Emrah Kağan YAŞAR, Murat Şahin ALAGÖZ, Ahmet DEMİR, Levent TRABZONLU

Rosuvastatin's effects on ischemic skin flaps: Facts aboutstatins' effects on skin flap viability

Aim: Statins are considered to be protective against ischemic injury because of their pleiotropic effects. In this animal study, theeffects of high dose (40 mg/kg) rosuvastatin on ischemic skin flaps were investigated.Materials and Methods: Eighteen Wistar Albino male rats randomly divided into the treatment and the sham groups in equal numbers(n=9 in each group). Orogastric tubes were used both in the treatment and the sham group. Differently, in our study orogastric feedingstarted one day before the surgery and ended on the postoperative day seven. By this way we aimed to have enough circulatinglevels of agent in acute ischemia. Only the treatment group received rosuvastatin-supplemented water. Twenty-four hours after thefirst gavage application, caudally based, modified McFarlane flaps were elevated in 3x10 cm in size. After flap elevation procedure,the flaps were returned to their original location immediately.Results: The day after the last gavage application on postoperative day seven animals were sacrificed. Thereafter the digital imageswere obtained. The skin biopsies were taken by pathologist from three zones on each flap for histopathological assessment. Skinflap viability rate (p=0.508) and necrosis rate (p=0.453) did not show any difference between the groups Interestingly, the finalweights of the animals were lower than their initial weights, but this was only significant for the study group (p=0.008), not for thesham group (p=0.400). There were no any expectations related with weight change of the animals before the statistical analysis.Conclusion: On the other hand, there are literature studies claiming that the statins are effective to increase ischemic skin flapsviability, this study contradicts earlier studies. Statins were not observed to have favorable effects on critically ischemic skin flapviability through their pleiotropic activity.

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1. Trujillo AN, Kesl SL, Sherwood J, et al. Demonstration of the rat ischemic skin wound model. JoVE 2015;98:52637.
2. Waters LM, Pearl RM & Macaulay RM. A comparative analysis of the ability of five classes of pharmacological agents to augment skin flap survival in various models and species: an attempt to standardize skin flap research. Ann Plast Surg1989;23:117-22.
3. Tan CM, Im MJ, Myers RA & Hoopes JE. Effects of hyperbaric oxygen and hyperbaric air on the survival of island skin flaps. Plast Reconstr Surg 1984;73:27- 30.
4. Guba JA. Study of the delay phenomenon in axial pattern flaps in pigs. Plast Reconstr Surg 1979;63:550- 4.
5. Sloan GM & Reinisch JF. Flap physiology and the prediction of flap viability. Hand Clin 1985;1:609-19.
6. Suzuki S, Isshiki N, Ohtsuka M & Maeda T. Experimental study on “delay” phenomenon in relation to flap width and ischaemia. Br J Plast Surg 1988:41:389-94.
7. Vaughan CJ & Gotto Jr AM. Update on statins: 2003. Circulation 2004;110:886-92.
8. De Loecker I & Preiser JC. Statins in the critically ill. Ann Intensive Care 2012;2:19.
9. McFarlane RM, DeYoung G, Henry RA & McFarlane RM. The design of a pedicle flap in the rat to study necrosis and its prevention. Plast Reconstr Surg 1965;35:177-82.
10. Lucas JB. The Physiology and Biomechanics of Skin Flaps. Facial Plast Surg Clin North Am 2017;25:303- 11.
11. Istvan ES & Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science 2001;292:1160-4.
12. Cortese F, Gesualdo M, Cortese A, et al. Rosuvastatin: Beyond the cholesterol-lowering effect. Pharmacol Res 2016;107:1-18.
13. Liao JK & Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005;45:89-118.
14. Zhou Q, & Liao JK. Pleiotropic effects of statins. Circ J 2010;74:818-26.
15. Miller PS, Smith DG & Jones P. Cost effectiveness of rosuvastatin in treating patients to lowdensity lipoprotein cholesterol goals compared with atorvastatin, pravastatin, and simvastatin (a US Analysis of the STELLAR Trial). Am J Cardiol 2005;95:1314-9.
16. Costa-Scharplatz M, Ramanathan K, Frial T, et al. Cost-effectiveness analysis of rosuvastatin versus atorvastatin, simvastatin, and pravastatin from a Canadian health system perspective. Clin Ther 2008;30:1345-57.
17. Jones PH, Hunninghake DB, Ferdinand KC, et al . Effects of rosuvastatin versus atorvastatin, simvastatin, and pravastatin on non-high-density lipoprotein cholesterol, apolipoproteins, and lipid ratios in patients with hypercholesterolemia: additional results from the STELLAR trial. Clin Ther 2004;26:1388-99.
18. Aydin MU, Aygul N, Altunkeser BB. Comparative effects of high-dose atorvastatin versus moderatedose rosuvastatin on lipid parameters, oxidized-LDL and inflammatory markers in ST elevation myocardial infarction. Atherosclerosis 2015;239439-43.
19. Ferreira TS, Lanzetti M, Barroso MV, et al. Oxidative stress and inflammation are differentially affected by atorvastatin, pravastatin, rosuvastatin, and simvastatin on lungs from mice exposed to cigarette smoke. Inflammation 2014;37:1355-65.
20. Liuni A, Luca MC, Gori T & Parker JD. Rosuvastatin Prevents Conduit Artery Endothelial Dysfunction Induced by Ischemia and Reperfusion by a Cyclooxygenase-2–Dependent Mechanism. J Am Coll Cardiol 2010;55:10026.
21. Laufs U, Gertz K, Dirnagl U, et al. Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice. Brain research 2002;942:23-30.
22. Pršić A, Kiwanuka E, Caterson SA & Caterson EJ. Anticoagulants and statins as pharmacological agents in free flap surgery: current rationale. Eplasty 2015;15:51.
23. Karsenti G, Le Manach Y, Bouvier S, et al. Statins: A new pharmacological agent for free flap surgery?. Plast Reconstr Surg 2010;63;870-4.
24. Uygur F, Noyan N & Hahaolu A. The effect of simvastatin on the survival of ischaemic skin flap: An experimental study in rats. Plast Reconstr Surg 2010;63:1723-32.
25. Chen JX, Chiu CW & Shih PK. The effect of atorvastatin on survival of rat ischemic flap. Kaohsiung J Med Sci 2013;29:187-93.
26. Jia YC, Xu J, Chen HH, et al. The Effect of atorvastatin on the viability of ischemic skin flaps in diabetic rats. Plast Reconstr Surg 2017;139:425-33.
27. Leiter LA, Rosenson RS, Stein E, et al. Efficacy and safety of rosuvastatin 40 mg versus atorvastatin 80 mg in high-risk patients with hypercholesterolemia: results of the POLARIS study. Atherosclerosis 2007; 194:154-64.
28. Zhang F, Hu EC, Topp S, et al. Proinflammatory cytokines gene expression in skin flaps with arterial and venous ischemia in rats. J Reconstr Microsurg 2006;22641-7.
29. Perna M, Baker M, Byrne TK & Morgan K. Statins and the bariatric patient: characterization and perioperative effects of statin therapy in the gastric bypass patient. Am Surg 2011;77:44-7.
30. Taylor BA, Ng J, Stone A, et al. Effects of statin therapy on weight loss and diabetes in bariatric patients. Surg Obes Relat Dis 2017;13:674-80.
31. Van den Heuvel MGW, Bast A, Ambergen AW & Van der Hulst RRWJ. The effect of statins and other cardiovascular medication on ischemia-reperfusion damage in a human DIEP Flap model: Theoretical and epidemiological considerations. J Transplant 2012.
32. Koolen PG, Nguyen JT, Ibrahim AM, et al. Effects of statins on ischemia–reperfusion complications in breast free flaps. J Surg Res 2014;190:378-84.
33. Zheng Z, Jayaram R, Jiang L, et al. Perioperative rosuvastatin in cardiac surgery. N Engl J Med 2016;374:1744-53.
34. Hu J & Lu Y. Statin and myocardial ischemiareperfusion injury. Int J Cardiol 2016;222:988.