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Stem Cell Therapy to Treat Heart Ischaemia: Implications for Diabetes Cardiovascular Complications

Current Diabetes Reports volume 14, Article number: 554 (2014) Cite this article

Abstract

Diabetes mellitus is a well-known risk factor for coronary artery disease (CAD), which can lead to acute myocardial infarction, chronic myocardial ischaemia and heart failure. Despite the advantages in medical treatment, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG), morbidity and mortality is still high in patients with CAD. Along with PCI and CABG or in patients without options for revascularization, stem cell regenerative therapy in controlled trials is a possibility. Stem cells are believed to exert their actions by angiogenesis and regeneration of cardiomyocytes. Recently published clinical trials and meta-analysis of stem cell studies have shown encouraging results with increased left ventricle ejection fraction and reduced symptoms in patients with CAD and heart failure. There is some evidence of mesenchymal stem cell being more effective compared to other cell types and cell therapy may be more effective in patients with known diabetes mellitus. However, further investigations are warranted.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Eurich DT, Weir DL, Majumdar SR, Tsuyuki RT, Johnson JA, Tjosvold L, et al. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail. 2013;6:395–402.

    CAS  PubMed  Article  Google Scholar 

  2. Giles TD, Sander GE. Diabetes mellitus and heart failure: basic mechanisms, clinical features, and therapeutic considerations. Cardiol Clin. 2004;22:553–68.

    PubMed  Article  Google Scholar 

  3. Askoxylakis V, Thieke C, Pleger ST, Most P, Tanner J, Lindel K, et al. Long-term survival of cancer patients compared to heart failure and stroke: a systematic review. BMC Cancer. 2010;10:105.

    PubMed Central  PubMed  Article  Google Scholar 

  4. Dimitropoulos G, Tahrani AA, Stevens MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes. 2014;5:17–39.

    PubMed Central  PubMed  Article  Google Scholar 

  5. Qayyum AA, Vejlstrup NG, Ahtarovski KA, Kofoed KF, Kastrup J. Coronary artery stent mimicking intracardiac thrombus on cardiac magnetic resonance imaging due to signal loss: case report. Magn Reson Imaging. 2012;30:889–92.

    PubMed  Article  Google Scholar 

  6. Qayyum AA, Kuhl JT, Mathiasen AB, Ahtarovski KA, Vejlstrup NG, Kofoed KF, et al. Value of cardiac 320-multidetector computed tomography and cardiac magnetic resonance imaging for assessment of myocardial perfusion defects in patients with known chronic ischemic heart disease. Int J Cardiovasc Imaging. 2013;29:1585–93.

    PubMed  Article  Google Scholar 

  7. Qayyum AA, Hasbak P, Larsson HB, Christensen TE, Ghotbi AA, Mathiasen AB, et al. Quantification of myocardial perfusion using cardiac magnetic resonance imaging correlates significantly to rubidium-82 positron emission tomography in patients with severe coronary artery disease: a preliminary study. Eur J Radiol. 2014;83:1120–8.

    PubMed  Article  Google Scholar 

  8. Qian H, Yang Y, Li J, Huang J, Dou K, Yang G. The role of vascular stem cells in atherogenesis and post-angioplasty restenosis. Ageing Res Rev. 2007;6:109–27.

    PubMed  Article  Google Scholar 

  9. Anversa P, Leri A, Kajstura J. Cardiac regeneration. J Am Coll Cardiol. 2006;47:1769–76.

    PubMed  Article  Google Scholar 

  10. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003;114:763–76.

    CAS  PubMed  Article  Google Scholar 

  11. Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S, et al. Evidence for cardiomyocyte renewal in humans. Science. 2009;324:98–102.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  12. Chan KM, Raikwar SP, Zavazava N. Strategies for differentiating embryonic stem cells (ESC) into insulin-producing cells and development of non-invasive imaging techniques using bioluminescence. Immunol Res. 2007;39:261–70.

    CAS  PubMed  Article  Google Scholar 

  13. Goumans MJ, de Boer TP, Smits AM, van Laake LW, van Vliet P, Metz CH, et al. TGF-beta1 induces efficient differentiation of human cardiomyocyte progenitor cells into functional cardiomyocytes in vitro. Stem Cell Res. 2007;1:138–49.

    CAS  PubMed  Article  Google Scholar 

  14. Urbanek K, Torella D, Sheikh F, De AA, Nurzynska D, Silvestri F, et al. Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proc Natl Acad Sci U S A. 2005;102:8692–7.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  15. Heiss C, Keymel S, Niesler U, Ziemann J, Kelm M, Kalka C. Impaired progenitor cell activity in age-related endothelial dysfunction. J Am Coll Cardiol. 2005;45:1441–8.

    CAS  PubMed  Article  Google Scholar 

  16. Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T, Gregg D, Ramaswami P, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation. 2003;108:457–63.

    PubMed  Article  Google Scholar 

  17. Haack-Sorensen M, Friis T, Kastrup J. Mesenchymal stromal cell and mononuclear cell therapy in heart disease. Future Cardiol. 2008;4:481–94.

    PubMed  Article  Google Scholar 

  18. Liu X, Zheng P, Wang X, Dai G, Cheng H, Zhang Z, et al. A preliminary evaluation of efficacy and safety of Wharton’s jelly mesenchymal stem cell transplantation in patients with type 2 diabetes mellitus. Stem Cell Res Ther. 2014;5:57.

    PubMed Central  PubMed  Article  Google Scholar 

  19. Li Q, Wang Y, Deng Z. Pre-conditioned mesenchymal stem cells: a better way for cell-based therapy. Stem Cell Res Ther. 2013;4:63.

    PubMed Central  PubMed  Article  Google Scholar 

  20. Krampera M, Galipeau J, Shi Y, Tarte K, Sensebe L. Immunological characterization of multipotent mesenchymal stromal cells—The International Society for Cellular Therapy (ISCT) working proposal. Cytotherapy. 2013;15:1054–61.

    PubMed  Article  Google Scholar 

  21. Qayyum AA, Kastrup J. Stem cell therapy in patients with ischemia heart disease. In: Gross G, Häupl T, editors. Cell-dependent therapies mesenchymal stem cells in chronic inflammatory disorders. Berlin: De gruyter; 2013. p. 157–76. This is a useful book about mesenchymal stem cell therapy for different disorders including cardiovascular disease.

  22. Williams AR, Hare JM. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res. 2011;109:923–40.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  23. Takashima S, Tempel D, Duckers HJ. Current outlook of cardiac stem cell therapy towards a clinical application. Heart. 2013;99:1772–84.

    CAS  PubMed  Article  Google Scholar 

  24. Raval Z, Losordo DW. Cell therapy of peripheral arterial disease: from experimental findings to clinical trials. Circ Res. 2013;112:1288–302.

    CAS  PubMed  Article  Google Scholar 

  25. van der Spoel TI, Jansen of Lorkeers SJ, Agostoni P, van Belle E, Gyongyosi M, Sluijter JP, et al. Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease. Cardiovasc Res. 2011;91:649–58.

    PubMed  Article  Google Scholar 

  26. Richardson JD, Bertaso AG, Psaltis PJ, Frost L, Carbone A, Paton S, et al. Impact of timing and dose of mesenchymal stromal cell therapy in a preclinical model of acute myocardial infarction. J Card Fail. 2013;19:342–53.

    PubMed  Article  Google Scholar 

  27. Freyman T, Polin G, Osman H, Crary J, Lu M, Cheng L, et al. A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. Eur Heart J. 2006;27:1114–22.

    PubMed  Article  Google Scholar 

  28. Perin EC, Silva GV, Assad JA, Vela D, Buja LM, Sousa AL, et al. Comparison of intracoronary and transendocardial delivery of allogeneic mesenchymal cells in a canine model of acute myocardial infarction. J Mol Cell Cardiol. 2008;44:486–95.

    CAS  PubMed  Article  Google Scholar 

  29. Jeevanantham V, Butler M, Saad A, Abdel-Latif A, Zuba-Surma EK, Dawn B. Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and meta-analysis. Circulation. 2012;126:551–68.

    PubMed  Article  Google Scholar 

  30. Zhao Q, Ye X. Additive value of adult bone-marrow-derived cell transplantation to conventional revascularization in chronic ischemic heart disease: a systemic review and meta-analysis. Expert Opin Biol Ther. 2011;11:1569–79.

    PubMed  Article  Google Scholar 

  31. Zimmet H, Porapakkham P, Porapakkham P, Sata Y, Haas SJ, Itescu S, et al. Short- and long-term outcomes of intracoronary and endogenously mobilized bone marrow stem cells in the treatment of ST-segment elevation myocardial infarction: a meta-analysis of randomized control trials. Eur J Heart Fail. 2012;14:91–105.

    PubMed  Article  Google Scholar 

  32. Li N, Yang YJ, Zhang Q, Jin C, Wang H, Qian HY. Stem cell therapy is a promising tool for refractory angina: a meta-analysis of randomized controlled trials. Can J Cardiol. 2013;29:908–14.

    PubMed  Article  Google Scholar 

  33. Bai Y, Sun T, Ye P. Age, gender and diabetic status are associated with effects of bone marrow cell therapy on recovery of left ventricular function after acute myocardial infarction: a systematic review and meta-analysis. Ageing Res Rev. 2010;9:418–23. A useful report about factors influencing the effect of stem cell therapy.

  34. Fisher SA, Brunskill SJ, Doree C, Mathur A, Taggart DP, Martin-Rendon E. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev. 2014;4:CD007888. This is an important review of stem cell therapy for ischemic heart disease and heart failure.

  35. Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, et al. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol. 2004;94:92–5.

    PubMed  Article  Google Scholar 

  36. Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol. 2009;54:2277–86.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  37. Friis T, Haack-Sorensen M, Mathiasen AB, Ripa RS, Kristoffersen US, Jorgensen E, et al. Mesenchymal stromal cell derived endothelial progenitor treatment in patients with refractory angina. Scand Cardiovasc J. 2011;45:161–8.

    PubMed  Article  Google Scholar 

  38. Haack-Sorensen M, Friis T, Mathiasen AB, Jorgensen E, Hansen L, Dickmeiss E, et al. Direct intramyocardial mesenchymal stromal cell injections in patients with severe refractory angina: one-year follow-up. Cell Transplant. 2013;22:521–8.

    PubMed  Article  Google Scholar 

  39. Mathiasen AB, Haack-Sorensen M, Jorgensen E, Kastrup J. Autotransplantation of mesenchymal stromal cells from bone-marrow to heart in patients with severe stable coronary artery disease and refractory angina—final 3-year follow-up. Int J Cardiol. 2013;170:246–51. This study demonstrates clinical benefit and safety of mesenchymal stem cell therapy for ischemic heart disease.

  40. Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, et al. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA. 2012;308:2369–79.

    CAS  PubMed  Article  Google Scholar 

  41. Karantalis V, Difede DL, Gerstenblith G, Pham S, Symes J, Zambrano JP, et al. Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: the Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) Trial. Circ Res. 2014;114:1302–10.

    CAS  PubMed  Article  Google Scholar 

  42. Heldman AW, Difede DL, Fishman JE, Zambrano JP, Trachtenberg BH, Karantalis V, et al. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA. 2014;311:62–73.

    CAS  PubMed  Article  Google Scholar 

  43. Mathiasen AB, Jorgensen E, Qayyum AA, Haack-Sorensen M, Ekblond A, Kastrup J. Rationale and design of the first randomized, double-blind, placebo-controlled trial of intramyocardial injection of autologous bone-marrow derived Mesenchymal Stromal Cells in chronic ischemic Heart Failure (MSC-HF Trial). Am Heart J. 2012;164:285–91.

    PubMed  Article  Google Scholar 

  44. Qayyum AA, Haack-Sorensen M, Mathiasen AB, Jorgensen E, Ekblond A, Kastrup J. Adipose-derived mesenchymal stromal cells for chronic myocardial ischemia (MyStromalCell Trial): study design. Regen Med. 2012;7:421–8.

    CAS  PubMed  Article  Google Scholar 

  45. Helder MN, Knippenberg M, Klein-Nulend J, Wuisman PI. Stem cells from adipose tissue allow challenging new concepts for regenerative medicine. Tissue Eng. 2007;13:1799–808.

    CAS  PubMed  Article  Google Scholar 

  46. Alexopoulos N, Katritsis D, Raggi P. Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis. Atherosclerosis. 2014;233:104–12.

    CAS  PubMed  Article  Google Scholar 

  47. Bays HE. Adiposopathy, diabetes mellitus, and primary prevention of atherosclerotic coronary artery disease: treating “sick fat” through improving fat function with antidiabetes therapies. Am J Cardiol. 2012;110:4B–12.

    PubMed  Article  Google Scholar 

  48. Neef K, Choi YH, Weichel A, Rahmanian PB, Liakopoulos OJ, Stamm C, et al. The influence of cardiovascular risk factors on bone marrow mesenchymal stromal cell fitness. Cytotherapy. 2012;14:670–8.

    CAS  PubMed  Article  Google Scholar 

  49. Friis T, Haack-Sorensen M, Hansen SK, Hansen L, Bindslev L, Kastrup J. Comparison of mesenchymal stromal cells from young healthy donors and patients with severe chronic coronary artery disease. Scand J Clin Lab Invest. 2011;71:193–202.

    CAS  PubMed  Article  Google Scholar 

  50. Mozid AM, Jones D, Arnous S, Saunders N, Wragg A, Martin J, et al. The effects of age, disease state, and granulocyte colony-stimulating factor on progenitor cell count and function in patients undergoing cell therapy for cardiac disease. Stem Cells Dev. 2013;22:216–23.

    CAS  PubMed  Article  Google Scholar 

  51. Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One. 2012;7:e47559.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  52. Nowbar AN, Mielewczik M, Karavassilis M, Dehbi HM, Shun-Shin MJ, Jones S, et al. Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis. BMJ. 2014;348:g2688.

    PubMed Central  PubMed  Article  Google Scholar 

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Conflict of Interest

Abbas A. Qayyum, Anders B. Mathiasen and Jens Kastrup declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Cardiac Catheterization Laboratory 2014 and Cardiac Stem Cell Laboratory, The Heart Centre, Rigshospitalet, Copenhagen University Hospital and Faculty of Health Sciences, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark

    Abbas Ali Qayyum, Anders Bruun Mathiasen & Jens Kastrup

Authors
  1. Abbas Ali Qayyum
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  2. Anders Bruun Mathiasen
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  3. Jens Kastrup
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Correspondence to Abbas Ali Qayyum.

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This article is part of the Topical Collection on Transplantation

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Qayyum, A.A., Mathiasen, A.B. & Kastrup, J. Stem Cell Therapy to Treat Heart Ischaemia: Implications for Diabetes Cardiovascular Complications. Curr Diab Rep 14, 554 (2014). https://doi.org/10.1007/s11892-014-0554-5

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  • DOI: https://doi.org/10.1007/s11892-014-0554-5

Keywords

  • Cardiovascular complications
  • Coronary artery disease
  • Diabetes mellitus
  • Mesenchymal stem cell
  • Myocardial ischaemia
  • Stem cells