CORRESPONDENCE: RESEARCH CORRESPONDENCE
Anterior Myocardial Infarction With Acute Percutaneous Coronary Intervention and Intracoronary Injection of Autologous Mononuclear Bone Marrow CellsSafety, Clinical Outcome, and Serial Changes in Left Ventricular Function During 12-Months’ Follow-Up
Ketil Lunde, MD*,
Svein Solheim, MD,
Kolbjørn Forfang, MD, PhD,
Harald Arnesen, MD, PhD,
Lorentz Brinch, MD, PhD,
Reidar Bjørnerheim, MD, PhD,
Asgrimur Ragnarsson, MD,
Torstein Egeland, MD, PhD,
Knut Endresen, MD, PhD,
Arnfinn Ilebekk, MD, PhD,
Arild Mangschau, MD, PhD and
Svend Aakhus, MD, PhD
* Department of Cardiology, Rikshospitalet University Hospital, 0027 Oslo, Norway (Email: ketil.lunde{at}rikshospitalet.no).
To the Editor: Intracoronary injection of bone marrow cells (BMC) has been introduced for improvement of left ventricular (LV) function after acute myocardial infarction (AMI). In the randomized ASTAMI (Autologous Stem cell Transplantation in Acute Myocardial Infarction) study, BMC treatment did not improve LV function after 6 months (1). The aim of this ASTAMI substudy was to investigate effects of BMC therapy on safety, clinical outcome, and serial changes in LV function during a 12-month follow-up.
The study design has been described previously (1). We randomized 100 patients between 40 and 75 years of age with anterior AMI to either intracoronary injection of autologous mononuclear bone marrow cells (mBMC) 4 to 8 days after the acute event (n = 50) or to a control group (n = 50). All received percutaneous coronary intervention (PCI) with stenting of left anterior descending (LAD) culprit lesions 2 to 12 h after onset of symptoms. Ficoll-hypaque density gradient centrifugation was used to isolate mBMC from 50 ml bone marrow. Median cell viability was 95% (interquartile range 94% to 97%), the number of injected viable mBMC 68 x 106 (interquartile range 54 x 106 to 130 x 106), and CD34+ cells 0.7 x 106 (interquartile range 0.4 x 106 to 1.6 x 106). A PCI stop-flow technique was used for injecting mBMC in the LAD (1). Three mBMC group patients did not receive cell treatment (1). Echocardiograms were obtained in all patients at baseline (4.5 ± 1.1 days after PCI) and at 3, 6, and 12 months, digitally stored, blinded, and analyzed as previously described (1) according to guidelines (2).
Signal-averaged electrocardiogram (ECG) (GE MAC 5000, GE Healthcare, Waukesha, Wisconsin) and 24-h Holter monitoring (Medilog FD4 and Medilog Excel-3 12.0 software, Oxford Instruments, Abingdon, United Kingdom) were obtained at baseline. Signal-averaged ECG was repeated at 3 months and Holter monitoring at 6 months.
Angiograms were obtained at 12.5 images/s in all patients after acute PCI and at 6-month follow-up and stored digitally. Quantitative coronary angiography was analyzed with CMS Medis software (Sectra Imtec AB, Linkøping, Sweden) by a single investigator (A.R.) unaware of treatment allocation.
Variables are presented as mean ± SD, median (interquartile range), or number (proportion), and groups were compared with the 2-sample t test, Mann-Whitney test, chi-square test, or Fisher’s exact test as appropriate. We used general linear regression to analyze the mean response over time (3). Variables with single follow-up measurements were compared with analysis of covariance. We used SPSS version 14.0 (SPSS Inc., Chicago, Illinois). Intention-to-treat was used throughout. Values of p < 0.05 were considered significant.
The protocol was approved by the regional ethics committee. All patients gave written informed consent.
There were no differences in patient characteristics between groups (1). Mean age was 57 ± 9 years, 16% were women, and peak creatine kinase-MB fraction mass was 369 µg/l (interquartile range 220 to 444 µg/l). All patients were treated with aspirin, clopidogrel, a beta-blocker, an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, and a statin during follow-up. All had sinus rhythm during echocardiography, except 1 patient in the mBMC group with atrial fibrillation at baseline.
There were no differences between groups for variables of LV function during 12 months’ follow-up (Fig. 1). Also, when the total patient population was dichotomized according to the median value for left ventricular ejection fraction (LVEF) at baseline (45%), we did not find any significant treatment effect for LVEF, LV end-diastolic volume, or wall motion score index, either for the baseline low or the baseline high group. For the total population, LVEF increased by 2.8 ± 8.4% (p < 0.01), and the wall motion score index decreased by 0.23 ± 0.24 (p < 0.001) at 3 months, and both remained significantly different from baseline. Left ventricular end-diastolic volume increased by 9.8 ± 28.7 ml (p < 0.01) at 6 months but was not different at 3 and 12 months compared with baseline.
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Figure 1 Changes in Left Ventricular Global and Regional Function and Volumes
Data are mean ± SD. Blue circles = mBMC group; red circles = control group. LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; WMSI = wall motion score index. P = change between groups over time (deviation from parallel time course).
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Moderate or severe mitral regurgitation was found in 2 patients in each group at baseline (p = 1.00) and in 5 patients in the mBMC group and 2 patients in the control group at 12 months (p = 0.44). Moderate or severe aortic regurgitation was not observed in any patient at baseline or 12 months.
Holter monitoring revealed nonsustained ventricular tachycardia in 7 mBMC group patients and in 9 control patients at baseline (p = 0.62) and in 2 patients in each group at 6 months (p = 1.00). The number of premature ventricular contractions and variables obtained by signal-averaged ECG (filtered QRS width, high frequency low amplitude duration, and root mean square voltage) was similar in both groups.
Quantitative coronary angiography of the LAD culprit lesion revealed a mean decrease in the minimal luminal diameter of 0.4 ± 0.9 mm in the mBMC group and 0.5 ± 0.6 mm in controls (p = 0.18). Significant culprit lesion restenosis was found in 7 (14%) patients in the mBMC group and 8 (16%) in the control group (p = 0.88). Thirteen were treated with new PCI and 2 with coronary artery bypass grafting. One patient in the mBMC group and 2 in the control group had PCI for nonculprit lesion LAD stenosis at 6-month follow-up (p = 1.00). There were no differences between groups in the number of adverse events (Table 1).
The main finding in this study is that injections of mBMC in the LAD 4 to 8 days after anterior wall AMI did not improve LV function during 12-month follow-up. No data indicated increased restenosis or arrhythmias. In the BOOST study, magnetic resonance imaging results indicated that BMC therapy accelerates LV recovery, since LVEF only increased in the treatment group at 6 months, whereas at 18 months, the increase in LVEF was similar in both groups (4). In the present study, we used echocardiography and found a similar improvement in LV function in both groups after 3 months followed by a stable state over the next 9 months. Magnetic resonance imaging is regarded more sensitive than echocardiography to detect changes in LV function. However, neither magnetic resonance imaging, single-photon emission computed tomography, nor echocardiography showed any difference between groups for changes in LVEF or left ventricular end-diastolic volume at 6 months in the ASTAMI study (1).
Results of the REPAIR-AMI study suggest that mBMC treatment improves the clinical outcome after AMI compared with placebo (5). In contrast, we found an excellent clinical outcome in both the treatment and the control group, concordant with other studies (6).
There are several possible explanations for why we did not find an effect of cell therapy. The number of regenerative cells used may have been too small (7). It has also been suggested (8) that although mBMC in ASTAMI were viable, cells may have been functionally impaired. However, bone marrow cells prepared according to the ASTAMI protocol are functional in bone marrow transplantation for patients with hematologic diseases (9), where homing of cells, such as along the SDF-1/CXCR4-axis, is important for therapeutic success (10). Furthermore, because the ASTAMI study was powered to detect a difference of 5% of the change in LVEF (1), our results do not exclude a less pronounced effect of mBMC therapy.
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Acknowledgments
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The authors are indebted to Magne Thoresen for statistical advice.
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Footnotes
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Please note: Supported by research fellowships from the Norwegian Council on Cardiovascular Diseases (K.L. and S.S.) and Medinnova (K.L.) and by grants from Inger and John Fredriksen’s Heart Foundation. (Autologous Stem Cell Transplantation in Acute Myocardial Infarction; NCT00199823)
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References
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1. Lunde K, Solheim S, Aakhus S, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction N Engl J Med 2006;355:1199-1209.[Abstract/Free Full Text]2. Gottdiener JS, Bednarz J, Devereux R, et al. American Society of Echocardiography recommendations for use of echocardiography in clinical trials: a report from the American Society of Echocardiography’s guidelines and standards committee and the task force on echocardiography in clinical trials J Am Soc Echocardiogr 2004;17:1086-1119.[Web of Science][Medline] 3. Fitzmaurice GM. Applied Longitudinal AnalysisHoboken, NJ: Wiley-Interscience; 2004XIX, 506. 4. Meyer GP, Wollert KC, Lotz J, et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial Circulation 2006;113:1287-1294.[Abstract/Free Full Text] 5. Schächinger V, Erbs S, Elsasser A, et al. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial Eur Heart J 2006;27:2775-2783.[Abstract/Free Full Text] 6. Arnesen H, Lunde K, Aakhus S, Forfang K. Cell therapy in myocardial infarction Lancet 2007;369:2142-2143.[CrossRef][Web of Science][Medline] 7. Nadal-Ginard B, Fuster V. Myocardial cell therapy at the crossroads Nat Clin Pract Cardiovasc Med 2007;4:1.[CrossRef][Web of Science][Medline] 8. Seeger FH, Tonn T, Krzossok N, Zeiher AM, Dimmeler S. Cell isolation procedures matter: a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction Eur Heart J 2007;28:766-772.[Abstract/Free Full Text] 9. Egeland T, Brinchmann JE. Cell quality in the ASTAMI study Eur Heart J 2007;28:2172.[Free Full Text] 10. Lapidot T, Dar A, Kollet O. How do stem cells find their way home? Blood 2005;106:1901-1910.[Abstract/Free Full Text]
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