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J Thorac Cardiovasc Surg 2007;133:717-725
© 2007 The American Association for Thoracic Surgery
Evolving Technology |
a Department of Cardiac Surgery, University of Rostock, Rostock, Germany
b Department of Hematology, University of Rostock, Rostock, Germany
c Department of Nuclear Medicine, University of Rostock, Rostock, Germany
d Department of Radiology, University of Rostock, Rostock, Germany
e Department of Cardiology, University of Rostock, Rostock, Germany
f Departments of Orthopedic Surgery and Biostatistics, Children’s Hospital Boston, Harvard Medical School, Boston, Mass.
Received for publication May 1, 2006; revisions received July 30, 2006; accepted for publication August 3, 2006. * Address for reprints: Gustav Steinhoff, MD, Klinik für Herzchirurgie, Universität Rostock, Schillingallee 35, 18057 Rostock, Germany (Email: gustav.steinhoff{at}med.uni-rostock.de).
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionLimitationsAppendix E1: Patient...Appendix E2Appendix E3 |
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Methods: Fifteen patients took part in the safety study, followed by 40 patients who underwent either CABG with cell therapy or CABG alone. Bone marrow was harvested from the iliac crest one day before surgery, and purified CD133+ progenitor cells were injected in the infarct border zone during the CABG operation. LV function was measured by echocardiography and myocardial perfusion by SPECT.
Results: In the safety study, no procedure-related complications were observed for up to 3 years. LV injection fraction (LVEF) increased from 39.0% ± 8.7% preoperatively to 50.2% ± 8.5% at 6 months and 47.9% ± 6.0% at 18 months (F = 6.03, P = .012). In the efficacy study, LCEF rose form 37.4% ± 8.4% to 47.1% ± 8.3% at 6 months in the group with CABG and cell therapy (F = 24.16, P < .0001) but only from 37.9% ± 10.3% to 41.3% ± 9.1% in the CABG-only group (F = 7.72, P = .012). LVEF was significantly higher at 6 months in the group with CABG and cell therapy than in the CABG-only group (P = .03). Similarly, perfusion of the infarcted myocardium improved more in patients treated with CABG and cell therapy than in those treated with CABG alone.
Conclusion: Intramyocardial delivery of purified bone marrow stem cells together with CABG surgery is safe and provides beneficial effects, though it remains to be seen whether thewe effects produce a lasting clinical advantage.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionLimitationsAppendix E1: Patient...Appendix E2Appendix E3 |
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Cellular therapy for ischemic heart disease has attracted tremendous attention, especially since initial experimental studies have suggested that somatic stem cells can regenerate both blood vessels and cardiomyocytes after myocardial infarction. Recently, the capacity of bone marrow–derived stem cells to form new heart muscle cells has been questioned, but clinical pilot trials have been initiated nevertheless.E1,E2 In the setting of acute myocardial infarction, several studies have shown a functional benefit of intracoronary infusion of bone marrow cells relative to the standard treatment alone,E3-E5 but patients with chronic ischemic heart disease and impaired heart function may require a different approach. Our group therefore developed a protocol for injection of purified CD133+ bone marrow stem cells directly into the diseased myocardium at the time of coronary artery bypass grafting (CABG). Because of the encouraging results in the first 6 patients,E6 we completed a dose-escalation safety trial and then conducted an efficacy study to compare the outcome with that of standard CABG. Results of both trials are presented here. |
Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionLimitationsAppendix E1: Patient...Appendix E2Appendix E3 |
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Surgical Procedure
All patients were operated on with cardiopulmonary bypass and cardioplegic arrest. The left thoracic artery was used in most but not all cases (depending on the presence of an anterior vessel that could be grafted), and saphenous vein grafts or radial artery grafts were harvested. When there was mitral regurgitation grade III or higher according to transesophageal echocardiography on the operating table, the mitral valve was repaired by ring annuloplasty. All coronary arteries with relevant stenoses and sufficient diameter were grafted, including, if possible, the previously infarcted vessel. Once the graft–coronary artery anastomoses had been completed, the infarcted area was visualized, and 10 injections of 0.2 mL of cell suspension were made into the infarct border zone if this could be clearly visualized. Otherwise, cells were injected in an area of myocardium that corresponded to the localization of the perfusion defect on scintigraphy and disturbed wall motion on echocardiography and LV angiography. A swab was used to occlude the injection channel for several seconds to minimize reflux of cell suspension. Immediately after the cell injection, the aortic clamp was removed, and the operation was completed as usual. In CABG alone patients, no sham injection was performed. After their stay in the intensive care unit and the intermediate care unit, patients recovered on the surgical ward for at least 12 days or were transferred to the referring cardiology unit earlier. Standard postoperative medication included aspirin (100 mg daily), ß-blockers, statins, and angiotensin-converting enzyme inhibitors and was adjusted by the cardiologist caring for the patient during follow-up as needed.
Outcomes and Follow-up
In the safety study, the primary outcome was freedom from death from cardiac disease or major cardiac event at 12 months. Secondary outcomes were ventricular arrhythmia and any class III or class IV event according to a modified Centers for Disease Control and Prevention classification. In the efficacy trial, the following null hypothesis was formulated: At 6 postoperative months, there would be no difference in average LVEF between CABG alone and CABG with cell injection. Secondary outcome parameters were myocardial perfusion in the infarcted area and the same safety parameters as in the safety study. Before referral to a cardiac rehabilitation program at approximately 2 postoperative weeks, Holter ECG, transthoracic echocardiography, and myocardial perfusion scintigraphy were performed. The next Holter ECG and echocardiogram were recorded at the end of the rehabilitation program in the respective institution; however, the echocardiography data were not used for quantitative analysis in the study. Echocardiography and myocardial perfusion scintigraphy were repeated in our institution at 6 postoperative months in the efficacy trial and also after 18 months in the safety trial.
Echocardiography
Cardiac transthoracic ultrasonographic studies were performed for measurement of global LV contractility and dimensions. The method is described in detail in Appendix E3. The studies were carried out by two experienced echocardiographers (A.D., C.N.) who were blinded to the presence and location of the cell injection. Measurements obtained by the two independent echocardiographers were consistent. In a separate set of patients, the echocardiographic data were validated with cardiac MRI, and a close correlation of the LVEF measurements was found (Figure E1).
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Statistical Analysis
Continuous data are presented as mean ± SD. For variables not normally distributed, medians and ranges are presented (cell isolation data, infarct time, myocardial perfusion data). To compare preoperative patient characteristics between the groups, the Student t test was used for continuous data and the 
2 test was used for categorical data. Comparisons of changes in functional data, including LVEF, LV end-systolic volume, LV end-diastolic volume, LV end-systolic diameter, and LV end-diastolic diameter with time, were done with repeated-measures analysis of variance with the Greenhouse–Geisser F test to evaluate treatment and time effects.E7 Variables not conforming to a normal distribution (myocardial perfusion data) were compared with the Mann–Whitney U test. Agreement between echocardiography-based and cardiac MRI determinations of LVEF was determined by the Bland-Altman method, and the mean difference was used to assess bias and 95% confidence intervals (2 SD).E8 On the basis of the results of the safety trial, the efficacy trial required (version 6.0, nQuery Advisor; Statistical Solutions, Saugus, Mass) 20 patients in each group to attain 80% power for detecting a relative difference of 10% in average LVEF between the groups, assuming an 8% SD (effect size of 1.25, 
= .05, ß = 0.2). Statistical analysis was performed with the SPSS software package (version 14.0; SPSS Inc, Chicago, Ill).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionLimitationsAppendix E1: Patient...Appendix E2Appendix E3 |
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Bone Marrow Cell Preparation
Between 91 and 265 mL (median 156 mL) of bone marrow was harvested by aspiration from the iliac crest. The median percentage of CD34+ cells in all bone marrow aspirates was 0.8% (range 0.26%-1.44%), corresponding to a median absolute number of 2.95 x 107 CD34+ cells (range 3.85 x 106-1.03 x 108). After cell selection with AC133/1(CD133) monoclonal antibody, the median number of CD133selected/CD34+ cells was 5.80 x 106 (range 1.08 x 106-8.35 x 107), with a median purity of 75.8% (range 53.1%-89.6%). In only 1 patient (aged 40 years) was the final cell dose higher than 10 x 106. Median recovery of CD34+ cells was 18.3%. Viability of the cell product, as measured by propidum iodide exclusion, ranged between 77% and 99% (median 94%). For details, see Table E2.
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The echocardiographic data on LV function are summarized in Table E3, and the data relevant for the primary outcome parameter, LVEF at 6 months, are depicted in Figure 4. The average LVEF rose, from 37.4% ± 8.4% to 47.1% ± 8.3% at 6 months in patients undergoing CABG with cell injection (P < .0001) and from 37.9% ± 10.3% to 41.3% ± 9.1% in patients undergoing CABG alone (P = .012). As required by the study protocol, direct comparison of the primary outcome parameter (average LVEF at 6 months) between the two treatment groups achieved significance (P = .03), with the 95% confidence interval for the mean difference in LVEF between 3% and 11%. Within the range of probability defined by the statistical power, the null hypothesis is therefore rejected, indicating that CABG with cell injection results in significantly better LVEF than does CABG alone. The average changes in LVEF were +9.7% ± 8.8% in the CABG with cell injection group and +3.4% ± 5.5% in the CABG alone group (P = .02). The mean difference between groups in the change in LVEF from preoperative baseline to 6 postoperative months was 6.3% (95% confidence interval for difference 3%-11%). Figure 5 shows that this difference developed late after CABG, during the interval between the time of discharge and 6-month follow-up.
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35%), the notion that patients with a poorer LVEF benefit more is further supported. Patients with a preoperative LVEF less than 35% showed a mean increase of 15.3% (95% confidence interval 10.8%-20.4%), significantly greater than the change in LVEF in patients with preoperative LVEF of at least 35% (increase of 7.8%, 95% confidence interval 4.1%-11.5%, F = 5.87, P = .02, 2-way analysis of variance; Figure 6, B).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionLimitationsAppendix E1: Patient...Appendix E2Appendix E3 |
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Adult stem or progenitor cells derived from blood or bone marrow are readily available for clinical use, although experimental evidence regarding their true myocardial regeneration capacity remains inconclusiveE1,E9,E10 Nevertheless, numerous small and large animal studies have provided evidence of functional benefits of bone marrow–derived stem cells in ischemic myocardium, even in the absence of quantitatively relevant cardiomyocyte differentiation.E2,E11 Clinically available CD34+ and CD133+ bone marrow stem cells have proved especially effective for improving blood supply to ischemic tissue.E10 CD133+ cells readily assume an endothelial cell phenotype in vitroE12 and have been shown to improve myocardial function in rats.E7 Our own preclinical evaluation in mice showed that human CD133+ bone marrow cells increase blood vessel count and reduce cardiomyocytes apoptosis in the infarct border zone.E8 Other possible mechanisms include beneficial effects on extracellular matrix composition.E13 In this context, recent research has identified the hibernating myocardium, which is to some degree nearly always present in the chronic infarct border zone, as a particularly responsive target of experimental and clinical cardiac cellular therapy.E14,E15 On the basis of the existing preclinical evidence, we and others have come to the decision that clinical pilot trials are justified and in fact needed. In 2001, we initiated a phase I analogous safety trial with incremental escalation of the cell dose. We chose to inject bone marrow cells enriched for CD133 to avoid potential proinflammatory side effects of unmodified mononuclear cell preparations on direct delivery to the myocardium. Furthermore, we deemed it important to work with a well characterized, distinct cell population. Data from the first patients have been reported before,E6,E16 and the encouraging results prompted us to complete the safety trial and proceed with an efficacy study. Even though the observed difference in LVEF at 6 months is modest, we believe it still serves to provide proof of principle, namely that direct intramyocardial injection of purified bone marrow stem/progenitor cells does have beneficial effects on chronically ischemic human hearts. This notion has recently been corroborated by other investigators. Erbs and colleaguesE14 showed functional improvement after intracoronary injection of peripheral blood-derived progenitor cells in patients with chronic ischemia, and Patel and associatesE17 reported on a trial similar to ours. In the latter study, CD34+ bone marrow cells were implanted at the time of off-pump CABG and induced a significantly greater improvement of contractile function than did CABG alone.
A number of reports on other clinical studies have described similar advantageous effects of bone marrow mononuclear cells injected in the infarct-related coronary artery of patients early after acute infarctionE3,E5,E18; however, other trials have shown little if any clinical effect.E19 Other than differences in cell type (CD133+ vs bone marrow mononuclear cells), delivery route (intramyocardial vs intracoronary), and concomitant procedures (percutaneous transluminal coronary angioplasty vs CABG), the most relevant distinction of our approach is patient selection. With an interval between myocardial infarction and cellular treatment of several months or years, acute ischemia and subsequent local inflammatory infiltration have abated, and myocardial remodeling processes, including scar formation, are most likely completed. The cellular mechanisms required to beneficially influence myocardial function may be completely different from those occurring in the face of cellular therapy in acutely ischemic hearts. In that respect, our patient cohort is not homogenous. In some cases, the interval between infarct and cellular treatment was a few weeks; in others, several years. It therefore seems likely that the amount of hibernating myocardium varies greatly among individual patients, and this confounding factor could contribute to the heterogeneity of the functional treatment response. In future studies, we plan to localize and quantify areas of hibernating myocardium before cellular treatment and use this information for patient selection or retrospective correlation with functional outcome data.
In any event, it should be noted that both cellular therapy targets (acutely and chronically ischemic myocardium) are not mutually exclusive or competitive. Even if treatment of acute myocardial infarction can be further optimized by rapid cellular therapy, there will always be a substantial number of patients who are first seen with heart function already impaired because of silent ischemic events or failure of emergency treatment.
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Limitations |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionLimitationsAppendix E1: Patient...Appendix E2Appendix E3 |
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Given that autologous bone marrow stem cells can indeed improve the function of chronically ischemic myocardium in addition to the beneficial effects of traditional revascularization procedures, we believe that there is room for substantial further improvement. The cell number we used is rather small (only 1 of our patients received 80 x 106 CD133+ cells; all others received between 1.2 and 10 x 106 cells), and the overnight storage of the cell product may have impaired its biologic activity. In a recent study by Asahara and coworkers,E20 there was a clear dose-response relationship of human CD34+ cells in rats, but it is not clear how this translates into the clinical setting. Other cell types with a greater likelihood for true cardiomyocyte differentiation (mesenchymal stem cell–derived cells) might ultimately prove more efficient. Strategies to precondition cells before implantation by pharmacologic, genetic, or physical means are also currently under evaluation. For the time being, however, clinicians have to resort to clinically available cell products. On that basis, we believe the approach that we have chosen to be effective.
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Appendix E1: Patient Stratification |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionLimitationsAppendix E1: Patient...Appendix E2Appendix E3 |
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gdallal/PLAN.HTM) based on 100 subjects and 5 subblocks. This plan was followed for the first 12 patients. Because of the limited availability of the hematology class B procedure room, pursuing the trial became increasingly more difficult. The stratification strategy was therefore modified. Patients who were operated on during a week when the procedure room was available were allocated to the treatment group. When the hematology class B clean room was not available, the patient was put in the CABG alone group. Availability of the clean room was beyond the control of the investigators, resulting in the following allocation sequence: 01000011001110010001 01010100101011110111, where 0 represents CABG alone and 1 represents CABG with cell injection. |
Appendix E2 |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionLimitationsAppendix E1: Patient...Appendix E2Appendix E3 |
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Flow Cytometry
Samples were drawn from the unmanipulated bone marrow, after incubation with anti-CD133 antibody (before CliniMACS column), from the purified CD133+ cell product, and from the waste fraction of the CliniMACS system. To avoid competitive binding between fluorochrome-conjugated AC133/1 monoclonal antibody (CD133) and the ferrite-conjugated AC133/1 antibody used for CliniMACS cell selection, stem cell enumeration was done with a CD34 (clone 8G12) monoclonal antibody (CD133selected/CD34+ cells). The clone AC133/2 was not available at the time of the safety trial. Later, fluorochrome-conjugated AC133/2 monoclonal antibody was used in addition for determination the stem cell number in the phase II trial. Cell counting was done according to the Interdisziplinäre Gruppe für Labor und Durchflusszytometrie and International Society of Hematotherapy and Graft Engineering protocol.E23,E24 In all samples derived from the selection procedure, cell viability was also measured with propidium iodide staining and flow cytometry.
Cell Products
The results of bone marrow cell preparation are summarized in Table E2. Because the preparation of the transplant of the first patient in the safety study was done without density centrifugation, the previously described analyses were performed without this patient (that cell preparation resulted in a final transplant dose of only 1.18 x 105 CD133selected/CD34+ cells with a purity of 3.5% and a recovery of only 2%). By the end of the safety study, a second CD133 antibody (clone AC133/2), not interfering with the AC133/1 used for cell selection, became available for diagnostic use. In 9 cell preparations of the efficacy trial, the stem cell number was calculated on the basis of both CD133+ and CD34+ cells. Comparison of the cell counts showed a median number of 6.75 x 106 CD133selected/CD34+, compared with 7.2 x 106 CD133selected/CD133+ cells in the final cell product. Median purities were 77% in the calculation with CD133selected/CD34+ cells and 80% when CD133selected/CD133+ cells were used for calculation. These results indicate that CD34 and CD133 measurements are equally valid for monitoring the efficacy of the cell selection procedure.
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Appendix E3 |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionLimitationsAppendix E1: Patient...Appendix E2Appendix E3 |
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Validation of Echocardiography by Cardiac MRI
Methods
To determine validity and reproducibility of echocardiography-based LVEF determination, a separate set of patients (n = 13) with similarly impaired LV function who were not included in the study were examined with cardiac MRI, and echocardiography was performed by the same investigators using the same protocol described previously. Cardiac MRI was done with ECG-gated sequences in a 1.5-T scanner (Avanto; Siemens AG, Munich, Germany). To determine LVEF, LV end-diastolic and end-systolic volumes were determined for calculation of LVEF with breath-hold gradient echo sequences (Cine-True Fast Imaging With Steady Precession). Sequence parameters were as follows: TR 40.05 ms, TE 1.3 ms, flip angle 80° to 65°, matrix 192 x 156, slice thickness 8 mm, and field of view 34 to 40 cm. The LV was covered by a continuous stack of short-axis slices. An end-diastolic, end-expiratory 4-chamber view served as a reference to plan the short-axis slices. Image analysis was done blinded, without knowledge of the echocardiographic data, with Argus software (Siemens).
Results
In 13 separate patients with ischemic heart disease and impaired LV contractility (average LVEF 31% ± 5%), LVEF was measured by both echocardiography (LVEFecho) and cardiac MRI (LVEFMRI). There was a significant positive linear correlation between LVEFecho and LVEFMRI (r
2 = 0.84, P < .001), described by the equation y = 0.97x + 3.7. Bland-Altman analysis indicated a mean difference (bias) between MRI and echocardiography of 2.8%, with an SD (precision) of 2.1% (95% confidence interval of difference –1.5% to 7.1%; Figure E1). Cardiac MRI measurements of LVEF on average are 2.8% higher than those obtained by echocardiography. The bias was constant across the range of LVEF, as indicated by a slope not different from 0 (P = .16).
| See related editorial on page 599.
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Footnotes |
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