Translation of Methdology used in Human Myocardial Imaging to a Sheep Model of Acute Myocardial Infarction

Document Type : Original Article


1 Department of Nuclear Medicine, Royal North Shore Hospital, Australia

2 Discipline of Medical Radiation Sciences, University of Sydney, Australia

3 Sydney Medical School, University of Sydney, Australia

4 Department of Cardiology, Royal North Shore Hospital, Australia

5 Cardiac Technology Centre, North Shore Heart Research Group, Kolling Institute, Australia

6 Charles Sturt University, Wagga Wagga, Australia


Objective(s): Pre-clinical investigation of stem cells for repairing damaged myocardium predominantly used rodents, however large animals have cardiac circulation closely resembling the human heart. The aim of this study was to evaluate whether SPECT/CT myocardial perfusion imaging (MPI) could be used for assessing sheep myocardium following an acute myocardial infarction (MI) and response to intervention.
Method: 18 sheep enrolled in a pilot study to evaluate [99mTc]-sestamibi MPI at baseline, post-MI and after therapy. Modifications to the standard MPI protocols were developed. All data was reconstructed with OSEM using CT-derived attenuation and scatter correction. Standard analyses were performed and inter-observer agreement were measured using Kappa (). Power determined the sample sizes needed to show statistically significant changes due to intervention.
Results: Ten sheep completed the full protocol. Data processed were performed using pre-existing hardware and software used in human MPI scanning. No improvement in perfusion was seen in the control group, however improvements of 15% - 35% were seen after intra-myocardial stem cell administration. Inter-observer agreement was excellent (К=0.89). Using a target power of 0.9, 28 sheep were required to detect a 10-12% change in perfusion.
Conclusions: Study demonstrates the suitability of large animal models for imaging with standard MPI protocols and it’s feasibility with a manageable number of animals. These protocols could be translated into humans to study the efficacy of stem cell therapy in heart regeneration and repair.


Main Subjects

  1. Rasmussen TL, Raveendran G, Zhang J, Garry DJ. Getting to the heart of myocardial stem cells and cell therapy. Circulation. 2011 Apr 26;123(16):1771-9.
  2. Fischer KM, Cottage CT, Wu W, Din S, Gude NA, Avitabile D, et al. Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase. Circulation. 2009;120(21):2077-87.
  3. Schuleri KH, Amado LC, Boyle AJ, Centola M, Saliaris AP, Gutman MR, et al. Early improvement in cardiac tissue perfusion due to mesenchymal stem cells. Am J Physiol Heart Circ Physiol. 2008;294(5)
  4. Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008;103(11):1204-19.
  5. Abdel-Latif A, Bolli R, Tleyjeh IM, Montori VM, Perin EC, Hornung CA, et al. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med. 2007;167(10):989-97.
  6. Janssens S, Dubois C, Bogaert J, Theunissen K, Deroose C, Desmet W, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet. 2006;367(9505):113-21.
  7. Nelson TJ, Martinez-Fernandez A, Yamada S, Perez-Terzic C, Ikeda Y, Terzic A. Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells. Circulation. 2009;120(5):408-16.
  8. Smart N, Bollini S, Dube KN, Vieira JM, Zhou B, Davidson S, et al. De novo cardiomyocytes from within the activated adult heart after injury. Nature. 2011;2011(8).
  9. Smart N, Bollini S, Dube KN, Vieira JM, Zhou B, Davidson S, et al. De novo cardiomyocytes from within the activated adult heart after injury. Nature. 2011;474(7353):640-4.
  10. Dixon JA, Spinale FG. Large animal models of heart failure: a critical link in the translation of basic science to clinical practice. Circ Heart Fail. 2009;2(3):262-71.
  11. Chin BB, Nakamoto Y, Bulte JW, Pittenger MF, Wahl R, Kraitchman DL. 111In oxine labelled mesenchymal stem cell SPECT after intravenous administration in myocardial infarction. Nucl Med Commun. 2003;24(11):1149-54.
  12. Zhang SJ, Wu JC. Comparison of imaging techniques for tracking cardiac stem cell therapy. J Nucl Med. 2007;48(12):1916-9.
  13. Nowak B, Weber C, Schober A, Zeiffer U, Liehn EA, von Hundelshausen P, et al. Indium-111 oxine labelling affects the cellular integrity of haematopoietic progenitor cells. Eur J Nucl Med Mol Imaging. 2007;34(5):715-21.
  14. Bailey DL, Roach PJ, Bailey EA, Hewlett J, Keijzers R. Development of a cost-effective modular SPECT/CT scanner. Eur J Nucl Med Mol Imaging. 2007;34(9):1415-26.
  15. Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs. 2001;169(1):12-20.
  16. Kawamoto A, Tkebuchava T, Yamaguchi J, Nishimura H, Yoon YS, Milliken C, et al. Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation. 2003;107(3):461-8.
  17. Hudson HM, Larkin RS. Accelerated image reconstruction using ordered subsets of projection data. IEEE Trans Med Imaging. 1994;13(4):601-9.
  18. Brown S, Bailey DL, Willowson K, Baldock C. Investigation of the relationship between linear attenuation coefficients and CT Hounsfield units using radionuclides for SPECT. Appl Radiat Isot. 2008;66(9):1206-12.
  19. Willowson K, Bailey DL, Baldock C. Quantitative SPECT reconstruction using CT-derived corrections. Phys Med Biol. 2008;53(12):3099-112.
  20. Germano G, Kavanagh PB, Waechter P, Areeda J, Van Kriekinge S, Sharir T, et al. A new algorithm for the quantitation of myocardial perfusion SPECT. I: technical principles and reproducibility. J Nucl Med. 2000;41(4):712-9.
  21. Ficaro EP, Lee BC, Kritzman JN, Corbett JR. Corridor4DM: the Michigan method for quantitative nuclear cardiology. J Nucl Cardiol. 2007;14(4):455-65.
  22. Hansen CL, Goldstein RA, Akinboboye OO, Berman DS, Botvinick EH, Churchwell KB, et al. Myocardial perfusion and function: single photon emission computed tomography. J Nucl Cardiol. 2007;14(6):e39-60.
  23. Hesse B, Tagil K, Cuocolo A, Anagnostopoulos C, Bardies M, Bax J, et al. EANM/ESC procedural guidelines for myocardial perfusion imaging in nuclear cardiology. Eur J Nucl Med Mol Imaging. 2005;32(7):855-97.
  24. Altman DG. Practical Statistics for Medical Research. First ed. TJ Press Ltd P, editor. Cornwall: Chapman & Hall, London; 1991 1991. 611 p.
  25. Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet. 2004;364(9429):141-8.
  26. Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N, et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002;106(24):3009-17.
  27. Assmus B, Walter DH, Lehmann R, Honold J, Martin H, Dimmeler S, et al. Intracoronary infusion of progenitor cells is not associated with aggravated restenosis development or atherosclerotic disease progression in patients with acute myocardial infarction. Eur Heart J. 2006;27(24):2989-95.
  28. Rowland DJ, Cherry SR. Small-animal preclinical nuclear medicine instrumentation and methodology. Semin Nucl Med. 2008;38(3):209-22.
  29. Zhou R, Thomas DH, Qiao H, Bal HS, Choi SR, Alavi A, et al. In vivo detection of stem cells grafted in infarcted rat myocardium. J Nucl Med. 2005;46(5):816-22.
  30. McDonald KM, Francis GS, Carlyle PF, Hauer K, Matthews J, Hunter DW, et al. Hemodynamic, left ventricular structural and hormonal changes after discrete myocardial damage in the dog. J Am Coll Cardiol. 1992;19(2):460-7.
  31. Yarbrough WM, Spinale FG. Large animal models of congestive heart failure: a critical step in translating basic observations into clinical applications. J Nucl Cardiol. 2003;10(1):77-86.
  32. Poulsen RH, Botker HE, Rehling M. Postreperfusion myocardial technetium-99m-sestamibi defect corresponds to area at risk Experimental results from an ischemia-reperfusion porcine model. Nucl Med Biol. 2011;38(6):819-25.
  33. Weaver ME, Pantely GA, Bristow JD, Ladley HD. A quantitative study of the anatomy and distribution of coronary arteries in swine in comparison with other animals and man. Cardiovasc Res. 1986;20(12):907-17.
  34. Huang Y, Hunyor SN, Jiang L, Kawaguchi O, Shirota K, Ikeda Y, et al. Remodeling of the chronic severely failing ischemic sheep heart after coronary microembolization: functional, energetic, structural, and cellular responses. Am J Physiol Heart Circ Physiol. 2004;286(6):H2141-50.
  35. Markovitz LJ, Savage EB, Ratcliffe MB, Bavaria JE, Kreiner G, Iozzo RV, et al. Large animal model of left ventricular aneurysm. Ann Thorac Surg. 1989;48(6):838-45.
  36. Rademaker MT, Cameron VA, Charles CJ, Espiner EA, Nicholls MG, Pemberton CJ, et al. Neurohormones in an ovine model of compensated postinfarction left ventricular dysfunction. Am J Physiol Heart Circ Physiol. 2000;278(3):H731-40.
  37. Skrypniuk JV, Bailey D, Cosgriff PS, Fleming JS, Houston AS, Jarritt PH, et al. UK audit of left ventricular ejection fraction estimation from equilibrium ECG gated blood pool images. Nucl Med Commun. 2005;26(3):205-15.
  38. Landis JR, Koch GG. An application of hierarchical kappa-type statistics in the assessment of majority agreement among multiple observers. Biometrics. 1977;33(2):363-74.