CLINICAL PERSPECTIVE

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(Circulation. 2006;113:1287-1294.)
© 2006 American Heart Association, Inc.

Coronary Heart Disease

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

Gerd P. Meyer, MD^*; Kai C. Wollert, MD^*; Joachim Lotz, MD; Jan Steffens, BS; Peter Lippolt, MD; Stephanie Fichtner, BS; Hartmut Hecker, MD; Arnd Schaefer, MD; Lubomir Arseniev, MD; Bernd Hertenstein, MD; Arnold Ganser, MD; Helmut Drexler, MD

From the Departments of Cardiology and Angiology (G.P.M., K.C.W., J.S., P.L., S.F., A.S., H.D.), Diagnostic Radiology (J.L.), Biometrics (H.H.), and Hematology and Oncology (L.A., B.H., A.G.), Hannover Medical School, Hannover, Germany.

Correspondence to Prof Dr Helmut Drexler, Abt. Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg Straße 1, 30625 Hannover, Germany. E-mail drexler.helmut{at}mh-hannover.de

Received July 14, 2005; revision received December 15, 2005; accepted January 9, 2006.

	Abstract

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Background— Intracoronary transfer of autologous bone marrow cells (BMCs) may enhance recovery of left ventricular (LV) function in patients after acute myocardial infarction (AMI). However, clinical studies addressing the effects of BMCs after AMI have covered only limited time frames ranging from 3 to 6 months. The critical question of whether BMC transfer can have a sustained impact on LV function remains unanswered.

Methods and Results– After percutaneous coronary intervention with stent implantation (PCI) of the infarct-related artery, 60 patients were randomized 1:1 to a control group with optimal postinfarction therapy and a BMC transfer group that also received an intracoronary BMC infusion 4.8±1.3 days after PCI. Cardiac MRI was performed 3.5±1.5 days, 6±1 months, and 18±6 months after PCI. BMC transfer was not associated with adverse clinical events. In the control group, mean global LV ejection fraction increased by 0.7 and 3.1 percentage points after 6 and 18 months, respectively. LV ejection fraction in the BMC transfer group increased by 6.7 and 5.9 percentage points. The difference in LVEF improvement between groups was significant after 6 months but not after 18 months (P=0.27). The speed of LV ejection fraction recovery over the course of 18 months was significantly higher in the BMC transfer group (P=0.001).

Conclusions– In this study, a single dose of intracoronary BMCs did not provide long-term benefit on LV systolic function after AMI compared with a randomized control group; however, the study suggests an acceleration of LV ejection fraction recovery after AMI by BMC therapy.

Key Words: myocardial infarction • magnetic resonance imaging • cells

	Introduction

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Modern reperfusion strategies and advances in pharmacological management have resulted in an increasing proportion of patients with acute myocardial infarction (AMI) surviving with significant impairment of left ventricular (LV) systolic function. On the basis of experimental studies that suggest that cardiac transfer of unfractionated bone marrow cells (BMCs) or bone marrow–derived stem and progenitor cells can promote functional improvements after AMI,^1–4 several clinical trials have explored the hypothesis that an intracoronary infusion of autologous BMCs may enhance recovery of LV systolic function after AMI.^5–8 The combined experience from these studies suggests that intracoronary delivery of unselected BMCs a few days after myocardial reperfusion is feasible and probably safe. It has also emerged from these trials that BMC transfer may improve regional wall motion in the infarcted area and global LV ejection fraction (LVEF) 3 to 6 months after cell transfer.⁹ However, the critical question of whether a single intracoronary dose of BMCs can have a sustained impact on LV function in patients after AMI has not been addressed in these previous studies. Data obtained in a subgroup of patients enrolled in the Transplantation Of Progenitor Cells And Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trial suggest that the increase in LVEF observed 4 months after intracoronary transfer of BMCs or circulating progenitor cells is maintained after 12 months.¹⁰ However, interpretation of these results is hampered by the fact that TOPCARE-AMI was designed as a safety and feasibility trial and therefore did not include a randomized control group.^6,10 The purpose of the present study was to assess the safety and efficacy of intracoronary BMC transfer over a longer period of follow-up (18±6 months) in the setting of the randomized, controlled BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) trial.

Editorial p 1272

Clinical Perspective p 1294

	Methods

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Study Design and Protocol
The randomized, controlled BOOST trial was approved by our local Ethics Committee. The detailed study protocol and 6 months’ follow-up results of the BOOST trial have been reported previously.⁸ In brief, patients were eligible if they were admitted to Hannover Medical School within 5 days after symptom onset of a first ST-segment elevation myocardial infarction, had undergone successful percutaneous coronary intervention (PCI) with stent implantation of the infarct-related artery, and demonstrated hypokinesia or akinesia that involved more than two thirds of the LV anteroseptal, lateral, or inferior wall. Exclusion criteria were the presence of multivessel coronary artery disease, pulmonary edema, cardiogenic shock, advanced renal or hepatic dysfunction, and documented terminal illness or cancer. Eligible patients who provided written informed consent were randomized in a 1:1 ratio to the control and BMC transfer groups. After randomization, all patients underwent baseline cardiac MRI (3.5±1.5 days after PCI). After MRI, bone marrow (128±33 mL) was harvested from patients randomized to the BMC transfer group (4.8±1.3 days after PCI). To reduce the volume of the BMC preparation and deplete erythrocytes and platelets, bone marrow was processed by gelatin-polysuccinate density gradient sedimentation according to current Good Manufacturing Practice regulations at Cytonet Hannover. The final BMC preparation (26±4 mL) contained 24.6±9.4x10⁸ nucleated cells, 9.5±6.3x10⁶ CD34+ cells, and 3.6±3.4x10⁶ hematopoietic colony-forming cells. Six to 8 hours after bone marrow harvest, BMCs were infused into the infarct-related artery with a stop-flow balloon catheter technique. At 6±1 and 18±6 months after discharge, cardiac MRI was repeated in all patients. At these time points, the patient’s clinical status was assessed, and a detailed history was taken to document interim hospitalizations, medical procedures, and serious adverse events. During the entire study period, all patients were treated according to current practice guidelines with aspirin, a statin (if LDL cholesterol levels were >100 mg/dL), a ß-blocker, and an ACE inhibitor or angiotensin-receptor blocker, unless these agents were contraindicated.¹¹

Cardiac MRI
All MRI image analyses were performed by 2 investigators blinded for treatment assignment (J.L. and J.S.) using the MASS 4.0.1-software (Medical Imaging Systems, Leiden, the Netherlands). MRI was performed with the patient in supine position in a 1.5-T scanner (CV/i, General Electric, Chalfont St. Giles, United Kingdom) with ECG gating and a 4-element phased-array surface coil. For evaluation of LV volumes, repeated breath-hold fast-gradient echo sequences in a steady state with retrospective gating were used. Sequence parameters were as follows: repetition time (TR)/echo time (TE) 3.8/1.6 ms, 40° flip angle, 224±224 matrix, field of view 36 to 38 cm, in-plane resolution 1.6±1.6 to 1.7±1.7 mm, and 10 mm slice thickness. Scan planes were planned according to standard procedures.¹² An end-diastolic, horizontal long-axis plane of the LV at end-expiration provided the reference image on which a stack of contiguous short-axis slices was positioned to cover the LV from the apex to the atrioventricular ring. Contrast-enhanced MRI has been widely used to evaluate myocardial injury after myocardial infarction.^13–15 A gated breath-hold k-space segmented T1-weighted inversion-recovery gradient-echo sequence was used to cover the entire LV with 7- to 8-mm short-axis slices as described above (TR/TE 7.1/3.1 ms, 256±192 matrix, field of view 36 to 38 cm, and in-plane resolution 1.4±1.9 to 1.5±2.0 mm). Inversion time (180 to 220 ms) was individually adapted to null the signal of the myocardium. End-diastolic images (trigger delay two thirds of TR) were obtained starting 15 minutes after an intravenous bolus injection of 0.15 mmol/kg bodyweight gadobutrol, a gadolinium-based extracellular contrast agent (Schering, Berlin, Germany). The endocardial and epicardial borders were traced in all end-diastolic and end-systolic short-axis slices to determine LV end-diastolic and end-systolic volumes (LVEDV and LVESV) and LV mass. Global LVEF was calculated as [(LVEDV–LVESV)/LVEDV]x100. LVEDV, LVESV indices, and LV mass index were calculated by dividing LVEDV, LVESV, and LV mass by body surface area, which was determined according to DuBois’ formula. Regional LV function was assessed by determining systolic wall motion in the infarct region and border zone with a 16-segment model. Regional wall motion was defined as the systolic radial displacement of the endocardial contour (with positive values denoting inward motion). Wall thickening was defined as percent increase of LV wall thickness during systole compared with diastole. Myocardial segments showing late contrast enhancement at baseline were defined as the infarct region. Myocardial segments adjacent to the infarct region were defined as the border zone.¹⁶ For an assessment of infarct sizes, LV myocardium with late contrast enhancement volumes were quantified. Within the LV myocardial sector that displayed late contrast enhancement, infarct transmurality was defined as the ratio of the hyperenhanced (mostly subendocardial) region to the hyperenhanced plus nonhyperenhanced (mostly subepicardial) regions. Microvascular obstruction was assessed by quantification of areas within the infarcted area that showed hypoenhancement.¹⁷

LVEF was assessed in 14 MRI data sets by the 2 observers to determine interobserver variability. Intraobserver variability was determined by 1 observer reassessing the same 14 MRI data sets twice (>4 weeks apart). Interobserver and intraobserver variabilities were calculated as the square root of the mean variance of pairs of measurements, divided by the means of the observations, expressed as percentages. Interobserver and intraobserver variabilities of LVEF determination were 2.1% and 1.6%, respectively.

Study End Points and Statistical Analysis
Data are presented as mean±SD unless otherwise stated. Homogeneity of treatment groups at baseline was assessed with the Student unpaired t test for continuous variables that showed no marked deviations from the normal distribution. For other continuous variables or ordinal baseline data, the Wilcoxon rank sum test was used. Categorical baseline data were investigated with ² tests. Global LVEF changes from baseline to 6 and 18 months’ follow-up were defined as the primary end points of the BOOST trial. Changes in LVEDV index, LVESV index, LV mass index, regional wall motion and wall thickening, and volume of late contrast enhancement represented secondary end points. Global LVEF changes in the 2 study groups were compared with a mixed-effect model (SAS 9.1 PROC MIXED SAS Institute Inc, Cary, NC), which included time, group (BMC treatment), time-by-group interaction, and LVEF at baseline as fixed effects and a random intercept. Secondary end points were analyzed with the same methods. Because 1 control patient died before the final (18 months) follow-up examination, we used the last value (ie, 6-month value) carried-forward method in this patient at the 18 months time point.

Within the framework of the mixed-effect model, exploratory analyses were performed to identify prognostic subgroups with different improvements in global LVEF or with different benefit from BMC transfer with regard to sustained long-term improvement of global LVEF. All tests were performed as 2-sided tests at a significance level of 0.05.

The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.

	Results

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Patient Population, Safety Issues, and Clinical Outcome at 18 Months
Sixty patients were included in the study and randomized to the control and BMC transfer groups (30 patients in each group). Demographic, clinical, and angiographic baseline characteristics are summarized in Table 1. BMC harvest was well tolerated, and no bleeding complications at the harvest site were observed. Intracoronary BMC transfer was performed safely in all patients. There were no increases in troponin T serum levels in any of the patients 24 hours after intracoronary BMC transfer, which indicates that the procedure did not inflict additional ischemic damage to the myocardium. All patients underwent MRI at baseline, 6 months, and 18 months, except for 1 patient from the control group who died of progressive heart failure 9 months after randomization and who therefore did not undergo the MRI study at 18 months. During 18 months of follow-up, 3 patients from the control group and 1 patient from the BMC transfer group had to be hospitalized with decompensated heart failure (Table 2). One patient from the BMC transfer group developed a non–ST-segment elevation myocardial infarction in the left circumflex territory 4 months after cell transfer into the left anterior descending coronary artery. This patient underwent PCI of the left circumflex coronary artery and completed the study. Four patients from the control group and 5 from the BMC transfer group had to undergo repeat PCI of the infarct-related vessel. No subacute or late in-stent thrombosis or recurrent AMI in the infarct-related vessel was observed in any patient from the BMC transfer group. There were no significant differences between the 2 groups with regard to these clinical end points, a composite clinical end point, the incidence of syncope or documented sustained ventricular arrhythmias, or the New York Heart Association functional class at 18 months (Table 2). Echocardiography did not reveal any evidence of intramyocardial tumor formation or calcifications in any of the patients at 18 months. No case of cancer was diagnosed during follow-up.

View this table: [in this window] [in a new window]   TABLE 1. Patients’ Baseline Characteristics

View this table: [in this window] [in a new window]   TABLE 2. Clinical End Points at 18-Month Follow-Up

MRI at Baseline and at 6 and 18 Months of Follow-Up
At baseline, there were no significant differences between the control and BMC transfer groups in LV volume and mass indices, global LVEF, regional wall motion and wall thickening, or late contrast enhancement volume (Table 3). Transmural extent of the infarct at baseline was 61.0±16.5% and 61.4±18.5% in the control and BMC transfer groups, respectively (P=0.93); microvascular obstruction volume at baseline was 2.7±2.8 and 2.6±2.9 mL, respectively (P=0.85).

View this table: [in this window] [in a new window]   TABLE 3. LV Volume and Mass Indices, Global LEVF, Regional Wall Motion and Thickening, and Late Contrast Enhancement

View this table: [in this window] [in a new window]   TABLE 3. Continued

As shown in the Figure and in Table 3, mean global LVEF in the control group increased by 0.7 and 3.1 percentage points after 6 and 18 months, respectively. Mean global LVEF in the BMC transfer group increased by 6.7 and 5.9 percentage points after 6 and 18 months, respectively. As previously reported,⁸ the increase in global LVEF at 6 months was significantly greater in the BMC transfer group than in the control group (P=0.0026); however, global LVEF change at 18 months was not significantly enhanced in the BMC transfer group compared with the control group (P=0.27). The speed to LVEF recovery over the entire course of 18 months was significantly higher in the BMC transfer group (P=0.001).

View larger version (29K): [in this window] [in a new window]   Global LVEF at baseline and at 6- and 18-month follow-up. Global LVEF was determined by MRI at baseline and at 6- and 18-month follow-up (n=30 patients per group). The last value carried-forward method was applied in 1 patient from the control group (dashed line). P=0.27 for LVEF change from baseline to 18-month follow-up in the BMC transfer group vs control group with the PROC MIXED statistical model. There was a significant deviation from a parallel time course between groups, with faster recovery of global LVEF in the BMC transfer group (P=0.001).

LVEDV index tended to increase in the entire study cohort over the course of 18 months (P=0.06), whereas LVESV index in the entire study cohort did not change significantly during 18 months of follow-up. LV mass index and late contrast enhancement volume decreased significantly in the entire study cohort over the course of 18 months (P=0.0002 and P<0.0001, respectively). Regional wall thickening in the infarcted area and the border zone improved significantly in the entire study cohort during the 18 months of follow-up (P=0.0009 and P=0.01, respectively). Wall motion in the infarct region tended to improve after 18 months in the entire cohort (P=0.07). None of the differences between groups were statistically significant for any of these parameters (Table 3). Wall motion in the infarct border zone did not change significantly in the entire study population at 18 months (P=0.89); analysis of the time course of change revealed a transient improvement in the BMC transfer group after 6 months (P=0.01; Table 3). Overall, however, recovery of regional LV function from baseline to 18 months was not significantly different between both groups (Table 3).

Baseline Predictors of Sustained LVEF Improvement After BMC Transfer
Exploratory subgroup analyses were performed to identify baseline MRI parameters that may help to discriminate patients who might derive lasting benefit from BMC transfer. As shown in Table 4, greater LVEDV indices and greater volumes of late contrast enhancement at baseline predicted poor improvement in LVEF over the course of 18 months in the entire study cohort. Patients with an infarct transmurality at baseline greater than the median tended to benefit from BMC transfer with regard to global LVEF improvement throughout the 18-month study period; however, this observation was no longer significant after Bonferroni correction for multiple comparisons (P=0.20; Table 4).

View this table: [in this window] [in a new window]   TABLE 4. Baseline Predictors of Sustained LVEF Change

	Discussion

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Several small-scale clinical trials have suggested that intracoronary transfer of autologous BMCs may stimulate LV functional recovery in patients with AMI beyond the recovery seen with PCI with stent implantation and optimal postinfarction pharmacotherapy.^5–8 On the basis of these early clinical data and experimental results showing that certain BMC populations can enhance tissue perfusion and contractile performance of the infarcted heart,^1–4,18 it has been proposed that BMC transfer may provide a means to achieve "functional regeneration" after AMI.^9,19 However, previous clinical studies addressing the effects of BMC transfer after AMI have covered only limited time frames ranging from 3 to 6 months.^5–8 We have recently reported the 6-month follow-up data from the randomized BOOST trial, which revealed a significant improvement in regional LV function and global LVEF after intracoronary BMC transfer.⁸ The present 18-month follow-up investigation of the BOOST trial patient population supports the notion that BMC transfer is safe and is not associated with adverse clinical events, but it does not provide evidence that a single dose of BMCs is able to promote sustained improvements of regional LV function and global LVEF after AMI compared with a randomized control group.

Compared with the baseline investigation 3.5±1.5 days after PCI, mean global LVEF in the BMC transfer group improved by 6.7 percentage points after 6 months and by 5.9 percentage points after 18 months, consistent with a sustained improvement of LVEF. However, global LVEF also increased somewhat in the control group, by 0.7 percentage points at 6 months and 3.1 percentage points at 18 months, thus making the intergroup comparison at 18 months no longer statistically significant. Notably, analysis of the time course of LV functional improvements after AMI revealed a significantly faster recovery of global LVEF in the BMC transfer group than in the control group (P=0.001).

Is the trend toward LVEF improvement that we observed in the control group biologically plausible? Four MRI studies have looked at the evolution of LVEF in patients after AMI and have reported improvements ranging from 0 to 7 percentage points at 3 to 8 months compared with a baseline investigation 5 to 7 days after the acute event.^16,20–22 Unfortunately, no previous study has addressed the temporal trends of LVEF changes beyond a time frame of 8 months in post-AMI patients receiving contemporary interventional and medical therapy. Recent data from post-AMI patients included in the VALIANT (VALsartan In Acute myocardial iNfarcTion) trial (only 17.4% of whom underwent primary PCI) indicate that optimal neurohormonal blockade can promote incremental improvements in LVEF (+2.7 percentage points at 20 months).²³ Unfortunately, the time course of LVEF changes has not been analyzed in the VALIANT trial.²³ However, because patients in the BOOST trial received optimal neurohormonal blockade similar to that given to patients in VALIANT, the trend toward an improvement in LVEF in the control group may be realistic and not a play of chance.

If the beneficial effects of BMC transfer in the overall study cohort compared with the control group are not maintained during long-term follow-up, identification of patients who might show persistent LVEF improvements after cell transfer becomes crucial. However, among several baseline MRI parameters, including LVEDV index, global LVEF, volume and transmural extent of late contrast enhancement, and microvascular obstruction, no parameter could be identified that discriminated patients who responded to BMC transfer with lasting improvements of LVEF. Larger studies are required to further address this issue. The present study raises the issue of whether BMCs only transiently enhance cardiac contractility without promoting structural repair, or alternatively, whether BMCs expedite regenerative processes that also occur endogenously, albeit at a slower pace, in post-AMI patients receiving state-of-the-art pharmacotherapy. Although the BOOST trial was not designed to assess the underlying mechanisms whereby BMCs might affect LV function after AMI, our observation that BMCs did not reduce late contrast enhancement at 6 and 18 months argues against a substantial formation of new myocardial tissue. In addition, BMC transfer had no significant impact on LVEDV, which suggests that BMCs may have a limited effect on LV remodeling after AMI. Similar to our observations with unfractionated BMCs, myocardial transfer of bone marrow–derived mesenchymal stem cells in a rat model of AMI has been shown to only transiently improve LVEF independently of cardiomyocyte formation.²⁴ These observations indicate that mechanisms apart from cell incorporation and (trans)differentiation may contribute to the early functional effects of cell transplantation.^4,9,25–27

Ongoing multicenter studies, such as REPAIR-AMI (Remodeling in Acute Myocardial Infarction) and BOOST-2, need to further explore the long-term effects of intracoronary BMC transfer on LVEF after AMI. These studies will also provide more definitive data regarding the effects of BMC transfer on infarct sizes and LV remodeling, as well as treatment effects in prespecified subgroups. If it turns out that BMCs mediate only transient functional benefits, the effects of BMC transfer on clinical end points, such as the incidence of heart failure or long-term survival, might be limited. Possibly, repeated BMC applications after AMI might improve the long-term results; however, the logistical and economic implications of such an approach need to be considered. We have recently shown that fewer than 5% of transplanted BMCs are actually retained in the infarcted myocardium after intracoronary delivery,²⁸ which suggests that pharmacological or genetic strategies are warranted to enhance myocardial engraftment and to increase the therapeutic efficacy of BMCs after AMI.

	Acknowledgments

 
Disclosures

Dr Arseniev is business unit leader of Cytonet Hannover, the company that performed bone marrow cell sedimentations during the trial; he has not been involved in any way in MRI data collection or data analysis in this trial.

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CLINICAL PERSPECTIVE

Intracoronary transfer of autologous bone marrow cells (BMCs) may enhance recovery of left ventricular (LV) function in patients after acute myocardial infarction (AMI); however, clinical studies addressing the effects of BMCs after AMI have covered only limited time frames ranging from 3 to 6 months. The critical question of whether BMC transfer can have a sustained impact on left ventricular (LV) function has remained unanswered. In the BOne MarrOw transfer to enhance ST-elevation infarct regeneration (BOOST) trial, after percutaneous coronary intervention (PCI) for AMI, 60 patients were randomized 1:1 to a control group with optimal postinfarction therapy or a group that also received an intracoronary BMC infusion 5 days after PCI. Cardiac MRI was performed 6 and 18 months after PCI. Intracoronary BMC infusion was not associated with adverse clinical events. In the control group, mean global LV ejection fraction increased by 0.7 and 3.1 percentage points after 6 and 18 months, respectively. LV ejection fraction in the BMC group increased by 6.7 and 5.9 percentage points. The difference in LV ejection fraction improvement between groups was significant after 6 months but not after 18 months. In summary, in this study, a single dose of intracoronary BMCs did not provide long-term benefit on LV systolic function after AMI compared with a randomized control group.

	Footnotes

 
*Drs Meyer and Wollert contributed equally to this work.

The URL for the clinical trial registry is www.clinicaltrials.gov. The registration number for the clinical trial is NCT00224536.

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