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J Reconstr Microsurg 2020; 36(04): 281-288
DOI: 10.1055/s-0039-1701030
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Effect of Simvastatin Use in Free Tissue Transfer: An Experimental Study in a Rat Epigastric Free Flap Model

Usama Abdelfattah
1   Department of Plastic and Reconstructive Surgery, Asan Medical Centre, Seoul, Korea
2   Department of Plastic and Reconstructive Surgery, Al-Azhar University Hospitals, Cairo, Egypt
,
Tarek Elbanoby
2   Department of Plastic and Reconstructive Surgery, Al-Azhar University Hospitals, Cairo, Egypt
,
Eun Na Kim
3   Department of Pathology, Asan Medical Centre, Seoul, Korea
,
Eun Jung Park
1   Department of Plastic and Reconstructive Surgery, Asan Medical Centre, Seoul, Korea
,
Hyunsuk Peter Suh
1   Department of Plastic and Reconstructive Surgery, Asan Medical Centre, Seoul, Korea
,
Joon Pio Jp Hong 
1   Department of Plastic and Reconstructive Surgery, Asan Medical Centre, Seoul, Korea
› Author Affiliations
Further Information

Publication History

03 July 2019

02 December 2019

Publication Date:
29 January 2020 (online)

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Abstract

Background Statins are traditionally used in lowering cholesterol and low-density lipoprotein biosynthesis, but recent reports show their beneficial effect on microcirculation. The aim of this study was to investigate the effect of simvastatin on the microcirculation and in conjunction with aspirin in a rat free epigastric flap model.

Methods Thirty-six Sprague–Dawley rats were divided into group A (control, n = 12), group B (simvastatin treated, n = 12), and group C (simvastatin and aspirin, n = 12). Bilateral free epigastric skin flap was used to evaluate the effect. At 48 hours, flaps biopsies were evaluated for inflammatory activity, nitric oxide content, and thrombomodulin regulation in the endothelial lining of microvessels. Flap survival was evaluated on day 7.

Results The diameter of microvessels and nitric oxide activity in groups B and C were significantly higher than in group A (p < 0.005 and 0.015, respectively). The perivascular inflammatory cell infiltrates and intravascular adhesions were predominant in group A compared with groups B and C (p < 0.005). Groups B and C demonstrated significant higher degree of thrombomodulin expression. The flap survival rate on day 7 was 70.8% for group A, and 87.5% and 91.7%, respectively, for groups B and C without significance between the two (p = 0.675).

Conclusion Simvastatin significantly improves the free flap survival by effective anti-inflammatory, vasodilator, and anticoagulant activities. Combined therapy did not have an antagonistic effect and further study is needed to see synergistic action through different mechanisms.

Keywords

simvastatin - free flap - microsurgery - anticoagulant - experiment
 

  • References

  • 1 Dornseifer U, Fichter AM, Von Isenburg S, Stergioula S, Rondak IC, Ninkovic M. Impact of active thermoregulation on the microcirculation of free flaps. Microsurgery 2016; 36 (03) 216-224
    CrossrefPubMedGoogle Scholar
  • 2 Glicksman A, Ferder M, Casale P, Posner J, Kim R, Strauch B. 1457 years of microsurgical experience. Plast Reconstr Surg 1997; 100 (02) 355-363
    CrossrefPubMedGoogle Scholar
  • 3 Fichter AM, Ritschl LM, Robitzky LK. , et al. Impact of different antithrombotics on the microcirculation and viability of perforator-based ischaemic skin flaps in a small animal model. Sci Rep 2016; 6: 35833
    Google Scholar
  • 4 Kroll SS, Miller MJ, Reece GP. , et al. Anticoagulants and hematomas in free flap surgery. Plast Reconstr Surg 1995; 96 (03) 643-647
    CrossrefPubMedGoogle Scholar
  • 5 LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999; 282 (24) 2340-2346
    CrossrefPubMedGoogle Scholar
  • 6 Ridker PM, Danielson E, Fonseca FA. , et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 (21) 2195-2207
    CrossrefPubMedGoogle Scholar
  • 7 Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science 2001; 292 (5519): 1160-1164
    CrossrefPubMedGoogle Scholar
  • 8 McKenney JM. Pharmacologic characteristics of statins. Clin Cardiol 2003; 26 (04) (Suppl. 03) III32-III38
    CrossrefPubMedGoogle Scholar
  • 9 Nagelschmitz J, Blunck M, Kraetzschmar J, Ludwig M, Wensing G, Hohlfeld T. Pharmacokinetics and pharmacodynamics of acetylsalicylic acid after intravenous and oral administration to healthy volunteers. Clin Pharmacol 2014; 6: 51-59
    Google Scholar
  • 10 Uygur F, Evinc R, Urhan M, Celikoz B, Haholu A. Salvaging the zone of stasis by simvastatin: an experimental study in rats. J Burn Care Res 2009; 30 (05) 872-879
    CrossrefPubMedGoogle Scholar
  • 11 Uygur F, Noyan N, Celiköz B, Hahaoğlu A. Expression of the endothelial thrombomodulin (TM) on the ischemic rat flap model: preliminary study. Ann Plast Surg 2009; 62 (06) 693-698
    CrossrefPubMedGoogle Scholar
  • 12 Schoemaker RG, Saxena PR, Kalkman EA. Low-dose aspirin improves in vivo hemodynamics in conscious, chronically infarcted rats. Cardiovasc Res 1998; 37 (01) 108-114
    CrossrefPubMedGoogle Scholar
  • 13 Libby P, Ridker PM, Hansson GK. ; Leducq Transatlantic Network on Atherothrombosis. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol 2009; 54 (23) 2129-2138
    CrossrefPubMedGoogle Scholar
  • 14 Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov 2005; 4 (12) 977-987
    CrossrefPubMedGoogle Scholar
  • 15 Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998; 97 (12) 1129-1135
    CrossrefPubMedGoogle Scholar
  • 16 Undas A, Celinska-Löwenhoff M, Brummel-Ziedins KE, Brozek J, Szczeklik A, Mann KG. Simvastatin given for 3 days can inhibit thrombin generation and activation of factor V and enhance factor Va inactivation in hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 2005; 25 (07) 1524-1525
    CrossrefPubMedGoogle Scholar
  • 17 Hanson SR, Griffin JH, Harker LA, Kelly AB, Esmon CT, Gruber A. Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates. J Clin Invest 1993; 92 (04) 2003-2012
    CrossrefPubMedGoogle Scholar
  • 18 Uygur F, Noyan N, Hahaolu A. The effect of simvastatin on the survival of ischaemic skin flap: an experimental study in rats. J Plast Reconstr Aesthet Surg 2010; 63 (10) 1723-1732
    CrossrefPubMedGoogle Scholar
  • 19 Undas A, Brummel KE, Musial J, Mann KG, Szczeklik A. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation. Circulation 2001; 103 (18) 2248-2253
    CrossrefPubMedGoogle Scholar
  • 20 Rezaie-Majd A, Prager GW, Bucek RA. , et al. Simvastatin reduces the expression of adhesion molecules in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 2003; 23 (03) 397-403
    CrossrefPubMedGoogle Scholar
  • 21 Pršić A, Kiwanuka E, Caterson SA, Caterson EJ. Anticoagulants and statins as pharmacological agents in free flap surgery: current rationale. Eplasty 2015; 15: e51
    PubMedGoogle Scholar
  • 22 Jaber BL, Madias NE. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352 (15) 1603-1605 , author reply 1603–1605
    CrossrefPubMedGoogle Scholar
  • 23 Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001; 21 (11) 1712-1719
    CrossrefPubMedGoogle Scholar
  • 24 Kureishi Y, Luo Z, Shiojima I. , et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 2000; 6 (09) 1004-1010
    CrossrefPubMedGoogle Scholar
  • 25 Shalom A, Friedman T, Westreich M. Effect of aspirin and heparin on random skin flap survival in rats. Dermatol Surg 2008; 34 (06) 785-790
    PubMedGoogle Scholar