Cell therapy is a promising tool to prevent and treat heart failure in congenital heart disease. We report the first case of intramyocardial injection of allogeneic mesenchymal stromal cells as rescue therapy in a neonate with ischemic heart failure following arterial switch procedure for isolated transposition of the great arteries. (Level of Difficulty: Advanced.

Caputo, M

Chen, Q

Iacobazzi, D

Lowdell, MW

Madeddu, P

Rapetto, F

Stoica, SC

Taliotis, D

Ttofi, I

Weil, B

English

UCL Discovery

J A C C : C A S E R E P O R T S V O L . 3 , N O . 5 , 2 0 2 1ª 2 0 2 1 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E AM E R I C A NC O L L E G E O F C A R D I O L O G Y F O U N DA T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E RT H E C C B Y L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y / 4 . 0 / ) .MINI-FOCUS ISSUE: CONGENITAL HEART DISEASECASE REPORT: CLINICAL CASEAllogeneic Mesenchymal StromalCell Injection to Alleviate IschemicHeart Failure Following ArterialSwitch OperationFilippo Rapetto, MD,a,b Demetris Taliotis, MD,c Qiang Chen, MD,a Iakovos Ttofi, MD,a Dominga Iacobazzi, PHD,bPaolo Madeddu, PHD,b Serban C. Stoica, MD,a Ben Weil, ENGD,d Mark W. Lowdell, PHD,d Massimo Caputo, MDa,bABSTRACTLISSFrobTanLoThinsvisMaCell therapy is a promising tool to prevent and treat heart failure in congenital heart disease. We report the first case ofintramyocardial injection of allogeneic mesenchymal stromal cells as rescue therapy in a neonate with ischemic heartfailure following arterial switch procedure for isolated transposition of the great arteries. (Level of Difficulty: Advanced.)(J Am Coll Cardiol Case Rep 2021;3:724–7) © 2021 The Authors. Published by Elsevier on behalf of the AmericanCollege of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).HISTORY OF PRESENTATIONA 3.7-kg male neonate underwent an arterial switchoperation for isolated transposition of the great ar-teries on day 4 of life. Intraoperatively, the left cor-onary artery (LCA) was found to have a longintramural course. The patient developed acute leftventricular (LV) dysfunction after separation fromcardiopulmonary bypass. Refashioning of the LCAEARNING OBJECTIVESTo highlight an uncommon and potentiallyfatal complication of the arterial switchoperation.To illustrate a novel promising application ofcell therapy in patients with CHD.N 2666-0849m the aDepartment of Cardiac Surgery, Bristol Heart Institute and Bristol Rranslational Health Sciences, University of Bristol, Bristol, United Kingdomd Bristol Royal Hospital for Children, Bristol, United Kingdom; and the dCendon NHS Foundation Trust, London, United Kingdom.e authors attest they are in compliance with human studies committetitutions and Food and Drug Administration guidelines, including patienit the Author Center.nuscript received January 27, 2021; accepted February 15, 2021.button was attempted, supplemented by a coronaryartery bypass graft (left internal mammary artery toleft anterior descending coronary artery). Venoarte-rial extracorporeal membrane oxygenation wasinstituted before transferring the patient to theintensive care unit and successfully discontinued onpost-operative day 6.MEDICAL HISTORYThe patient had been born at 39 þ 2 weeks of gesta-tion by normal vaginal delivery and had developedoxygen desaturation (50% despite fraction of inspiredoxygen of 100%) and hypotension (mean arterialblood pressure of 25 mm Hg) at 6 h of life. He had thenbeen diagnosed with transposition of the great ar-teries with intact ventricular septum. Percutaneoushttps://doi.org/10.1016/j.jaccas.2021.02.039oyal Hospital for Children, Bristol, United Kingdom;; cDepartment of Cardiology, Bristol Heart Institutentre for Cell, Gene & Tissue Therapeutics, Royal Freees and animal welfare regulations of the authors’t consent where appropriate. For more information,AB BR E V I A T I O N SAND ACRONYM SCHD = congenital heart diseaseFAC = fractional area changeGLS = global longitudinalstrainLCA = left coronary arteryLV = left ventricularMSC = mesenchymal stromalcellJ A C C : C A S E R E P O R T S , V O L . 3 , N O . 5 , 2 0 2 1 Rapetto et al.M A Y 2 0 2 1 : 7 2 4 – 7 Cell Therapy Following Arterial Switch725balloon atrial septostomy had been undertaken andsurgery had been planned.DIFFERENTIAL DIAGNOSISAcute intraoperative heart failure during the arterialswitch operation is virtually always caused bymyocardial ischemia related to suboptimal coronarytransfer. Severe pulmonary vascular disease is anuncommon cause of right ventricular failure, whichwas not the case in this patient, who had isolated LVdysfunction.INVESTIGATIONSCoronary angiography on post-operative day 2showed LCA and internal mammary artery occlusion.Angiography was repeated on post-operative day 50,confirming the LCA occlusion and demonstrating onlymodest collateral circulation from the right coronaryartery (Video 1). Serial transthoracic echocardiogramswere obtained post-operatively to assess the evolu-tion of LV function (Figure 1).MANAGEMENTOver the first 2 post-operative months, the patientdeveloped inotrope- and ventilator-dependent LVsystolic dysfunction, with failure to thrive and echo-cardiographic signs of anterolateral LV ischemicinjury, including anterior wall akinesia, a smallanterior wall LV aneurysm, and basal to mid anteriorwall hyperechogenicity.The patient was deemed suitable for intra-myocardial injection of allogeneic mesenchymalstromal cells (MSCs). The treatment was approved ona compassionate basis by the University HospitalBristol and Weston NHS Foundation Trust.The Centre for Cell, Gene and Tissue Therapeutics(Royal Free Hospital, University College London) pro-vided pharmaceutical-grade MSCs. The MSCs werederived from a single umbilical cord, supplied by theAnthony Nolan Cord Blood Bank from a registeredvolunteer cord blood donor procured under HumanTissueAuthority license.Umbilical cord tissue-derivedMSCs were isolated by plastic adherence, expanded,and cryopreserved until the day of administration;they were tested for purity (following InternationalSociety for Cellular Therapy criteria [1]), sterility, andendotoxin. The drug product was prescribed, manu-factured, and supplied as an unlicensed medicinalproduct (special) in accordance with U.K. law.MSC injection was undertaken on post-operative day 60. The anterolateral LV wall wasaccessed via a small left anterior thoracotomy. Thetarget dose of 3 million cells/kg body weightwas administered with 4 separate sub-epicardial injections following a techniquepreviously used in patients with hypoplasticleft heart syndrome (HLHS) (2). The patientwas extubated and weaned from all intrave-nous inotropes 16 and 77 days after MSC in-jection, respectively. He was dischargedhome 97 days after the procedure on oralheart failure therapy and remained clinicallystable.LV ejection fraction was 58% after extracorporealmembrane oxygenation discontinuation and haddeteriorated to 23% at MSC injection despite inotropicsupport. After MSC injection, LV function was moni-tored mainly with LV fractional area change and LVglobal longitudinal strain. Videos 2 and 3 show cor-responding views of pre-injection and pre-dischargetransthoracic echocardiograms, respectively. Clinicalcourse and LV function changes after MSC injectionare summarized in Figure 1.DISCUSSIONCoronary artery abnormalities remain a surgicalchallenge when performing the arterial switch oper-ation, increasing surgical morbidity and mortalitybecause of myocardial ischemic injury (3).Cell therapy can be delivered in different waysaccording to 3 main parameters. First, a cell type mustbe selected. To date, umbilical cord cells, peripheralblood or bone marrow–derived mononuclear cells,cardiac stem cells, and MSCs have been used clini-cally in congenital heart disease (CHD). MSCs can beeasily isolated from different tissues and expandedin vitro, have intrinsic differentiation potential, andshow marked modulatory properties that are thoughtto enhance the host’s regenerative processes, whichis believed to be more important than the MSCexpansion itself. It is known that MSCs can stimulaterecovery from cardiac injury through paracrine ac-tivity, promoting reduction of fibrosis, neo-vascularization, immunomodulation, and stimulationof endogenous tissue regeneration (4).Second, the selected cells can be of autologous orallogeneic origin. The main theoretical advantage ofautologous cells is their immunologic compatibility;nevertheless, there is little evidence that allogeneicMSCs, which express low levels of major histocom-patibility complex class I and lack major histocom-patibility complex class II antigens, inducealloantibodies. In contrast, the immediate availabilityof allogeneic cells renders them more feasible in anFIGURE 1 Clinical Events and LV Function(A) Hospital course and (B) evolution of left ventricular (LV) function after intramyocardial mesenchymal stromal cell (MSC) injection topalliate ischemic heart failure following arterial switch operation. The blue line on the plot represents LV global longitudinal strain, and thered line represents LV fractional area change measured by transthoracic echocardiography. ECMO ¼ extracorporeal membrane oxygenation.Rapetto et al. J A C C : C A S E R E P O R T S , V O L . 3 , N O . 5 , 2 0 2 1Cell Therapy Following Arterial Switch M A Y 2 0 2 1 : 7 2 4 – 7726urgent setting. Moreover, the recent POSEIDON-DCM(Percutaneous Stem Cell Injection Delivery Effects onNeomyogenesis in Dilated Cardiomyopathy) ran-domized trial showed superiority of allogeneic MSCsover autologous MSCs in an adult cohort of patientswith dilated cardiomyopathy, possibly due to bettermodulatory properties (5).Third, the route of delivery must be chosen; todate, intramyocardial and intracoronary administra-tion have been undertaken clinically (6).Cell therapy has been used in preclinical models ofCHD and showed initial promising results in patientswith hypoplastic left heart syndrome (2,7–9). To thebest of our knowledge, this is the first report of suc-cessful use of allogeneic MSCs for inotrope- andventilator-dependent ischemic heart failure followingarterial switch operation. Our choice to use allogeneiccells was driven mainly by the urgent scenario;intramyocardial delivery was dictated by the occlu-sion of the LCA.MSC injection does not resolve the culprit coro-nary lesion, and the exact mechanism of action inthis particular patient cannot be precisely demon-strated. However, we observed a correlation betweenMSC injection and the patient’s clinical improve-ment; the rationale behind this specific application isthat boosts of MSCs may aid the ischemic myocar-dium, thanks to their acknowledged proangiogenicactivity.FOLLOW-UPOne year after arterial switch, the patient remains onoral heart failure therapy with no clinical signs ofongoing myocardial ischemia, and he has beengrowing along the ninth weight centile. LV function ismildly impaired (Figure 1).CONCLUSIONSCell therapy is an emerging therapeutic strategy inpatients with CHD. Its medium- and long-term resultsare not known, and further studies are needed todelineate potential candidates and outcomes in thepediatric population.ACKNOWLEDGMENTS The authors thank Dr. OwenBain and Dr. Rita Rego for their roles in getting theproduct to the patient in time for treatment.FUNDING SUPPORT AND AUTHOR DISCLOSURESThis work was funded by the British Heart Foundation, the Sir JulesThorn Award for Biomedical Research, and the Enid Linder Founda-tion. The authors have reported that they have no relationshipsrelevant to the contents of this paper to disclose.ADDRESS FOR CORRESPONDENCE: Dr. FilippoRapetto, Bristol Heart Institute, Upper MaudlinStreet, Bristol BS2 8HW, United Kingdom. E-mail:filippo.rapetto@gmail.com.J A C C : C A S E R E P O R T S , V O L . 3 , N O . 5 , 2 0 2 1 Rapetto et al.M A Y 2 0 2 1 : 7 2 4 – 7 Cell Therapy Following Arterial Switch727RE F E RENCE S1. Dominici M, Le Blanc K, Mueller I, et al. Minimalcriteria for defining multipotent mesenchymalstromal cells. The International Society for CellularTherapy position statement. Cytotherapy 2006;8:315–7.2. Burkhart HM, Qureshi MY, Rossano JW, et al.Autologous stem cell therapy for hypoplastic leftheart syndrome: safety and feasibility of intra-operative intramyocardial injections. J ThoracCardiovasc Surg 2019;158:1614–23.3. Kouchoukos NT, Blackstone EH, Hanley FL,Kirklin JK, Complete transposition of the greatarteries. In: Cardiac Surgery. 4th ed. Philadelphia:Elsevier Saunders, 2013:1855–930.4. Pittenger MF, Discher DE, Péault BM,Phinney DG, Hare JM, Caplan AI. Mesenchymalstem cell perspective: cell biology to clinicalprogress. NPJ Regen Med 2019;4:22.5. Hare JM, DiFede DL, Rieger AC, et al. Ran-domized comparison of allogeneic versus autolo-gous mesenchymal stem cells for nonischemicdilated cardiomyopathy: POSEIDON-DCM trial.J Am Coll Cardiol 2017;69:526–37.6. Tsilimigras DI, Oikonomou EK, Moris D,Schizas D, Economopoulos KP, Mylonas KS. Stemcell therapy for congenital heart disease: a sys-tematic review. Circulation 2017;136:2373–85.7. Rupp S, Zeiher AM, Dimmeler S, et al.A regenerative strategy for heart failure in hypo-plastic left heart syndrome: intracoronary admin-istration of autologous bone marrow-derivedprogenitor cells. J Heart Lung Transplant 2010;29:574–7.8. Tarui S, Ishigami S, Ousaka D, et al. Trans-coronary infusion of cardiac progenitor cells inhypoplastic left heart syndrome: three-yearfollow-up of the Transcoronary Infusion ofCardiac Progenitor Cells in Patients With Single-Ventricle Physiology (TICAP) trial. J Thorac Car-diovasc Surg 2015;150:1198–208. e2.9. Ishigami S, Ohtsuki S, Eitoku T, et al. Intra-coronary cardiac progenitor cells in singleventricle physiology: the PERSEUS (Cardiac Pro-genitor Cell Infusion to Treat Univentricular HeartDisease) randomized phase 2 trial. Circ Res 2017;120:1162–73.KEY WORDS acute heart failure, coronaryvessel anomaly, transposition of the greatarteriesAPPENDIX For supplemental videos,please see the online version of this paper.

Allogeneic Mesenchymal Stromal Cell Injection to Alleviate Ischemic Heart Failure Following Arterial Switch Operation.

https://discovery.ucl.ac.uk/10129756/1/1-s2.0-S2666084921002242-main.pdf

Allogeneic Mesenchymal Stromal Cell Injection to Alleviate Ischemic Heart Failure Following Arterial Switch Operation.

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