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Stem Cell Therapy in Heart Failure

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Heart Failure

Abstract

Despite declining mortality from cardiovascular diseases, the prevalence of heart failure continues to increase and is itself associated with increasing morbidity, mortality and economic burden to the United States population. Myocardial regeneration is a new therapeutic option for advanced heart failure, which has demonstrated rational progression from initial translational studies to current phase 2 clinical trials. Stem cells are cells that can continuously self-renew and undergo differentiation. Stem cell therapy attempts to augment the inadequate endogenous regenerative capacity of the heart, and to prevent the maladaptive sequelae of myocardial diseases. A number of stem cell types have been evaluated in clinical studies and include skeletal myoblasts, bone marrow derived stem cells, cardiac stem cells, pluripotent stem cells and adipose derived stem cells. A variety of stem cell delivery methods have also been evaluated which include intravenous, intracoronary and intramyocardial transplantation. In this chapter we will review some of the key pre-clinical and clinical trials in both ischemic and non-ischemic cardiomyopathy, focusing particularly on safety, heterogeneity in cell types and delivery methods, and clinical endpoints.

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References

  1. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. Executive summary: heart disease and stroke statistics – 2012 update: a report from the American Heart Association. Circulation. 2012;125(1):188–97.

    Article  PubMed  Google Scholar 

  2. Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123(8):933–44.

    Article  PubMed  Google Scholar 

  3. van Berlo JH, Kanisicak O, Maillet M, Vagnozzi RJ, Karch J, Lin SC, et al. C-Kit+ cells minimally contribute cardiomyocytes to the heart. Nature. 2014;509(7500):337–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Quaini F, Urbanek K, Beltrami AP, Finato N, Beltrami CA, Nadal-Ginard B, et al. Chimerism of the transplanted heart. N Engl J Med. 2002;346(1):5–15.

    Article  PubMed  Google Scholar 

  5. Beltrami AP, Urbanek K, Kajstura J, Yan S, Finato N, Bussani R, et al. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med. 2001;344(23):1750–7.

    Article  CAS  PubMed  Google Scholar 

  6. Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S, et al. Evidence for cardiomyocyte renewal in humans. Science. 2009;324(5923):98–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410(6829):701–5.

    Article  CAS  PubMed  Google Scholar 

  8. 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(6):763–76.

    Article  CAS  PubMed  Google Scholar 

  9. Rubart M, Field LJ. Cardiac regeneration: repopulating the heart. Annu Rev Physiol. 2006;68:29–49.

    Article  CAS  PubMed  Google Scholar 

  10. Hare JM, Bolli R, Cooke JP, Gordon DJ, Henry TD, Perin EC, et al. Phase II clinical research design in cardiology: learning the right lessons too well: observations and recommendations from the Cardiovascular Cell Therapy Research Network (CCTRN). Circulation. 2013;127(15):1630–5.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Becker AJ, McCulloch EA, Till JE. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature. 1963;197:452–4.

    Article  CAS  PubMed  Google Scholar 

  12. Watt FM, Hogan BL. Out of Eden: stem cells and their niches. Science. 2000;287(5457):1427–30.

    Article  CAS  PubMed  Google Scholar 

  13. EC P, GV S. What are stem cells and what do they do? In:An essential guide to cardiac cell therapy. New York: Taylor & Francis Ltd; 2006. p. 3–12.

    Google Scholar 

  14. Lodi D, Iannitti T, Palmieri B. Stem cells in clinical practice: applications and warnings. J Exp Clin Cancer Res. 2011;30:9 , 9966-30-9.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Fratz S, Hager A, Schreiber C, Schwaiger M, Hess J, Stern HC. Long-term myocardial scarring after operation for anomalous left coronary artery from the pulmonary artery. Ann Thorac Surg. 2011;92(5):1761–5.

    Article  PubMed  Google Scholar 

  16. Quevedo HC, Hatzistergos KE, Oskouei BN, Feigenbaum GS, Rodriguez JE, Valdes D, et al. Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proc Natl Acad Sci U S A. 2009;106(33):14022–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Menasche P, Hagege AA, Vilquin JT, Desnos M, Abergel E, Pouzet B, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol. 2003;41(7):1078–83.

    Article  PubMed  Google Scholar 

  18. Atkins BZ, Hueman MT, Meuchel JM, Cottman MJ, Hutcheson KA, Taylor DA. Myogenic cell transplantation improves in vivo regional performance in infarcted rabbit myocardium. J Heart Lung Transplant. 1999;18(12):1173–80.

    Article  CAS  PubMed  Google Scholar 

  19. Tambara K, Sakakibara Y, Sakaguchi G, Lu F, Premaratne GU, Lin X, et al. Transplanted skeletal myoblasts can fully replace the infarcted myocardium when they survive in the host in large numbers. Circulation. 2003;108(Suppl 1):II259–63.

    PubMed  Google Scholar 

  20. Siminiak T, Kalawski R, Fiszer D, Jerzykowska O, Rzezniczak J, Rozwadowska N, 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(3):531–7.

    Article  PubMed  Google Scholar 

  21. Smits PC, van Geuns RM, Poldermans D, Bountioukos M, Onderwater EEM, Lee CH, et al. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure. J Am Coll Cardiol. 2003;42(12):2063–9.

    Article  PubMed  Google Scholar 

  22. Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest. 2001;107(11):1395–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dawn B, Bolli R. Adult bone marrow-derived cells: regenerative potential, plasticity, and tissue commitment. Basic Res Cardiol. 2005;100(6):494–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gunsilius E, Gastl G, Petzer AL. Hematopoietic stem cells. Biomed Pharmacother. 2001;55(4):186–94.

    Article  CAS  PubMed  Google Scholar 

  25. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001;7(4):430–6.

    Article  CAS  PubMed  Google Scholar 

  26. Nygren JM, Jovinge S, Breitbach M, Sawen P, Roll W, Hescheler J, et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med. 2004;10(5):494–501.

    Article  CAS  PubMed  Google Scholar 

  27. Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res. 2004;95(4):343–53.

    Article  CAS  PubMed  Google Scholar 

  28. Kawamoto A, Gwon HC, Iwaguro H, Yamaguchi JI, Uchida S, Masuda H, et al. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation. 2001;103(5):634–7.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  PubMed  Google Scholar 

  30. Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res. 2004;95(1):9–20.

    Article  CAS  PubMed  Google Scholar 

  31. Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007;25(11):2739–49.

    Article  CAS  PubMed  Google Scholar 

  32. Shake JG, Gruber PJ, Baumgartner WA, Senechal G, Meyers J, Redmond JM, et al. Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg. 2002;73(6):1919–25 ; discussion 1926.

    Article  PubMed  Google Scholar 

  33. Hatzistergos KE, Quevedo H, Oskouei BN, Hu Q, Feigenbaum GS, Margitich IS, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res. 2010;107(7):913–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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):H2002–11.

    Article  CAS  PubMed  Google Scholar 

  35. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371(9624):1579–86.

    Article  CAS  PubMed  Google Scholar 

  36. Amado LC, Schuleri KH, Saliaris AP, Boyle AJ, Helm R, Oskouei B, et al. Multimodality noninvasive imaging demonstrates in vivo cardiac regeneration after mesenchymal stem cell therapy. J Am Coll Cardiol. 2006;48(10):2116–24.

    Article  PubMed  Google Scholar 

  37. Psaltis PJ, Carbone A, Nelson AJ, Lau DH, Jantzen T, Manavis J, et al. Reparative effects of allogeneic mesenchymal precursor cells delivered transendocardially in experimental nonischemic cardiomyopathy. JACC Cardiovasc Interv. 2010;3(9):974–83.

    Article  PubMed  Google Scholar 

  38. Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci U S A. 2003;100(21):12313–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Martin CM, Meeson AP, Robertson SM, Hawke TJ, Richardson JA, Bates S, 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(1):262–75.

    Article  CAS  PubMed  Google Scholar 

  40. Matsuura K, Honda A, Nagai T, Fukushima N, Iwanaga K, Tokunaga M, et al. Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice. J Clin Invest. 2009;119(8):2204–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang X, Hu Q, Nakamura Y, Lee J, Zhang G, From AH, et al. The role of the sca-1+/CD31- cardiac progenitor cell population in postinfarction left ventricular remodeling. Stem Cells. 2006;24(7):1779–88.

    Article  PubMed  Google Scholar 

  42. Pfister O, Mouquet F, Jain M, Summer R, Helmes M, Fine A, et al. CD31- but Not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res. 2005;97(1):52–61.

    Article  CAS  PubMed  Google Scholar 

  43. Urbanek K, Cesselli D, Rota M, Nascimbene A, De Angelis A, Hosoda T, et al. Stem cell niches in the adult mouse heart. Proc Natl Acad Sci U S A. 2006;103(24):9226–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Smith RR, Barile L, Cho HC, Leppo MK, Hare JM, Messina E, et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation. 2007;115(7):896–908.

    Article  PubMed  CAS  Google Scholar 

  45. Messina E, De Angelis L, Frati G, Morrone S, Chimenti S, Fiordaliso F, et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res. 2004;95(9):911–21.

    Article  CAS  PubMed  Google Scholar 

  46. Johnston PV, Sasano T, Mills K, Evers R, Lee ST, Smith RR, et al. Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation. 2009;120(12):1075–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Boheler KR, Czyz J, Tweedie D, Yang HT, Anisimov SV, Wobus AM. Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Circ Res. 2002;91(3):189–201.

    Article  CAS  PubMed  Google Scholar 

  48. Blum B, Benvenisty N. The tumorigenicity of human embryonic stem cells. Adv Cancer Res. 2008;100:133–58.

    Article  PubMed  Google Scholar 

  49. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.

    Article  CAS  PubMed  Google Scholar 

  50. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.

    Article  CAS  PubMed  Google Scholar 

  51. Yan B, Abdelli LS, Singla DK. Transplanted induced pluripotent stem cells improve cardiac function and induce neovascularization in the infarcted hearts of db/db mice. Mol Pharm. 2011;8(5):1602–10.

    Article  CAS  PubMed  Google Scholar 

  52. Broxmeyer HE, Douglas GW, Hangoc G, Cooper S, Bard J, English D, et al. Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci U S A. 1989;86(10):3828–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol. 2000;109(1):235–42.

    Article  CAS  PubMed  Google Scholar 

  54. Salahuddin SZ, Markham PD, Ruscetti FW, Gallo RC. Long-term suspension cultures of human cord blood myeloid cells. Blood. 1981;58(5):931–8.

    CAS  PubMed  Google Scholar 

  55. Rocha V, Broxmeyer HE. New approaches for improving engraftment after cord blood transplantation. Biol Blood Marrow Transplant. 2010;16(1 Suppl):S126–32.

    Article  PubMed  Google Scholar 

  56. Kogler G, Sensken S, Airey JA, Trapp T, Muschen M, Feldhahn N, et al. A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med. 2004;200(2):123–35.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Ma N, Stamm C, Kaminski A, Li W, Kleine HD, Muller-Hilke B, et al. Human cord blood cells induce angiogenesis following myocardial infarction in NOD/scid-mice. Cardiovasc Res. 2005;66(1):45–54.

    Article  CAS  PubMed  Google Scholar 

  58. Hu CH, Wu GF, Wang XQ, Yang YH, Du ZM, He XH, et al. Transplanted human umbilical cord blood mononuclear cells improve left ventricular function through angiogenesis in myocardial infarction. Chin Med J. 2006;119(18):1499–506.

    CAS  PubMed  Google Scholar 

  59. Henning RJ, Abu-Ali H, Balis JU, Morgan MB, Willing AE, Sanberg PR. Human umbilical cord blood mononuclear cells for the treatment of acute myocardial infarction. Cell Transplant. 2004;13(7–8):729–39.

    Article  PubMed  Google Scholar 

  60. van de Ven C, Collins D, Bradley MB, Morris E, Cairo MS. The potential of umbilical cord blood multipotent stem cells for nonhematopoietic tissue and cell regeneration. Exp Hematol. 2007;35(12):1753–65.

    Article  PubMed  CAS  Google Scholar 

  61. Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13(12):4279–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gaustad KG, Boquest AC, Anderson BE, Gerdes AM, Collas P. Differentiation of human adipose tissue stem cells using extracts of rat cardiomyocytes. Biochem Biophys Res Commun. 2004;314(2):420–7.

    Article  CAS  PubMed  Google Scholar 

  63. Planat-Benard V, Menard C, Andre M, Puceat M, Perez A, Garcia-Verdugo JM, et al. Spontaneous cardiomyocyte differentiation from adipose tissue stroma cells. Circ Res. 2004;94(2):223–9.

    Article  CAS  PubMed  Google Scholar 

  64. De Ugarte DA, Morizono K, Elbarbary A, Alfonso Z, Zuk PA, Zhu M, et al. Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs. 2003;174(3):101–9.

    Article  PubMed  Google Scholar 

  65. Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C, et al. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol 2005; 129(1):118–29.

    Google Scholar 

  66. Miyahara Y, Nagaya N, Kataoka M, Yanagawa B, Tanaka K, Hao H, et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med. 2006;12(4):459–65.

    Article  CAS  PubMed  Google Scholar 

  67. McCall FC, Telukuntla KS, Karantalis V, Suncion VY, Heldman AW, Mushtaq M, et al. Myocardial infarction and intramyocardial injection models in swine. Nat Protoc. 2012;7(8):1479–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Pouly J, Hagege AA, Vilquin JT, Bissery A, Rouche A, Bruneval P, et al. Does the functional efficacy of skeletal myoblast transplantation extend to nonischemic cardiomyopathy? Circulation. 2004;110(12):1626–31.

    Article  PubMed  Google Scholar 

  69. Kondoh H, Sawa Y, Fukushima N, Matsumiya G, Miyagawa S, Kitagawa-Sakakida S, et al. Combined strategy using myoblasts and hepatocyte growth factor in dilated cardiomyopathic hamsters. Ann Thorac Surg. 2007;84(1):134–41.

    Article  PubMed  Google Scholar 

  70. Yoo KJ, Li RK, Weisel RD, Mickle DA, Jia ZQ, Kim EJ, et al. Heart cell transplantation improves heart function in dilated cardiomyopathic hamsters. Circulation. 2000;102(19 Suppl 3):III204–9.

    CAS  PubMed  Google Scholar 

  71. Suzuki K, Murtuza B, Suzuki N, Smolenski RT, Yacoub MH. Intracoronary infusion of skeletal myoblasts improves cardiac function in doxorubicin-induced heart failure. Circulation. 2001;104(12 Suppl 1):I213–7.

    Article  CAS  PubMed  Google Scholar 

  72. Scorsin M, Hagege AA, Dolizy I, Marotte F, Mirochnik N, Copin H, et al. Can cellular transplantation improve function in doxorubicin-induced heart failure? Circulation. 1998;98(19 Suppl):II151–5 ; discussion II155–6.

    CAS  PubMed  Google Scholar 

  73. Nagaya N, Kangawa K, Itoh T, Iwase T, Murakami S, Miyahara Y, et al. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation. 2005;112(8):1128–35.

    Article  PubMed  Google Scholar 

  74. Werner L, Deutsch V, Barshack I, Miller H, Keren G, George J. Transfer of endothelial progenitor cells improves myocardial performance in rats with dilated cardiomyopathy induced following experimental myocarditis. J Mol Cell Cardiol. 2005;39(4):691–7.

    Article  CAS  PubMed  Google Scholar 

  75. Hata H, Matsumiya G, Miyagawa S, Kondoh H, Kawaguchi N, Matsuura N, et al. Grafted skeletal myoblast sheets attenuate myocardial remodeling in pacing-induced canine heart failure model. J Thorac Cardiovasc Surg. 2006;132(4):918–24.

    Article  PubMed  Google Scholar 

  76. Takahashi M, Li TS, Suzuki R, Kobayashi T, Ito H, Ikeda Y, et al. Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury. Am J Physiol Heart Circ Physiol. 2006;291(2):H886–93.

    Article  CAS  PubMed  Google Scholar 

  77. 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(11):1414–21.

    Article  CAS  PubMed  Google Scholar 

  78. Gnecchi M, He H, Noiseux N, Liang OD, Zhang L, Morello F, et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J. 2006;20(6):661–9.

    Article  CAS  PubMed  Google Scholar 

  79. Williams AR, Hatzistergos KE, Addicott B, McCall F, Carvalho D, Suncion V, et al. Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation. 2013;127(2):213–23.

    Article  PubMed  Google Scholar 

  80. Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med. 2005;11(4):367.

    Article  CAS  PubMed  Google Scholar 

  81. Kolf CM, Cho E, Tuan RS. Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation. Arthritis Res Ther. 2007;9(1):204.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Torella D, Ellison GM, Karakikes I, Nadal-Ginard B. Resident cardiac stem cells. Cell Mol Life Sci. 2007;64(6):661–73.

    Article  CAS  PubMed  Google Scholar 

  83. Gnecchi M, He H, Melo LG, Noiseaux N, Morello F, de Boer RA, et al. Early beneficial effects of bone marrow-derived mesenchymal stem cells overexpressing Akt on cardiac metabolism after myocardial infarction. Stem Cells. 2009;27(4):971–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Dhein S, Garbade J, Rouabah D, Abraham G, Ungemach FR, Schneider K, et al. Effects of autologous bone marrow stem cell transplantation on beta-adrenoceptor density and electrical activation pattern in a rabbit model of non-ischemic heart failure. J Cardiothorac Surg. 2006;1:17.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Metzele R, Alt C, Bai X, Yan Y, Zhang Z, Pan Z, et al. Human adipose tissue-derived stem cells exhibit proliferation potential and spontaneous rhythmic contraction after fusion with neonatal rat cardiomyocytes. FASEB J. 2011;25(3):830–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Heldman AW, Hare JM. Cell therapy for myocardial infarction: special delivery. J Mol Cell Cardiol. 2008;44(3):473–6.

    Article  CAS  PubMed  Google Scholar 

  87. Hou D, Youssef EA, Brinton TJ, Zhang P, Rogers P, Price ET, et al. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation. 2005;112(9 Suppl):I150–6.

    PubMed  Google Scholar 

  88. Bartunek J, Wijns W, Heyndrickx GR, Vanderheyden M. Timing of intracoronary bone-marrow-derived stem cell transplantation after ST-elevation myocardial infarction. Nat Clin Pract Cardiovasc Med. 2006;3(Suppl 1):S52–6.

    Article  PubMed  Google Scholar 

  89. Grieve SM, Bhindi R, Seow J, Doyle A, Turner AJ, Tomka J, et al. Microvascular obstruction by intracoronary delivery of mesenchymal stem cells and quantification of resulting myocardial infarction by cardiac magnetic resonance. Circ Heart Fail. 2010;3(3):e5–6.

    Article  PubMed  Google Scholar 

  90. 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(8):1302–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Suncion VY, Ghersin E, Fishman JE, Zambrano JP, Karantalis V, Mandel N, et al. Does transendocardial injection of mesenchymal stem cells improve myocardial function locally or globally? An analysis from the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) randomized trial. Circ Res. 2014;114(8):1292–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Trachtenberg B, Velazquez DL, Williams AR, McNiece I, Fishman J, Nguyen K, et al. Rationale and design of the Transendocardial Injection of Autologous Human Cells (bone marrow or mesenchymal) in Chronic Ischemic Left Ventricular Dysfunction and Heart Failure Secondary to Myocardial Infarction (TAC-HFT) trial: a randomized, double-blind, placebo-controlled study of safety and efficacy. Am Heart J. 2011;161(3):487–93.

    Article  CAS  PubMed  Google Scholar 

  93. Kornowski R, Leon MB, Fuchs S, Vodovotz Y, Flynn MA, Gordon DA, et al. Electromagnetic guidance for catheter-based transendocardial injection: a platform for intramyocardial angiogenesis therapy. Results in normal and ischemic porcine models. J Am Coll Cardiol. 2000;35(4):1031–9.

    Article  CAS  PubMed  Google Scholar 

  94. Wolf T, Gepstein L, Dror U, Hayam G, Shofti R, Zaretzky A, et al. Detailed endocardial mapping accurately predicts the transmural extent of myocardial infarction. J Am Coll Cardiol. 2001;37(6):1590–7.

    Article  CAS  PubMed  Google Scholar 

  95. Barbash IM, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A, et al. Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution. Circulation. 2003;108(7):863–8.

    Article  PubMed  Google Scholar 

  96. 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(9):1114–22.

    Article  PubMed  Google Scholar 

  97. Larose E, Proulx G, Voisine P, Rodes-Cabau J, De Larochelliere R, Rossignol G, et al. Percutaneous versus surgical delivery of autologous myoblasts after chronic myocardial infarction: an in vivo cardiovascular magnetic resonance study. Catheter Cardiovasc Interv. 2010;75(1):120–7.

    PubMed  Google Scholar 

  98. Telukuntla KS, Suncion VY, Schulman IH, Hare JM. The advancing field of cell-based therapy: insights and lessons from clinical trials. J Am Heart Assoc. 2013;2(5):e000338.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Behfar A, Crespo-Diaz R, Terzic A, Gersh BJ. Cell therapy for cardiac repair – lessons from clinical trials. Nat Rev Cardiol. 2014;11(4):232–46.

    Article  PubMed  Google Scholar 

  100. Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. 2006;355(12):1199–209.

    Article  CAS  PubMed  Google Scholar 

  101. Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med. 2006;355(12):1210–21.

    Article  CAS  PubMed  Google Scholar 

  102. 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):1807–18.

    Article  CAS  PubMed  Google Scholar 

  103. 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.

    Article  PubMed  Google Scholar 

  104. 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(24):2277–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Leon MB, Kornowski R, Downey WE, Weisz G, Baim DS, Bonow RO, et al. A blinded, randomized, placebo-controlled trial of percutaneous laser myocardial revascularization to improve angina symptoms in patients with severe coronary disease. J Am Coll Cardiol. 2005;46(10):1812–9.

    Article  PubMed  Google Scholar 

  106. Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation. 2003;107(18):2294–302.

    Article  PubMed  Google Scholar 

  107. Perin EC, Willerson JT, Pepine CJ, Henry TD, Ellis SG, Zhao DX, 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(16):1717–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 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(1):62–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H, et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet. 2003;361(9351):45–6.

    Article  PubMed  Google Scholar 

  110. Archundia A, Aceves JL, Lopez-Hernandez M, Alvarado M, Rodriguez E, Diaz Quiroz G, et al. Direct cardiac injection of G-CSF mobilized bone-marrow stem-cells improves ventricular function in old myocardial infarction. Life Sci. 2005;78(3):279–83.

    Article  CAS  PubMed  Google Scholar 

  111. Patel AN, Geffner L, Vina RF, Saslavsky J, Urschel Jr HC, Kormos R, et al. Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: a prospective randomized study. J Thorac Cardiovasc Surg. 2005;130(6):1631–8.

    Article  PubMed  Google Scholar 

  112. Stamm C, Kleine HD, Choi YH, Dunkelmann S, Lauffs JA, Lorenzen B, 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(3):717–25.

    Article  PubMed  Google Scholar 

  113. Kuethe F, Richartz BM, Kasper C, Sayer HG, Hoeffken K, Werner GS, et al. Autologous intracoronary mononuclear bone marrow cell transplantation in chronic ischemic cardiomyopathy in humans. Int J Cardiol. 2005;100(3):485–91.

    Article  PubMed  Google Scholar 

  114. Yelda T, Berrin U, Murat S, Aytac O, Sevgi B, Yasemin S, et al. Intracoronary stem cell infusion in heart transplant candidates. Tohoku J Exp Med. 2007;213(2):113–20.

    Article  PubMed  Google Scholar 

  115. Diederichsen AC, Moller JE, Thayssen P, Junker AB, Videbaek L, Saekmose SG, et al. Effect of repeated intracoronary injection of bone marrow cells in patients with ischaemic heart failure the Danish stem cell study – congestive heart failure trial (DanCell-CHF). Eur J Heart Fail. 2008;10(7):661–7.

    Article  PubMed  Google Scholar 

  116. Rouy D, Lebrun F, Berchem G, Delagardelle C, Beissel J, Wagner DR. Cell therapy for severe chronic heart failure: the Luxembourg experience. Biomed Mater Eng. 2008;18(1 Suppl):S27–31.

    CAS  PubMed  Google Scholar 

  117. Strauer BE, Yousef M, Schannwell CM. The acute and long-term effects of intracoronary stem cell transplantation in 191 patients with chronic heARt failure: the STAR-heart study. Eur J Heart Fail. 2010;12(7):721–9.

    Article  PubMed  Google Scholar 

  118. Menasche P, Hagege AA, Scorsin M, Pouzet B, Desnos M, Duboc D, et al. Myoblast transplantation for heart failure. Lancet. 2001;357(9252):279–80.

    Article  CAS  PubMed  Google Scholar 

  119. Menasche P, Alfieri O, Janssens S, McKenna W, Reichenspurner H, Trinquart L, et al. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation. 2008;117(9):1189–200.

    Article  PubMed  Google Scholar 

  120. Dib N, Dinsmore J, Lababidi Z, White B, Moravec S, Campbell A, et al. One-year follow-up of feasibility and safety of the first U.S., randomized, controlled study using 3-dimensional guided catheter-based delivery of autologous skeletal myoblasts for ischemic cardiomyopathy (CAuSMIC study). JACC Cardiovasc Interv. 2009;2(1):9–16.

    Article  PubMed  Google Scholar 

  121. Bolli R, Chugh AR, D’Amario D, Loughran JH, Stoddard MF, Ikram S, et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet. 2011;378(9806):1847–57.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Malliaras K, Makkar RR, Smith RR, Cheng K, Wu E, Bonow RO, et al. Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction). J Am Coll Cardiol. 2014;63(2):110–22.

    Article  PubMed  Google Scholar 

  123. Arguero R, Careaga-Reyna G, Castano-Guerra R, Garrido-Garduno MH, Magana-Serrano JA, de Jesus Nambo-Lucio M. Cellular autotransplantation for ischemic and idiopathic dilated cardiomyopathy. Preliminary report Arch Med Res. 2006;37(8):1010–4.

    Article  PubMed  Google Scholar 

  124. Arom KV, Ruengsakulrach P, Jotisakulratana V. Intramyocardial angiogenic cell precursor injection for cardiomyopathy. Asian Cardiovasc Thorac Ann. 2008;16(2):143–8.

    Article  PubMed  Google Scholar 

  125. Fischer-Rasokat U, Assmus B, Seeger FH, Honold J, Leistner D, Fichtlscherer S, et al. A pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy. Circ Heart Fail. 2009;2(5):417–23.

    Article  CAS  PubMed  Google Scholar 

  126. Martino HF, Oliveira PS, Souza FC, Costa PC, Assunção e Silva E, Villela R, et al. A safety and feasibility study of cell therapy in dilated cardiomyopathy. Braz J Med Biol Res. 2010;43(10):989–95.

    Article  CAS  PubMed  Google Scholar 

  127. Seth S, Narang R, Bhargava B, Ray R, Mohanty S, Gulati G, et al. Percutaneous intracoronary cellular cardiomyoplasty for nonischemic cardiomyopathy: clinical and histopathological results: the first-in-man ABCD (Autologous Bone Marrow Cells in Dilated Cardiomyopathy) trial. J Am Coll Cardiol. 2006;48(11):2350–1.

    Article  PubMed  Google Scholar 

  128. Seth S, Bhargava B, Narang R, Ray R, Mohanty S, Gulati G, et al. The ABCD (Autologous Bone Marrow Cells in Dilated Cardiomyopathy) trial a long-term follow-up study. J Am Coll Cardiol. 2010;55(15):1643–4.

    Article  PubMed  Google Scholar 

  129. Vrtovec B, Poglajen G, Lezaic L, Sever M, Domanovic D, Cernelc P, et al. Effects of intracoronary CD34+ stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up. Circ Res. 2013;112(1):165–73.

    Article  CAS  PubMed  Google Scholar 

  130. 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(9):1441–8.

    Article  CAS  PubMed  Google Scholar 

  131. Penn MS, Ellis S, Gandhi S, Greenbaum A, Hodes Z, Mendelsohn FO, et al. Adventitial delivery of an allogeneic bone marrow-derived adherent stem cell in acute myocardial infarction: phase I clinical study. Circ Res. 2012;110(2):304–11.

    Article  CAS  PubMed  Google Scholar 

  132. 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. 2012:1–11.

    Google Scholar 

  133. Noiseux N, Gnecchi M, Lopez-Ilasaca M, Zhang L, Solomon SD, Deb A, et al. Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther. 2006;14(6):840–50.

    Article  CAS  PubMed  Google Scholar 

  134. Zhang G, Hu Q, Braunlin EA, Suggs LJ, Zhang J. Enhancing efficacy of stem cell transplantation to the heart with a PEGylated fibrin biomatrix. Tissue Eng Part A. 2008;14(6):1025–36.

    Article  CAS  PubMed  Google Scholar 

  135. Leri A, Anversa P. Stem cells and myocardial regeneration: cooperation wins over competition. Circulation. 2013;127(2):165–8.

    Article  PubMed  Google Scholar 

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Shah, S., Heldman, A.W. (2017). Stem Cell Therapy in Heart Failure. In: Eisen, H. (eds) Heart Failure. Springer, London. https://doi.org/10.1007/978-1-4471-4219-5_31

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