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J Thorac Cardiovasc Surg 2007;134:1347-1349
© 2007 The American Association for Thoracic Surgery

Brief Communication

Long-term efficacy and safety of the intramyocardial implantation of autologous bone marrow cells for the treatment of ischemic heart disease

Department of Surgery and Clinical Science, Division of Cardiovascular Surgery, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.

Received for publication May 28, 2007; revisions received June 19, 2007; accepted for publication July 12, 2007.

^_* Address for reprints: Kimikazu Hamano, MD, PhD, Department of Surgery and Clinical Science, Division of Cardiovascular Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, Japan 755-8505. (Email: litaoshe{at}yamaguchi-u.ac.jp).

The delivery of autologous bone marrow–derived cells has developed as a revolutionary concept for repairing the injured heart,¹ and many clinical trials have been conducted all over the world. Although there are conflicting reports about the beneficial effects of bone marrow cells for myocardial repair,² early- and middle-phase clinical trials have not found any severe side effects of cell-based therapy. However, its long-term safety and feasibility have not yet been established. We report the results of more than 5 years’ follow-up of patients treated with the intramyocardial injection of autologous bone marrow mononuclear cells (BM-MNCs) after coronary artery bypass grafting (CABG).

Clinical Summary

Between November 1999 and March 2002, 8 selected patients undergoing standard CABG were given an intramyocardial injection of BM-MNCs into the ungrafted ischemic area (Table 1). The collection and separation of BM-MNCs was detailed previously.¹ After the completion of CABG, 322 x 10⁸ BM-MNCs were injected directly, with 622 injections, into the targeted area, where there was no indication for CABG or intervention therapy (Figure 1). To determine the safety and feasibility of this therapy, we monitored the patients with blood tests (white blood cell count, hemoglobin, C-reactive protein, glutamic oxaloacetic transminase, glutamic pyruvic transaminase, blood urea nitrogen, creatinine, creatine phosphokinase, and creatine phosphokinase-MB isoenzyme) and electrocardiograms 1, 3, 7, 14, and 30 days after treatment in the acute phase and then 3, 6, 12, 24, 36, and 60 months after treatment in the chronic phase. Furthermore, echocardiography, single photon emission computed tomography myocardial perfusion scintigraphy, Holter echocardiography, chest radiography, and cardiac computed tomography were performed 1, 6, 12, 24, 36, and 60 months after treatment.

View larger version (97K): [in this window] [in a new window]   Figure 1. Procedure used for the intramyocardial injection of bone marrow mononuclear cells. A, Image of the target zone of cell injection. B, The volume was 0.1 mL per injection. Injections were spaced about 1 cm apart and given via a 1-mL syringe and a 26-gauge needle.

As we¹ reported previously, the serum levels of C-reactive protein, blood urea nitrogen, creatinine, aspartate aminotransferase, glutamic pyruvic transaminase, creatine kinase, and creatine kinase MB at the acute phase did not increase significantly compared with those in patients who underwent CABG alone in our institution during the same period. No anemia, leukocytopenia, or any other sign of hemopoietic abnormality was found in any patient by 1, 2, 3, and 5 years’ follow-up blood tests. A Holter electrocardiogram showed no new-onset malignant arrhythmias within 5 years after the intramyocardial injection of BM-MNCs, although premature ventricular contraction was recorded 1 year (3 couplets/24 hours) and 3 years (1 couplets/24 hours) after treatment in 1 patient (patient 7), who had had premature ventricular contraction before treatment. No sign of atopic tissue formation, including hematoma, teratogenic tumor, or bone, was detected in the myocardium on chest radiographic, echocardiographic, or cardiac computed tomographic scanning in any patient during the 5 years of follow-up.

Discussion

Our long-term follow-up examinations, carried out for more than 5 years, indicated that the intramyocardial injection of freshly collected autologous BM-MNCs had minimal, if any, systemic or local influences. However, it is possible that some latent adverse effects related to the cell therapy may not have been detected because of the scheduled timing of our follow-up examinations and their limited terms and sensitivity. Furthermore, we must investigate continuously the most disputed side effects of BM-MNCs, which consist of heterogeneous cell fractions, including mature blood cells and immature stem cells.

First, multiple cytokines, including some inflammatory cytokines, are released from the implanted BM-MNCs.³ Some of these BM-MNCs will die soon after implantation because of their short life span or the ischemic microenvironment. Thus, there is a possibility that the injection of BM-MNCs into ischemic myocardium could trigger a local and systemic inflammatory response, which may result in myocardial edema, myocarditis, or other myocardial damage. Fortunately, we detected no evidence of inflammatory response or myocardial damage after the delivery of up to about 2 x 10⁹ BM-MNCs in this clinical trial. It is unknown whether a severe inflammatory response would be evoked by implanting a greater number of BM-MNCs.

The second major concern relates to the possible formation of atopic tissue in the myocardium. As the hematopoietic, mesenchymal, and other pluripotential stem cells in BM-MNCs can propagate and differentiate into mature blood cells, osteoblasts, chondrocytes, and other types of cells,⁴ it is possible that a hematoma,⁵ teratogenic tumor, bone, or other atopic tissue could form in the heart after the intramyocardial injection of BM-MNCs. However, 5 years of follow-up examinations did not reveal any evidence of mass formation, calcification, or other abnormal signs. Moreover, unlike myoblasts, the intramyocardial implantation of BM-MNCs did not trigger malignant arrhythmias in our patients, in accordance with the findings of other early or middle-phase clinical trials.

Although further extended clinical trials are required to confirm its effectiveness, the intramyocardial implantation of BM-MNCs appears to be a safe and feasible treatment for ischemic heart diseases.

References

1. Li TS, Hamano K, Hirata K, Kobayashi T, Nishida M. The safety and feasibility of the local implantation of autologous bone marrow cells for ischemic heart disease. J Card Surg 2003;18(Suppl 2):S69-S75.[Medline]
   
2. Rosenzweig A. Cardiac cell therapy—mixed results from mixed cells. N Engl J Med 2006;355:1274-1277.[Medline]
   
3. Kamihata H, Matsubara H, Nishiue T, Fujiyama S, Tsutsumi Y, Ozono R, et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 2001;104:1046-1052.[Abstract/Free Full Text]
   
4. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41-49.[Medline]
   
5. Kawamoto A, Iwasaki H, Kusano K, Murayama T, Oyamada A, Silver M, et al. CD34-positive cells exhibit increased potency and safety for therapeutic neovascularization after myocardial infarction compared with total mononuclear cells. Circulation 2006;114:2163-2169.[Abstract/Free Full Text]
   

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Bungo Shirasawa Kimikazu Hamano Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, T.-S. Articles by Hamano, K. Search for Related Content PubMed Articles by Li, T.-S. Articles by Hamano, K. Related Collections Transplantation - heart