CLINICAL PERSPECTIVE

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(Circulation. 2007;116:366-374.)
© 2007 American Heart Association, Inc.

Coronary Heart Disease

Restoration of Microvascular Function in the Infarct-Related Artery by Intracoronary Transplantation of Bone Marrow Progenitor Cells in Patients With Acute Myocardial Infarction

The Doppler Substudy of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) Trial

Sandra Erbs, MD; Axel Linke, MD; Volker Schächinger, MD; Birgit Assmus, MD; Holger Thiele, MD; Klaus-Werner Diederich, MD; Christina Hoffmann, MD; Stefanie Dimmeler, PhD; Torsten Tonn, MD; Rainer Hambrecht, MD; Andreas M. Zeiher, MD; Gerhard Schuler, MD

From the University of Leipzig, Heart Center, Department of Cardiology, Leipzig (S.E., A.L., H.T., K.-W.D., R.H., G.S.); J.W. Goethe University Frankfurt, Departments of Cardiology (V.S., B.A., S.D., A.M.Z.) and Transfusion Medicine (T.T.), Frankfurt; and Heart and Diabetes Center NRW, Ruhr University of Bochum, Bad Oeynhausen (C.H.), Germany.

Correspondence to Sandra Erbs, MD, University of Leipzig, Heart Center, Department of Internal Medicine/Cardiology, Struempellstrasse 39, 04289 Leipzig, Germany. E-mail Sandra.Erbs{at}medizin.uni-leipzig.de

Received November 3, 2006; accepted May 3, 2007.

	Abstract

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Background— The Doppler Substudy of the randomized, double-blind, placebo-controlled Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial aimed to investigate the effects of intracoronary infusion of bone marrow–derived progenitor cells (BMCs) on coronary blood flow regulation in patients with reperfused acute myocardial infarction.

Methods and Results— In a total of 58 patients (BMC group, n=30; placebo group, n=28), coronary flow reserve (CFR) in the infarct artery and a reference vessel was assessed by intracoronary Doppler at the time of study therapy (4.2±0.1 days after acute myocardial infarction) and at the 4-month follow-up. Initial CFR was reduced in the infarct artery compared with the reference vessel in both groups (BMC: 2.0±0.1 versus 2.9±0.2, P<0.05; placebo: 1.9±0.1 versus 2.8±0.2; P<0.05). At the 4-month follow-up, CFR in the infarct artery had slightly improved in the placebo group (+0.88±0.18; P<0.001 versus initial) but was markedly increased by 90% (+1.80±0.25; P=0.005 versus placebo) in BMC-treated patients, resulting in a normalization of CFR (3.8±0.2; P<0.001 versus initial and placebo at 4 months). In the infarct vessel, adenosine-induced minimal vascular resistance index declined slightly in the placebo group (from 1.77±0.12 to 1.52±0.15 mm Hg · s/cm; P<0.05) but considerably decreased by –29±6% in the BMC group (from 1.86±0.19 to 1.20±0.12 mm Hg · s/cm; P<0.05 versus initial and placebo at 4 months).

Conclusions— Intracoronary BMC therapy after acute myocardial infarction restores microvascular function of the infarct-related artery, which is associated with a significant improvement in maximal vascular conductance capacity. These data provide clinical proof of concept that progenitor cell transplantation promotes vascular repair.

Key Words: angiogenesis • cells • microcirculation • myocardial infarction

	Introduction

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Therapeutic application of bone marrow–derived progenitor cells (BMCs) was shown to be associated with functional cardiac repair, as evidenced by an attenuation of left ventricular remodeling, an improvement in contractile function, and an increase in myocardial perfusion in both experimental and clinical studies of acute or chronic myocardial ischemia.^1–10 The Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial, which was the first double-blind, placebo-controlled, randomized multicenter study to evaluate the effect of intracoronary transplantation of BMCs on infarct remodeling, recently confirmed that intracoronary infusion of enriched BMCs is indeed linked to improved global left ventricular function in patients with acute myocardial infarction (MI).^11,12 However, it is less clear how progenitor cells exert their beneficial effects in humans. The following mechanisms are anticipated: prevention of apoptosis of cardiomyocytes in the infarct border zone by survival factors, which are secreted form the injected progenitor cells; induction of collateral growth; and reconstitution of the microcirculation either directly through promotion of vasculogenesis or as a result of repair of the damaged endothelial layer.^13–16 The last hypothesis is supported by the Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trial, which was not placebo controlled and suggested that intracoronary transplantation of progenitor cells effectively improves coronary flow reserve (CFR) in the infarct-related artery in patients with successfully reperfused acute MI (AMI).^6,16 On the basis of these results, the Doppler Substudy of the randomized, double-blind, placebo-controlled, multicenter REPAIR-AMI trial was conducted to determine the effects of intracoronary transplantation of BMCs on the recovery of vasomotor function in the infarct-related artery and therefore to provide mechanistic insights into the effects of BMCs on the healing process after ischemic myocardial damage.

Clinical Perspective p 374

	Methods

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Patient Selection and Study Protocol
The study design, inclusion and exclusion criteria, primary and secondary end points, and prespecified substudies have been described previously.^11,12 Briefly, patients with acute ST-segment elevation MI successfully treated by percutaneous coronary intervention with stent implantation in the acute phase of the infarction were included in the study. At 3 to 7 days after MI, mononuclear cells were recovered from 50 mL bone marrow aspirate by Ficoll-Hypaque (Pharmacia, Uppsala, Sweden) in a total of 204 patients. The entire process, from bone marrow aspiration to the finished product, was performed according to Good Manufacturing Practice guidelines, and a manufacturing license according to the German drug law was granted by the local authorities to the central cell processing laboratory. The detailed processing of the bone marrow aspirate and the characterization of the progenitor cells have been reported previously.^11,12 The study was approved by the Paul-Ehrlich Institute (Langen, Germany) and the ethics committees of all participating centers and was conducted in accordance with the Declaration of Helsinki.

Fifty-eight of the above-mentioned patients participated in the Doppler Substudy. Patients randomized to the BMC group were treated by intracoronary administration of the BMCs, whereas patients in the placebo group received cell-free medium and autologous serum in the coronary circulation of the reopened infarct-related artery.

Invasive Measurement of Coronary Vasodilator Function
Coronary vasodilator capacity was measured as previously described in detail.^12,16 Briefly, the left or right coronary artery was cannulated with a 5F or 6F catheter. Before the assessment of coronary blood flow, 0.2 mg nitroglycerin was administered directly into the coronary circulation to achieve a maximal dilatation of the epicardial vessels without substantially affecting the microcirculation. Afterward, a guidewire containing a 12-MHz pulsed Doppler ultrasound velocimeter (Flowire, Volcano Corp, Rancho Cordova, Calif; FlowMAP, Cardiometrics and Endosonics, Rancho Cordova, Calif) was positioned in the infarct-related artery directly distal to the previously implanted stent. The average peak flow velocity (APV) measured by the Doppler velocimeter was continuously registered under baseline conditions and during intravenous adenosine infusion (140 µg/kg body weight). Subsequently, the Doppler wire was advanced into a noninfarcted reference vessel not undergoing percutaneous coronary intervention, and the measurements were repeated. The position of the Doppler wire in the infarct and the reference vessel was documented by biplane coronary angiography. After Doppler measurements, an over-the-wire balloon catheter (Opensail, Guidant, Santa Clara, Calif) was advanced into the stent previously implanted during the reperfusion procedure, and administration of BMCs or placebo was performed by the stop-flow technique as previously described.^11,12 At the 4-month follow-up, intracoronary Doppler recordings were repeated using identical positioning of the tip of the Doppler wire in both the infarct-related and reference vessels.

Reproducibility of the intracoronary Doppler measurements was assessed in 20 patients of the present study. Very close correlation existed between different baseline measurements of APV at 1 investigation (r=0.99, P<0.0001; n=20), with an intrameasurement variability of 6.6±1.6% documenting excellent reproducibility. Similar correlations with regard to baseline APV assessment and CFR measurements were observed in our previous validation studies.^8,17

Parameters of Coronary Flow
Volumetric blood flow at baseline or hyperemic conditions was calculated as 0.125 times times APV (basal or after adenosine infusion) times the square of inner lumen diameter of the coronary artery.¹⁶ Lumen diameter immediately distal to the Doppler tip was determined by quantitative coronary angiography as previously described.¹⁶ Basal and minimal coronary vascular resistance indexes were calculated as mean arterial pressure divided by APV measured by the Doppler wire at baseline and during adenosine-induced maximal coronary vasodilatation, respectively. CFRs of the infarct-related artery and the reverence vessel were computed as the ratio of adenosine-induced APV and APV at baseline.¹⁸ Relative CFR was calculated by dividing the CFR of the infarct-related artery by the CFR of the reference vessel.¹⁶

Statistical Analysis
Continuous variables were tested for normal distribution by the Kolmogorov-Smirnov test and for homogeneity of variance by Levene’s test. Comparisons within each group and between the groups were performed with 2-way repeated-measures ANOVA, followed by a Tukey post hoc test, when appropriate. In case of a nonnormal distribution of the data, a Mann-Whitney U test or a Wilcoxon signed-rank test was applied for the intergroup or intragroup comparisons, respectively.

A Mann-Whitney U test was used to compare the absolute and the percentage changes (from the initial study to the follow-up assessment at 4 months) between the 2 groups in case of a nonnormal distribution of the data. Otherwise, a t test was applied. Categorical variables were tested by ² test or Fisher exact test. A value of P<0.05 by 2-sided testing was considered to indicate statistical significance, which is liberal in the context of multiple testing because it does not control for type I error at the 5% level. In this case, use of a Bonferroni-adjusted threshold (0.05/20) would prevent severe inflation of type I error.

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

	Results

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Patient Population and Baseline Characteristics
A total of 58 patients signed informed consent to participate in the Doppler Substudy of the REPAIR-AMI trial: 32 patients at the University of Leipzig, 23 at the J.W. Goethe University in Frankfurt, and 3 at the Heart and Diabetes Center NRW in Bad Oeynhausen. Thirty of these patients were randomized to receive BMCs (BMC group) and 28 to receive placebo medium (placebo group) in the infarct-related artery at 3 to 7 days after AMI (Figure 1). The 2 groups did not differ with respect to demographic, clinical, or angiographic parameters and medication during the study course (Table 1).

View larger version (11K): [in this window] [in a new window]   Figure 1. Study flow diagram. In the REPAIR-AMI trial, after successful bone marrow aspiration, 101 patients were randomized to receive BMCs, and 103 patients were randomized to placebo. Thirty patients in the BMC group and 28 in the placebo group participated in the intracoronary Doppler Substudy. One patient in the placebo group died before the 4-month follow-up; in 2 patients, a significant restenosis in the infarct-related artery or the left main coronary artery requiring percutaneous coronary intervention prevented a reliable assessment of coronary endothelial function at the 4-month follow-up (1 patient in the BMC group, 1 patient in the placebo group); and in 1 patient (BMC group), the measurements could not be performed at the 4-month follow-up because of technical problems with the equipment. Therefore, paired data on the coronary hemodynamics in the infarct-related artery are available in 28 patients in the BMC group and 26 patients in the placebo group.

View this table: [in this window] [in a new window]   TABLE 1. Clinical Characteristics, Infarct Treatment, and Study Therapy

Paired measurements of coronary hemodynamics in the infarct-related artery were available in 28 patients of the BMC group and in 26 patients of the placebo group at the initial study and the 4-month follow-up (Figure 1). One patient in the placebo group died before the 4-month follow-up, excluding a paired analysis; in 2 patients, a significant stenosis in the infarct-related artery (restenosis) or a reference vessel requiring percutaneous coronary intervention prevented reliable assessment of coronary vasodilator function at the 4-month follow-up (1 patient in the BMC group, 1 patient in the placebo group); and in 1 patient (BMC group), the measurements could not be performed at the 4-month follow-up because of technical problems with the equipment. In another patient of the BMC group, the Doppler guidewire could not be advanced into the reference vessel; therefore, paired data on the coronary hemodynamics in the reference vessel are available in 27 patients in the BMC group and in 26 patients in the placebo group (Figure 1).

Initial Coronary Microvascular Function at the Time of Study Therapy
Combined Analysis of the Placebo and BMC Groups
At the initial study before intracoronary administration of BMCs or placebo, basal APV in the infarct-related artery (25±1 cm/s) was 25% higher compared with the reference vessel (20±2 cm/s; P=0.006). Consequently, the baseline coronary vascular resistance index in the infarct vessel (3.7±0.3 mm Hg · s/cm) was reduced by –23% compared with the reference artery (4.8±0.3 mm Hg · s/cm; P=0.005).

In contrast, CFR was severely impaired in the infarct-related coronary artery (1.96±0.08) compared with the reference vessel (2.84±0.12; P<0.001). Consistently, the adenosine-mediated minimal coronary vascular resistance index was slightly higher in the infarct vessel (1.88±0.13 mm Hg · s/cm) than in the reference artery (1.62±0.08 mm Hg · s/cm; P=0.037).

Coronary Microvascular Function at the 4-Month Follow-Up
Lumen diameter of the infarct-related artery and the reference vessel remained constant over time in the BMC and placebo groups, respectively. In contrast, resting mean blood pressure increased, whereas heart rate declined in both groups during the study period. However, no significant differences existed between the 2 groups (Table 2).

View this table: [in this window] [in a new window]   TABLE 2. Coronary Hemodynamics

Infarct-Related Artery
In the BMC group, CFR in the infarct-related artery increased by 90% from 2.0±0.1 at the initial study to 3.8±0.2 at the 4-month follow-up (P<0.001 versus initial, P=0.004 versus placebo at 4 months), implicating a normalization of microvascular function in response to BMC administration (Table 2 and Figure 2). This was associated with a considerable decrease in adenosine-induced minimal vascular resistance by –29±6% in the BMC group (P<0.001 versus initial, P=0.026 versus placebo; Table 2 and Figure 3A). In contrast, in the placebo group, only a partial recovery of CFR by 47% from 1.9±0.1 at the initial study to 2.8±0.2 at the 4-month follow-up was observed in the infarct artery (P<0.001 versus initial; Table 2 and Figure 2), and the adenosine-induced minimal vascular resistance index declined only slightly by –14% during this time period (Table 2 and Figure 3A). The results did not differ when those patients suffering a clinical event (revascularization of infarct vessel in 1 patient in each group; no reinfarctions within the 4-months follow-up period) were excluded from analysis.

View larger version (15K): [in this window] [in a new window]   Figure 2. CFR in the infarct artery. A, Individual changes in CFR from the initial study (initial) to the 4-month follow-up in the BMC group (left) and placebo group (right). The mean±SEM values for the CFR at the initial study and 4-month follow-up also are depicted. P<0.001 vs initial study within the BMC and placebo groups; P=0.004 vs placebo group at the 4-month follow-up (2-way repeated-measures ANOVA, followed by a Tukey post hoc test). B, Absolute change in infarct vessel CFR in the BMC group (left, open bar) and placebo group (right, filled bar). P=0.005 vs placebo group (t test).

View larger version (10K): [in this window] [in a new window]   Figure 3. A, Change in minimal resistance index during adenosine infusion in the infarct-related artery in patients in the BMC group (left, open bar) and placebo group (right, filled bar) from the initial study to the 4-month follow-up. P=0.026 vs placebo group (by t test). B, Change in reference vessel CFR in patients of the BMC group (left, open bar) and placebo group (right, filled bar) from the initial study to the 4-month follow-up. P=NS (t test). C, Change in relative CFR in patients in the BMC group (left, open bar) and placebo group (right, filled bar) from the initial study to the 4-month follow-up. The change in relative CFR was calculated as the difference between the ratio of CFR of the infarct-related artery and the CFR of the reference vessel at the initial study and at the 4-month follow-up. P=0.021 vs placebo group (t test).

Reference Vessel
In the BMC group, CFR in the reference vessel tended to increase by 14% during the study period of 4 months. In the placebo group, the improvement in CFR from 2.8±0.2 at the initial study to 3.4±0.2 at 4 months reached the level of statistical significance (P=0.02 versus initial study; Figure 3B). Nevertheless, adenosine-induced minimal vascular resistance index did not change significantly in the reference vessel in either the BMC group or the placebo group (Table 2). Again, the results did not differ when the patients with revascularizations of the reference vessel were excluded (n=3 in the placebo, n=1 in the BMC group; no reinfarctions within the 4-month follow-up period).

Relative Changes in Coronary Hemodynamics
The improvement in relative CFR was 0.6±0.2 in BMC-treated patients but only 0.2±0.2 in the placebo group (P<0.05) during the study period (Figure 3C). Consistently, in the placebo group, the CFR in the infarct vessel was still blunted compared with the reference vessel, suggesting a persistent impairment of microvascular function in the target vessel in these patients 4 months after the index infarction (Table 2). In contrast, in BMC-treated patients, CFR in the infarct-related artery and reference vessel did not differ significantly any more at the 4-month follow-up, which is consistent with a restoration of microvascular vasodilator function in the infarct-related coronary artery (Table 2). In the BMC group, no correlation existed between the increase in CFR and improvement in global left ventricular ejection fraction as measured by quantitative angiography (r=0.02, P=0.915; n=27).

	Discussion

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In the Doppler Substudy of the REPAIR-AMI trial, intracoronary infusion of BMCs in patients with reperfused AMI was associated with a normalization of CFR in the infarct-related artery within 4 months and hence a profound improvement in maximal vascular conductance capacity. Therefore, these data support the hypothesis that BMCs infused into the coronary circulation reconstitute damaged endothelium and promote neovascularization in the area of the infarct vessel in patients with AMI.

Vasodilator Function in the Infarct-Related Artery
The normalization of CFR in the infarct-related artery of BMC-treated patients is consistent with the hypothesis that BMCs counteract the adverse remodeling of the vascular tree in the infarcted area. The following mechanism might account for this observation: dysfunctional microvessels in the infarcted area and/or the border zone were replaced by new, functionally competent vessels, leading to enhanced neovascularization. This hypothesis is supported by numerous animal and human studies, connecting an intra-arterial or intramyocardial injection of BMCs to an enhanced neovascularization, repair of damaged endothelium in the target area, or improvement in left ventricular performance.^{1–9,15,19,20} Moreover, it is conceivable that growth factors and cytokines released from the injected progenitor cells promote the remodeling and growth of surviving blood vessels in the infarct border zone, thereby reconstituting blood supply to the myocardium.^1,13,14,21 Those cytokines and growth factors also might prevent the death of myocytes in the border zone of the infarct in a paracrine fashion.^1,13 Because blood supply matches the metabolic demands, the progenitor cell–mediated rescue of myocardial tissue and consequently higher metabolic demand might lead to better recovery of CFR compared with placebo-treated patients.²² Additionally, it cannot be ruled out that cytokines released from the injected progenitor cells promote the recruitment of endogenous cardiac stem cells, which contribute to neovascularization and cardiac repair.^21,23,24

However, besides improved microvascular perfusion, other effects on myocyte function and tissue biomechanics may contribute to recovery of left ventricular contractile function after progenitor cell therapy. Because of this pathophysiological heterogeneity and the limited sample size in the present study, it is not surprising that we could not demonstrate a direct correlation between the improvement in ejection fraction and CFR in the present data set.

In accordance with previous studies, CFR also improved significantly in the infarct-related artery of the placebo group.^25–28 This augmentation is most likely the combined result of changes in vasomotor tone, in regional wall motion and hence oxygen demand, and in the distribution volume of the microcirculation.²⁹ Additionally, enhancement of microcirculatory function as a result of vasoactive properties of statins and angiotensin-converting enzyme inhibitors has to be taken into account.^30,31 These adaptations also play a role in the recovery of CFR in BMC-treated patients.³² However, in line with previous studies, at the 4-month follow-up, CFR remained blunted in the infarct-related artery of patients in the placebo group compared with the BMC-treated patients and healthy subjects.³²

Vasodilator Function in the Reference Vessel
CFR in the reference vessel increased by approximately the same amount in both groups during the study period. These data suggest that BMCs selectively administered into the infarct-related artery do not exert systemic vascular effects. The increase in CFR by 0.6±0.1 in the reference vessel in the BMC group is in agreement with data from the previously published TOPCARE-AMI trial.¹⁶ The improvement in vasodilator function in the reference vessel in both groups is not surprising and most likely is related to the fact that the concentration of inflammatory cytokines, which are maximally elevated during the acute phase of MI and are known to cause vascular dysfunction, decline during infarct healing.³³ Additionally, most of the patients received statins and angiotensin-converting enzyme inhibitors, which are known to improve vascular function and therefore also reduce minimal coronary resistance.^{25–28,30,31}

Validity of CFR as a Measure of Microvascular Function
CFR, as assessed invasively, represents a combined measure of the resistance of epicardial vessels, small arteries, arterioles, and the intramyocardial capillary system.¹⁷ Although, in the absence of flow-limiting obstruction, resistance of the epicardial coronary arteries is almost negligible and small arteries and arterioles with a diameter of >400 µm have only minimal resistance to flow, it should be emphasized that coronary arteries with seemingly nonsignificant disease often show multiple irregularities in series that eventually produce significant obstacles to flow at the epicardial level.^34,35 Because we did not measure hyperemic gradients across the epicardial vasculature, we cannot exclude that this may potentially confound our CFR measurements and calculations of vascular resistance. However, given the double-blind, placebo-controlled design of the study and the virtually identical CFR responses in the reference vessels in both groups, it is unlikely that differences in gradients across the epicardial vasculature could explain the profound differences observed in the infarct-related artery.

Study Limitations
Obviously, the clinical relevance of restoring microvascular function by infusing BMCs into the infarct-related artery is restricted to the study procedures applied in the REPAIR-AMI trial. It should be noted that previous, smaller randomized trials of intracoronary infusion of BMCs provided controversial results. Although the Janssens et al¹⁰ trial demonstrated a significant decrease in infarct size as measured by magnetic resonance imaging–derived late enhancement, no significant difference in the increase in global ejection fraction could be observed between the BMC and placebo groups. Although the cell isolation procedures appear to be similar in the Janssens et al study and the REPAIR-AMI trial, the timing of intracoronary BMC administration differed significantly; cells were administered within 24 hours after reperfusion therapy for AMI in the Janssens et al trial compared with 3 to 7 days after reperfusion in REPAIR-AMI. Indeed, as previously published,¹¹ the beneficial effects of BMC administration on ejection fraction in REPAIR-AMI were confined to patients receiving cells at day 4 to 7 after AMI reperfusion therapy. In the randomized but not placebo-controlled Autologous Stem Cell Transplantation in Acute Myocardial Infarction (ASTAMI) trial, recovery of ejection fraction did not differ between the cell- treated and control groups.³⁶ However, it was recently demonstrated that cell isolation procedures and storage conditions used in the ASTAMI protocol are associated with a profound functional impairment of BMCs compared with the extensively characterized and functionally validated BMCs used in the REPAIR-AMI trial.³⁷ Moreover, as reported in the original ASTAMI publication, 2 of the cell preparations obtained in the ASTAMI protocol were contaminated by staphylococcus.³⁶ Thus, differences in the functional activity of the isolated BMC might at least in part account for some of the controversial results reported previously.

Conclusions and Clinical Implications
It has been demonstrated that coronary microvascular dysfunction is associated with a poor cardiovascular outcome in various stages of disease^38,39 and predicts mortality after an AMI.⁴⁰ Therefore, it is intriguing to speculate that improvement in CFR may have contributed importantly to the reduced cardiovascular event rate at the 1-year follow-up observed in the overall REPAIR-AMI trial in patients treated with BMCs.⁴¹ Thus, larger randomized outcome trials are urgently needed to assess the effects of progenitor cell therapy on prognosis in patients with AMI.

	Acknowledgments

 
Sources of Funding

This work was supported by an unrestricted research grant from Guidant. Guidant provided balloon catheters, and Elli Lilly provided the abciximab.

Disclosures

Dr Schächinger and Dr Zeiher report having received consulting fees from Guidant. Dr Dimmeler reports having received consulting fees from Guidant and Genzyme. Drs Dimmeler and Zeiher report that they are cofounders of t2cure, a for-profit company focused on regenerative therapies for cardiovascular disease. They serve as scientific advisors and are shareholders. The other authors report no conflicts.

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CLINICAL PERSPECTIVE

The Doppler Substudy of the randomized, double-blind, placebo-controlled Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial evaluated the effects of intracoronary infusion of bone marrow–derived progenitor cells on coronary blood flow regulation in patients with reperfused acute myocardial infarction. At the 4-month follow-up, coronary flow reserve in the infarct artery was markedly increased in bone marrow–derived progenitor cell–treated patients, resulting in normalization of coronary flow reserve compared with only a moderate improvement in the placebo group. Therefore, these data support the hypothesis that bone marrow–derived progenitor cells, which are infused into the coronary circulation, reconstitute damaged endothelium and promote neovascularization in the area of the infarct vessel in patients with acute myocardial infarction. Because coronary microvascular dysfunction is associated with a poor cardiovascular outcome in various stages of disease and predicts mortality after acute myocardial infarction, it is intriguing to speculate that improvement of coronary flow reserve may have contributed to a reduced cardiovascular event rate at the 1-year follow-up observed in the overall REPAIR-AMI trial in patients treated with bone marrow–derived progenitor cells. However, larger randomized outcome trials are urgently needed to assess the effects of progenitor cell therapy on prognosis in patients with acute myocardial infarction.

	Footnotes

 
Clinical trial registration information—URL:http://www.clinicaltrials.gov. Unique identifier: NCT00279175.

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