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Stem cell therapy for CHD: towards translation*

Published online by Cambridge University Press:  17 September 2015

Brody Wehman ,
Osama T. Siddiqui ,
Rachana Mishra ,
Sudhish Sharma  and
Sunjay Kaushal
Brody Wehman
Affiliation:
Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
Osama T. Siddiqui
Affiliation:
Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
Rachana Mishra
Affiliation:
Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
Sudhish Sharma
Affiliation:
Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
Sunjay Kaushal*
Affiliation:
Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
*
Correspondence to: S. Kaushal, MD, PhD, Division of Cardiac Surgery, University of Maryland Medical Center, 110S. Paca St., 7th Floor, Baltimore, MD 21201, United States of America. Tel: +410 328 5842; Fax: +410 328 2750; E-mail: skaushal@smail.umaryland.edu
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Abstract

Stem cell therapy has the optimistic goal of regenerating the myocardium as defined by re-growth of lost or destroyed myocardium. As applied to patients with heart failure, many confuse or limit the regenerative definition to just improving myocardial function and/or decreasing myocardial scar formation, which may not be the most important clinical outcome to achieve in this promising field of molecular medicine. Many different stem cell-based therapies have been tested and have demonstrated a safe and feasible profile in adult patients with heart failure, but with varied efficacious end points reported. Although not achieved as of yet, the encompassing goal to regenerate the heart is still believed to be within reach using these cell-based therapies in adult patients with heart failure, as the first-generation therapies are now being tested in different phases of clinical trials. Similar efforts to foster the translation of stem cell therapy to children with heart failure have, however, been limited. In this review, we aim to summarise the findings from pre-clinical models and clinical experiences to date that have focussed on the evaluation of stem cell therapy in children with heart failure. Finally, we present methodological considerations pertinent to the design of a stem cell-based trial for children with heart failure, as they represent a population of patients with very different sets of issues when compared with adult patients. As has been taught by many learned clinicians, children are not small adults!

Keywords

CHDstem cellhypoplastic left heart syndromesingle ventricle
Type
Original Articles
Information
Cardiology in the Young , Volume 25 , Supplement S2: Special Supplement of Cardiology in the Young: Proceedings of the 2015 International Paediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute , August 2015 , pp. 58 - 66
Copyright
© Cambridge University Press 2015 

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Footnotes

*

Presented at Johns Hopkins All Children’s Heart Institute, International Pediatric Heart Failure Summit, Saint Petersburg, Florida, United States of America, 4–5 February, 2015.

References

1. Rossano, JW, Kim, JJ, Decker, JA, et al. Prevalence, morbidity, and mortality of heart failure-related hospitalizations in children in the United States: a population-based study. J Card Fail 2012; 18: 459–470.Google Scholar
2. Rossano, JW, Shaddy, RE. Heart failure in children: etiology and treatment. J Pediatr 2014; 165: 228–233.Google Scholar
3. Karantalis, V, Balkan, W, Schulman, IH, Hatzistergos, KE, Hare, JM. Cell-based therapy for prevention and reversal of myocardial remodeling. Am J Physiol Heart Circ Physiol 2012; 303: H256–H270.Google Scholar
4. Williams, AR, Hare, JM. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res 2011; 109: 923–940.Google Scholar
5. 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: e000338.CrossRefGoogle ScholarPubMed
6. 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.Google Scholar
7. Schachinger, V, Erbs, S, Elsasser, A, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006; 355: 1210–1221.CrossRefGoogle ScholarPubMed
8. Schachinger, V, Erbs, S, Elsasser, A, et al. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J 2006; 27: 2775–2783.Google Scholar
9. 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: 2380–2389.Google Scholar
10. 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: 2110–2119.Google Scholar
11. Sürder, D, Manka, R, Lo Cicero, V, et al. Intracoronary injection of bone marrow derived mononuclear cells, early or late after acute myocardial infarction: effects on global left ventricular function four months results of the SWISS-AMI trial. Circulation 2013; 127: 1968–1979.Google Scholar
12. Perin, EC, Willerson, JT, Pepine, CJ. 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: 1717–1726.Google Scholar
13. Karantalis, V, DiFede, DL, Gerstenblith, G, et al. Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: the prospective randomized study of mesenchymal stem cell therapy in patients undergoing cardiac surgery (prometheus) trial. Circ Res 2014; 114: 1302–1310.Google Scholar
14. Hare, JM, Fishman, JE, Gerstenblith, G, et al. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 2012; 308: 2369–2379.Google Scholar
15. 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.Google Scholar
16. Selem, SM, Kaushal, S, Hare, JM. Stem cell therapy for pediatric dilated cardiomyopathy. Curr Cardiol Rep 2013; 15: 369.Google Scholar
17. Karantalis, V, Schulman, IH, Balkan, W, Hare, JM. Allogeneic cell therapy: a new paradigm in therapeutics. Circ Res 2015; 116: 12–15.Google Scholar
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: 2277–2286.Google Scholar
19. 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.Google Scholar
20. Makkar, R, Schatz, R, Traverse, J, et al. Abstract 20536: allogeneic heart stem cells to achieve myocardial regeneration (ALLSTAR): the one year phase I results. Circulation 2014; 130: A20536.Google Scholar
21. Davies, B, Elwood, NJ, Li, S, et al. Human cord blood stem cells enhance neonatal right ventricular function in an ovine model of right ventricular training. Ann Thorac Surg 2010; 89: 585–593; 593.e1–4.Google Scholar
22. Cantero Peral, S, Burkhart, HM, Oommen, S, et al. Safety and feasibility for pediatric cardiac regeneration using epicardial delivery of autologous umbilical cord blood-derived mononuclear cells established in a porcine model system. Stem Cells Transl Med 2015; 4: 195–206.Google Scholar
23. Hoashi, T, Matsumiya, G, Miyagawa, S, et al. Skeletal myoblast sheet transplantation improves the diastolic function of a pressure-overloaded right heart. J Thorac Cardiovasc Surg 2009; 138: 460–467.Google Scholar
24. Tarui, S, Sano, S, Oh, H. Stem cell therapies in patients with single ventricle physiology. Methodist Debakey Cardiovasc J 2014; 10: 77–81.Google Scholar
25. Limsuwan, A, Pienvichit, P, Limpijankit, T, et al. Transcoronary bone marrow-derived progenitor cells in a child with myocardial infarction: first pediatric experience. Clin Cardiol 2010; 33: E7–E12.Google Scholar
26. Rupp, S, Zeiher, AM, Dimmeler, S, et al. A regenerative strategy for heart failure in hypoplastic left heart syndrome: intracoronary administration of autologous bone marrow-derived progenitor cells. J Heart Lung Transplant 2010; 29: 574–577.Google Scholar
27. Burkhart, HM, Qureshi, MY, Peral, SC, et al. Regenerative therapy for hypoplastic left heart syndrome: first report of intraoperative intramyocardial injection of autologous umbilical-cord blood-derived cells. J Thorac Cardiovasc Surg 2014; 149: e35–37.Google Scholar
28. Newburger, JW, Sleeper, LA, Frommelt, PC. Transplantation-free survival and interventions at 3 years in the single ventricle reconstruction trial. Circulation 2014; 129: 2013–2020.CrossRefGoogle ScholarPubMed
29. Feinstein, JA, Benson, DW, Dubin, AM, et al. Hypoplastic left heart syndrome: current considerations and expectations. J Am Coll Cardiol 2012; 59: S1–S42.Google Scholar
30. Lee, TM, Aiyagari, R, Hirsch, JC, Ohye, RG, Bove, EL, Devaney, EJ. Risk factor analysis for second-stage palliation of single ventricle anatomy. Ann Thorac Surg 2012; 93: 614–618; discussion 619.Google Scholar
31. Altmann, K, Printz, BF, Solowiejczyk, DE, Gersony, WM, Quaegebeur, J, Apfel, HD. Two-dimensional echocardiographic assessment of right ventricular function as a predictor of outcome in hypoplastic left heart syndrome. Am JournalCardiol 2000; 86: 964–968.Google Scholar
32. Kaneko, S, Khoo, NS, Smallhorn, JF, Tham, EB. Single right ventricles have impaired systolic and diastolic function compared to those of left ventricular morphology. J Am Soc Echocardiogr 2012; 25: 1222–1230.CrossRefGoogle ScholarPubMed
33. d’Udekem, Y, Xu, MY, Galati, JC, et al. Predictors of survival after single-ventricle palliation: the impact of right ventricular dominance. J Am Coll Cardiol 2012; 59: 1178–1185.CrossRefGoogle ScholarPubMed
34. Walsh, MA, McCrindle, BW, Dipchand, A, et al. Left ventricular morphology influences mortality after the Norwood operation. Heart 2009; 95: 1238–1244.Google Scholar
35. Voelkel, NF, Quaife, RA, Leinwand, LA, et al. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation 2006; 114: 1883–1891.Google Scholar
36. Ishigami, S, Ohtsuki, S, Tarui, S, et al. Intracoronary autologous cardiac progenitor cell transfer in patients with hypoplastic left heart syndrome (TICAP): a prospective phase 1 controlled trial. Circ Res 2014; 116: 653–664.Google Scholar
37. Ibrahim, AG, Cheng, K, Marban, E. Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Rep 2014; 2: 606–619.CrossRefGoogle ScholarPubMed
38. Suzuki, G, Weil, BR, Leiker, MM, et al. Global intracoronary infusion of allogeneic cardiosphere-derived cells improves ventricular function and stimulates endogenous myocyte regeneration throughout the heart in swine with hibernating myocardium. PLoS One 2014; 9: e113009.Google Scholar
39. Bergersen, L, Marshall, A, Gauvreau, K, et al. Adverse event rates in congenital cardiac catheterization – a multi-center experience. Catheter Cardiovasc Interv 2010; 75: 389–400.Google Scholar
40. Lin, CH, Hegde, S, Marshall, AC, et al. Incidence and management of life-threatening adverse events during cardiac catheterization for congenital heart disease. Pediatr Cardiol 2014; 35: 140–148.Google Scholar
41. 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.Google Scholar
42. Simpson, DL, Mishra, R, Sharma, S, et al. A strong regenerative ability of cardiac stem cells derived from neonatal hearts. Circulation 2012; 126: S46–S53.Google Scholar
43. D’Amario, D, Leone, AM, Iaconelli, A, et al. Growth properties of cardiac stem cells are a novel biomarker of patients’ outcome after coronary bypass surgery. Circulation 2014; 129: 157–172.CrossRefGoogle ScholarPubMed
44. 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: 942–953.Google Scholar
45. Mirotsou, M, Jayawardena, TM, Schmeckpeper, J, Gnecchi, M, Dzau, VJ. Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol 2011; 50: 280–289.Google Scholar
46. Wehman, B, Kaushal, S. The emergence of stem cell therapy for patients with congenital heart disease. Circ Res 2015; 116: 566–569.Google Scholar
47. Hatzistergos, KE, Quevedo, H, Oskouei, BN, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res 2010; 107: 913–922.CrossRefGoogle ScholarPubMed
48. Ghanayem, NS, Allen, KR, Tabbutt, S, et al. Interstage mortality after the Norwood procedure: results of the multicenter single ventricle reconstruction trial. J Thorac Cardiovasc Surg. 2012; 144: 896–906.Google Scholar