Current Atherosclerosis Reports

, Volume 14, Issue 5, pp 491–503 | Cite as

Cardiac Stem Cells in Patients with Ischemic Cardiomyopathy: Discovery, Translation, and Clinical Investigation

  • John H. Loughran
  • Julius B. Elmore
  • Momina Waqar
  • Atul R. Chugh
  • Roberto Bolli
Clinical Trials and Their Interpretations (J Plutzky, Section Editor)

Abstract

The increasing prevalence of heart failure, in the US and worldwide, poses a significant burden to patients, practitioners, and healthcare systems. Hence, there is a pressing need for alternative therapies to enhance the current treatment armamentarium. Accordingly, when considering heart failure of ischemic etiology, an intervention designed to regenerate the attending loss of myocardium could potentially result in improved cardiac function, functional status, and quality of life. Significant strides have been made by investigators in the study of stem cell therapy for cardiac repair; recently with cardiac-derived progenitor cells. These cells include cardiospheres, cardiosphere-derived cells, and c-kit positive cardiac stem cells. Herein, a review of both preclinical studies and phase I clinical trials of these cell types is presented. A detailed account of in vitro characterization, in vivo bioactivity, and safety and efficacy in humans is outlined. Thus far, encouraging results have been realized, although larger studies have yet to be undertaken.

Keywords

Cardiac stem cells Stem cell therapy CAD Chronic ischemic heart disease Myogenesis 

Notes

Disclosure

No potential conflicts of interest relevant to this article were reported.

References

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

  1. 1.
    • Bergmann O, Bhardwaj RD, Bernard S, et al. Evidence for cardiomyocyte renewal in humans. Science. 2009;324:98–102. Results of carbon-14 studies in human cardiac tissue provides convincing evidence that post-natal myocyte turnover is a natural phenomenon; indicating that regenrative therapies could potentially provide an important form of therapy for those in need. PubMedCrossRefGoogle Scholar
  2. 2.
    Beltrami AP, Urbanek K, Kajstura J, et al. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med. 2001;344:1750–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Quaini F, Urbanek K, Beltrami AP, et al. Chimerism of the transplanted heart. N Engl J Med. 2002;346:5–15.PubMedCrossRefGoogle Scholar
  4. 4.
    Messina E, De Angelis L, Frati G, et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res. 2004;95:911–21.PubMedCrossRefGoogle Scholar
  5. 5.
    Martin CM, Meeson AP, Robertson SM, et al. Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev Biol. 2004;265:262–75.PubMedCrossRefGoogle Scholar
  6. 6.
    Beltrami AP, Barlucchi L, Torella D, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003;114:763–76.PubMedCrossRefGoogle Scholar
  7. 7.
    • Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation. 2011;123:e18–e209. The importance of the incidence, prevalenceand poor prognosis of patients suffering from heart failure is documented in this publication. Despite the advancement of modern medical treatment options, the US, and the remainder of the global community, continue to see an increase in the number of patients suffering from this disease process. PubMedCrossRefGoogle Scholar
  8. 8.
    Givertz MM. Heart allocation in the United States: intended and unintended consequences. Circ Heart Fail. 2012;5:140–3.PubMedCrossRefGoogle Scholar
  9. 9.
    Daneshmand MA, Rajagopal K, Lima B, et al. Left ventricular assist device destination therapy versus extended criteria cardiac transplant. Ann Thorac Surg. 2010;89:1205–9. discussion 10.PubMedCrossRefGoogle Scholar
  10. 10.
    Menasche P, Hagege A, Scorsin M, et al. Autologous skeletal myoblast transplantation for cardiac insufficiency. First clinical case. Arch Mal Coeur Vaiss. 2001;94:180–2.PubMedGoogle Scholar
  11. 11.
    Menasche 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.PubMedCrossRefGoogle Scholar
  12. 12.
    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.PubMedCrossRefGoogle Scholar
  13. 13.
    Lunde K, Solheim S, Aakhus S, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. 2006;355:1199–209.PubMedCrossRefGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    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 J Am Med Assoc. 2011;306:2110–9.CrossRefGoogle Scholar
  16. 16.
    Meyer GP, Wollert KC, Lotz J, et al. Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial. Eur Hear J. 2009;30:2978–84.CrossRefGoogle Scholar
  17. 17.
    Assmus B, Rolf A, Erbs S, et al. Clinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction. Circ Heart Fail. 2010;3:89–96.PubMedCrossRefGoogle Scholar
  18. 18.
    Hare JM, Traverse JH, Henry TD, 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.PubMedCrossRefGoogle Scholar
  19. 19.
    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 Hear J. 2009;30:1313–21.CrossRefGoogle Scholar
  20. 20.
    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:I178–83.PubMedGoogle Scholar
  21. 21.
    Hierlihy AM, Seale P, Lobe CG, Rudnicki MA, Megeney LA. The post-natal heart contains a myocardial stem cell population. FEBS Lett. 2002;530:239–43.PubMedCrossRefGoogle Scholar
  22. 22.
    Galli R, Gritti A, Bonfanti L, Vescovi AL. Neural stem cells: an overview. Circ Res. 2003;92:598–608.PubMedCrossRefGoogle Scholar
  23. 23.
    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.PubMedCrossRefGoogle Scholar
  24. 24.
    Lushaj EB, Anstadt E, Haworth R, et al. Mesenchymal stromal cells are present in the heart and promote growth of adult stem cells in vitro. Cytotherapy. 2011;13:400–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Johnston PV, Sasano T, Mills K, et al. Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation. 2009;120:1075–83. 7 p following 83.PubMedCrossRefGoogle Scholar
  26. 26.
    Smith RR, Barile L, Messina E, Marban E. Stem cells in the heart: what’s the buzz all about? part 2: arrhythmic risks and clinical studies. Heart Rhythm Off J Heart Rhythm Soc. 2008;5:880–7.Google Scholar
  27. 27.
    •• 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. Results from the seminal investigation of this cell type in human subjects demonstrating the short-term safety of this cell type for the treatment of patients with post-infarction LV dysfunction. PubMedCrossRefGoogle Scholar
  28. 28.
    Chimenti I, Smith RR, Li TS, et al. Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ Res. 2010;106:971–80.PubMedCrossRefGoogle Scholar
  29. 29.
    Li TS, Marban E. Physiological levels of reactive oxygen species are required to maintain genomic stability in stem cells. Stem Cells. 2010;28:1178–85.PubMedCrossRefGoogle Scholar
  30. 30.
    Li TS, Cheng K, Malliaras K, et al. Expansion of human cardiac stem cells in physiological oxygen improves cell production efficiency and potency for myocardial repair. Cardiovasc Res. 2011;89:157–65.PubMedCrossRefGoogle Scholar
  31. 31.
    Terrovitis J, Lautamaki R, Bonios M, et al. Noninvasive quantification and optimization of acute cell retention by in vivo positron emission tomography after intramyocardial cardiac-derived stem cell delivery. J Am Coll Cardiol. 2009;54:1619–26.PubMedCrossRefGoogle Scholar
  32. 32.
    Shen D, Cheng K, Marban E. Dose-dependent functional benefit of human cardiosphere transplantation in mice with acute myocardial infarction. J. Cell Mol. Med. 2012.Google Scholar
  33. 33.
    Davis DR, Zhang Y, Smith RR, et al. Validation of the cardiosphere method to culture cardiac progenitor cells from myocardial tissue. PLoS One. 2009;4:e7195.PubMedCrossRefGoogle Scholar
  34. 34.
    Malliaras K, Li TS, Luthringer D, et al. Safety and efficacy of allogeneic cell therapy in infarcted rats transplanted with mismatched cardiosphere-derived cells. Circulation. 2012;125:100–12.PubMedCrossRefGoogle Scholar
  35. 35.
    Lee ST, White AJ, Matsushita S, et al. Intramyocardial injection of autologous cardiospheres or cardiosphere-derived cells preserves function and minimizes adverse ventricular remodeling in pigs with heart failure post-myocardial infarction. J Am Coll Cardiol. 2011;57:455–65.PubMedCrossRefGoogle Scholar
  36. 36.
    Bearzi C, Rota M, Hosoda T, et al. Human cardiac stem cells. Proc Natl Acad Sci U S A. 2007;104:14068–73.PubMedCrossRefGoogle Scholar
  37. 37.
    Van Ziffle JA, Baerlocher GM, Lansdorp PM. Telomere length in subpopulations of human hematopoietic cells. Stem Cells. 2003;21:654–60.PubMedCrossRefGoogle Scholar
  38. 38.
    Bolli R. Abstract 1267: intracoronary administration of cardiac stem cells improves cardiac function in pigs with old infarction. Circulation. 2006;114:Il_239.Google Scholar
  39. 39.
    Dawn B, Stein AB, Urbanek K, et al. Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc Natl Acad Sci U S A. 2005;102:3766–71.PubMedCrossRefGoogle Scholar
  40. 40.
    Rota M, Padin-Iruegas ME, Misao Y, et al. Local activation or implantation of cardiac progenitor cells rescues scarred infarcted myocardium improving cardiac function. Circ Res. 2008;103:107–16.PubMedCrossRefGoogle Scholar
  41. 41.
    Tang XL, Rokosh G, Sanganalmath SK, et al. Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30-day-old infarction. Circulation. 2010;121:293–305.PubMedCrossRefGoogle Scholar
  42. 42.
    Linke A, Muller P, Nurzynska D, et al. Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci U S A. 2005;102:8966–71.PubMedCrossRefGoogle Scholar
  43. 43.
    Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008;103:1204–19.PubMedCrossRefGoogle Scholar
  44. 44.
    Bogaard HJ, Natarajan R, Mizuno S, et al. Adrenergic receptor blockade reverses right heart remodeling and dysfunction in pulmonary hypertensive rats. Am J Respir Crit Care Med. 2010;182:652–60.PubMedCrossRefGoogle Scholar
  45. 45.
    Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000;6:389–95.PubMedCrossRefGoogle Scholar
  46. 46.
    Tao Z, Chen B, Tan X, et al. Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart. Proc Natl Acad Sci U S A. 2011;108:2064–9.PubMedCrossRefGoogle Scholar
  47. 47.
    D'Amario D, Cabral-Da-Silva MC, Zheng H, et al. Insulin-like growth factor-1 receptor identifies a pool of human cardiac stem cells with superior therapeutic potential for myocardial regeneration. Circ Res. 2011;108:1467–81.PubMedCrossRefGoogle Scholar
  48. 48.
    Urbanek K, Cesselli D, Rota M, et al. Stem cell niches in the adult mouse heart. Proc Natl Acad Sci U S A. 2006;103:9226–31.PubMedCrossRefGoogle Scholar
  49. 49.
    Itzhaki-Alfia A, Leor J, Raanani E, et al. Patient characteristics and cell source determine the number of isolated human cardiac progenitor cells. Circulation. 2009;120:2559–66.PubMedCrossRefGoogle Scholar
  50. 50.
    D'Amario D, Fiorini C, Campbell PM, et al. Functionally competent cardiac stem cells can be isolated from endomyocardial biopsies of patients with advanced cardiomyopathies. Circ Res. 2011;108:857–61.PubMedCrossRefGoogle Scholar
  51. 51.
    Kajstura J, Gurusamy N, Ogorek B, et al. Myocyte turnover in the aging human heart. Circ Res. 2010;107:1374–86.PubMedCrossRefGoogle Scholar
  52. 52.
    •• Bolli R, Chugh AR, D'Amario D, et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet. 2011;378:1847–57. An original report outlining a first-in-human clinical investigation of endogenous cardiac-derived progenitor cell types for the treatment of ischemic cardiomyopathy. This report describes a favorable safety profile, feasible procedure for delivery, and encouraging exploratory efficacy data; including, dramatic reduction in scar size and improvement in cardiac function. PubMedCrossRefGoogle Scholar
  53. 53.
    Assmus B, Schachinger V, Teupe C, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation. 2002;106:3009–17.PubMedCrossRefGoogle Scholar
  54. 54.
    Fernandez-Aviles F, San Roman JA, Garcia-Frade J, et al. Experimental and clinical regenerative capability of human bone marrow cells after myocardial infarction. Circ Res. 2004;95:742–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002;106:1913–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Willerson JT, Perin EC, Ellis SG, et al. Intramyocardial injection of autologous bone marrow mononuclear cells for patients with chronic ischemic heart disease and left ventricular dysfunction (first mononuclear cells injected in the US [FOCUS]): rationale and design. Am Hear J. 2010;160:215–23.CrossRefGoogle Scholar
  57. 57.
    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 Hear J. 2007;28:766–72.CrossRefGoogle Scholar
  58. 58.
    White AJ, Smith RR, Matsushita S, et al. Intrinsic cardiac origin of human cardiosphere-derived cells. Eur. Heart J. 2011.Google Scholar
  59. 59.
    Ferreira-Martins J, Ogorek B, Cappetta D, et al. Cardiomyogenesis in the developing heart is regulated by c-kit-positive cardiac stem cells. Circ Res. 2012;110:701–15.PubMedCrossRefGoogle Scholar
  60. 60.
    Gupta R, Losordo DW. Challenges in the translation of cardiovascular cell therapy. J Nucl Med Off Publ Soc Nucl Med. 2010;51 Suppl 1:122S–7S.Google Scholar
  61. 61.
    Hung J, Francois C, Nelson NA, et al. Cardiac image modeling tool for quantitative analysis of global and regional cardiac wall motion. Investig Radiol. 2009;44:271–8.CrossRefGoogle Scholar
  62. 62.
    Flett AS, Hasleton J, Cook C, et al. Evaluation of techniques for the quantification of myocardial scar of differing etiology using cardiac magnetic resonance. JACC Cardiovasc Imaging. 2011;4:150–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Morton G, Jogiya R, Plein S, Schuster A, Chiribiri A, Nagel E. Quantitative cardiovascular magnetic resonance perfusion imaging: inter-study reproducibility. Eur. Heart J. Cardiovasc. Imaging. 2012.Google Scholar
  64. 64.
    Hulten EA, Bittencourt MS, Ghoshhajra B, Blankstein R. Stress CT perfusion: coupling coronary anatomy with physiology. J Nucl Cardiol Off Publ Am Soc Nucl Cardiol. 2012;19:588–600.CrossRefGoogle Scholar
  65. 65.
    Baer FM, Voth E, Schneider CA, Theissen P, Schicha H, Sechtem U. Comparison of low-dose dobutamine-gradient-echo magnetic resonance imaging and positron emission tomography with [18F]fluorodeoxyglucose in patients with chronic coronary artery disease. A functional and morphological approach to the detection of residual myocardial viability. Circulation. 1995;91:1006–15.PubMedCrossRefGoogle Scholar
  66. 66.
    Tillisch J, Brunken R, Marshall R, et al. Reversibility of cardiac wall-motion abnormalities predicted by positron tomography. N Engl J Med. 1986;314:884–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Haas F, Haehnel CJ, Picker W, et al. Preoperative positron emission tomographic viability assessment and perioperative and postoperative risk in patients with advanced ischemic heart disease. J Am Coll Cardiol. 1997;30:1693–700.PubMedCrossRefGoogle Scholar
  68. 68.
    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.PubMedCrossRefGoogle Scholar
  69. 69.
    Frangogiannis NG. The stromal cell-derived factor-1/CXCR4 axis in cardiac injury and repair. J Am Coll Cardiol. 2011;58:2424–6.PubMedCrossRefGoogle Scholar
  70. 70.
    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 Hear J. 2008;29:1807–18.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • John H. Loughran
    • 1
  • Julius B. Elmore
    • 1
  • Momina Waqar
    • 2
  • Atul R. Chugh
    • 1
  • Roberto Bolli
    • 1
  1. 1.Division of Cardiovascular MedicineUniversity of LouisvilleLouisvilleUSA
  2. 2.Dow Medical CollegeDow University of Health SciencesKarachiPakistan

Personalised recommendations