Establishment of an animal model to study the effects of amputation on the cardiovascular system_Journal of Biomedical Engineering

Authors：

MIN Lei ¹ ,  JIANG Wentao ¹ , LI Zhongyou ¹ , LI Xiao ¹ , WEI Junru ¹ , DIAO Junjie ¹ , BAI Taoping ¹ , YAN Fei ²

1. Department of Mechanics & Engineering, College of Architecture and Environment, Sichuan University, Chengdu 610065, P. R. China;
2. Chongqing University Three Gorges Hospital, Chongqing 404000, P. R. China;

Corresponding author：

JIANG Wentao, Email: scubme_jwt@outlook.com

Keywords：

Amputation; Cardiovascular system; Animal model; Biochemical index; Pathological examination

DOI：

10.7507/1001-5515.202203064

Video：

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Lower limb amputation is a significant change in body structure. Loss of muscle, blood vessels, and blood leads to a redistribution of blood flow and changes in resistance at the end of blood vessels. In view of the significant increase in the prevalence of cardiovascular disease after lower limb amputation, the mechanism of which is still unclear, this study aims to establish an animal research model that can verify and explore the effects of amputation on cardiovascular system, and provide the experimental basis for subsequent animal experiments when exploring the effect of different amputation levels on the cardiovascular system. SPF New Zealand rabbits were divided into normal group (n = 6) and amputation group (n = 6). The amputation group was treated with above-knee amputation. The changes of low-density liptein cholesterol (LDL-C) and total cholesterol (TC) in serum of all the rabbits were monitored regularly after the surgery. The arterial pathological examination was conducted after the experimental rabbits were executed. The results showed that compared with the normal group, serum LDL-C content and TC content in the amputation group were significantly increased (P<0.05); The blood vessels of the amputated rabbits had pathological changes such as degeneration and necrosis of smooth muscle cells in the middle membrane layer and rupture of elastic fibers. At the abdominal aorta and aortic arch, the elastic fiber area expression percentage (EFEP) of the experimental group was significantly lower than that of the normal group. The results suggest that the cardiovascular system of rabbits has the tendency of decreased arterial elasticity and lipid deposition in blood after amputation, indicating that the animal research model on the effect of amputation on the cardiovascular system has been successfully established, and can provide an experimental platform for further study on the mechanism of the effect of amputation on the cardiovascular system.

Citation： MIN Lei, JIANG Wentao, LI Zhongyou, LI Xiao, WEI Junru, DIAO Junjie, BAI Taoping, YAN Fei. Establishment of an animal model to study the effects of amputation on the cardiovascular system. Journal of Biomedical Engineering, 2022, 39(5): 991-996. doi: 10.7507/1001-5515.202203064 Copy

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2.	Neugebauer J, Guse D, Heyn G. Arterial embolism of the extremities. Z Arztl Fortbild, 1969, 63(11): 593-596.
3.	Modan M, Peles E, Halkin H, et al. Increased cardiovascular disease mortality rates in traumatic lower limb amputees. Am J Cardiol, 1998, 82(10): 1242-1247.
4.	Wang Mian, LI Wen, Chang Guangqi, et al. MicroRNA-21 regulates vascular smooth muscle cell function via targeting tropomyosin 1 in arteriosclerosis obliterans of lower extremities. Arterioscler Thromb Vasc Biol, 2011, 31: 2044-2053.
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6.	Piazza G, Creager M A. Thromboangiitis obliterans. Circulation, 2010, 121: 1858-1861.
7.	Yan Fei, Jiang Wentao, Dong Ruiqi, et al. Blood flow and oxygen transport in the descending branch of lateral femoral circumflex arteries after transfemoral amputation: a numerical study. J Med Biol Eng, 2017, 37: 63-73.
8.	Ochi M, Kohara K, Tabara Y, et al. Arterial stiffness is associated with low thigh muscle mass in middle-aged to elderly men. Atherosclerosis, 2010, 212(1): 327-332.
9.	Pyle A L, Young P P. Atheromas feel the pressure: biomechanical stress and atherosclerosis. Am J Pathol, 2010, 177(1): 4-9.
10.	Liao F, Garrison D W, Jan Y K. Relationship between nonlinear properties of sacral skin blood flow oscillations and vasodilatory function in people at risk for pressure ulcers. Microvasc Res, 2010, 80(1): 44-53.
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15.	Getz G S, Reardon C A. Animal models of atherosclerosis. Arterioscler Thromb Vasc Biol, 2012, 32(5): 1104-1115.
16.	Litwin S E, Katz S E, Morgan J P, et al. Serial echocardiographic assessment of left ventricular geometry and function after large myocardial infarction in the rat. Circulation, 1994, 89(1): 345-354.
17.	van Veldhuisen D J, van Gilst W H, De Smet B J G L, et al. Neurohumoral and hemodynamic effects of ibopamine in a rat model of chronic myocardial infarction and heart failure. Cardiovasc Drugs Ther, 1994, 8(2): 245-250.
18.	Li Z, Bing O H L, Long X, et al. Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat. Am J Pathol, 1997, 272(5 Pt 2): H2313-H2319.
19.	王玉伟. 截肢手术对兔心脏功能及电活动的影响研究. 北京: 中国人民解放军医学院, 2013.
20.	祝俊杰. 猪在心血管研究中的应用. 实验动物科学, 1987(3): 108-110.
21.	Marques A, Marques M G, Silveira B C R, et al. Lidocaine administered at a continuous rate infusion does not impair left ventricular systolic and diastolic function of healthy rabbits sedated with midazolam. Vet Anim Sci, 2020, 10: 100151.
22.	Weisbroth S H, Flatt R E, Kraus A L. The biology of the laboratory rabbit. New York: Academic Press, 2013: 155-156.
23.	Dutta S, Sengupta P. Rabbits and men: relating their ages. J Basic Clin Physiol Pharmacol, 2018, 29(5): 427-435.
24.	吴兆苏, 姚崇华, 赵冬, 等. 11省市队列人群心血管病发病前瞻性研究. 中华心血管病杂志, 1999(1): 5-8.
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28.	Ference B A, Ginsberg H N, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J, 2017, 38(32): 2459-2472.
29.	Karr S. Epidemiology and management of hyperlipidemia. Am J Manag Care, 2017, 23(9 Suppl): S139-S148.
30.	Sun J H, Min D, Nam K, et al. Effect of dietary fats on blood cholesterol and lipid and the development of atherosclerosis in rabbits. Nutr Res, 2005, 25(10): 925-935.
31.	Anitschkow N. Uber die Veranderungen der Kannichenaorta bei experimentaeller Cholesterinsteatose. Beitrz Path Anatalllg Pathol, 1913, 56: 379-404.
32.	Yanni A E. The laboratory rabbit: an animal model of atherosclerosis research. Lab Anim, 2004, 38(3): 246-256.
33.	刘鹏, 王广新, 苏国海. 兔动脉粥样硬化模型建立方法的研究进展. 中国比较医学杂志, 2021, 31(4): 150-154.
34.	诸骏仁, 高润霖, 赵水平, 等. 中国成人血脂异常防治指南(2016年修订版). 中国循环杂志, 2016, 31(10): 937-953.
35.	Sorrentino M J. Cholesterol reduction to prevent CAD. What do the data show? Postgrad Med, 2000, 108(7): 40.
36.	Expert Panel on Detection Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). J Am Med Assoc, 2001, 285(19): 2486-2497.
37.	Lafont A. Basic aspects of plaque vulnerability. Heart, 2003, 89(10): 1262-1267.
38.	Willerson J T, Ridker P M. Inflammation as a cardiovascular risk factor. Circulation, 2004, 109(21 Suppl 1): II-2-II-10.
39.	Cohn J N. Vascular wall function as a risk marker for cardiovascular disease. J Hypertens Suppl Off J Int Soc Hypertens, 1999, 17(5): S41-S44.
40.	Cohn J N. Arterial compliance to stratify cardiovascular risk: more precision in therapeutic decision making. Am J Hypertens, 2001, 14(8 Pt 2): S258-S263.

1. Blevins W A, Schneider P A. Endovascular management of critical limb ischemia. J Vasc Endovasc Surg, 2010, 39: 756-761.
2. Neugebauer J, Guse D, Heyn G. Arterial embolism of the extremities. Z Arztl Fortbild, 1969, 63(11): 593-596.
3. Modan M, Peles E, Halkin H, et al. Increased cardiovascular disease mortality rates in traumatic lower limb amputees. Am J Cardiol, 1998, 82(10): 1242-1247.
4. Wang Mian, LI Wen, Chang Guangqi, et al. MicroRNA-21 regulates vascular smooth muscle cell function via targeting tropomyosin 1 in arteriosclerosis obliterans of lower extremities. Arterioscler Thromb Vasc Biol, 2011, 31: 2044-2053.
5. Frugoli B A, Guion K W, Joyner B A, et al. Cardiovascular disease risk factors in an amputee population. J Prosthet Orthot, 2000, 12(3): 80-87.
6. Piazza G, Creager M A. Thromboangiitis obliterans. Circulation, 2010, 121: 1858-1861.
7. Yan Fei, Jiang Wentao, Dong Ruiqi, et al. Blood flow and oxygen transport in the descending branch of lateral femoral circumflex arteries after transfemoral amputation: a numerical study. J Med Biol Eng, 2017, 37: 63-73.
8. Ochi M, Kohara K, Tabara Y, et al. Arterial stiffness is associated with low thigh muscle mass in middle-aged to elderly men. Atherosclerosis, 2010, 212(1): 327-332.
9. Pyle A L, Young P P. Atheromas feel the pressure: biomechanical stress and atherosclerosis. Am J Pathol, 2010, 177(1): 4-9.
10. Liao F, Garrison D W, Jan Y K. Relationship between nonlinear properties of sacral skin blood flow oscillations and vasodilatory function in people at risk for pressure ulcers. Microvasc Res, 2010, 80(1): 44-53.
11. John T H, Bruce M K. 奈特人体生理学彩色图谱. 第1版. 北京: 人民卫生出版社, 2005: 66-78.
12. Chen L, Shannon R P, Shen Y T. Animal models for the study of human disease. Boston: Academic Press, 2013: 173-194.
13. Fan J, Kitajima S, Watanabe T, et al. Rabbit models for the study of human atherosclerosis: from pathophysiological mechanisms to translational medicine. Pharmacol Ther, 2015, 146: 104-119.
14. Armstrong M L, Heistad D D. Animal models of atherosclerosis. Atherosclerosis, 1990, 85(1): 15-23.
15. Getz G S, Reardon C A. Animal models of atherosclerosis. Arterioscler Thromb Vasc Biol, 2012, 32(5): 1104-1115.
16. Litwin S E, Katz S E, Morgan J P, et al. Serial echocardiographic assessment of left ventricular geometry and function after large myocardial infarction in the rat. Circulation, 1994, 89(1): 345-354.
17. van Veldhuisen D J, van Gilst W H, De Smet B J G L, et al. Neurohumoral and hemodynamic effects of ibopamine in a rat model of chronic myocardial infarction and heart failure. Cardiovasc Drugs Ther, 1994, 8(2): 245-250.
18. Li Z, Bing O H L, Long X, et al. Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat. Am J Pathol, 1997, 272(5 Pt 2): H2313-H2319.
19. 王玉伟. 截肢手术对兔心脏功能及电活动的影响研究. 北京: 中国人民解放军医学院, 2013.
20. 祝俊杰. 猪在心血管研究中的应用. 实验动物科学, 1987(3): 108-110.
21. Marques A, Marques M G, Silveira B C R, et al. Lidocaine administered at a continuous rate infusion does not impair left ventricular systolic and diastolic function of healthy rabbits sedated with midazolam. Vet Anim Sci, 2020, 10: 100151.
22. Weisbroth S H, Flatt R E, Kraus A L. The biology of the laboratory rabbit. New York: Academic Press, 2013: 155-156.
23. Dutta S, Sengupta P. Rabbits and men: relating their ages. J Basic Clin Physiol Pharmacol, 2018, 29(5): 427-435.
24. 吴兆苏, 姚崇华, 赵冬, 等. 11省市队列人群心血管病发病前瞻性研究. 中华心血管病杂志, 1999(1): 5-8.
25. Zhu Yao, Lu Jieming, Yu Zhebin, et al. Intra-individual variability of total cholesterol is associated with cardiovascular disease mortality: A cohort study. Nutr Metab Cardiovasc Dis, 2019, 29(11): 1205-1213.
26. Lewington S, Whitlock G, Clarke R, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet, 2007, 370(9602): 1829-1839.
27. Stamler J, Daviglus M L, Garside D B, et al. Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity. J Am Med Assoc, 2000, 284(3): 311-318.
28. Ference B A, Ginsberg H N, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J, 2017, 38(32): 2459-2472.
29. Karr S. Epidemiology and management of hyperlipidemia. Am J Manag Care, 2017, 23(9 Suppl): S139-S148.
30. Sun J H, Min D, Nam K, et al. Effect of dietary fats on blood cholesterol and lipid and the development of atherosclerosis in rabbits. Nutr Res, 2005, 25(10): 925-935.
31. Anitschkow N. Uber die Veranderungen der Kannichenaorta bei experimentaeller Cholesterinsteatose. Beitrz Path Anatalllg Pathol, 1913, 56: 379-404.
32. Yanni A E. The laboratory rabbit: an animal model of atherosclerosis research. Lab Anim, 2004, 38(3): 246-256.
33. 刘鹏, 王广新, 苏国海. 兔动脉粥样硬化模型建立方法的研究进展. 中国比较医学杂志, 2021, 31(4): 150-154.
34. 诸骏仁, 高润霖, 赵水平, 等. 中国成人血脂异常防治指南(2016年修订版). 中国循环杂志, 2016, 31(10): 937-953.
35. Sorrentino M J. Cholesterol reduction to prevent CAD. What do the data show? Postgrad Med, 2000, 108(7): 40.
36. Expert Panel on Detection Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). J Am Med Assoc, 2001, 285(19): 2486-2497.
37. Lafont A. Basic aspects of plaque vulnerability. Heart, 2003, 89(10): 1262-1267.
38. Willerson J T, Ridker P M. Inflammation as a cardiovascular risk factor. Circulation, 2004, 109(21 Suppl 1): II-2-II-10.
39. Cohn J N. Vascular wall function as a risk marker for cardiovascular disease. J Hypertens Suppl Off J Int Soc Hypertens, 1999, 17(5): S41-S44.
40. Cohn J N. Arterial compliance to stratify cardiovascular risk: more precision in therapeutic decision making. Am J Hypertens, 2001, 14(8 Pt 2): S258-S263.

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