CORRESPONDENCE: RESEARCH CORRESPONDENCE
Percutaneous Intracoronary Cellular Cardiomyoplasty for Nonischemic Cardiomyopathy: Clinical and Histopathological Results
The First-in-Man ABCD (Autologous Bone Marrow Cells in Dilated Cardiomyopathy) Trial
Sandeep Seth, MD, DM*,
Rajiv Narang, MD, DM,
Balram Bhargava, MD, DM, FACC,
Ruma Ray, MD, MRCPath,
Sujata Mohanty, PhD,
Gurpreet Gulati, MD,
Lalit Kumar, MD,
K. Srinath Reddy, MD, DM,
Panangipalli Venugopal, MS, MCh AIIMS Cardiovascular Stem Cell Study Group
* Department of Cardiology, Cardiothoracic Sciences Center, All India Institute of Medical Sciences, New Delhi, 110029, India (Email: drsandeepseth{at}hotmail.com).
To the Editor: Stem cell therapy has shown potential benefit in heart failure caused by ischemic heart disease (1). There is no data on the role of stem cell therapy in nonischemic dilated cardiomyopathy. We undertook a pilot study of intracoronary stem cell implantation in patients with dilated cardiomyopathy.
From a cohort of 44 patients, 24 were randomly allocated to the stem cell therapy arm and 20 to the control arm. All patients were having dilated cardiomyopathy with an ejection fraction (EF) of  35%, were New York Heart Association (NYHA) functional class II or more symptomatic for more than 6 months, had normal coronary arteries, and had no other comorbidities such as chronic renal or liver failure or any malignancy.
Patients in the treatment arm underwent bone marrow aspiration (50 to 60 ml) from the iliac crest. Mononuclear cells were separated from the bone marrow using Ficoll density gradient separation. The mononuclear cells constituted 89 ± 2% of the cells, were 28 ± 16 million /ml, and CD 34+ cells were 1.6 million/ml. The viability of these cells was 99 ± 1%. The patients then underwent right heart catheterization and endomyocardial biopsy from the right side of the interventricular septum. The coronary sinus was then engaged using a Swan-Ganz catheter (Arrow International, Reading, Pennsylvania) that was passed up the coronary sinus, and the balloon was inflated. This was done so that the coronary circulation was slowed and the stem cells would get more time to transmigrate into the myocardium. Once the coronary sinus catheter was inflated, the stem cells were slowly injected into the coronary arteries by hooking the arteries with a Judkins catheter. Two-thirds of the mononuclear cell concentrate was injected into the left coronary artery and one-third was injected into the right coronary artery. The coronary sinus balloon was kept inflated for 3 min during the intracoronary injection. The patients were kept under monitoring for 24 h with electrocardiographic monitoring and serial cardiac enzymes. Follow-up was done at 1 week, 1 month, and then every 3 months for 1 year. At 3 months, Holter monitoring, an echocardiogram, and an endomyocardial biopsy were repeated. An echocardiogram was also repeated at 1 year. Left ventricular function assessment was performed offline by the modified Simpson method by 2 observers blinded to the underlying treatment. All patients were on the maximum tolerated doses of angiotensin-converting enzyme inhibitors and beta-blockers. Diuretic doses (including frusemide and torsemide, and spironolactone) were adjusted to ensure the absence of pedal edema. Informed consent was obtained from all patients, including control patients. The end points of the study were: 1) change in NYHA functional class, 2) a change in left ventricular function, 3) mortality, and 4) endomyocardial biopsy and histopathologic evaluation.
Continuous variables were compared by a Wilcoxon 2-sample test (for within-group differences) and the Mann-Whitney U test (between-group differences). Differences in mortality and change in functional class between the 2 groups were compared by the Fisher exact test. A value of p < 0.05 was considered statistically significant. All analyses were performed with SPSS for Windows (version 10.0.1, 1999, SPSS Inc., Chicago, Illinois).
The data of the analysis at 6 months are presented. Four patients died between 1 and 3 months in the treatment arm. Three died of progressive heart failure and 1 experienced sudden cardiac death. The mortality was not significantly different (p value not significant) between the treatment and control (2 patients died) arms.
There was a significant improvement (p < 0.001) in NYHA functional class in the treatment arm, with 16 patients (62%) improving by at least 1 functional class, as compared with only 2 patients (10%) improving in the control arm.
The EF improved by 5.4% (20 ± 7.4% to 25 ± 12%, p < 0.05) (Fig. 1) with a reduction in end-systolic volumes (144 ± 85 ml to 116 ± 68 ml, p < 0.05) and no change in end-diastolic volumes. None of the patients who were functional class IV and had recently required inotropic infusions showed any improvement. There was no significant improvement in the EF in the control arm (baseline EF = 16 ± 5.4% to final EF = 16 ± 4.7%).
Endomyocardial biopsy was performed at 3 months. Histopathology revealed no evidence of persisting stem cells, no evidence of any new immature myocytes, and also no evidence of any inflammation, infarction, or neovascularization.
Two patients had scattered binucleate cells and evidence of cell proliferation (Ki 67/MIB 1 [M7240; Dako stain positive cells, Dako, Glostrup, Denmark]). Morphometric analysis (Image Pro Plus software with 20x magnification, version 4.1, 1999, Media Cybernetics Inc., Silver Spring, Maryland) showed no change in the absolute number of myocytes (457 ± 210 cells/mm2 [before] and 340 ± 150 cells/mm2 [after]). There was also no change in the number of capillary endothelial cells (stained by CD34 class II, 696 ± 206 cells/mm2 [before] and 569 ± 150 cells/mm2 [after]). The ratio of capillaries to myocytes showed an increase, but it was not significant (1.7 ± 0.7 to 1.9 ± 0.8). There was no significant difference between the mortality in the treatment (16.7%) and control (10%) arms. In the control group, 2 patients died. There was no significant change in functional class or left ventricular function in this group.
In summary, 24 patients underwent intracoronary stem cell injection with coronary sinus blockage. Four patients died during the 6-month follow-up. Overall EF showed a small but significant improvement of 5.4%. There was a decrease in end-systolic volumes, but no change in end-diastolic volumes. Endomyocardial biopsy done at 3 months showed no significant change in the number of myocytes or capillaries, but the ratio of capillaries to myocytes showed an insignificant increase. There were soft data to suggest cell proliferation (binucleate cells and Ki 67 positivity).
This is the first study of stem cell therapy in dilated nonischemic cardiomyopathy. Over a 6-month period, there was a small albeit significant improvement in ventricular function. Previous clinical studies have also shown a small degree of change in ventricular function of a similar magnitude (1,2). Laboratory experiments in nonischemic dilated cardiomyopathy (3) have previously suggested that benefit from stem cell therapy in this group comes mainly from a decrease in fibrosis and an increase in vascularity, but no evidence has been found supporting transdifferentiation of stem cells to myocytes. Our data also suggest that the benefit of stem cell therapy could be a paracrine effect with changes in vascularity, perhaps stimulation of cell proliferation, or by some still-unexplored mechanism. We did not find any evidence of transdifferentiation.
In this study we wish to highlight a number of issues. It is the first study to show the benefit of stem cells in nonischemic dilated cardiomyopathy, and the first study that uses coronary sinus occlusion to increase cell contact time. It is also the first study in which we have endomyocardial biopsies performed after stem cell therapy.
It provides a stimulus for exploring the benefits of stem cell therapy in nonischemic dilated cardiomyopathy. A double-blind study is being planned to further explore the benefit seen in this preliminary study. The small magnitude of benefit could perhaps be because all patients in this study were in very late stages of their cardiomyopathy, and we probably need to consider stem cell therapy at a much earlier stage. Endomyocardial biopsy, performed for the first time in stem cell therapy, shows no evidence of transdifferentiation of stem cells to myocytes but provides soft data pointing to a possible paracrine effect.
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Footnotes
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Please note: supported by the research funds of the All India Institute of Medical Sciences (AIIMS) under the Stem Cell Research Program. AIIMS Cardiovascular Stem Cell Study Group: S. Seth, R. Narang, B. Bhargava, S. Mohanty, R. Ray, G. Gulati, K. Kumawat, N. Parakh, A. K. Bisoi, N. Naik, R. Yadav, K. Lalit, B. Airan, S. Sharma, K. S. Reddy, P. Venugopal.
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References
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1. Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium Nature 2001;410:701-705.[CrossRef][Medline]2. Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans Circulation 2002;106:1913-1918.[Abstract/Free Full Text] 3. Nagaya N, Kangawa K, Itoh T, et al. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy Circulation 2005;112:1128-1135.[Abstract/Free Full Text]
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