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J Am Coll Cardiol, 2005; 46:1651-1658, doi:10.1016/j.jacc.2005.01.069 © 2005 by the American College of Cardiology Foundation |
* Department of Internal Medicine, Division of Cardiology, Pneumology and Angiology, Heinrich-Heine-University, Düsseldorf, Germany
Department of Nuclear Medicine, Heinrich-Heine-University, Düsseldorf, Germany
Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine-University, Düsseldorf, Germany
Manuscript received October 31, 2004; revised manuscript received December 13, 2004, accepted January 25, 2005.
* Reprint requests and correspondence: Dr. Bodo E. Strauer, Head of Department of Medicine, Division of Cardiology, Pneumology, and Angiology, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany. (Email: strauer{at}med.uni-duesseldorf.de).
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Abstract |
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BACKGROUND: After acute MI, bone marrow-derived cells improve cardiac function.
METHODS: We treated 18 consecutive patients with chronic MI (5 months to 8.5 years old) by the intracoronary transplantation of autologous bone marrow mononuclear cells and compared them with a representative control group without cell therapy.
RESULTS: After three months, in the transplantation group, infarct size was reduced by 30% and global left ventricular ejection fraction (+15%) and infarction wall movement velocity (+57%) increased significantly, whereas in the control group no significant changes were observed in infarct size, left ventricular ejection fraction, or wall movement velocity of infarcted area. Percutaneous transluminal coronary angioplasty alone had no effect on left ventricular function. After bone marrow cell transplantation, there was an improvement of maximum oxygen uptake (VO2max, +11%) and of regional 18F-fluor-desoxy-glucose uptake into infarct tissue (+15%).
CONCLUSIONS: These results demonstrate that functional and metabolic regeneration of infarcted and chronically avital tissue can be realized in humans by bone marrow mononuclear cell transplantation.
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Experimental (4) and clinical (5,6) studies have shown recently for the first time that bone marrow mononuclear cells (BMCs) may regenerate damaged myocardium in acute MI in humans. Because the regenerative potential of bone marrow-derived cells ought also to be expected to exist in chronically ischemic heart disease as well (7–12), we have assembled in an ongoing clinical investigation 18 patients with chronic MI to prove this new therapeutic possibility.
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The cell-treated patients had stable ventricular dynamics for infarct size, ejection fraction, and wall movement velocity of infarcted area at least 9 ± 6 months before cell transplantation. Infarct size at the time of cell therapy showed an amount of 27 ± 8% of the circumference of the left ventricle (LV), determined by ventriculography.
Preparation of BMCs. One day before cell therapy, bone marrow was taken (80 ml from the iliac crest) and mononuclear cells were isolated and identified including CD34-positive cells, AC133-positive cells and CD45/CD14 negative cells (6). The cells were isolated under good manufacturing practice conditions by Ficoll density separation on Lymphocyte Separation Medium (Bio Whittaker, Walkersville, Maryland), before the residual erythrocytes were lysed with H2O. For overnight cultivation, 1 x 106 BMCs/ml were placed in Teflon bags (Vuelife, Cell Genix, Gaithersburg, Maryland) and cultivated in X-Vivo 15 Medium (Bio Whittaker) supplemented with 2% heat-inactivated autologous plasma. The next day, BMCs were harvested and washed three times with heparinized saline before final resuspension in heparinized saline. Viability was 93 ± 3%. Heparinization and filtration (cell strainer, FALCON) was carried out to prevent cell clotting and microembolization during intracoronary transplantation. These cells were used for therapy. All microbiologic tests of the clinically used cell preparations proved negative. All patients received extensive information about the procedure, which was approved by the ethical committee of our university, and all gave written informed consent.
Administration of BMCs. Following assessment of baseline examinations (coronary angiography, left ventriculography, spiroergometry, 99mTc-tetrofosmin single-photon emission computed tomography (SPECT) and 18F-fluor-deoxy-glucose (18F-FDG) positron emission tomography (PET), cell transplantation was performed via the intracoronary administration route (6,13) using four to six fractional infusions parallel to balloon inflation over 2 to 4 min of 3 to 5 ml of cell suspension, each containing 15 to 22 x 106 mononuclear cells. All cells were infused directly into the infarcted zone through the infarct-related artery via an angioplasty balloon catheter, which was inflated at a low pressure (2 to 4 atm) and was located within the previously stented coronary segments. This prevented backflow of cells and produced stop flow beyond the site of balloon inflation to facilitate high-pressure infiltration of cells into the infarcted zone. Prolonged contact time for cellular migration was also enabled. Three months after catheter-guided cell transplantation, all functional tests were repeated, including coronary angiography and left ventriculography. There were no procedural or cell-induced complications, and there were no side effects in any patient.
Spiroergometry. Aerobic exercise capacity was examined before (<10 days) intracoronary cell transplantation and three months later during follow-up. All patients (n = 18) were subjected to initial bicycle spiroergometry to assess their functional fitness and to determine the limit of safe intensity of exercise. We chose a protocol with an intensified workload up to the symptom-limited maximum (basic load of 50 W, intensification at 25 W, 2-min duration of each workload step). We determined the anaerobic threshold for prescribing a suitable load intensity. During the whole spiroergometry, monitoring by a 12-lead electrocardiogram (ECG) was carried out. The exercise capacity was assessed on the basis of maximum load levels expressed in watts (Wmax) and maximum peak oxygen uptake (VO2max).
Coronary angiography and left ventriculography. Coronary angiography and biplane left ventriculography were performed 9 ± 6 months before cell transplantation and also a second time, within 10 days, immediately before cell therapy. The therapeutic follow-up was three months after the treatment. Thus, stable baseline conditions were documented (coronary vessel involvement, ventricular function, and geometry). Cardiac function was evaluated by left ventricular (LV) ejection fraction and by auxotonic myocardial contractility index, evaluated by the wall movement velocity of the infarcted area. The infarct size was calculated according to the method of Sheehan (14) by plotting five axes perpendicular to the long axis of the heart in the main akinetic or dyskinetic segment of the ventricular wall. Systolic and diastolic lengths were then measured by two independent observers, and the mean difference was divided by the systolic duration in seconds.
Quantification of coronary stenosis (restenosis).
Cinecoronarangiograms were obtained during stem cell transplantation and at three months thereafter according to standard acquisition guidelines. The angiograms were evaluated by two independent observers and quantitative analysis was performed (15). Standard morphologic criteria were used to characterize the complexity of baseline lesions. The user-defined reference diameter proximal to the stenosis and the minimal luminal diameter within the culprit of the stenosis were used to calculate the percentage of stenosis. A value of 0 mm was assigned for the minimal luminal diameter in case of total occlusion at baseline or follow-up. Restenosis was defined as 
50% stenosis of the initial target lesion at follow-up. Calculations of restenosis were performed in both groups, with and without stem cell therapy, in the same way, thus enabling evaluation the differential effects of PTCA-guided cell therapy and of PTCA effects alone.
Ventricular function after PTCA in the control group. For the evaluation of a potential effect on the PTCA intervention itself on LV function, all patients in the control group were analyzed with regard to infarct size, ejection fraction, and infarction wall movement velocity.
Nuclear cardiologic investigations (PET and SPECT). 18F-FDG-positron emission tomography (18F-FDG PET) was performed with a Scanditronix SCX 4096 WB-Scanner (FWHM = 6 mm transaxial, axial field of view = 4.6 cm). Patients received an oral glucose load of 1 g/kg body weight 80 ± 30 min before the intravenous application of 18F-FDG (380 ± 60 MBq). The 18F-FDG was administered at the time of decrease of blood glucose level <130 mg/dl. An initial transmission scan was obtained using a 68Ga-filled pin source to correct the subsequent emission scans for attenuation. The data acquisition was started 45 min after administration of FDG. Image data were recorded with a 256 x 256 matrix in 3 consecutive bed positions over 15 min per position. The data were reconstructed backprojected with a Hanning filter (5 mm).
99mTc-tetrofosmin SPECT. Sixty minutes after intravenous injection of 600 ± 140 MBq of the perfusion-marker 99mTc-tetrofosmin under a "rest" condition, the images were obtained using a SPECT scanner with double-head detector (PRISM 2000, Marconi/Phillips), a low-energy, high-resolution collimator, and a 128 x 128 matrix. Image data were collected over 360° at 3° every 30 s. The images were reconstructed backprojected with a low-pass filter (order 12, cutoff 0.2).
PET and SPECT evaluation. Normalized values for FDG uptake and perfusion were calculated by comparing regional with maximum tracer uptake on the reconstructed images. We performed a regional analysis of glucose metabolism and perfusion using a set of standardized, individually adjusted circular regions of interest (diameter 18.06 mm, surface 256 mm2). The reconstructed metabolic and perfusion images were realigned for each patient (MPI-Tool, version 3.0; Advanced Tomo Vision, Erftstadt, Germany) and were resliced according to cardiac axis (short-axis and horizontal and vertical long-axis views). The regions were positioned immediately neighboring, with no overlap, according to an overlay of the co-registrated metabolic and perfusion images. The regions covered the infarct lesion as well as normal myocardium. In this way, we generated templates of regions for each patient, which could be used for the evaluation of metabolism and perfusion, before and after BMC transplantation without further modification. According to Segall et al. (16), regions with a normalized FDG uptake <50% were rated as transmural scar and regions with an uptake of 50% to 60% as non-transmural scar.
Further analysis was restricted to regions with FDG uptake <60% in the PET scans, pursuant to our intention to focus on the effects of BMC transplantation on scar tissue.
Safety parameters. To assess any inflammatory response and myocardial reaction after cell therapy, white blood cell count, the serum levels of C-reactive protein (CRP) and of creatine phosphokinase (CPK) were determined immediately before as well as after treatment. Additional analysis was done directly after transplantation and three months later: ECG at rest, 24-h Holter ECG, and echocardiography.
Statistical analysis. All data are presented as mean ± SD. Statistical significance was accepted when p < 0.05. Intra-individual comparison of variables of investigation 1 (9 ± 6 months before cell transplantation for Tx group, 9 ± 5 months before investigation 2 for control patients) and investigation 2 (<10 days before cell transplantation for Tx group, no transplantation for control patients) and of variables of investigation 2 and follow-up investigation 3 (3 months after cell therapy for Tx group, 8 ± 5 months after investigation 2 for control patients) was performed using Wilcoxon rank-sum test. The missing values (Table 2) were omitted and not calculated for statistical analysis. The p values (by analysis of variance) have been given for LV ejection fraction, area of infarction, and infarction wall movement velocity. Statistical analysis was performed with SPSS-Windows 10.1 software.
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In parallel, the clinical performance improved (Table 4), as evidenced by a higher work load demonstrated by a 11% increase in maximum oxygen uptake (VO2max). SPECT investigation presented enhanced tetrofosmin uptake in the infarcted zone by 5%, and PET examination showed enhanced glucose uptake in the infarcted zone by 15%, demonstrating regeneration of formerly avital, chronically infarcted heart muscle (Fig. 2). An unchanged or even impaired LV function was not observed in any patient.
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Discussion |
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The effects of stem cell transplantation on infarct size, cardiac function, and contractility demonstrate significant improvement of these three parameters in the therapy group (before and after stem cell therapy) as well as in the comparison between the stem cell therapy group and the control group, thus giving evidence for a beneficial therapeutic effect of stem cell therapy on cardiac performance in chronic MI.
Patients in both the stem-cell group and the control group were recruited in parallel to each other and consecutively between January 2003 and March 2004. They all (n = 36) fulfilled the same inclusion criteria. Thus, representative patient characteristics were present for the stem cell group (n = 18) and the control group (n = 18) as well as in comparing both of them. Moreover, two subsequent investigations before stem cell transplantation have been performed for each patient: investigation 1 and 2 demonstrated the stability of LV dynamics before cell therapy (9 months respectively 10 days before transplantation) and investigation 3 compared the effects of stem cell therapy with the control group. The stable hemodynamics during the preceding 9 ± 6 months before stem-cell therapy and the stable hemodynamics within the control group at all three points of investigation underline the significant alterations of the left ventriculography-derived parameters investigated after stem cell transpantation.
The regenerative potential of bone-marrow–derived stem cells may be explained by any of four mechanisms: 1) direct cell differentiation from mononuclear cells to cardiac myocytes (17), 2) cytokine-induced growing and increase of residual viable myocytes, especially within the border zone of the infarcted area (18), 3) stimulation of intrinsic myocardial stem cells (endogenous stem cells) (19,20), and 4) induction of cell fusion between transplanted bone marrow cells and resident myocytes (21–24).
Transdifferentiation has been described by previous investigators (4); however, it has been questioned by recent experimental studies (25). The influence of cytokines has shown to restore coronary blood vessels and muscle cells after experimental myocardial infarction. This regeneration of blood vessels and muscle cells is most pronounced in the border zone of ischemic and/or infarcted tissue (26), demonstrating an enhancement of mitotic cells and cell cycles up four-fold, when compared to areas remote from the necrotic myocardium. Moreover, mononuclear bone marrow stem cells contain a lot of cytokines (VEGF, insulin-like growth factor, platelet-derived growth factor, and so on), thereby stimulating residual normal myocytes for regeneration and proliferation and instrinsic myocardial stem cells (endogenous stem cells) for cell regeneration and for cell fusion (27–31).
Mitotic indexes are three to four times more frequent within the border zone of myocardial necrosis when compared with non-injured heart muscle (26). Moreover, 20% to 40% of intracoronarily transplanted bone-marrow–derived stem cells may be accumulated within the border zone of MI. There were no signs of apparent microcirculation disturbances because all patients had Thrombolysis In Myocardial Infarction flow grade 3. Thus, it is conceivable that in MI the border zone represents the optimum "niche" for exogenously transplanted stem cells, stimulating mitosis rates and heart muscle regeneration, preferably originating in and expanding from these areas. Cell fusion may also contribute to heart muscle regeneration, which takes its origin from the border zone, expanding gradually to the necrotic core of the infarcted area.
Our study cannot determine which cell-biologic and molecular mechanims are responsible for heart muscle repair or which of the studied factors may play the predominant role. However, the final functional outcome of this cell therapy demonstrates three main target effects: improvement in muscle function (pumping ability and contractility), myocardial perfusion (SPECT), and myocardial glucose metabolism (PET), thus giving evidence that heart muscle repair must have taken place by this intracoronary bone marrow cell transplantation procedure.
The clinical significance of this novel therapeutic approach may embrace a large number of patients with chronic coronary artery disease, preferably after previous or longstanding MI. It is conceivable that remodeling after infarction may be ameliorated or even stopped by this procedure. Thus, cell therapy may represent a new option of basic and causal therapy in chronic infarcted myocardium. It is an open question whether variations of the amount and kind of bone marrow cells, the administration technique, and the transplantation procedure itself, by enhanced environment and improvement of the angiogenic micromilieu, can further improve the milieu-dependent differentiation or regeneration of bone marrow cells in chronic infarcted heart disease. Therefore, our clinical results represent a stable basis to proceed to the next necessary step: to a larger prospective randomized study.
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