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Circ Res. Author manuscript; available in PMC 2017 July 07. Published in final edited form as: Circ Res. 2017 March 31; 120(7): 1060–1062. doi:10.1161/CIRCRESAHA.117.310702.

Clinical Progress in Cell Therapy for Single Ventricle Congenital Heart Disease Gregory J. Bittle, Brody Wehman, Sotirios K. Karathanasis, and Sunjay Kaushal Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore (G.J.B., B.W., S.K.); and Cardiovascular and Metabolic Diseases, Innovative Medicines Biotech Unit, Medimmune, Inc, Gaithersburg, MD (S.K.K.)

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Keywords Editorials; cell transplantation; congenital heart disease; hypoplastic left heart syndrome; single ventricle; stem cell

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One of the fundamental goals of congenital cardiac surgery is to correct the circulatory and structural physiology of congenital heart disease (CHD) by skillfully reconstructing the cardiac anatomy. In the majority of CHD patients, complete correction is achieved with low mortality and reasonable durability, a tribute to surgical strides during the last 2 decades. However, the most challenging CHD patients present with a developmentally hypoplastic heart chamber, which necessitates heroic palliative operations to establish a single ventricle that delivers oxygenated blood to the body, leaving deoxygenated blood to be delivered passively to the pulmonary circulation.

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This anatomy is crafted in a staged fashion. Typically, the stage I palliative operation (Norwood operation) is performed in the first weeks of life and commits the single ventricle to pumping to both the systemic and pulmonary circulations. The stage II operation (bidirectional cavopulmonary anastomosis), at ≈6 months, redirects superior vena caval blood to the pulmonary circulation by transecting the proximal superior vena caval and performing a direct anastomosis to the right pulmonary artery. The stage III operation (Fontan), at ≈3 years, directs the remaining inferior vena caval blood flow to the pulmonary artery. Though outcomes have been improving over the past few decades, these procedures are not curative, and overall life expectancy with these conditions remains markedly diminished.1 Much of this mortality is because of dysfunction of the single ventricle, which is usually the morphological right ventricle (RV). The RV is not intended to pump against systemic pressures long term and in the best circumstances fails by the second or third decade of life.2 The only viable option for the failing ventricle is heart transplantation; however, survival after heart transplantation is poor after single ventricle staged palliation.3

Correspondence to Sunjay Kaushal, MD, PhD, Pediatric and Adult Congenital Surgery, 110 S Paca St, 7th Floor, Baltimore, MD 21201. [email protected]. Disclosures None. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

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Along with increased mortality because of inevitable failure, there is also high morbidity attributed to nonlethal ventricular arrhythmias, protein-losing enteropathy, plastic bronchitis, cirrhosis, and thromboembolism.4 Because of the high morbidity and mortality in these patients under the current treatment plan, new options need to be explored that will positively remodel or regenerate the native myocardium.

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The PERSEUS (Cardiac Progenitor Cell Infusion to Treat Univentricular Heart Disease) phase II randomized clinical trial of intracoronary administration of autologous cardiosphere-derived cells (CDCs), reported in this issue, demonstrated the clinical efficacy of cell therapy in a small but complex population of children with single ventricle CHD. The investigators isolated autologous CDCs, expanded them ex vivo, and administered the cells via the intracoronary route after the stage II (n=4, 24%) or the stage III palliative operation (n=13, 76%). The CDC-treated patients experienced no adverse events in the form of procedural complications, life-threatening dysrhythmia, myocardial necrosis, or sudden death. At 3 months of follow-up, the CDC-treated patients demonstrated improved ventricular ejection fraction (6.4±5.5%), while minimal change was observed in the control group (1.3±3.7%). Of note, RV ejection fraction was assessed by 3 modalities: cardiac magnetic resonance imaging, ventriculogram, and echocardiography. Given the complex geometry of the RV, cardiac magnetic resonance imaging has become the favored method of quantitatively assessing ventricular size and function. In practice, echocardiography can be simpler to perform (less sedation, allows free breathing), and the demonstrated correlation with magnetic resonance imaging is of particular clinical interest.

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In the second part of study, a late CDC infusion was performed in the 17 control patients, resulting in increased ventricular function, although the magnitude of this effect was smaller than that seen in the primary treatment group. Considering the entire treated cohort at 12 months postadministration, there were significant improvements in ventricular size, ventricular function, and several quality of life indicators (secondary end points). Because of ethical concerns, there was no true control group available for 12-month comparison (all primary controls received late infusion after 3-month data were collected), but the cumulative results certainly justify a phase III trial.

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Despite these encouraging results, the PERSEUS trial has some limitations that must be addressed before the general application of cell therapy in single ventricle patients. First, the cardiac anatomy was heterogeneous within the study population, with ≈88% presenting with a single RV and just under half of these patients carrying a diagnosis of hypoplastic left heart syndrome. Second, the timing of the CDC administration was not standardized, with the majority occurring after the stage III palliative surgery, but others being treated years earlier after the stage II operation. Because the volume unloading of the single ventricle may change with each operation, the functional improvements may not necessarily reflect CDC treatment but, instead, natural remodeling of the ventricle over time after surgical intervention. Finally, the CDC treatment failed to affect mortality, which likely reflects the limited follow-up available for review in this study. Even so, the outcomes presented are encouraging, and the PERSEUS trial provides the initial framework for discussing some important issues in cell therapy for CHD.

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Best Responders to Cell Therapy May Be Children

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Myocardial regeneration using cell-based therapies is an emerging field that offers optimism for single ventricle patients, but the initial trials of these therapeutics for heart disease were performed in adults with ischemic disease, with variable results.5 We expect that cell therapy in children, however, will be much more successful. In fact, the young may be the best responders because their myocardium is inherently more pliable and will respond more vigorously to the biological cues of the transplanted cells. This hypothesis underlies our own pursuits and is consistent with the available clinical data in single ventricle patients. Case reports using bone marrow–derived cell preparations and autologous cord blood have shown striking improvements of ventricular function in patients with hypoplastic left heart syndrome.6,7 On a larger scale, both the TICAP (Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single Ventricle Physiology) and PERSEUS trials demonstrated that the best response to CDC therapy may occur in infants of the smallest size, youngest age, and lowest ejection fraction.8 These trials, along with others targeting pediatric patients, are described in Table. The clinical observations are in line with our own data showing that endogenous human c-kit+ cardiac progenitor cells (CPCs) are 3× more numerous in neonates than in infants9 and that children with heart failure maintain these high neonatal progenitor cell numbers, regardless of age.10 Because transplanted cells stimulate the proliferation and differentiation of endogenous CPCs, these age- and diseasebased differences in CPC number may partially explain the increased efficacy of cell therapy in children compared with that in adults.11 In addition to being more numerous, cells from younger patients have also been shown to exhibit more potent regenerative characteristics.12

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The PERSEUS trial used autologous cell transplantation, and therefore, the CDCs and their constituent CPCs were derived from young children. This combination of young donors and young recipients may have contributed to the positive results, and it is, therefore, unclear as to whether autologous CDC transplantation would be similarly effective in teenagers or adults, even those comparable single ventricle physiology. Foregoing autologous cell preparations in favor or allogeneic neonatal CDCs or c-kit+ CPCs, on the other hand, may provide a more effective cell preparation for adult cardiac repair.

Are Cells Really Necessary?

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The central paradox of cell therapy is the observation of favorable myocardial remodeling in the absence of significant engraftment of exogenous cells. These seemingly conflict-ing phenomena have been reconciled in the paradigm of durable paracrine mechanisms underlying the benefits of cell administration. Indeed, we have recently made extensive efforts to catalog the various components of the CPC secretome and have shown that in a rat myocardial infarction model, a single peri-infarct injection of total conditioned medium from neonatal human CPCs was actually more effective in preventing functional deterioration and myocardial fibrosis than the injection of the CPCs themselves.13 When the exosomal fraction of the total conditioned medium was isolated and administered, its effects were comparable to administration of whole CPCs. The further elucidation of the pathways responsible for the cardioprotective effects of total conditioned medium is currently an area of intense inquiry because the answers to these questions are critical to the design of the next

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generation of cell-based—and potentially cell-free—therapeutics. The promising clinical findings in young patients from studies, such as PERSEUS, and the preclinical observations that cardiac stem cells from young subjects retain substantial regenerative capacity in their secretomes raise the exiting possibility of using cultured human neonatal CPC cells as biofactories to generate complex therapeutics for cardiac rejuvenation and repair in both children and adult heart disease.

Conclusions

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Despite the extraordinary potential of cell therapy for the treatment of CHD, clinical data remain limited. The PERSEUS trial is among the seminal contributions to the field and encourages further exploration of immune modulation, utility of repeat dosing, durability of effect, mechanism of action, and countless other key questions yet to be studied. Because this promising field is in rapid evolution, the opportunities for investigation in cell therapy are many—from molecular mechanism to clinical follow-up—and each of these individual contributions tangibly advances our ability to improve the lives of children with CHD.

Acknowledgments Sources of Funding G.J. Bittle is supported through National Institutes of Health grant 2T32AR007592-21. S. Kaushal is supported partly through National Institutes of Health grants 1R01HL118491, MedImmune, and the Maryland Stem Cell Research Fund.

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1. Ohye RG, Schonbeck JV, Eghtesady P, et al. Pediatric Heart Network Investigators. Cause, timing, and location of death in the Single Ventricle Reconstruction trial. J Thorac Cardiovasc Surg. 2012; 144:907–914. DOI: 10.1016/j.jtcvs.2012.04.028 [PubMed: 22901498] 2. Arnold RR, Loukanov T, Gorenflo M. Hypoplastic left heart syndrome - unresolved issues. Front Pediatr. 2014; 2:125.doi: 10.3389/fped.2014.00125 [PubMed: 25426478] 3. Everitt MD, Boyle GJ, Schechtman KB, Zheng J, Bullock EA, Kaza AK, Dipchand AI, Naftel DC, Kirklin JK, Canter CE. Pediatric Heart Transplant Study Investigators. Early survival after heart transplant in young infants is lowest after failed single-ventricle palliation: a multi-institutional study. J Heart Lung Transplant. 2012; 31:509–516. DOI: 10.1016/j.healun.2011.12.013 [PubMed: 22325692] 4. Frommelt MA. Challenges and controversies in fetal diagnosis and treatment: hypoplastic left heart syndrome. Clin Perinatol. 2014; 41:787–798. DOI: 10.1016/j.clp.2014.08.004 [PubMed: 25459774] 5. Nguyen PK, Rhee JW, Wu JC. Adult stem cell therapy and heart failure, 2000 to 2016: a systematic review. JAMA Cardiol. 2016; 1:831–841. DOI: 10.1001/jamacardio.2016.2225 [PubMed: 27557438] 6. Rupp S, Jux C, Bönig H, Bauer J, Tonn T, Seifried E, Dimmeler S, Zeiher AM, Schranz D. Intracoronary bone marrow cell application for terminal heart failure in children. Cardiol Young. 2012; 22:558–563. DOI: 10.1017/S1047951112000066 [PubMed: 22329889] 7. Burkhart HM, Qureshi MY, Peral SC, O’Leary PW, Olson TM, Cetta F, Nelson TJ. Wanek Program Clinical Pipeline Group. Regenerative therapy for hypoplastic left heart syndrome: first report of intraoperative intramyocardial injection of autologous umbilical-cord blood-derived cells. J Thorac Cardiovasc Surg. 2015; 149:e35–e37. DOI: 10.1016/j.jtcvs.2014.10.093 [PubMed: 25466856] 8. Tarui S, Ishigami S, Ousaka D, Kasahara S, Ohtsuki S, Sano S, Oh H. Transcoronary infusion of cardiac progenitor cells in hypoplastic left heart syndrome: Three-year follow-up of the Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single-Ventricle Physiology

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(TICAP) trial. J Thorac Cardiovasc Surg. 2015; 150:1198–1207. 1208.e1. DOI: 10.1016/j.jtcvs. 2015.06.076 [PubMed: 26232942] 9. Mishra R, Vijayan K, Colletti EJ, Harrington DA, Matthiesen TS, Simpson D, Goh SK, Walker BL, Almeida-Porada G, Wang D, Backer CL, Dudley SC Jr, Wold LE, Kaushal S. Characterization and functionality of cardiac progenitor cells in congenital heart patients. Circulation. 2011; 123:364– 373. DOI: 10.1161/CIRCULATIONAHA.110.971622 [PubMed: 21242485] 10. Wehman B, Sharma S, Mishra R, Guo Y, Colletti EJ, Kon ZN, Dalta SR, Siddiqui OT, Balachandran K, Kaushal S. Pediatric end-stage failing heart demonstrate increased cardiac stem cells. Ann Thorac Surg. 2015; 100:615–622. DOI: 10.1016/j.athoracsur.2015.04.088 [PubMed: 26138767] 11. 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. DOI: 10.1161/ CIRCRESAHA.110.222703 [PubMed: 20671238] 12. Simpson DL, Mishra R, Sharma S, Goh SK, Deshmukh S, Kaushal S. A strong regenerative ability of cardiac stem cells derived from neonatal hearts. Circulation. 2012; 126:S46–S53. DOI: 10.1161/ CIRCULATIONAHA.111.084699 [PubMed: 22965993] 13. Sharma S, Mishra R, Bigham GE, et al. A deep proteome analysis identifies the complete secretome as the functional unit of human cardiac progenitor cells. Circ Res. 2017; 120:816–834. DOI: 10.1161/CIRCRESAHA.116.309782 [PubMed: 27908912]

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2016

Phase I Safety and Feasibility Study of Intracoronary Delivery of Autologous BMDerived MN Cells

APOLLON (Cardiac Stem/Progenitor Cell Infusion in Univentricular Physiology)

Randomized, controlled phase III

Single treatment group phase I

Randomized, controlled phase I/II

Single treatment group phase I

Randomized, controlled phase II

Nonrandomized, controlled phase I

Design

Japanese Regenerative Medicine Co., Ltd

Mayo Clinic

University of Maryland

University of Miami

University of Oklahoma

Mayo Clinic

Translational Research Informatics Ctr., Kobe

Okayama University

National Cerebral and Cardiovasc. Ctr. (Japan)

Okayama University

Sponsor and Collaborators

JRM-001 (cardiac stem cells)*

BM-Derived MN cells (autologous)

MSC (allogeneic)

UCB-Derived MN cells (autologous)

CPC (autologous)

CPC (autologous)

Cell Type

IC

IC

IM

IM

IC

IC

Route

Stage II or III operation

After stage III (with ventricular dysfunction)

Stage II operation

Stage II operation

Stage II or III operation

Stage II or III operation

Timing

Ongoing

Ongoing

Ongoing

Ongoing

Reported

Reported

Status

A proprietary agent, described as such in the NIH listing. Okayama University is a participating site under the direction of Dr Hidemasa Oh.

*

All data obtained from ClinicalTrials.gov and verified on February 25, 2017. Stages refer to palliative procedures for single ventricle CHD. BM indicates bone marrow; CHD, congenital heart disease; CPC, cardiac progenitor cell; IC, intracoronary; IM, intramyocardial; MN, mononuclear; MSC, mesenchymal stem cell; NIH, National Institutes of Health; and UCB, umbilical cord blood.

2015

ELPIS (Allogeneic hMSC Injection in Patients with Hypoplastic Left Heart Syndrome)

2013

PERSEUS (Cardiac Progenitor Cell Infusion to Treat Univentricular Heart Disease) 2013

2011

TICAP (Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single Ventricle Physiology)

Safety Study of Autologous Umbilical Cord Blood Cells for Treatment of Hypoplastic Left Heart Syndrome

Year

Trial

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Clinical Trials of Stem Cell Therapy for Single Ventricle Hearts

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Table Bittle et al. Page 6

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Clinical Progress in Cell Therapy for Single Ventricle Congenital Heart Disease.

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