Innovations: Technology & Techniques in Cardiothoracic & Vascular Surgery:
Cardiac Biointerventions: Whatever Happened to Stem Cell and Gene Therapy?
Rosengart, Todd K. MD*†; Fallon, Eleanor BS†; Crystal, Ronald G. MD‡
From the *Division of Cardiothoracic Surgery, Department of Surgery, †Stony Brook University Medical Center, Stony Brook, NY USA; and ‡Department of Genetic Medicine, Weill Cornell Medical College, New York, NY USA.
Accepted for publication June 20, 2012.
Presented at the Annual Scientific Meeting of the 21st Century Cardiothoracic Surgical Society, February 17–19, 2012, Boca Raton, FL USA.
Disclosure: The authors declare no conflict of interest.
Address correspondence and reprint requests to Todd K. Rosengart, MD, Division of Cardiothoracic Surgery, Department of Surgery, Stony Brook University Medical Center, Health Sciences Center T19-020, Stony Brook, NY 11794-8020 USA. E-mail: email@example.com.
Abstract: Angiogenic gene therapy and stem cell administration represent two “biologic” interventions for the treatment of cardiac disease that were first introduced more than 15 years ago but still have not achieved approval for clinical use for the treatment of myocardial ischemia and heart failure. Challenges that have been encountered in the clinical testing of these new treatment strategies have included a lack of placebo controls in phase I surgical trials and the incorporation of potentially ineffectual agent delivery via intracoronary routes. Although enthusiasm for these approaches may therefore have ebbed, new refinements in these technologies and insights into their appropriate clinical testing suggest that a resurgence of interest in these “biointerventions” may be expected in the near future.
Many hundreds of individuals were enrolled in dozens of clinical trials in the late 1990s and the first half of the past decade exploring “biologic” means of treating cardiac disease. Predominantly, these studies not only involved (angiogenic) gene therapy and stem cell interventions but also included gene therapy for the treatment of heart failure, protein-based interventions for inducing myocardial revascularization, and even mechanical (laser) means of creating transmyocardial revascularization (TMR).1–6 These trials have largely disappeared from the agenda of scientific meetings, none have advanced to approvals for commercial use (with the exception of TMR), and enthusiasm for these fields of investigation has significantly dissipated from the lay and scientific community. What has happened? Are these “biointerventions” a clinical failure, has the initial enthusiasm simply waned, or is work still ongoing? These are all true, to a degree.
To understand the current state of the field, it is first important to consider that both gene therapy and stem cell therapy were greeted with an almost unrealistic enthusiasm when they first appeared in the clinical arena. As detailed below, these interventions were translated from animal studies into clinical trials with what, in retrospect, seems to have been a significant disregard for the basic tenet of new drug testing: the diligent incorporation of the pharmacokinetics and bioactivity of candidate agents into a careful and probative trial design. In part, these lapses may have occurred because this new class of therapy was imbued with almost magical properties that negated these standard principles of drug testing, whereas in reality, these agents—gene transfer vectors and stem cells—were no more than a new generation of biologics. Unfortunately, support for these innovative cardiac treatments rapidly collapsed when the initially hyperbolic enthusiasm for these potential new modalities encountered the reality of failed trials, regardless that many of these trials were likely destined to failure, as discussed below, because of their improper conception and design.
CARDIAC GENE THERAPY AND THERAPEUTIC ANGIOGENESIS
The new era of cardiac biointervention was ushered in during the late 1990s with a series of phase I “therapeutic angiogenesis” trials designed to revascularize the myocardium of “no option” patients with diffuse coronary disease not amenable to conventional interventions and with symptomotology refractory to medical therapy.7–14 These small, phase I trials involved several different angiogenic peptides (eg, vascular endothelial growth factor [VEGF]-121, VEGF-165, VEGF-2, fibroblast growth factor) that were delivered to ischemic myocardium via a variety of methodologies (typically via intracoronary or direct myocardial administration of protein, plasmids, or viral vectors). Similar studies were conducted for peripheral vascular disease and coincided with the advent of laser-based TMR for treatment of the same population.6,15,16
Whereas nearly all of these phase I trials yielded promising results, subsequent, larger randomized controlled trials (RCTs) generally failed to demonstrate efficacy.17–20 The explanation for these failures may be rooted in the need for investigators to incorporate a placebo control in these trials. This objective led investigators to choose relatively noninvasive approaches, such as intracoronary delivery strategies, to mitigate ethical concerns associated with the use of placebo controls by potentially less well-tolerated surgical delivery. Unfortunately, intracoronary administration had already been shown to yield very low uptake by the target myocardium compared with direct myocardial delivery,21 and these trials likely proved ineffective because of subtherapeutic agent administration to target tissues.1,2,4 In alternative trial designs, a catheter-based endocardial delivery methodology was used to allow for placebo controls and theoretically more effective direct myocardial vector delivery to target tissues using this minimally invasive approach.22–24 Unfortunately, these trials also failed to demonstrate efficacy, likely because these remote delivery strategies also yielded low total “drug” delivery to the myocardium.24,25
Careful analysis of these pharmacokinetic considerations should have suggested that the negative outcomes of the intracoronary and catheter-based trials were to be expected. Instead, the results of these larger “pivotal” trials were extrapolated to the field in general, including the (surgical) trials using direct myocardial delivery under direct vision that had, in contrast, yielded some evidence of efficacy (Tables 1 and 2). The lack of placebo controls in the surgical trials nevertheless led critics to dismiss the data from these studies as invalidated by a potential placebo effect,28 despite the inclusion of objective endpoints (eg, “time to 1 mm ST depression” on exercise treadmill). As a result, because the only RCTs in the field had yielded negative results, the field was largely abandoned, despite the potential design flaws in these RCTs.
To address these issues, we recently proposed and received unanimous approval from the National Institutes of Health Recombinant Advisory Committee to perform a randomized, placebo-controlled trial using what we believe to be an appropriate delivery strategy—direct myocardial administration via a surgical approach (minithoracotomy)—and using a “nontherapeutic” adenovirus with an empty expression cassette (AdNull) as a placebo control arm in a 3:1 randomization protocol.29 As a further improvement on previous studies, we plan to incorporate a “genomic” angiogenic cassette (VEGF-All6A+) that expresses all three isoforms of VEGF (121, 165, and 189) more potently than our VEGF-121 vector,30 mimicking the endogenous expression of the VEGF gene to enhance the efficacy of this intervention (Fig. 1), but the cornerstone of this proposal will be the use of a placebo-controlled randomized surgical intervention (Fig. 2).
This proposed trial will be one of only a very few placebo-controlled surgical trials to have been undertaken in the United States in recent history.31,32 The relative absence of such trials is largely related to ethical constraints on the use of (nontherapeutic) placebos in (invasive/“risky”) surgical interventions (theoretically violating ethical risk-benefit considerations), but we believe the history of the field and other considerations supports and even mandates this approach.28,29,33,34 The rationale for this placebo-controlled surgical trial design is, more specifically, based on several tenets: (1) our previous clinical results with a minithoracotomy approach have demonstrated that it is safe, with no unanticipated serious adverse events and no deaths associated with the procedure, and is associated with only the expected risks of postoperative discomfort and recovery from surgery12,13; (2) these limited risks are balanced against the potential opportunity for this subject population, with about a 50% 5-year mortality risk to receive this theoretically beneficial intervention in a 3:1 randomization6; (3) true sham surgery (ie, skin incision) or use of saline controls would not allow testing of the central hypothesis—that the VEGF-All6A+ expression cassette is more efficacious than simple needle sticks to the heart and/or the adenovirus per se induce angiogenesis35; and (4) the potential participants are adults and, with proper informed consent process, are capable of properly evaluating and deciding on whether to take on this risk and avoid therapeutic misconception.33
Thus, together with a few other ongoing efforts in the field, there exists the possibility that the field of angiogenesis and cardiac gene therapy will overcome the obstacles of early failures in the clinical testing of this new field of intervention.
CARDIAC STEM CELL THERAPIES
As opposed to angiogenic interventions that target ischemic but viable myocardium, cardiac stem cell interventions are designed to repopulate otherwise permanently scarred myocardium with contractile cells to restore and improve cardiac function.5,36,37 Given the ill-fated track record of clinical trials for angiogenic interventions for the treatment of heart disease, it could have been hoped that the advent of stem cell therapies to treat myocardial infarction would have avoided the pitfalls of ill-advised trial design. Unfortunately, this cellular cardiomyoplasty strategy has generated only limited demonstrated improvements in cardiac function in animal studies, and although generally well tolerated as assessed by safety measures in clinical trials, even these limited successes have generally not translated into significant improvements in efficacy metrics in clinical studies (Table 3).5,36,37 As further considered below, inappropriate trial strategies, perhaps based on “magical” thinking surrounding this new class of agents, again appear to lie at the core of these disappointing results.
In our view, the disappointing efficacy outcomes of cellular cardiomyoplasty animal studies and clinical trials to date (involving stem cell administration into infarcted myocardium) are likely related, at a minimum, to the well-demonstrated failure of the great majority (>90%) of exogenously delivered cells to survive implantation. This deficiency is likely a result of peri-infarct inflammation/ischemia or inefficient cell delivery.48,49 Transfection of implants with survival factors, or with angiogenic transgenes that could generate a nutrient neovasculature, has therefore been proposed as a remedy.50,51 We and others have shown, however, that scar prevascularization with angiogenic mediators before cell implantation yields greater implant survival and functional efficacy than concomitant strategies do, likely on the basis of the weeks-long latent period between angiogenic mediator delivery and target tissue reperfusion.52,53 Likewise, we and others have shown functional benefits to the use of biomatrices in improving cell implantation efficiency and myocardial integration.54–57
Unfortunately, as with the angiogenic trials that preceded them, none of the significant number of stem cell clinical trials have been undertaken so far have incorporated either angiogenic pretreatment of the host myocardium, biomatrix platforms, or other enhanced stem cell delivery strategies. In contrast, a number of these studies have again incorporated intracoronary administration strategies, likely on the basis, again, of this approach facilitating incorporation of a placebo-controlled study design.5,36,37 As of yet, these clinical trial have likewise generally failed to take into consideration these cell delivery parameters or the bioactivity of these cells following myocardial incorporation (eg, electrical or contractile integration into the host syncytium) or even careful extrapolation from preclinical work as to the critical number of cells needed for generating efficacy. As with the angiogenic trials before them, it seems that the stem cell field may be hindered by an “irrational enthusiasm” surrounding this new biointervention.
A NEXT GENERATION OF BIOINTERVENTION: IN SITU CARDIAC TRANSDIFFERENTIATION
New advances in stem cell technologies are today offering a third opportunity at effective biointerventions. These advances relate to the lack of an ideal candidate cardiomyocyte implant, in that source cells such as myoblasts and mesenchymal stem cells do not clearly differentiate adequately into contractile cardiomyocytes, and use of embryonic stem cells are limited by well-known ethical and procurement issues.
A breakthrough in this regard seemed to have come in the creation of induced pluripotent stem (iPS) cells from somatic cells such as fibroblasts and the demonstration by groups, including our own, that cardiomyocyte-like cells can be redifferentiated from iPS cells.58,59 Although redifferentiated iPS cells may well express an appropriate cardiomyocyte phenotype, recent concerns about iPS tumorogenicity and immunogenicity may, however, ultimately limit the clinical applicability of these cells.60
The more recent advent of “induced cardiomyocyte” (iCM) generation directly from somatic cells without passing through an iPS stage (using a trio of “cardio-differentiating” transcription factors [as now validated in our own laboratory]) offers the exciting new possibility of autologous cardiomyocyte implant production that bypasses potentially deleterious iPS staging.61,62 This capability would offer the even more intriguing possibility of converting scar fibroblasts into functional iCMs in situ, obviating the challenges of cell implant harvest, expansion, and delivery.63 On a cautionary note, even this technology will need thoughtful design of clinical trials. For example, iCM generation in situ in the infarct milieu would in our estimation need to incorporate angiogenic pretreatment to support the survival of transdifferentiated iCMs in an ischemic host environment.
Taken together, we believe that these past two decades of clinical trials in angiogenic therapy and stem cell interventions largely reflect a naiveté that because these treatment trials involve relatively “exotic” approaches (gene therapy, stem cells), they are somehow special or different than other “drugs.” Clearly, the past 20 years of trial results has demonstrated that they are not. These trials must be designed with appropriate attention to drug delivery pharmacokinetics, postadministration bioactivity, and objective endpoint metrics. We hope to address some of these issues in our proposed placebo-controlled trial of angiogenic gene therapy using adenoviral-mediated transfer of VEGF, using what we believe to be an appropriate delivery strategy of a “drug” with apparent biologic efficacy, measured with objective endpoints (electrocardiogram changes on stress testing and computed tomography angiography). It will be important that subsequent trials in this new field be thoughtfully designed as well.
1. Zachary I, Morgan RD. Therapeutic angiogenesis for cardiovascular disease: biological context, challenges, prospects. Heart
. 2011; 97: 181–189.
2. Simons M, Banno RO, Chronos N, et al.. Clinical trials in coronary angiogenesis: issues, problems, consensus. Circulation
. 2000; 102: E73–E86.
3. Yee AI, Rosengart TK. Angiogenesis and gene therapy for the treatment of coronary artery disease. In: Franco K, Verrier ED, eds. Advanced Therapy in Cardiac Surgery
. 2nd ed. Hamilton, Ontario: B.C. Decker, Inc; 2003: 138–146.
4. Gupta R, Tongers J, Losordo D. Human studies of angiogenic gene therapy. Circulation
. 2009; 105: 724–773.
5. Wollert KC, Drexler H. Cell-based therapy for heart failure. Curr Opin Cardiol
. 2006; 21: 234–239.
6. Allen KB, Dowling RD, Angell WW, et al.. Transmyocardial revascularization: 5-year follow-up of a prospective, randomized multicenter trial. Ann Thorac Surg
. 2004; 77: 1228–1234.
7. Schumacher B, Stegmann T, Pecher P. The stimulation of neoangiogenesis in the ischemic human heart by the growth factor FGF: first clinical results. J Cardiovasc Surg
. 1998; 39: 783–789.
8. Stewart DJ, Hilton JD, Arnold JM, et al.. Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF (121) versus maximum medical treatment. Gene Ther
. 2006; 21: 1503–1511.
9. Laham R, Sellke FW, Edelman ER, et al.. Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery. Circulation
. 1999; 100: 1865–1871.
10. Ruel M, Laham RJ, Parker JA, et al.. Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein. J Thorac Cardiovasc Surg
. 2002; 124: 28–34.
11. Symes JF, Losordo DW, Vale PR, et al.. Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease. Ann Thorac Surg
. 1999; 68: 830–837.
12. Rosengart TK, Lee LY, Patel SR, et al.. Six-month assessment of a phase I trial of angiogenic gene therapy for the treatment of coronary artery disease using direct intramyocardial administration of an adenovirus vector expressing the VEGF121 cDNA. Ann Surg
. 1999; 230: 466–472.
13. Rosengart TK, Lee LY, Patel SR, et al.. Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing the VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. Circulation
. 1999; 100: 468–474.
14. Laham RJ, Chronos NA, Marilyn P, et al.. Intracoronary basic fibroblast growth factor (FGF-2) in patients with ischemic heart disease: results of a phase I open-label dose escalation study. J Am Coll Cardiol
. 2000; 36: 2132–2139.
15. Isner JM, Walsh K, Symes J, et al.. Arterial gene therapy for therapeutic angiogenesis in patients with peripheral artery disease. Circulation
. 1995; 91: 2687–2692
16. Horvath KA. Clinical studies of TMR with the CO2
laser. J Clin Laser Med Surg
. 1997; 15: 281–285.
17. Hendel RC, Henry TD, Rocha-Singh K, et al.. Effect of intracoronary recombinant human vascular endothelial growth factor on myocardial perfusion: evidence for a dose-dependent effect. Circulation
. 2000; 101: 118–121.
18. Simons M, Annex BH, Laham RJ, et al.. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2. Double-blind, randomized, controlled clinical trial. Circulation
. 2002; 105: 788–793.
19. Henry TD, Annex BH, McKendall GR, et al.; for the VIVA Investigators. The VIVA trial: Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis. Circulation
. 2003; 107: 1359–1365.
20. Henry TD, Grines CL, Watkins MW, et al.. Effects of Ad5FGF-4 in patients with angina. An analysis of pooled data from the AGENT-3’ and AGENT-4 trials. J Am Coll Cardiol
. 2007; 50: 1038–1046.
21. Lee LY, Patel SR, Hackett NR, et al.. Focal angiogen therapy using intramyocardial delivery of an adenovirus vector coding for vascular endothelial growth factor121. Ann Thorac Surg
. 2000; 69: 14–24.
22. Losordo DW, Vale PR, Hendel RC, et al.. Phase 1/2 placebo-controlled, double blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation
. 2002; 105: 2012–2018.
23. Kastrup J, Joergensen E, Rück A, et al.; for the Euroinject One Group. Direct intra-myocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable angina pectoris – A randomized double-blind placebo-controlled study. The Euroinject One Trial. J Am Coll Cardiol
. 2005; 45: 982–988.
24. Stewart DJ, Kutryk MJB, Fitchett D, et al.. VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary artery disease: results of the NORTHERN trial. Mol Med
. 2009; 17: 1109–1115.
25. Gyöngyösi M, Khorsand A, Zamini S, et al.. NOGA-guided analysis of regional myocardial perfusion abnormalities treated with intramyocardial injections of plasmid encoding VEGF A-165 in patients with chronic myocardial ischemia. Subanalysis of the EUROINJECT-ONE multicenter double-blind randomized study. Circulation
. 2005; 112 (suppl I): I-157–I-165.
26. Grines CL, Watkins MW, Mahmarian JJ. A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina. J Am Coll Cardiol. 2003; 42: 1339–1347.
27. Vale PR, Losordo DW, Milliken CE, et al.. Left ventricular electromechanical mapping to assess efficacy of phVEGF165 gene transfer for therapeutic angiogenesis in chronic myocardial ischemia. Circulation. 2000; 102: 965–974.
28. Finniss DG, Kaptchuk TJ, Miller F, et al.. Biological, clinical, and ethical advances of placebo effects. Lancet
. 2010; 375: 686–695.
29. Crystal RG, Kaminsky SM, Hackett NR, et al.. Double blinded, placebo controlled, randomized gene therapy using surgery for vector delivery. Hum Gene Ther
. 2012; 27: 438–441.
30. Amano H, Hackett NR, Kaner RJ, et al.. Alteration of splicing signals in a genomic/cDNA hybrid VEGF gene to modify the ratio of expressed VEGF isoforms enhances safety of angiogenic gene therapy. Mol Ther
. 2005; 12: 716–724.
31. Dekkers W, Boer G. Sham neurosurgery in patients with Parkinson’s disease: is it morally acceptable? J Med Ethics
. 2001; 27: 151–156.
32. Moseley JB, O’Malley K, Petersen NJ, et al.. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med
. 2002; 347: 81–88.
33. Arkin LM, Sondhi D, Worgall S, et al.. Confronting the issues of therapeutic misconception, enrollment decisions, and personal motives in genetic medicine-based clinical research studies for fatal disorders. Hum Gene Ther
. 2005; 16: 1028–1036.
34. Bostick NA, Sade R, Levine MA, et al.. Placebo use in clinical practice: report of the American Medical Association Council on Ethical and Judicial Affairs. J Clin Ethics
. 2008; 19: 58–61.
35. Pelletier MP, Giaid A, Sivaraman S, et al.. Angiogenesis and growth factor expression in a model of transmyocardial revascularization. Ann Thorac Surg
. 1998; 66: 12–18.
36. Hare JM, Chaparro SV. Cardiac regeneration and stem cell therapy. Curr Opin Organ Transplant
. 2008; 13: 536–542.
37. Rosenzweig A. Cardiac cell therapy—mixed results from mixed cells. N Engl J Med
. 2006; 355: 1274–1277.
38. Assmus B, Schächinger V, Teupe C, et al.. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002; 106: 3009–3017.
39. Siminiak T, Fiszer D, Jerzykowska O, et al.. Percutaneous trans-coronary-venous transplantation of autologous skeletal myoblasts in the treatment of post-infarction myocardial contractility impairment: the POZNAN trial. Eur Heart J. 2005; 26: 1188–1195.
40. Biagini E, Valgimigli M, Smits PC, et al.. Stress and tissue Doppler echocardiographic evidence of effectiveness of myoblast transplantation in patients with ischaemic heart failure. Eur J Heart Fail. 2006; 8: 641–648.
41. 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: 1847–1857.
42. 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.
43. 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: 141–148.
44. Janssens S, Dubois C, Bogaer 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: 113–121.
45. Schächinger V, Erbs S, Elsässer A, et al.. Intracoronary bone marrow–derived progenitor cells in acute myocardial infarction. N Engl J Med. 2006; 355: 1210–1221.
46. Traverse JH, McKenna DH, Harvey K, et al.. A controlled trial of bone marrow mononuclear stem cell administration in patients following ST-elevation myocardial infarction. Am Heart J. 2010; 160: 428–434.
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: 989–999.
48. Zhang M, Method D, Poppa V, et al.. Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies. J Mol Cell Cardiol
. 2001; 33: 907–921.
49. Segers VFM, Lee RT. Stem-cell therapy for cardiac disease. Nature
. 2008; 451: 937–939.
50. Yau TM, Kim C, Ng D, et al.. Increased transplanted cell survival with cell-based angiogenic gene therapy. Ann Thorac Surg
. 2005; 80: 1779–1786.
51. Tang YL, Tang Y, Zhang YC, et al.. Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector. J Am Coll Cardiol
. 2005; 46: 1339–1350.
52. Retuerto MA, Schalch P, Patejunas G, et al.. Angiogenic pre-treatment improves the efficacy of cellular cardiomyoplasty performed with fetal cardiomyocyte implantation. J Thorac Cardiovasc Surg
. 2004; 127: 1041–1049.
53. Retuerto MA, Beckmann JT, Carbray J, et al.. Angiogenic pre-treatment enhances myocardial function following cellular cardiomyoplasty with skeletal myoblasts. J Thorac Cardiovasc Surg
. 2007; 133: 478–484.
54. Madden LR, Mortisen DJ, Sussman EM, et al.. Proangiogenic scaffolds as functional templates for cardiac tissue engineering. Proc Natl Acad Sci U S A
. 2010; 107: 15211–15216.
55. Guo HD, Cui GH, Wang HJ, et al.. Transplantation of marrow derived cardiac stem cells carried in designer self-assembling peptide nanofibers improves cardiac function after myocardial infarction. Biochem Biophys Res Comm
. 2010; 399: 42–48.
56. Miyagawa S, Sawa Y, Sakakida S, et al.. Tissue cardiomyoplasty using bioengineered contractile cardiomyocyte sheets to repair damaged myocardium: their integration with recipient myocardium. Transplantation
. 2005; 80: 1586–1595.
57. Kochupura PV, Azeloglu EU, Kelly DJ, et al.. Tissue-engineered myocardial patch derived from extracellular matrix provides regional mechanical function. Circulation
. 2005; 112: I144–I149.
58. Takahashi K, Tanabe K, Ohnuki M, et al.. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell
. 2007; 131: 861–872.
59. Gai H, Leung ELH, Costantino PD, et al.. Generation and characterization of functional cardiomyocytes using induced pluripotent stem cells derived from human fibroblasts. Cell Biol Int
. 2009; 33: 1184–1193.
60. Mummery C. Induced pluripotent stem cells—a cautionary note. N Engl J Med
. 2011; 364: 2160.
61. Ieda M, Fu JD, Delgado-Olguin P, et al.. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell
. 2010; 142: 375–386.
62. Efe JA, Hilcove S, Kim J, et al.. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat Cell Biol
. 2011; 13: 215–222.
63. Qian L, Huang Y, Spencer I, et al.. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature
. 2012; 485: 593–598.
Gene therapy; Stem cells; Angiogenesis; Heart failure; VEGF
Copyright © 2012 by the International Society for Minimally Invasive Cardiothoracic Surgery. Unauthorized reproduction of this article is prohibited.
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