery with and without intraoperative application of aprotinin using a Mulvany Myograph. Human internal mammary arteries were treated with aprotinin ex vivo and tested for changes in vascular function. We analyzed the impact of aprotinin on vascular function in rat aortic rings. Finally, impact of aprotinin on expression and activity of endothelial nitric oxide synthase was tested in human endothelial cells. Intraoperative application of aprotinin did not impair ex vivo vascular function of internal mammary arteries of patients undergoing coronary artery bypass graft surgery. Endothelium-dependent and -independent relaxations were not different in patients with or without aprotinin after nitric oxide synthase blockade. A maximum vasorelaxation of 94.5%±11.4vs. 96.1%±5.5% indicated a similar vascular smooth muscle function in both patient groups (n=13 each). Long-term application of aprotinin under physiological condition preserved vascular function of the rat aorta. In vitro application of increasing concentrations of aprotinin on human endothelial cells resulted in a similar expression and activity of endothelial nitric oxide synthase. In conclusion, intraoperative and ex vivo application of aprotinin does not impair the endothelial function in human internal mammary arteries and experimental models.



Publication History

Received: 15 August 2022

Accepted after revision: 14 November 2022

Article published online:
04 January 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Jimenez Rivera JJ, Iribarren JL, Raya JM. et al. Factors associated with excessive bleeding in cardiopulmonary bypass patients: a nested case-control study. J Cardiothorac Surg 2007; 2: 17
  • 2 Howell N, Senanayake E, Freemantle N. et al. Putting the record straight on aprotinin as safe and effective: results from a mixed treatment meta-analysis of trials of aprotinin. J Thorac Cardiovasc Surg 2013; 145: 234-240
  • 3 Waldow T, Krutzsch D, Wils M. et al. Low dose aprotinin and low dose tranexamic acid in elective cardiac surgery with cardiopulmonary bypass. Clin Hemorheol Microcirc 2009; 42: 269-277
  • 4 Sodha NR, Boodhwani M, Bianchi C. et al. Aprotinin in cardiac surgery. Expert Rev Cardiovasc Ther 2006; 4: 151-160
  • 5 Davis R, Whittington R. Aprotinin. A review of its pharmacology and therapeutic efficacy in reducing blood loss associated with cardiac surgery. Drugs 1995; 49: 954-983
  • 6 Levy JH, Bailey JM, Salmenpera M. Pharmacokinetics of aprotinin in preoperative cardiac surgical patients. Anesthesiology 1994; 80: 1013-1018
  • 7 Royston D, Bidstrup BP, Taylor KM. et al. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987; 2: 1289-1291
  • 8 Smith CR. Management of bleeding complications in redo cardiac operations. Ann Thorac Surg 1998; 65: S2-S8
  • 9 Mangano DT, Tudor IC, Dietzel C. et al. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354: 353-365
  • 10 Schneeweiss S, Seeger JD, Landon J. et al. Aprotinin during coronary-artery bypass grafting and risk of death. N Engl J Med 2008; 358: 771-783
  • 11 Shaw AD, Stafford-Smith M, White WD. et al. The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 2008; 358: 784-793
  • 12 Fergusson DA, Hebert PC, Mazer CD. et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358: 2319-2331
  • 13 Kristeller JL, Roslund BP, Stahl RF. Benefits and risks of aprotinin use during cardiac surgery. Pharmacotherapy 2008; 28: 112-124
  • 14 European Medicines Agency 2013. https://www.ema.europa.eu/en/documents/referral/questions-answers-review-antifibrinolytic-medicines-aprotinin-aminocaproic-acid-tranexamic-acid_en.pdf; Accessed September 18, 2013
  • 15 Hebert PC, Fergusson DA, Hutton B. et al. Regulatory decisions pertaining to aprotinin may be putting patients at risk. CMAJ 2014; 186: 1379-1386
  • 16 Walkden GJ, Verheyden V, Goudie R. et al. Increased perioperative mortality following aprotinin withdrawal: a real-world analysis of blood management strategies in adult cardiac surgery. Intensive Care Med 2013; 39: 1808-1817
  • 17 Royston D, De Hert S, van der Linden J. et al. A special article following the relicence of aprotinin injection in Europe. Anaesth Crit Care Pain Med 2017; 36: 97-102
  • 18 Benedetto U, Altman DG, Gerry S. et al. Safety of perioperative aprotinin administration during isolated coronary artery bypass graft surgery: insights from the ART (Arterial Revascularization Trial). J Am Heart Assoc 2018; 7: e007570
  • 19 Schmaier AH. The plasma kallikrein-kinin system counterbalances the renin-angiotensin system. J Clin Invest 2002; 109: 1007-1009
  • 20 Ishizawa K, Izawa Y, Ito H. et al. Aldosterone stimulates vascular smooth muscle cell proliferation via big mitogen-activated protein kinase 1 activation. Hypertension 2005; 46: 1046-1052
  • 21 Velez JC. The importance of the intrarenal renin-angiotensin system. Nat Clin Pract Nephrol 2009; 5: 89-100
  • 22 Hofmann A, Brunssen C, Wolk S. et al. Soluble LOX-1: a novel biomarker in patients with coronary artery disease, stroke, and acute aortic dissection?. J Am Heart Assoc 2020; 9: e013803
  • 23 Morawietz H, Rueckschloss U, Niemann B. et al. Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein. Circulation 1999; 100: 899-902
  • 24 Niemann B, Rohrbach S, Miller MR. et al. Oxidative stress and cardiovascular risk: obesity, diabetes, smoking, and pollution: Part 3 of a 3-Part series. J Am Coll Cardiol 2017; 70: 230-251
  • 25 Punch E, Klein J, Diaba-Nuhoho P. et al. Effects of PCSK9 targeting: alleviating oxidation, inflammation, and atherosclerosis. J Am Heart Assoc 2022; 11: e023328
  • 26 Siow RC, Li FY, Rowlands DJ. et al. Cardiovascular targets for estrogens and phytoestrogens: transcriptional regulation of nitric oxide synthase and antioxidant defense genes. Free Radic Biol Med 2007; 42: 909-925
  • 27 Sealey JE, Atlas SA, Laragh JH. et al. Activation of a prorenin-like substance in human plasma by trypsin and by urinary kallikrein. Hypertension 1979; 1: 179-189
  • 28 Derkx FH, Bouma BN, Schalekamp MP. et al. An intrinsic factor XII- prekallikrein-dependent pathway activates the human plasma renin-angiotensin system. Nature 1979; 280: 315-316
  • 29 Bruda NL, Hurlbert BJ, Hill GE. Aprotinin reduces nitric oxide production in vitro and in vivo in a dose-dependent manner. Clin Sci (Lond) 1998; 94: 505-509
  • 30 Hill GE, Springall DR, Robbins RA. Aprotinin is associated with a decrease in nitric oxide production during cardiopulmonary bypass. Surgery 1997; 121: 449-455
  • 31 Cybularz M, Langbein H, Zatschler B. et al. Endothelial function and gene expression in perivascular adipose tissue from internal mammary arteries of obese patients with coronary artery disease. Atheroscler Suppl 2017; 30: 149-158
  • 32 Morawietz H, Erbs S, Holtz J. et al. Endothelial protection, AT1 blockade and cholesterol-dependent oxidative stress: the EPAS trial. Circulation 2006; 114: I296-I301
  • 33 Zatschler B, Dieterich P, Muller B. et al. Improved vessel preservation after 4 days of cold storage: experimental study in rat arteries. J Vasc Surg 2009; 50: 397-406
  • 34 Riedel K, Deussen AJ, Tolkmitt J. et al. Estrogen determines sex differences in adrenergic vessel tone by regulation of endothelial beta-adrenoceptor expression. Am J Physiol Heart Circ Physiol 2019; 317: H243-H254
  • 35 Goettsch C, Goettsch W, Brux M. et al. Arterial flow reduces oxidative stress via an antioxidant response element and Oct-1 binding site within the NADPH oxidase 4 promoter in endothelial cells. Basic Res Cardiol 2011; 106: 551-561
  • 36 Schubert A, Cattaruzza M, Hecker M. et al. Shear stress-dependent regulation of the human beta-tubulin folding cofactor D gene. Circ Res 2000; 87: 1188-1194
  • 37 Giebe S, Hofmann A, Brux M. et al. Comparative study of the effects of cigarette smoke versus next generation tobacco and nicotine product extracts on endothelial function. Redox Biol 2021; 47: 102150
  • 38 Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001; 29: e45
  • 39 Allen S, Anastasiou N, Royston D. et al. Effect of aprotinin on vascular reactivity of coronary bypass grafts. J Thorac Cardiovasc Surg 1997; 113: 319-326
  • 40 Veres G, Radovits T, Schultz H. et al. Effect of recombinant aprotinin on postoperative blood loss and coronary vascular function in a canine model of cardiopulmonary bypass. Eur J Cardiothorac Surg 2007; 32: 340-345
  • 41 Ulker S, Cinar MG, Bayraktutan U. et al. Aprotinin impairs endothelium-dependent relaxation in rat aorta and inhibits nitric oxide release from rat coronary endothelial cells. Cardiovasc Res 2001; 50: 589-596
  • 42 Ulker S, McKeown PP, Bayraktutan U. Aprotinin impairs coronary endothelial function and down-regulates endothelial NOS in rat coronary microvascular endothelial cells. Cardiovasc Res 2002; 55: 830-837
  • 43 Pruefer D, Makowski J, Dahm M. et al. Aprotinin inhibits leukocyte-endothelial cell interactions after hemorrhage and reperfusion. Ann Thorac Surg 2003; 75: 210-215
  • 44 Asimakopoulos G, Lidington EA, Mason J. et al. Effect of aprotinin on endothelial cell activation. J Thorac Cardiovasc Surg 2001; 122: 123-128
  • 45 Day JR, Taylor KM, Lidington EA. et al. Aprotinin inhibits proinflammatory activation of endothelial cells by thrombin through the protease-activated receptor 1. J Thorac Cardiovasc Surg 2006; 131: 21-27
  • 46 Day JR, Punjabi PP, Randi AM. et al. Clinical inhibition of the seven-transmembrane thrombin receptor (PAR1) by intravenous aprotinin during cardiothoracic surgery. Circulation 2004; 110: 2597-2600
  • 47 Julius U, Schatz U, Tselmin S. et al. COVID-19 and lipid disorders. Horm Metab Res 2022; 54: 514-521
  • 48 Redondo-Calvo FJ, Padin JF, Munoz-Rodriguez JR. et al. Aprotinin treatment against SARS-CoV-2: A randomized phase III study to evaluate the safety and efficacy of a pan-protease inhibitor for moderate COVID-19. Eur J Clin Invest 2022; 52: e13776