Ann Thorac Surg 2007;83:661-662
© 2007 The Society of Thoracic Surgeons
Case Reports
Cardiac Resurrection After Bone-Marrow-Derived Mononuclear Cell Transplantation During Left Ventricular Assist Device Support
Satoshi Gojo, MD, PhDa,*,
Shunei Kyo, MD, PhDa,b,
Shigeyuki Nishimura, MD, PhDc,
Nobuyuki Komiyama, MD, PhDc,
Nobutaka Kawai, MD, PhDd,
Masami Bessho, MD, PhDd,
Hiroshige Sato, MD, PhDa,
Toshihisa Asakura, MD, PhDa,
Motonobu Nishimura, MD, PhDb,
Kenji Ikebuchi, MD, PhDe
a Department of Cardiovascular Surgery, Saitama Medical Center, Saitama, Japan
b Department of Cardiovascular Surgery, Saitama Medical School, Saitama, Japan
c Department of Cardiology, Saitama Medical School, Saitama, Japan
d Department of Hematology, Saitama Medical School, Saitama, Japan
e Department of Transfusion and Cell Therapy, Saitama Medical School, Saitama, Japan
Accepted for publication June 23, 2006.
* Address correspondence to Dr Gojo, Department of Cardiovascular Surgery, Saitama Medical Center 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan. (Email: satoshi{at}saitama-med.ac.jp).
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Abstract
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We describe a novel therapy of mononuclear cell transplantation combined with a left ventricular assist device (LVAD) for severe ischemic heart failure. Significant myocardial recovery by the LVAD rarely occurs in the severely failing heart. We undertook successful mononuclear cell transplantation in a patient who sustained an acute myocardial infarction that had resulted in the LVAD therapy. The heart regained good function after cell transplantation, and the LVAD was explanted 6 weeks later. These results suggest that this novel therapy could be an alternative to cardiac transplantation for severe ischemic heart failure.
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Introduction
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The discovery of pluripotent stem cells in an adult has opened a novel clinical research field, regenerative medicine [1]. Many studies have demonstrated that bone-marrow-derived progenitor cells can differentiate into cardiomyocytes and endothelial cells, and they can be involved in repairing injured hearts [2]. Several clinical trials of autologous bone-marrow-derived mononuclear cell transplantation after acute myocardial infarction revealed the steady improvement in cardiac function [3]. We report a successful myocardial recovery with mononuclear cell transplantation and left ventricular assist device (LVAD) support after cardiogenic shock due to acute myocardial infarction.
A 61-year-old man who had diabetes mellitus was transferred in a shock state due to acute myocardial infarction. Emergency cardiac catheterization demonstrated the diagnosis of complete occlusion of the #7 left anterior descending artery (LAD) and 90% stenosis of the #2 right coronary artery (RCA). The culprit lesion, #7LAD, was not eligible for percutaneous coronary intervention because the wire could not cross it. Thereafter, the patient’s shock state was worse, and percutaneous cardiopulmonary support was initiated.
Despite maximum pharmacologic support, the patient lapsed into multiple organ failure. The decision was made implant a Toyobo LVAD (Toyobo, Inc, Osaka, Japan), and simultaneously perform a coronary artery bypass graft to the LAD and RCA with saphenous veins.
The status of multiple organ failure was gradually improved, but an ejection fraction (EF) by echocardiography was 0.13 on day 97 after LVAD implantation (Fig 1). Scintigraphy demonstrated complete infarctions in the anteroseptal and inferior walls (Fig 2). The patient was briefed in detail about mononuclear cell transplantation. This clinical study had been approved by the Ethics Committee of the Saitama Medical School, Saitama, Japan.
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Fig 1. Left ventricular ejection fraction (EF) in transthoracic echocardiography. After left ventricular assist system (LVAS) implantation, the first evaluation showed an EF of 6.4%. In the time course under LVAS support, EF gradually improved, but the value began decreasing 2 months later. (POD = postoperative day; CABG = coronary artery bypass grafting; MNCs = mononuclear cells; LVAD = left ventricular assist device.)
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Fig 2. Technetium (Tc 99m)-tetrofosmin-gated single photon emission computed tomography. (Upper panels) Thirty-seven days after left ventricular assist device (LVAD) implantation and two coronary artery bypass grafts. (Middle panels) Twenty-nine days after mononuclear cell transplantation. (Lower panels) Twenty-five days after LVAD explantation (57 days after mononuclear cell transplantation).
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Bone marrow (600 mL) was aspirated under general anesthesia from both posterior ilia and enriched to the mononuclear cell fraction. The mononuclear cells were implanted in the infarcted zone through the saphenous grafts to the LAD and RCA on day 99 after LVAD implantation. During the procedure, the electrocardiogram was monitored and did not demonstrate any significant changes to suggest ischemic events. The possibility of microemboli was also negative on the basis of the stable normal values for creatine kinase-MB fraction and troponin-T after the procedure.
The patient’s cardiac function became gradually better with time after the cell transplantation. The LVAD was removed on day 43 after mononuclear cell transplantation. The EF increased from 0.064 to .40 and remained stable, as assessed by echocardiography. Analysis of LV function by scintigraphy demonstrated a sustained improvement in blood perfusion and regional EF in the apical and inferior walls and growing thickness of the septal and inferior walls in the time course (Fig 2). The patient was discharged 58 days after explantation of the LVAD. After mononuclear cell transplantation, there were no complications, including acute inflammatory response, novel infarction, malignant arrhythmias, or ectopic differentiation.
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Comment
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Our aim was to extend the target of cell transplantation from the mild to the severely failing heart. The requirements were (1) a donor cell type, (2) an implantation procedure, including duration, route, and targets for cell delivery, and (3) a timing of cell transplantation after LVAD implantation. We chose bone-marrow-derived mononuclear cells to contain all of the cell fractions because (1) there is a controversy about the cell source to be grafted, (2) nobody can deny the possibility that the enrichment procedure will cause the useful cell population to be lost based on the current experimental data, and (3) pure, dense stem cells in a site might induce an ectopic differentiation.
As a grafting route, an antegrade intracoronary infusion through the saphenous vein grafts was chosen to avoid the isolated islet-like formation of grafted cells by direct injection into the myocardium, which could not effectively induce neogenesis of either cardiomyocytes or coronary capillaries.
The final important issue of the protocol was the timing of the cell transplantation after LVAD implantation. Although the LVAD improves cardiac milieu interne in the early phase, long-term LVAD support induces ventricular atrophy so that the LVAD is a double-edged sword. We had been examining EF, LV wall thickness, and motions by echocardiography. Because the decline of EF commenced on day 72 after LVAD implantation, we judged that the global effects of LVAD for cardiac recovery had turned from benefits to drawbacks and performed mononuclear cell transplantation on day 99 after LVAD implantation.
The structural and functional improvements in last scintigraphy compared with that 1 month after mononuclear cell transplantation suggest that the cells engrafted, survived, and functioned in recipient heart. Grafted mononuclear cells release a wide array of cytokines related to the regeneration process. Mononuclear cell transplantation might stimulate the native environment to promote angiogenesis and cardiomyogenesis through the paracrine fashion in addition to vasculogenesis by the mononuclear cells themselves.
Many reports demonstrated that the LVAD support could induce reverse remodeling. In addition to relief of myocardium from the mechanical stretch of LVAD, the reverse remodeling of diseased heart could facilitate the engraftment, survival, and differentiation process of the grafted cells. Taken together, we think that mononuclear cell transplantation could fully work to repair the end-stage failing heart under the resting state created by LVAD support. This synergy effect of mononuclear cell transplantation and LVAD could be an explanation of this cardiac resurrection.
In conclusion, mononuclear cell transplantation for the treatment of ischemic cardiomyopathy with LVAD led to successful recovery of the failing heart and the LVAD to be unnecessary. We believe that this combination therapy might be an alternative to cardiac transplantation in the treatment of ischemic end-stage heart failure.
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Acknowledgments
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This work was supported in part by a Research Grant for Cardiovascular Diseases (16C-6) from the Ministry of Health, Labour and Welfare.
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References
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- Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells Science 1999;284:143-147.[Abstract/Free Full Text]
- Gojo S, Umezawa A. Plasticity of mesenchymal stem cells—regenerative medicine for diseased hearts Hum Cell 2003;16:23-30.[Medline]
- 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.[Medline]
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Abstract
Introduction
