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Current State of Stem Cell Therapy for Ischemic Heart Disease

  • Interventional Cardiology (S Rao, Section Editor)
  • Published:
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Abstract

Improvements in the care of patients with ischemic cardiovascular disease have led to improved survival but also a burgeoning population of patients with advanced ischemic heart disease. Cell therapies offer a novel approach toward cardiac “rejuvenation” via stimulation of new blood vessel growth, enhancing tissue perfusion, and via preservation or even regeneration of myocardial tissue, leading to improvements in cardiac performance after myocardial infarction and in patients with advanced heart failure. Here, we summarize and offer some thoughts on the state of the field of cell therapy for ischemic heart disease, targeting three separate conditions that have been the subject of significant clinical research: enhancing left ventricular recovery after MI, improving outcomes and symptoms in patients with congestive heart failure (CHF), and treatment of patients with refractory angina, despite maximal medical therapy.

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References

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

  1. Povsic TJ, Broderick S, Anstrom KJ, et al. Predictors of long‐term clinical endpoints in patients with refractory angina. J Am Heart Assoc 2015;4.

  2. Williams B, Menon M, Satran D, et al. Patients with coronary artery disease not amenable to traditional revascularization: prevalence and 3-year mortality. Catheter Cardiovasc Interv. 2010;75:886–91.

    PubMed  Google Scholar 

  3. Henry TD, Satran D, Hodges JS, et al. Long-term survival in patients with refractory angina. Eur Heart J. 2013;34:2683–8.

    Article  PubMed  Google Scholar 

  4. Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008;103:1204–19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Suuronen EJ, Price J, Veinot JP, et al. Comparative effects of mesenchymal progenitor cells, endothelial progenitor cells, or their combination on myocardial infarct regeneration and cardiac function. J Thorac Cardiovasc Surg. 2007;134:1249–58.

    Article  PubMed  Google Scholar 

  6. Uemura R, Xu M, Ahmad N, Ashraf M. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ Res. 2006;98:1414–21.

    Article  CAS  PubMed  Google Scholar 

  7. Poss KD, Wilson LG, Keating MT. Heart regeneration in Zebrafish. Science. 2002;298:2188–90.

    Article  CAS  PubMed  Google Scholar 

  8. Laflamme MA, Myerson D, Saffitz JE, Murry CE. Evidence for cardiomyocyte repopulation by extracardiac progenitors in transplanted human hearts. Circ Res. 2002;90:634–40.

    Article  CAS  PubMed  Google Scholar 

  9. Quaini F, Urbanek K, Beltrami AP, et al. Chimerism of the transplanted heart. N Eng J Med. 2002;346:5–15.

    Article  Google Scholar 

  10. Bergmann O, Bhardwaj RD, Bernard S, et al. Evidence for cardiomyocyte renewal in humans. Science. 2009;324:98–102. This utilized an exceptionally creative approach to establish the rate of natural turnover and regeneration of human myocytes during the human lifespan.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964–7.

    Article  CAS  PubMed  Google Scholar 

  12. Hill JM, Zalos G, Halcox JPJ, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Eng J Med. 2003;348:593–600.

    Article  Google Scholar 

  13. Povsic T, Zavodni K, Vainorius E, et al. Common endothelial progenitor cell assays identify discrete EPC populations. Am Heart J. 2008;157:334–44.

    Google Scholar 

  14. Povsic T, Zavodni K, Kelly F, et al. Circulating endogenous progenitor cells can be reliably identified on the basis of aldehyde dehydrogenase activity. J Am Coll Cardiol. 2007;53:2243–8.

    Article  Google Scholar 

  15. Sandri M, Adams V, Gielen S, et al. Effects of exercise and ischemia on mobilization and functional activation of blood-derived progenitor cells in patients with ischemic syndromes: results of 3 randomized studies. Circulation. 2005;111:3391–9.

    Article  PubMed  Google Scholar 

  16. Shintani S, Murohara T, Ikeda H, et al. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation. 2001;103:2776–9.

    Article  CAS  PubMed  Google Scholar 

  17. Wojakowski W, Tendera M, Kucia M, et al. Mobilization of bone marrow-derived Oct-4+ SSEA-4+ very small embryonic-like stem cells in patients with acute myocardial infarction. J Am Coll Cardiol. 2009;53:1–9.

    Article  CAS  PubMed  Google Scholar 

  18. Kawamoto A, Tkebuchava T, Yamaguchi JI, et al. Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation. 2003;107:461–8.

    Article  PubMed  Google Scholar 

  19. Kawamoto A, Iwasaki H, Kusano K, et al. CD34-positive cells exhibit increased potency and safety for therapeutic neovascularization after myocardial infarction compared with total mononuclear cells. Circulation. 2006;114:2163–9.

    Article  PubMed  Google Scholar 

  20. Povsic TJ, Junge C, Nada A, et al. A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: Design of the RENEW study. Am Heart J. 2013;165:854–61. Design of the largest stem cell trial for refractory angina, and the first example of a trial of stem cell therapy for cardiovascular disease aimed to definitively assess effectiveness with goal of regulatory approval.

    Article  CAS  PubMed  Google Scholar 

  21. Bartunek J, Davison B, Sherman W, et al. Congestive heart failure cardiopoietic regenerative therapy (CHART-1) trial design. Eur J Heart Fail 2015; in press. The first trial powered to assess the effectiveness of a stem cell therapeutic for ischemic heart failure. This trial may lead to approval of a stem cell product in Europe.

  22. Makkar RR, Smith RR, Cheng K, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet. 2012;379:895–904. The first trial to demonstrate regeneration of myocardial mass in humans.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Ozbaran M, Omay SB, Nalbantgil S, et al. Autologous peripheral stem cell transplantation in patients with congestive heart failure due to ischemic heart disease. Eur J Cardiothoracic Surg. 2004;25:342–51.

    Article  Google Scholar 

  24. Patel AN, Geffner L, Vina RF, et al. Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: A prospective randomized study. J Thorac Cardiovasc Surg. 2005;130:1631–8.

    Article  PubMed  Google Scholar 

  25. Stamm C, Kleine HD, Choi YH, et al. Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: Safety and efficacy studies. J Thorac Cardiovasc Surg. 2007;133:717–25.

    Article  PubMed  Google Scholar 

  26. Stamm C, Westphal B, Kleine HD, et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet. 2003;361:45–6.

    Article  PubMed  Google Scholar 

  27. Britten M, Abolmaali ND, Assmus B, et al. Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI). Circulation. 2003;108:2212–8.

    Article  CAS  PubMed  Google Scholar 

  28. Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet. 2004;364:141–8.

    Article  PubMed  Google Scholar 

  29. Meyer GP, Wollert KC, Lotz J, et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen month follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation. 2006;113:1287–94.

    Article  PubMed  Google Scholar 

  30. Hirsch A, Nijveldt R, van der Vleuten PA, et al. Intracoronary infusion of mononuclear cells from bone marrow or peripheral blood compared with standard therapy in patients after acute myocardial infarction treated by primary percutaneous coronary intervention: results of the randomized controlled HEBE trial. Eur Heart J. 2010;32:1736–47.

    Article  PubMed  Google Scholar 

  31. Huikuri HV, Kervinen K, Niemela M, et al. Effects of intracoronary injection of mononuclear bone marrow cells on left ventricular function, arrthythmia risk profile, and restenosis after thrombolytic therapy of acute myocardial infarction. Eur Heart J. 2008;29:2723–32.

    Article  PubMed  Google Scholar 

  32. Janssens S, Dubois C, Bogaert J, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet. 2006;367:113–21.

    Article  PubMed  Google Scholar 

  33. Lunde K, Solheim S, Aakhus SA, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. 2006;355:1199–209.

    Article  CAS  PubMed  Google Scholar 

  34. Meluzín J, Mayer J, Groch L, et al. Autologous transplantation of mononuclear bone marrow cells in patients with acute myocardial infarction: the effect of the dose of transplanted cells on myocardial function. Am Heart J. 2006;152:975.

    Article  PubMed  Google Scholar 

  35. Plewka M, Krzeminska-Pakula M, Lipiec P, et al. Effect of intracoronary injection of mononuclear bone marrow stem cells on left ventricular function in patients with acute myocardial infarction. Am J Cardiol. 2009;104:1336–42.

    Article  PubMed  Google Scholar 

  36. Schachinger V, Erbs S, Elsasser A, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med. 2006;355:1210–21. Remains the largest trial of stem cell therapy for cardivascular indication, and laid the foundation for larger-scale trials in this field in Europe.

    Article  CAS  PubMed  Google Scholar 

  37. Tendera M, Wojakowski W, Ruzyllo W, et al. 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. Eur Heart J. 2009;30:1313–21.

    Article  PubMed  Google Scholar 

  38. Traverse JH, Henry TD, Ellis SG, et al. Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the latetime randomized trial. JAMA. 2011;306:2110–9. Important NIH-sponsored US network trial of stem cell therapy after myocardial infarction, establishing the feasibility of multicenter stem cell research in the United States.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Traverse JH, Henry TD, Pepine CJ, et al. Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial. JAMA. 2012;308:2380–9. The second of three important NIH-sponsored US network trials of stem cell therapy after myocardial infarction, establishing the feasibility of multicenter stem cell research in the United States.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Seeger FH, Tonn T, Krzossok N, Zeiher AM, Dimmeler S. Cell isolation procedures matter: a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction. Eur Heart J. 2007;28:766–72.

    Article  PubMed  Google Scholar 

  41. Traverse JH, Henry TD, Vaughn DE, et al. Rationale and design for TIME: a phase II, randomized, double-blind, placebo-controlled pilot trial evaluating the safety and effect of timing of administration of bone marrow mononuclear cells after acute myocardial infarction. Am Heart J. 2009;158:356–63.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Fisher SA, Doree C, Mathur A, Martin-Rendon E. Meta-analysis of cell therapy trials for patients with heart failure. Circulation Res. 2015;116:1361–77.

    Article  CAS  PubMed  Google Scholar 

  43. Delewi R, Andriessen A, Tijssen JGP, Zijlstra F, Piek JJ, Hirsch A. Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a meta-analysis of randomised controlled clinical trials. Heart. 2013;99:225–32. Most recent meta-analyses demonstrating consistent benefits of stem cell therapy post-MI on ejection fraction, and trends toward improvements in cardiac outcomes.

    Article  PubMed  Google Scholar 

  44. Zimmet H, Porapakkham P, Porapakkham P, 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. Most recent meta-analyses demonstrating consistent benefits of stem cell therapy post-MI on ejection fraction, and trends toward improvements in cardiac outcomes.

    Article  PubMed  Google Scholar 

  45. 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. Most recent meta-analyses demonstrating consistent benefits of stem cell therapy post-MI on ejection fraction, and trends toward improvements in cardiac outcomes.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Lipinski MJ, Biondi-Zoccai GGL, Abbate A, et al. Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: A collaborative systematic review and meta-analysis of controlled clinical trials. J Am Coll Cardiol. 2007;50:1761–7.

    Article  PubMed  Google Scholar 

  47. Abdel-Latif A, Bolli R, Tleyjeh IM, et al. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med. 2007;167:989–97.

    Article  PubMed  Google Scholar 

  48. Hristov M, Heussen N, Schober A, Weber C. Intracoronary infusion of autologous bone marrow cells and left ventricular function after acute myocardial infarction: a meta-analysis. J Cell Mol Med. 2006;10:727–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Martin-Rendon E, Brunskill SJ, Hyde CJ, Stanworth SJ, Mathur A, Watt SM. Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review. Eur Heart J. 2008;29(15):1807–1818.

  50. de Jong R, Houtgraaf JH, Samiei S, Boersma E, Duckers HJ. Intracoronary stem cell infusion after acute myocardial infarction: a meta-analysis and update on clinical trials. Circulatio:cardiovasc Interv. 2014;7(20):156–167.

  51. Kang HJ, Kim HS, Zhang SY, et al. Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet. 2004;363:751–6.

    Article  CAS  PubMed  Google Scholar 

  52. Bartunek J, Vanderheyden M, Vandekerckhove B, et al. Intracoronary injection of CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction: Feasibility and safety. Circulation 2005;112(9_suppl):I-178-83.

  53. Quyyumi A, Vasquez A, Klapholz M, et al. PreSERVE-AMI: a randomized, double-blind, placebo-controlled clinical trial of intracoronary administration of autologous CD34+ cells in patients with left ventricular dysfunction post STEMI. Circulation. 2014;130 Suppl 2:A17457.

    Google Scholar 

  54. Quyyumi AA, Waller EK, Murrow J, et al. CD34+ cell infusion after ST elevation myocardial infarction is associated with improved perfusion and is dose dependent. Am Heart J. 2011;161:98–105.

    Article  PubMed  Google Scholar 

  55. Smith RR, Barile L, Cho HC, et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation. 2007;115:896–908.

    Article  PubMed  Google Scholar 

  56. Li TS, Cheng K, Malliaras K, et al. Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells. J Am Coll Cardiol. 2012;59(10):942–53.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Makkar R, Schatz R, Traverse J, et al. Allogeneic heart stem cells to achieve myocardial regeneration (ALLSTAR): the one-year phase I results. Circulation. 2014;130 Suppl 2:A20536. Established the safety of allogenic cardiosphere-derived stem cell therapy for cardiac regeneration post-MI and laid the foundation for the ongoing ALLSTAR phase 2 trial.

    Google Scholar 

  58. Taylor DA, Atkins BZ, Hungsprugs P, et al. Regenerating functional myocardium: improved performance after skeletal myobalst transplantation. Nat Med. 1998;4:929–33.

    Article  CAS  PubMed  Google Scholar 

  59. Dib N, Dinsmore J, Lababidi Z, et al. One-year follow-up of feasibility and safety of the first US, randomized, controlled study using 3-dimensional guided catheter-based delivery of autologous skeletal myoblasts for ischemic cardiomyopathy (CAuSMIC Study). JACC Cardiovasc Interv. 2009;2:9–16.

    Article  PubMed  Google Scholar 

  60. Herreros J, Prosper F, Perez A, et al. Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction. Eur Heart J. 2003;24:2012–20.

    Article  PubMed  Google Scholar 

  61. Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol. 2003;41:1078–83.

    Article  PubMed  Google Scholar 

  62. Duckers HJ, Houtgraaf J, Hehrlein C, et al. Final results of a phase IIa, randomised, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: the SEISMIC trial. EuroInterv. 2011;6:805–12.

    Article  Google Scholar 

  63. Sherman W. MYOHEART US Phase I Study: 12 Month Data. 4th Annual Conference on Cell Therapy for Cardiovascular Disease. 2008; New York.

  64. Siminiak T, Kalawski R, Fiszer D, et al. Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up. Am Heart J. 2004;148:531–7.

    Article  PubMed  Google Scholar 

  65. Smits PC, van Geuns RJM, Poldermans D, et al. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-Up. J Am Coll Cardiol. 2003;42:2063–9.

    Article  PubMed  Google Scholar 

  66. Menasché P, Alfieri O, Janssens S, et al. The myoblast autologous grafting in ischemic cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation. 2008;117:1189–200.

    Article  PubMed  Google Scholar 

  67. Povsic TJ, O'Connor CM, Henry T, et al. A double-blined, randomized, controlled, multicenter study to assess the safety and cardiovascular effects of skeletal myoblast implantation by catheter delivery in patients with chronic heart failure after myocardial infarction. Am Heart J. 2011;162:654–62.

    Article  PubMed  Google Scholar 

  68. Perin EC, Dohmann HFR, Borojevic R, et al. Transendocardial, autologous bone marrow cell transplantation for severe chronic ischemic heart failure. Circulation. 2003;107:2294–302.

    Article  PubMed  Google Scholar 

  69. Perin EC, Willerson JT, Pepine CJ, et al. Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA. 2012;307:1717–26. The third of three important NIH-sponsored US network trials of stem cell therapy, establishing the feasibility of multicenter stem cell research in the United States for treatment of congestive heart failure.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Psaltis PJ, Carbone A, Nelson AJ, et al. Reparative effects of allogeneic mesenchymal precursor cells delivered transendocardially in experimental nonischemic cardiomyopathy. JACC Cardiovasc Interv. 2010;3:974–83.

    Article  PubMed  Google Scholar 

  71. Huang NF, Li S. Mesenchymal stem cells for vascular regeneration. Regen Med. 2008;3:877–92.

    Article  PubMed Central  PubMed  Google Scholar 

  72. Perin EC, Borow KM, Silva GV, et al. A phase II dose-escalation study of allogeneic mesenchymal precursor cells in patients with ischemic or nonischemic heart failure. Circ Res. 2015;117:576–84.

    Article  CAS  PubMed  Google Scholar 

  73. Armiñán A, Gandía C, García-Verdugo JM, et al. Mesenchymal stem cells provide better results than hematopoietic precursors for the treatment of myocardial infarction. J Am Coll Cardiol. 2010;55:2244–53.

    Article  PubMed  Google Scholar 

  74. Heldman AW, DiFede DL, Fishman JE, et al. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA. 2014;311:62–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Dimmeler S, Leri A. Aging and disease as modifiers of efficacy of cell therapy. Circ Res. 2008;102:1319–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Fadini GP, Sartore S, Albiero M, et al. Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler Thromb Vasc Biol. 2006;26:2140–6.

    Article  CAS  PubMed  Google Scholar 

  77. Liguori A, Fiorito C, Balestrieri ML, et al. Functional impairment of hematopoietic progenitor cells in patients with coronary heart disease. Eur J Haematol. 2008;80:258–64.

    Article  PubMed  Google Scholar 

  78. Povsic TJ, Sloane R, Green JB, et al. Depletion of circulating progenitor cells precedes overt diabetes: a substudy from the VA enhanced fitness trial. J Diabet Complications. 2013;27:633–6.

    Article  Google Scholar 

  79. Walter DH, Haendeler J, Reinhold J, et al. Impaired CXCR4 signaling contributes to the reduced neovascularization capacity of endothelial progenitor cells from patients with coronary artery disease. Circ Res. 2005;97:1142–51.

    Article  CAS  PubMed  Google Scholar 

  80. Kissel CK, Lehmann R, Assmus B, et al. Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure. J Am Coll Cardiol. 2007;49:2341–9.

    Article  PubMed  Google Scholar 

  81. Behfar A, Yamada S, Crespo-Diaz R, et al. Guided cardiopoiesis enhances therapeutic benefit of bone marrow human mesenchymal stem cells in chronic myocardial infarction. J Am Coll Cardiol. 2010;56:721–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Bartunek J, Behfar A, Dolatabadi D, et al. Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) Multicenter Randomized Trial With Lineage-Specified Biologics. J Am Coll Cardiol. 2013;61:2329–38. Established the feasibility of the first autologous cell product specifically programmed to a cardiopoietic lineage for treatment of congestive heart failure, and established techniques for the CHART program, investigating the safety and efficacy of this cell type.

    Article  PubMed  Google Scholar 

  83. Henry T, Satran D, Jolicoeur EM. Treatment of refractory angina in patients not suitable for revascularization. Nat Rev Cardiol. 2014;11:78–95.

    Article  CAS  PubMed  Google Scholar 

  84. Verheye S, Jolicœur EM, Behan MW, et al. Efficacy of a device to narrow the coronary sinus in refractory angina. N Engl J Med. 2015;372:519–27.

    Article  CAS  PubMed  Google Scholar 

  85. Fisher SA, Dorée C, Brunskill SJ, Mathur A, Martin-Rendon E. Bone marrow stem cell treatment for ischemic heart disease in patients with no option of revascularization: a systematic review and meta-analysis. PLoS ONE. 2013;8:e64669.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Kandala J, Upadhyay GA, Pokushalov E, Wu S, Drachman DE, Singh JP. Meta-analysis of stem cell therapy in chronic ischemic cardiomyopathy. Am J Cardiol. 2013;112:217–25.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  88. Beeres SL, Bax JJ, Dibbets-Schneider P, et al. Sustained effect of autologous bone marrow mononuclear cell injection in patients with refractory angina pectoris and chronic myocardial ischemia: twelve-month follow-up results. Am Heart J. 2006;152:684.

    Article  PubMed  Google Scholar 

  89. van Ramshorst J, Bax JJ, Beeres SL, et al. Intramyocardial bone marrow cell injection for chronic myocardial ischemia. JAMA. 2009;301:1997–2004.

    Article  PubMed  Google Scholar 

  90. Rodrigo SF, van Ramshorst J, Beeres SL, et al. Intramyocardial injection of bone marrow mononuclear cells in chronic myocardial ischemia patients after previous placebo injection improves myocardial perfusion and anginal symptoms: an intra-patient comparison. Am Heart J. 2012;164:771–8.

    Article  PubMed  Google Scholar 

  91. van Ramshorst J, Rodrigo SF, Beeres SL, et al. Long term effects of intramyocardial bone marrow cell injection on anginal symptoms and quality of life in patients with chronic myocardial ischemia. Int J Cardiol. 2013;168:3031–2.

    Article  PubMed  Google Scholar 

  92. Tse HF, Thambar S, Kwong YL, et al. Prospective randomized trial of direct endomyocardial implantation of bone marrow cells for treatment of severe coronary artery diseases (PROTECT-CAD trial). Eur Heart J. 2007;28:2998–3005.

    Article  PubMed  Google Scholar 

  93. Mann I, Rodrigo SF, van Ramshorst J, et al. Repeated intramyocardial bone marrow cell injection in previously responding patients with refractory angina again improves myocardial perfusion, anginal complaints, and quality of life. Circ Cardiovasc Interv 2015;8. One of the few attempts to assess the effectiveness of repeat cell administration for treatment of cardiovascular disease.

  94. Henry TD, Povsic TJ. Repeat cell therapy for refractory angina: déjà vu all over again? Circ Cardiovasc Interv 2015;8.

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

    Article  PubMed  Google Scholar 

  96. Mathiasen AB, Qayyum AA, Jørgensen E, et al. Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial (MSC-HF trial). Eur Heart J. 2015;36:1744–53.

    Article  PubMed  Google Scholar 

  97. Kawamoto A, Gwon HC, Iwaguro H, et al. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial infarction. Circulation. 2001;103:634–7.

    Article  CAS  PubMed  Google Scholar 

  98. Kalka C, Masuda H, Takahashi T, et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A. 2000;97:3422–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Losordo DW, Schatz RA, White CJ, et al. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation. 2007;115:3165–72.

    Article  PubMed  Google Scholar 

  100. Losordo DW, Henry TD, Davidson C, et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res. 2011;109:428–36. The largest US trial of stem cell therapy, ACT-34 established the effectiveness of autologous CD34+ cells for treatment of refractory angina.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  101. Chaitman BR, Skettino SL, Parker JO, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43:1375–82.

    Article  CAS  PubMed  Google Scholar 

  102. Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina. JAMA. 2004;291:309–16.

    Article  CAS  PubMed  Google Scholar 

  103. Arora RR, Chou TM, Jain D, et al. The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes. J Am Coll Cardiol. 1999;33:1833–40.

    Article  CAS  PubMed  Google Scholar 

  104. Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) Trial. J Am Coll Cardiol. 2006;48:566–75.

    Article  CAS  PubMed  Google Scholar 

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  1. Duke Clinical Research Institute and Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, 27708, USA

    Thomas J. Povsic

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Thomas J. Povsic reports personal fees from Pluristem Inc., Capricor, and Amorcyte, and grants from Baxter Healthcare, Cardio3 Biosciences, and Janssen Pharmaceuticals.

Human and Animal Rights and Informed Consent

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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This article is part of the Topical Collection on Interventional Cardiology

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Povsic, T.J. Current State of Stem Cell Therapy for Ischemic Heart Disease. Curr Cardiol Rep 18, 17 (2016). https://doi.org/10.1007/s11886-015-0693-6

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