Abstract
Purpose of Review
The purpose of this review is to discuss recent advances in the field of cell therapy in patients with heart failure with reduced ejection fraction (HFrEF) of ischemic (iCMP) and nonischemic (dCMP) etiology, heart failure with preserved ejection fraction (HFpEF), and in advanced heart failure patients undergoing mechanical circulatory support (LVAD).
Recent Findings
In HFrEF patients (iCMP and dCMP cohorts), autologous and/or allogeneic cell therapy was shown to improve myocardial performance, patients’ functional capacity, and neurohumoral activation. In HFpEF patient population, the concept of cell therapy in novel and remains largely unexplored. However, initial data are very encouraging and suggest at least a similar benefit in improvements of myocardial performance (also diastolic function of the left ventricle), exercise capacity, and neurohumoral activation. Recently, cell therapy was explored in the sickest population of advanced heart failure patients undergoing LVAD support also showing a potential benefit in promoting myocardial reverse remodeling and recovery.
Summary
In the past decade, several cell therapy-based clinical trials showed promising results in various chronic and advanced heart failure patient cohorts. Future cell treatment strategies should aim for more personalized therapeutic approaches by defining optimal stem cell type or their combination, dose, and delivery method for an individual patient adjusted for patient’s age and stage/duration of heart failure.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135(10):e146–603. https://doi.org/10.1161/CIR.0000000000000485.
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891–975. https://doi.org/10.1002/ejhf.592.
•• Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410:701–5. https://doi.org/10.1038/35070587First data to suggest myocardial regeneration after injury is possible.
Lund LH, Edwards LB, Dipchand AI, Goldfarb S, Kucheryavaya AY, Levvey BJ, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-third adult heart transplantation Report-2016; focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant. 2016;35(10):1158–69. https://doi.org/10.1016/j.healun.2016.08.017.
St John Sutton MG, Sharpe N. Left ventricular remodelling after myocardial infarction: pathophysiology and therapy. Circulation. 2000;101:2981–8. https://doi.org/10.1161/01.cir.101.25.2981.
Jugdutt BI. Ventricular remodelling after infarction and the extracellular collagen matrix. Circulation. 2003;108:1395–403. https://doi.org/10.1161/01.CIR.0000085658.98621.49.
Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P. Transplanted adult bone marrow cells repair myocardial infarcts in mice. Ann N Y Acad Sci. 2001;938:221–30. https://doi.org/10.1111/j.1749-6632.2001.tb03592.x.
Orlic D. Adult bone marrow stem cells regenerate myocardium in ischemic heart disease. Ann N Y Acad Sci. 2003;996:152–7. https://doi.org/10.1111/j.1749-6632.2003.tb03243.x.
Kinnaird T, Stabile E, Burnett SM, Shou M, Lee CW, Barr S, et al. Local delivery ofmarrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation. 2004;109(12):1543–9. https://doi.org/10.1161/01.CIR.0000124062.31102.57.
Du YY, Zhou SH, Zhou T, Su H, Pan HW, Du WH, et al. Immuno-inflammatory regulation effect of mesenchymal stem cell transplantation in a rat model ofmyocardial infarction. Cytotherapy. 2008;10(5):469–78. https://doi.org/10.1080/14653240802129893.
Stumpf C, Seybold K, Petzi S, Wasmeier G, Raaz D, Yilmaz A, et al. Interleukin-10 improves left ventricular function in rats with heart failure subsequent to myocardial infarction. Eur J Heart Fail. 2008;10(8):733–9. https://doi.org/10.1016/j.ejheart.2008.06.007.
Onai Y, Suzuki JI, Maejima Y, Haraguchi G, Muto S, Itai M, et al. Inhibition of NF-κB improves left ventricular remodeling and cardiac dysfunction after myocardial infarction. Am J Phys. 2007;292(1):H530–8. https://doi.org/10.1152/ajpheart.00549.2006.
•• Perin EC, Dohmann HFR, Borojevic R, Silva SA, Sousa ALS, Mesquita CT, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation. 2003;107(18):2294–302. https://doi.org/10.1161/01.CIR.0000070596.30552.8BThis was the first study to explore effects of cell therapy in clinical settings.
Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Hölschermann, et al. Improved clinical outcome after intracoronary administration of bone-marrowderived progenitor cells in acutemyocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J. 2006;27(23):2775–83. https://doi.org/10.1093/eurheartj/ehl388.
Lunde K, Solheim S, Aakhus S, Arnsen H, Abdelnoor M, Egeland T, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. New Eng J Med. 2006;355(12):1199–209. https://doi.org/10.1056/NEJMoa055706.
Assmus B, Fischer-Rasokat U, Honold J, Seeger FH, Fichtlscherer S, Tonn T, et al. Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure: results of the TOPCARE-CHD registry. Circ Res. 2007;100(8):1234–41. https://doi.org/10.1161/01.RES.0000264508.47717.6b.
Meyer GP, Wollert KC, Lotz J, Pirr J, Rager U, Lippolt P, et al. Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial. Eur Heart J. 2009;30(24):2978–84. https://doi.org/10.1093/eurheartj/ehp374.
Perin EC, Silva GV, Henry TD, Cabreira-Hansen MG, Moore WH, Coulter SA, et al. A randomized study of transendocardial injection of autologous bone marrow mononuclear cells and cell function analysis in ischemic heart failure (FOCUS-HF). Am Heart J. 2011;161(6):1078–87. https://doi.org/10.1016/j.ahj.2011.01.028.
Perin EC, Willerson JT, Pepine CJ, Henry TD, Ellis SG, Zhao DXM, 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. https://doi.org/10.1001/jama.2012.418.
Makkar RR, Smith RR, Cheng K, Malliaras K, Thomson LE, Berman D, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet. 2012;379(9819):895–904. https://doi.org/10.1016/S0140-6736(12)60195-0.
Paitazoglou C, Bergmann MW, Vrtovec B, Chamuleau SAJ, van Klarenbosch B, Wojakowski W, et al. Rationale and design of the European multicentre study on stem cell therapy in IschEmic non-treatable cardiac diseasE (SCIENCE). Eur J Heart Fail. 2019;21(8):1032–41. https://doi.org/10.1002/ejhf.1412.
Borow KM, Yaroshinsky A, Greenberg B, Perin EC. Phase 3 DREAM-HF trial of mesenchymal precursor cells in chronic heart failure. Circ Res. 2019;125(3):265–81. https://doi.org/10.1161/CIRCRESAHA.119.314951.
Tendera M, Wojakowski W, Ruzyllo W, Chojnowska L, Kepka C, Tracz W, et al. Intracoronary infusion of bone marrow-derived selected CD34(+)CXCR4(+) cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicentre myocardial regeneration by intracoronary infusion of selected population of stem cells in acute myocardial infarction (REGENT) trial. Eur Heart J. 2009;30(11):1313–21. https://doi.org/10.1093/eurheartj/ehp073.
Losordo DW, Henry TD, Davidson C, Sup Lee J, Costa MA, Bass T, et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res. 2011;109(4):428–36. https://doi.org/10.1161/CIRCRESAHA.111.245993.
Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O'Connell J, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation. 1996;93(5):841–2. https://doi.org/10.1161/01.cir.93.5.841.
Nakahara S, Tung R, Ramirez RJ, Michowitz Y, Vaseghi M, Buch E, et al. Characterization of the arrhythmogenic substrate in ischemic and nonischemic cardiomyopathy implications for catheter ablation of hemodynamically unstable ventricular tachycardia. J Am Coll Cardiol. 2010;55(21):2355–65. https://doi.org/10.1016/j.jacc.2010.01.041.
Roura S, Bayes-Genis A. Vascular dysfunction in idiopathic dilated cardiomyopathy. Nat Rev Cardiol. 2009;6(9):590–8. https://doi.org/10.1038/nrcardio.2009.130.
Schäfer R, Abraham D, Paulus P, Blumer R, Grimm M, Wojta J, et al. Impaired VE-cadherin/beta-catenin expression mediates endothelial cell degeneration in dilated cardiomyopathy. Circulation. 2003;108(13):1585–91. https://doi.org/10.1161/01.CIR.0000091085.12422.19.
• Theiss HD, David R, Engelmann MG, Barth A, Schotten K, Naebauer M, et al. Circulation of CD34+ progenitor cell populations in patients with idiopathic dilated and ischaemic cardiomyopathy (DCM and ICM). European Heart Journal. 2007;28:1258–64. https://doi.org/10.1093/eurheartj/ehm011This study outline the correlation with stem cell reserve and heart failure type and stage.
Valgimigli M, Rigolin GM, Fucili A, Della Porta M, Soukhomovskaia O, Malagutti P, et al. CD34+ and ePCs in patients with various degrees of congestive heart failure. Circulation. 2004;110:1209–12. https://doi.org/10.1161/01.CIR.0000136813.89036.21.
Kissel CK, Lehmann R, Assmus B, Aicher A, Honold J, Fischer-Rasokat U, et al. Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure. J Am Coll Cardiol. 2007;49(24):2341–9. https://doi.org/10.1016/j.jacc.2007.01.095.
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;2:417–23. https://doi.org/10.1161/CIRCHEARTFAILURE.109.855023.
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;48:2350–1. https://doi.org/10.1016/j.jacc.2006.07.057.
Bocchi EA, Bacal F, Guimarães G, Mendroni A, Mocelin A, Esteves Filho A, et al. Granulocyte-colony stimulating factor or granulocyte-colony stimulating factor associated to stem cell intracoronary infusion effects in non ischemic refractory heart failure. Int J Cardiol. 2010;138(1):94–7. https://doi.org/10.1016/j.ijcard.2008.06.002.
Hamshere S, Arnous S, Choudhury T, Choudry F, Mozid A, Yeo C, et al. Randomized trial of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with non-ischaemic dilated cardiomyopathy: the REGENERATE-DCM clinical trial. Eur Heart J. 2015;36(44):3061–9. https://doi.org/10.1093/eurheartj/ehv390.
•• Vrtovec B, Poglajen G, Sever M, Lezaic L, Domanovic D, Cernelc P, et al. Effects of intracoronary stem cell transplantation in patients with dilated cardiomyopathy. J Card Fail. 2011;17:272–81. https://doi.org/10.1016/j.cardfail.2010.11.007First randomized prospective study to evaluate cell therapy in non-ishcemic cardiomyopathy.
• 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. https://doi.org/10.1161/CIRCRESAHA.112.276519Study to present the longest follow-up data of cell therapy in non-ischemic cardiomyopathy and suggests potential survival benefit of cell therapy in this patient cohort.
• Vrtovec B, Poglajen G, Lezaic L, Sever M, Socan A, Domanovic D, et al. Comparison of transendocardial and intracoronary CD34+ cell transplantation in patients with nonischemic dilated cardiomyopathy. Circulation. 2013;128(11 Suppl 1):S42–9. https://doi.org/10.1161/CIRCULATIONAHA.112.000230This study presents one of the strongest clinical data to support transendocardial cell delivery over intracoronary cell injections.
Butler J, Epstein SE, Greene SJ, Quyyumi AA, Sikora S, Kim RJ, et al. Intravenous allogeneic mesenchymal stem cells for nonischemic cardiomyopathy: safety and efficacy results of a phase II-A randomized trial. Circ Res. 2017;120(2):332–40. https://doi.org/10.1161/CIRCRESAHA.116.309717.
• Hare JM, DL DF, Rieger AC, Florea V, Landin AM, El-Khorazaty J, et al. Randomized comparison of allogeneic versus autologous mesenchymal stem cells for nonischemic dilated cardiomyopathy: POSEIDON-DCM Trial. J Am Coll Cardiol. 2017;69(5):526–37. https://doi.org/10.1016/j.jacc.2016.11.009First study to compare autologous to allogeneic cell therapy in non-ischemic cardiomyopathy patients.
• Vrtovec B, Poglajen G, Sever M, Zemljic G, Frljak S, Cerar A, et al. Effects of repetitive Transendocardial CD34 + cell transplantation in patients with nonischemic dilated cardiomyopathy. Circ Res. 2018;123(3):389–96. https://doi.org/10.1161/CIRCRESAHA.117.312170First study to compare repetetive cell therapy to single cell therapy approach.
Owan TE, Hodge DO, Herges RM, Jacobsen JS, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355:251–9. https://doi.org/10.1056/NEJMoa052256.
Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation. 2015;131:550–9.
Goligorsky MS. Microvascular rarefaction: the decline and fall of blood vessels. Organogenesis. 2010;6:1–10. https://doi.org/10.4161/org.6.1.10427.
Drakos SG, Kfoury AG, Hammond EH, Reid BB, Revelo MP, Rasmusson BY, et al. Impact of mechanical unloading onmicrovasculature and associated central remodeling features of the failing human heart. J Am Coll Cardiol. 2010;56:382–91. https://doi.org/10.1016/j.jacc.2010.04.019.
Gallet R, de Couto G, Simsolo E, Valle J, Sun B, Liu W, et al. Cardiosphere-derived cells reverse heart failure with preserved ejection fraction (HFpEF) in rats by decreasing fibrosis and inflammation. JACC Basic Transl Sci. 2016;1(1–2):14–28. https://doi.org/10.1016/j.jacbts.2016.01.003.
Poglajen G, Gregoric ID, Radovancevic R, Vrtovec B. Stem cell and left ventricular assist device combination therapy. Circ Heart Fail. 2019;12(2):e005454. https://doi.org/10.1161/CIRCHEARTFAILURE.118.005454.
Topkara VK, Garan AR, Fine B, Godier-Furnemont AF, Breskin A, Cagliostro B, et al. Myocardial recovery in patients receiving contemporary left ventricular assist devices: results from the interagency registry for mechanically assisted circulatory support (INTERMACS). Circ Heart Fail. 2016;9. https://doi.org/10.1161/CIRCHEARTFAILURE.116.003157.
Drakos SG, Wever-Pinzon O, Selzman CH, Gilbert EM, Alharethi R, Reid BB, et al. Magnitude and time course of changes induced by continuous-flow left ventricular assist device unloading in chronic heart failure: insights into cardiac recovery. J Am Coll Cardiol. 2013;61:1985–94. https://doi.org/10.1016/j.jacc.2013.01.072.
Ascheim DD, Gelijns AC, Goldstein D, Moye LA, Smedira N, Lee S, et al. Mesenchymal precursor cells as adjunctive therapy in recipients of contemporary left ventricular assist devices. Circulation. 2014;129:2287–96. https://doi.org/10.1161/CIRCULATIONAHA.113.007412.
Stempien-Otero A, Helterline D, Plummer T, Farris S, Prouse A, Polissar N, et al. Mechanisms of bone marrow-derived cell therapy in ischemic cardiomyopathy with left ventricular assist device bridge to transplant. J Am Coll Cardiol. 2015;65:1424–34. https://doi.org/10.1016/j.jacc.2015.01.042.
•• Yau TM, Pagani FD, Mancini DM, Chang HL, Lala A, Woo YJ, et al. Intramyocardial injection of mesenchymal precursor cells and successful temporary weaning from left ventricular assist device support in patients with advanced heart failure: a randomized clinical trial. JAMA. 2019;321(12):1176–86. https://doi.org/10.1001/jama.2019.2341The largest clinical trial of cell therapy in LVAD-supported patients.
Zheng Y, Sampaio LC, Li K, Silva GV, Cabreira-Hansen M, Vela D, et al. Safety and feasibility of mapping and stem cell delivery in the presence of an implanted left ventricular assist device: a preclinical investigation in sheep. Tex Heart Inst J. 2013;40:229–34.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
Not applicable.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Nonpharmacologic Therapy: Surgery, Ventricular Assist Devices, Biventricular Pacing, and Exercise
Rights and permissions
About this article
Cite this article
Poglajen, G., Frljak, S., Zemljič, G. et al. Stem Cell Therapy for Chronic and Advanced Heart Failure. Curr Heart Fail Rep 17, 261–270 (2020). https://doi.org/10.1007/s11897-020-00477-9
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11897-020-00477-9