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An Improved Monkey Model of Myocardial Ischemic Infarction for Cardiovascular Drug Development

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Abstract

Non-human primate monkey model of myocardial ischemic infarction is precious for translational medicine research. Ligation of the left anterior descending (LAD) artery is a common procedure to induce myocardial ischemic infarction. However, the consistency of the myocardial infarction thus generated remains problematic. The present study was undertaken to critically evaluate the monkey model of myocardial ischemic infarction to develop a procedure for a consistent cross-study comparison. Forty male Rhesus monkeys were divided into 4 groups and subjected to LAD artery ligation at different levels along the artery. In addition, the major diagonal branch was selectively ligated parallel to the ligation site of the LAD artery according to the diagonal branch distribution. Analyses of MRI, echocardiography, cardiac hemodynamics, electrocardiography, histopathology, and cardiac injury biomarkers were undertaken to characterize the monkeys with myocardial infarction. Ligation at 40% of the total length of the artery, measured from the apex end, produced variable infarct areas with inconsistent functional alterations. Ligation at 60% or above coupled with selective ligation of diagonal branches produced a consistent myocardial infarction with uniform dysfunction. However, ligation at 70% caused a lethal threat. After a thorough analysis, it is concluded that ligation at 60% of the total length coupled with selective ligation of diagonal branches, enables standardization of the location of occlusion and the subsequent ischemic area, as well as avoids the influence of the diagonal branches, are ideal to produce a consistent monkey model of myocardial ischemic infarction.

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Data Availability

All data generated or analyzed during this study are included in this published article.

References

  1. Ilia, R., Rosenshtein, G., Weinstein, J., Cafri, C., Abu-Ful, A., & Gueron, M. (2001). Left anterior descending artery length in left and right coronary artery dominance. Coronary Artery Disease, 12(1), 77–78. https://doi.org/10.1097/00019501-200102000-00011

    Article  CAS  PubMed  Google Scholar 

  2. James, T.N. (1961). Anatomy of the coronary arteries. P.B. Hoeber.

  3. Buss, D. D., Hyde, D. M., & Steffey, E. P. (1983). Coronary collateral development in the rhesus monkey (Macaca mulatta). Basic Research in Cardiology, 78(5), 510–517. https://doi.org/10.1007/BF01906462

    Article  CAS  PubMed  Google Scholar 

  4. Ginis, I., Luo, Y., Miura, T., Thies, S., Brandenberger, R., Gerecht-Nir, S., Amit, M., Hoke, A., Carpenter, M. K., Itskovitz-Eldor, J., & Rao, M. S. (2004). Differences between human and mouse embryonic stem cells. Developmental Biology, 269(2), 360–380. https://doi.org/10.1016/j.ydbio.2003.12.034

    Article  CAS  PubMed  Google Scholar 

  5. Banka, N., Anand, I. S., Nirankari, O. P., Gulati, S., Sharma, P. L., Chakravarti, R. N., & Wahi, P. L. (1982). Macroscopic and microscopic measurement of myocardial infarct size. A comparison. Research Express in Medicine (Berlin), 181(2), 125–133. https://doi.org/10.1007/BF01852189

    Article  CAS  Google Scholar 

  6. Flameng, W., Lesaffre, E., & Vanhaecke, J. (1990). Determinants of infarct size in non-human primates. Basic Research in Cardiology, 85(4), 392–403. https://doi.org/10.1007/BF01907131

    Article  CAS  PubMed  Google Scholar 

  7. Sun, X., Cai, J., Fan, X., Han, P., Xie, Y., Chen, J., Xiao, Y., & Kang, Y. J. (2013). Decreases in electrocardiographic R-wave amplitude and QT interval predict myocardial ischemic infarction in Rhesus monkeys with left anterior descending artery ligation. PLoS ONE, 8(8), e71876. https://doi.org/10.1371/journal.pone.0071876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Xie, Y., Chen, J., Han, P., Yang, P., Hou, J., & Kang, Y. J. (2012). Immunohistochemical detection of differentially localized up-regulation of lysyl oxidase and down-regulation of matrix metalloproteinase-1 in rhesus monkey model of chronic myocardial infarction. Experimental Biology and Medicine (Maywood, N.J.), 237(7), 853–859. https://doi.org/10.1258/ebm.2012.012070

    Article  CAS  Google Scholar 

  9. Yang, P., Han, P., Hou, J., Zhang, L., Song, H., Xie, Y., Chen, Y., Xie, H., Gao, F., & Kang, Y. J. (2011). Electrocardiographic characterization of rhesus monkey model of ischemic myocardial infarction induced by left anterior descending artery ligation. Cardiovascular Toxicology, 11(4), 365–372. https://doi.org/10.1007/s12012-011-9129-8

    Article  PubMed  Google Scholar 

  10. Grayson, J., & Irvine, M. (1968). Myocardial infarction in the monkey: Studies on the collateral circulation after acute coronary occlusion. Cardiovascular Research, 2(2), 170–178. https://doi.org/10.1093/cvr/2.2.170

    Article  CAS  PubMed  Google Scholar 

  11. Hill, J. D., Malinow, M. R., McNulty, W. P., & Ochsner, A. J., 3rd. (1972). Experimental myocardial infarction in unanesthetized monkeys. American Heart Journal, 84(1), 82–94. https://doi.org/10.1016/0002-8703(72)90310-9

    Article  CAS  PubMed  Google Scholar 

  12. Anand, I. S., Sharma, P. L., Chakravarti, R. N., & Wahi, P. L. (1980). Experimental myocardial infarction in rhesus monkeys. Verapamil pretreatment in the reduction of infarct size. Advances in Myocardiology, 2, 425–433.

    CAS  PubMed  Google Scholar 

  13. Wu, C., Yan, L., Depre, C., Dhar, S. K., Shen, Y. T., Sadoshima, J., Vatner, S. F., & Vatner, D. E. (2009). Cytochrome c oxidase III as a mechanism for apoptosis in heart failure following myocardial infarction. American Journal of Physiology. Cell Physiology, 297(4), C928-934. https://doi.org/10.1152/ajpcell.00045.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yoshioka, T., Ageyama, N., Shibata, H., Yasu, T., Misawa, Y., Takeuchi, K., Matsui, K., Yamamoto, K., Terao, K., Shimada, K., Ikeda, U., Ozawa, K., & Hanazono, Y. (2005). Repair of infarcted myocardium mediated by transplanted bone marrow-derived CD34+ stem cells in a nonhuman primate model. Stem Cells, 23(3), 355–364. https://doi.org/10.1634/stemcells.2004-0200

    Article  CAS  PubMed  Google Scholar 

  15. Cai, J., Sun, X., Han, P., Xiao, Y., Fan, X., Shang, Y., & Kang, Y. J. (2014). The effect of myocardial infarct size on cardiac reserve in rhesus monkeys. Cardiovascular Toxicology. https://doi.org/10.1007/s12012-014-9253-3

    Article  PubMed  Google Scholar 

  16. Lian, W. S., Cheng, W. T., Cheng, C. C., Hsiao, F. S., Chen, J. J., Cheng, C. F., & Wu, S. C. (2011). In vivo therapy of myocardial infarction with mesenchymal stem cells modified with prostaglandin I synthase gene improves cardiac performance in mice. Life Sciences, 88(9–10), 455–464. https://doi.org/10.1016/j.lfs.2010.12.020

    Article  CAS  PubMed  Google Scholar 

  17. Loffredo, F. S., Steinhauser, M. L., Gannon, J., & Lee, R. T. (2011). Bone marrow-derived cell therapy stimulates endogenous cardiomyocyte progenitors and promotes cardiac repair. Cell Stem Cell, 8(4), 389–398. https://doi.org/10.1016/j.stem.2011.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Haghighi, K., Kolokathis, F., Pater, L., Lynch, R. A., Asahi, M., Gramolini, A. O., Fan, G. C., Tsiapras, D., Hahn, H. S., Adamopoulos, S., Liggett, S. B., Dorn, G. W., 2nd., MacLennan, D. H., Kremastinos, D. T., & Kranias, E. G. (2003). Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. The Journal of Clinical Investigation, 111(6), 869–876. https://doi.org/10.1172/JCI17892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chu, G., Haghighi, K., & Kranias, E. G. (2002). From mouse to man: Understanding heart failure through genetically altered mouse models. Journal of Cardiac Failure, 8(6 Suppl), S432-449. https://doi.org/10.1054/jcaf.2002.129284

    Article  CAS  PubMed  Google Scholar 

  20. Hackam, D. G., & Redelmeier, D. A. (2006). Translation of research evidence from animals to humans. JAMA, 296(14), 1731–1732. https://doi.org/10.1001/jama.296.14.1731

    Article  CAS  PubMed  Google Scholar 

  21. Huang, J., Zhang, Z., Guo, J., Ni, A., Deb, A., Zhang, L., Mirotsou, M., Pratt, R. E., & Dzau, V. J. (2010). Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circulation Research, 106(11), 1753–1762. https://doi.org/10.1161/CIRCRESAHA.109.196030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Orlic, D., Kajstura, J., Chimenti, S., Limana, F., Jakoniuk, I., Quaini, F., Nadal-Ginard, B., Bodine, D. M., Leri, A., & Anversa, P. (2001). Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proceedings for National Academics in Science USA, 98(18), 10344–10349. https://doi.org/10.1073/pnas.181177898

    Article  CAS  Google Scholar 

  23. Orlic, D., Kajstura, J., Chimenti, S., Jakoniuk, I., Anderson, S. M., Li, B., Pickel, J., McKay, R., Nadal-Ginard, B., Bodine, D. M., Leri, A., & Anversa, P. (2001). Bone marrow cells regenerate infarcted myocardium. Nature, 410(6829), 701–705. https://doi.org/10.1038/35070587

    Article  CAS  PubMed  Google Scholar 

  24. Zohlnhofer, D., Ott, I., Mehilli, J., Schomig, K., Michalk, F., Ibrahim, T., Meisetschlager, G., von Wedel, J., Bollwein, H., Seyfarth, M., Dirschinger, J., Schmitt, C., Schwaiger, M., Kastrati, A., & Schomig, A. (2006). Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: A randomized controlled trial. JAMA, 295(9), 1003–1010. https://doi.org/10.1001/jama.295.9.1003

    Article  PubMed  Google Scholar 

  25. Tendera, M., Wojakowski, W., Ruzyllo, W., Chojnowska, L., Kepka, C., Tracz, W., Musialek, P., Piwowarska, W., Nessler, J., Buszman, P., Grajek, S., Breborowicz, P., Majka, M., Ratajczak, M. Z., & Investigators, R. (2009). Intracoronary infusion of bone marrow-derived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: Results of randomized, multicentre Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) Trial. European Heart Journal, 30(11), 1313–1321. https://doi.org/10.1093/eurheartj/ehp073

    Article  PubMed  Google Scholar 

  26. Singh, R., Chakravarti, R. N., Chhuttani, P. N., & Wahi, P. L. (1970). Electrocardiographic studies in rhesus monkeys. Journal of Applied Physiology, 28(3), 346–349. https://doi.org/10.1152/jappl.1970.28.3.346

    Article  CAS  PubMed  Google Scholar 

  27. Teofilovski-Parapid, G., & Kreclovic, G. (1998). Coronary artery distribution in Macaca fascicularis (Cynomolgus). Laboratory Animals, 32(2), 200–205. https://doi.org/10.1258/002367798780600007

    Article  CAS  PubMed  Google Scholar 

  28. Buss, D. D., Hyde, D. M., & Poulos, P. W., Jr. (1982). Coronary artery distribution in bonnet monkeys (Macaca radiata). Anatomical Record, 203(3), 411–417. https://doi.org/10.1002/ar.1092030311

    Article  CAS  PubMed  Google Scholar 

  29. Nikolic, V., Blagojevic, Z., Malobabic, S., Arandelovic, A., Malis, M., Teofilovski-Parapid, G., & Stankovic, I. (2003). Distribution of left coronary artery branches in the African green monkey. Acta Veterinaria-Beograd, 53(2–3), 139–150. https://doi.org/10.2298/Avb0303139n

    Article  Google Scholar 

  30. Schaper, W., Piek, J., Munoz-Chapuli, R., Wolf, C., & Ito, W. (1999). Collateral circulation of the heart. Angiogenesis and Cardiovascular Disease, 11, 159–198.

    Google Scholar 

  31. Vignaux, O. (2005). Cardiac sarcoidosis: Spectrum of MRI features. AJR. American Journal of Roentgenology, 184(1), 249–254. https://doi.org/10.2214/ajr.184.1.01840249

    Article  PubMed  Google Scholar 

  32. Suzuki, M., Asano, H., Tanaka, H., & Usuda, S. (1999). Development and evaluation of a new canine myocardial infarction model using a closed-chest injection of thrombogenic material. Japanese Circulation Journal, 63(11), 900–905. https://doi.org/10.1253/jcj.63.900

    Article  CAS  PubMed  Google Scholar 

  33. Haines, D. E., Verow, A. F., Sinusas, A. J., Whayne, J. G., & DiMarco, J. P. (1994). Intracoronary ethanol ablation in swine: Characterization of myocardial injury in target and remote vascular beds. Journal of Cardiovascular Electrophysiology, 5(1), 41–49. https://doi.org/10.1111/j.1540-8167.1994.tb01113.x

    Article  CAS  PubMed  Google Scholar 

  34. Doty, D. B., DiRusso, G. B., & Doty, J. R. (1998). Full-spectrum cardiac surgery through a minimal incision: Mini-sternotomy (lower half) technique. Annals of Thoracic Surgery, 65(2), 573–577. https://doi.org/10.1016/s0003-4975(97)01368-4

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was financially supported by the National Natural Science Foundation of China (NSFC 81230004 and 81300109) and West China Hospital.

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Authors and Affiliations

  1. Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, 610041, Sichuan, China

    Keke Wang, Pengfei Han, Lu Huang, Ying Xiao, Jianglong Hou, Pingliang Yang, Yuping Xie, Jindan Cai, Hongge Wang & Y. James Kang

  2. Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Jianglong Hou

  3. Department of Anesthesiology, First Affiliated Hospital of Chengdu Medical College, Xindu, 610050, Sichuan, China

    Pingliang Yang

  4. Department of Oncology, Chengdu First People’s Hospital, Chengdu, 610041, Sichuan, China

    Yuping Xie

  5. Department of Cardiology, Affiliated Renhe Hospital, China Three Gorges University, Yichang, 443001, Hubei, China

    Jindan Cai

  6. Tennessee Institute of Regenerative Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

    Y. James Kang

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  1. Keke Wang
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Contributions

YJK conceptualized the study, and KW, PH, KW and YJK designed the experiments; KW, PH, LH, YX, JH, PY, YP, JC, and HW carried out the experiments. KW, PH, and LH analyzed the data and interpreted the results; YJK and PH drafted the manuscript; YJK revised the draft and approved the final version of the manuscript.

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Correspondence to Y. James Kang.

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The authors declare no potential conflicts of interest.

Research Involving Human and Animal Studies

No human studies were carried out by the authors of this article. All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the Institutional Animal Care and Use Committee (IACUC) of Sichuan University West China Hospital (2015017A).

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Handling Editor: Yu-Ming Kang.

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Wang, K., Han, P., Huang, L. et al. An Improved Monkey Model of Myocardial Ischemic Infarction for Cardiovascular Drug Development. Cardiovasc Toxicol 22, 787–801 (2022). https://doi.org/10.1007/s12012-022-09754-6

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