Effects of peripheral blood stem cell mobilization with granulocyte ...

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Sheehan et al13 was performed by an independent specialist using the Quantcor V4.0 ..... Giugliano RP, Braunwald E. Selecting the best reperfusion strategy in ST-elevation ... Chakraborty A, Hentzen ER, Seo SM, et al. Granulocyte colony-.
Effects of peripheral blood stem cell mobilization with granulocyte–colony stimulating factor and their transcoronary transplantation after primary stent implantation for acute myocardial infarction Clemens Steinwender, MD,a Robert Hofmann, MD,a Ju ¨ rgen Kammler, MD,a Alexander Kypta, MD,a b b Robert Pichler, MD, Wilma Maschek, MD, Gerhard Schuster, MD,c Christian Gabriel, MD,c and Franz Leisch, MDa Linz, Austria

Background There is increasing evidence that transplantation of autologous stem cells improves cardiac function after acute myocardial infarction (AMI). For propagation of peripheral blood stem cells (PBSCs), application of granulocyte–colony stimulating factor (G-CSF) has been shown to be feasible, effective, and safe. We sought to evaluate a clinical and angiographic long-term safety profile of G-CSF application combined with transcoronary PBSC transplantation after recent stent implantation for AMI. Methods In patients with AMI and successful primary stenting of the infarct-related coronary artery, pharmacological bone marrow stimulation with G-CSF was initiated on the second postinterventional day. At least after 4 days of G-CSF therapy, apheresis as well as transcoronary transplantation of PBSCs was performed. The PBSCs were infused via a balloon catheter which was inflated inside the stent. Ventriculography and quantitative coronary angiography were performed at baseline and after 6 months. Results In the 20 patients who received PBSCs, mean left ventricular ejection fraction improved from 46.4% F 8.1% at baseline to 54.3% F 11% after 6 months ( P b .001) because of an increase in systolic function in the infarct region. Control coronary angiography revealed a significant in-stent restenosis of the infarct-related coronary artery, defined as N50% stenosis, in 8 patients (40%), which was complicated by reinfarction in 2 patients (10%). Conclusions Transcoronary transplantation of G-CSF–mobilized PBSCs favorably influences cardiac function and can be performed without adverse periprocedural events. However, significant in-stent restenosis and reinfarction seem to occur frequently during the following 6 months. (Am Heart J 2006;151:1296.e72 1296.e13.) In patients with acute myocardial infarction (AMI), reperfusion of the occluded coronary artery by percutaneous coronary intervention (PCI) significantly improves acute and late clinical outcome.1 Nevertheless, myocardial necrosis cannot be completely prevented in the vast majority of patients.2 The evolving scar causes regional akinesis and secondarily triggers adverse myocardial remodeling, resulting in chamber dilatation and diffuse contractile dysfunction.3-5

From the aCardiovascular Division, City Hospital Linz, Linz, Austria, bDepartment of Nuclear Medicine, City Hospital Linz, Linz, Austria, and cBlood-Central Linz, Linz, Austria. Submitted January 1, 2006; accepted March 20, 2006. Reprint requests: Clemens Steinwender, MD, Cardiovascular Division, City Hospital Linz, Krankenhausstrage 9, A-4020 Linz, Austria. E-mail: [email protected] 0002-8703/$ - see front matter n 2006, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2006.03.012

Although medical therapy can positively influence remodeling processes, the primum movens, the scar itself, remains unaffected. In animal experiments, transplantation of embryonic stem cells or pluripotent progenitor cells into necrotic myocardium has been shown to improve perfusion and systolic function.6,7 Small clinical studies reported that transplantation of bone marrow cells including hematopoietic stem cells promotes neovascularization and sustained improvement of ventricular performance after AMI. However, these patient collectives differed as well as the methods of cell harvest and the time and route of transplantation, giving rise to various methodical challenges and complications.8-11 We performed an observational study to investigate the feasibility, effectiveness, and side-effects of transcoronary transfer of adult hematopoetic peripheral blood stem cells (PBSCs) in patients with AMI. The cells

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were derived from peripheral blood by apheresis after pharmacological bone marrow stimulation with granulocyte–colony stimulating factor (G-CSF). To evaluate the effects of cell therapy as a pure add-on therapy, only patients with recent successful stenting of the infarctrelated coronary artery (IRA) were enrolled.

Methods Study protocol The study was a nonrandomized prospective observational trial, which was designed to investigate the feasibility, effectiveness, and potential harm of the transcoronary transplantation of G-CSF–mobilized PBSCs after recent primary stent implantation for AMI. The local institutional review board approved the protocol. A written informed consent was obtained from the patients after having explained the procedure and its risks. Only patients with acute transmural myocardial infarction, successful primary stenting of the IRA, and extensive akinetic myocardium in ventriculography were enrolled. To induce proliferation and mobilization of PBSCs, we initiated pharmacological stimulation with G-CSF on the second day after primary PCI. Having achieved a peak of PBSCs in the peripheral blood, we performed cell apheresis and transplantation on the same day. For this purpose, the PBSC suspension was injected into the IRA through a balloon catheter, which was inflated within the implanted stent. Stress echocardiography and treadmill ergometer exercise with 201-thallium single-photon emission computed tomography (SPECT) were performed 2 weeks after enrolment and after 6 months, whereas ventriculography and coronary angiography were done at baseline and at 6-month follow-up. All data and measured values were obtained prospectively.

Patient selection Patients with a first ST-segment elevation myocardial infarction and successful stenting of the IRA who had been admitted within 12 hours after the onset of symptoms were eligible for enrolment. With regard to cytokine therapy, we excluded patients who were older than 75 years or had splenomegaly, thrombocytopenia (b120 000/mm3), recent major surgery, or evidence of bacterial infections.

Primary PCI Primary PCI was performed immediately after admission to the intermediate care unit. Antithrombotic premedication consisted of a loading dose of 500 mg of aspirin, 300 mg of clopidogrel, and a weight-adjusted abciximab bolus. Percutaneous intervention of the IRA was performed according to standard techniques with stent implantation being mandatory. Guiding catheters, guidewires, balloons, and stents (bare-metal or drug-eluting stents) were chosen at the investigators decision. After primary PCI, an observational period of 48 hours in the intermediate care unit followed.

Bone marrow stimulation and apheresis The second day after primary PCI pharmacological stimulation with subcutaneous injections of filgastrim, a G-CSF (Neupogen, Amgen, Thousand Oaks, CA) was initiated.

The daily dose of G-CSF at 10 lg/kg body weight was divided into 2 applications with a maximum dose of 960 lg/d. At a minimal application period of 4 days, the ideal time for apheresis was identified by the CD34+ cell/leukocyte ratio in peripheral blood probes, which had to exceed 0.1%. To ensure a minimum concentration of 1  106 CD34+ cells per milliliter of produced cell suspension, irrespective of the ratio, we considered patients with a maximum CD34+ cell count b10 per microliter of blood as bpoor mobilizersQ and therefore not qualified for apheresis. Having achieved the defined boost of CD34+ cells in the peripheral blood, we produced a highly concentrated mononuclear cell suspension by the use of COBE spectra apheresis (Gambro BCT, Lakewood, CO) with mononuclear cell collection methods as recommended by the manufacturer.12 No additional procedures of cell preparation were performed. Considering the unavoidable high number of platelets in the produced suspension, a negative platelet activation test of a product probe was mandatory before intracoronary infusion.

Cell transfer Direct injection of PBSCs into the IRA was performed via an over-the-wire angioplasty balloon catheter (Maverick, Boston Scientific, Natick, MA) on the same day as apheresis. Moderate but prolonged inflation of the balloon was planned to prevent backflow of PBSC and to ensure a sufficient contact time of the cells with the infarcted tissue. Before the procedure, 0.8 mg of sublingual nitrogycerin and an intravenous heparin bolus (100 IE/kg body weight) were administered. The balloon was positioned and inflated inside the stent. During a continuous inflation time of 3 minutes, 3 mL of PBSC suspension was slowly injected through the lumen of the catheter. Balloon inflation pressures did not exceed 4 atm. The procedure was repeated twice after an interval of another 3 minutes with the balloon deflated. After balloon catheter retraction, a control angiography of the IRA was done to demonstrate unimpeded antegrade blood flow. After cell transplantation, all patients were monitored in the intermediate care unit until the next morning and were scheduled for discharge after another day.

Angiography and hemodynamics Left ventriculography using a 308 right anterior oblique as well as a 608 left anterior oblique plane and coronary angiography were performed immediately before PBSC transplantation and after 6 months. Calculation of left ventricular volumes and ejection fraction as well as quantification of the infarct region using the centerline method according to Sheehan et al13 was performed by an independent specialist using the Quantcor V4.0 software (Pie Medical Imaging, Maastricht, The Netherlands). Quantitative coronary angiography (Quantcor V4.0) of the stented segment of the IRA was performed after PBSC transplantation and after 6 months. Coronary angiograms were evaluated for binary in-stent restenosis (ISR), in-stent late lumen loss, minimal lumen diameter, and plaque volume of the stented segment. Restenosis was defined as a diameter stenosis of N50% within the stent.

Stress echocardiography and 201-thallium SPECT Transthoracic dobutamine stress echocardiography was performed to calculate the left ventricular wall motion score

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index (WMSI), defined as the average sum of wall motion scores at rest and after 20 lg/kg dobutamine infusion according to the standards of the American Society of Echocardiography.14 Ergometric stress by treadmill exercise was combined with intravenous 70 to 100 MBq thallium-201–chloride injection at peak stress. Using the PICKER PRISM 1000 gamma camera (Philips Marconi Medical Systems, Eindhoven, The Netherlands), we performed a SPECT immediately and 4 hours after exercise. Standardized quantitative analysis was performed with 201-thallium SPECT bull’s-eye views, calculating the dimension of the scar (defined as a combined defect in stressrest pattern) in the respective areas supplied by the 3 major coronary arteries.

Follow-up After primary PCI, all patients were treated with aspirin (100 mg daily), clopidogrel (75 mg daily for 1-6 months, depending on the implanted stent), a b-blocker, an angiotensin converting enzyme inhibitor or angiotensin-receptor blocker, and a statin (if low-density lipoprotein cholesterol concentrations were N2.6 mmol/L), unless these agents were contraindicated. At 3 and 6 months after discharge, patients were followed up during an inhospital stay to assess history, clinical status, and to adjust the dosage of medical treatment according to current guidelines. 201-Thallium SPECT, stress echocardiography, left heart ventriculography, and quantitative coronary angiography were performed during the 6-month follow-up visit.

Statistical analysis Continuous data are presented as mean F SD. For comparison of continuous variables, a paired or unpaired t test, as appropriate, was used. Correlation between variables was calculated with the Spearman q test. All data analyzed were normally distributed. Statistical significance was assumed at a P value of b.05. All statistical analysis was performed with SPSS 11.0 for Windows (SPSS, Chicago, IL).

Results Patients Twenty-two patients (19 males, mean age 55.3 F 9.5 years) with AMI and successful primary PCI were included in the study. Median duration of chest pain was 6 (range 3-12) hours before intervention. Target vessels were the left anterior descending coronary artery (LAD, n = 12), left circumflex coronary artery (CX, n = 2), the right coronary artery (RCA, n = 7), and one venous bypass graft to the right coronary artery. A median of 1 (range 1-5) stent per patient was used. In 4 patients, single drug-eluting stents (1 paclitaxel and 3 sirolimus eluting stents) were implanted; in all of them in the infarct-related LAD. The mean maximum level of creatine kinase (CK) was 3450 F 2860 U/L and of its MB fraction 312 F 179 U/L. Demographic, clinical, and angiographic characteristics of the follow-up study population are reported in Table I.

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Table I. Demographic, clinical, and angiographic characteristics of the follow-up study population Age (y) Men Median time from symptom onset to PCI (h) (range) Killip class 1 2 3 4 Infarct-related coronary artery Left anterior descendent branch Circumflex branch Right coronary artery Venous bypass graft to right coronary artery TIMI flow grade Before PCI Grade 0 or I Grade II Grade III After PCI Grade 0 or I Grade II Grade III Maximum serum CK concentration (U/L) Maximum serum CK-MB concentration (U/L) Maximum serum troponine T concentration (lg/L) Peri-interventional abciximab Median number of implanted stents (range) Size of implanted stent (mm) Length of stent (mm) Medication at discharge Aspirin and clopidogrel b blockers ACE inhibitors or angiotensin receptor blockers Statins Medication at discharge Aspirin or clopidogrel b blockers ACE inhibitors or angiotensin receptor blockers Statins

55 F 9 19 (95%) 6 (3-12) 14 (70%) 4 (20%) 1 (5%) 1 (5%) 11 (55%) 2 (10%) 6 (30%) 1 (5%)

18 (90%) 2 (10%) 0 0 0 20 (100%) 3357 F 2785 322 F 169 8.9 F 3.4 20 (100%) 1 (1-5) 3.1 F 0.4 32.6 F 26.0 20 (100%) 18 (90%) 13 (65%) 16 (80%) 20 (100%) 19 (95%) 14 (70%) 18 (90%)

ACE, angiotensin converting enzyme. Data are means F SD or number (%) unless otherwise stated.

Granulocyte–colony stimulating factor and apheresis Granulocyte–colony stimulating factor administration at a mean daily dose of 810 F 64 lg/d for 5.5 F 1.2 days mobilized 62.2 F 27.1 CD34+ cells per microliter of peripheral blood in 21 of 22 patients. In one patient, the number of CD34+ cells did not increase enough to warrant apheresis. No G-CSF–related adverse reactions arose during bone marrow stimulation. One patient reported transient slight discomfort of both femurs and hip bones for 2 days during G-CSF therapy. During apheresis, which was accomplished without complications in all patients, we collected 48.4 F 16.2  109 leucocytes, containing 1.0% F 0.9% CD34+ cells. The infused suspension of 9 mL contained a mean of 4.8 F 1.6  109 leucocytes, including 48.6 F 37.2  106 CD34+ cells; the platelet count was 1.8 F 0.8  109 per milliliter.

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Table II. Results of SPECT and stress echocardiography

% of perfusion defect (SPECT) In the area supplied by the IRA In the reference territory WMSI During rest During dobutamine stress Difference between rest and stress

Figure 1

Baseline

6 months

P

52.7 F 20.7

41.7 F 23.3

.043

12.4 F 11.5

9.2 F 14.5

.156

1.5 F 0.2 1.4 F 0.2 0.2 F 0.1

.005 .008 .106

1.7 F 0.3 1.5 F 0.3 0.2 F 0.1

Improvement in LVEF (%) between baseline and 6-month follow-up.

Transcoronary transplantation of PBSCs Transcoronary transplantation of PBSCs was performed in all patients on the day of apheresis. Prior coronary angiography demonstrated the absence of thrombi or in-stent restenosis in 20 patients but one asymptomatic re-occlusion of an RCA. In all 20 patients with unimpeded antegrade coronary blood flow, injection of 9 mL of PBSC suspension was successfully performed. As procedure-related coronary complication, one RCA was dissected with the guidewire from the ostium to the distally implanted stent. Another 4 stents had to be deployed to restore normal antegrade perfusion. Subsequently, PBSC transplantation could be performed as intended. No postinterventional elevation of CK or its MB fraction nor a novel rise in troponine T or electrocardiographic signs of new ischemia or arrhythmia was observed. All patients could be discharged from the hospital on the second day after transplantation. Clinical follow-up No patient died or was lost to follow-up. One person was hospitalized for worsening heart failure without signs of new ischemia 3 weeks after PBSC transplantation. Two patients developed anterior ST-elevation myocardial reinfarction 2 and 6 months after cell transfer in the LAD. Both patients underwent acute coronary angiography, which revealed a thrombotic occlusion inside the stent based on a subtotal ISR. Successful recanalization with implantation of a drug-eluting stent could be performed in each patient. Coronary angiography and ventriculography were repeated in both patients after 4 months and 6 weeks, respectively. 201-Thallium SPECT and stress echocardiography Comparing baseline and 6-month follow-up recordings, 201-thallium SPECT revealed a significant reduction of the scar, expressed as percentage of potentially perfused myocardium in the respective area supplied by the IRA, whereas no changes in the reference territory were recorded.

The WMSI detected by stress echocardiography during rest and dobutamine infusion significantly decreased between baseline and 6-month follow-up. However, the difference between resting and stress values, indicating the presence of viable but stunned or hibernated myocardium, did not change during the observed period. Detailed results from 201-thallium SPECT and stress echocardiography are listed in Table II.

Invasive measurements Ventriculography and coronary angiography were performed in all 20 patients with a mean follow-up of 6 F 1 months. Several significant differences indicating improvement in left ventricular function were recorded: left ventricular ejection fraction (LVEF) improved from 46.4% F 8.1% at baseline to 54.3% F 11% ( P b .001) (Figure 1), end-systolic volumes decreased from 108.7 F 58.6 to 96.9 F 51.9 mL ( P = .027), whereas end-diastolic volumes remained unchanged (baseline 197.6 F 66.1 mL, follow-up 204.1 F 57.7, P = .36). Regarding regional left ventricular function, the infarct region itself, defined as the percentage of akinetic, hypokinetic, or dyskinetic segments of the whole left ventricular circumference, decreased significantly from 25% F 11% to 19% F 10% ( P = .039). Changes, as determined by ventriculography, are reported in Table III. During the 6 months after PBSC transplantation, 8 patients (40%) presented with a significant ISR of the IRA, defined as a percentage of N50% of the luminal diameter. Six of these patients were asymptomatic until the 6-month follow-up, whereas 2 patients had acute myocardial reinfarction due to a stent thrombosis based on a subtotal ISR 2 and 6 months after cell transfer, respectively. Quantitative coronary angiography, performed after 6 months or at the time of reinfarction, demonstrated a mean ISR of the IRA of 46% F 32%.

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Table III. Left ventricular volumes, global LVEF, and regional systolic function as determined by left ventriculography Baseline LVEDV (mL) LVESV (mL) SV (mL) SV index (mL/m2) Global LVEF (%) % of akinetic, hypokinetic, or dyskinetic segments

197.5 108.7 88.7 45.8 46.4 25

F F F F F F

66.1 58.6 15.4 8.5 8.1 11

6 months 204.1 96.9 107.3 55.2 54.3 19

F F F F F F

57.7 51.9 19.8 9.8 11.0 10

Figure 2 P

.36 .027 b.001 b.001 b.001 .039

LVEDV, left ventricular end-diastolic volume; LVES, left ventricular end-systolic volume; SV, stroke volume.

Table IV. Procedural characteristics of patients with and without in-stent restenosis N50%

Implanted stents (n) Total stent length (mm) Stent diameter (mm) Drug-eluting stents Improvement in global LVEF (%) CD34+ cells transplanted (n*10E6)

ISR bbb 50%

_z _ 50% ISR z

P

1.3 F 23.5 F 3.1 F 4 7.3 F

2.4 F 1.6 46.3 F 35.9 3.2 F 0.4 0 8.8 F 5.8

.061 .059 .541 / .671

54.1 F 43.8

.443

0.6 7.9 0.4 7.4

40.3 F 21.5

The minimal lumen diameter of the stented segment decreased significantly from 2.81 F 0.54 to 1.61 F 1.16 mm ( P = .0001), implicating a late lumen loss of 1.21 F 1.04 mm. Control coronary angiography in the 2 patients with PCI for myocardial reinfarction showed no ISR after 4 months and 6 weeks, respectively. The 4 patients with primarily implanted drug-eluting stents did not develop significant in-stent restenosis (mean late lumen loss 0.18 F 0.09 mm). Regarding left ventricular function, improvement in global LVEF did not differ between patients with and without significant ISR (Table IV). Analyzing the quantity of transplanted cells, we found no correlation between the number of infused CD34+ cells and the degree of LVEF improvement (r = 0.176, P = .459) (Figure 2). Furthermore, we did not find a correlation between the number of transplanted CD34+ cells and in-stent plaque volume at 6-month follow-up (r = 0.081, P = .734) or between plaque volume and improvement of LVEF (r = 0.257, P = .274).

Discussion This is the first study that addresses the feasibility, effectiveness, and side-effects of the combination of

No correlation between the number of implanted CD34-positive cells and the change in LVEF between baseline and 6-month follow-up (r = 0.176, P = .459).

G-CSF application for PBSC mobilization and transcoronary cell transplantation after recent primary stent implantation for AMI. We could show that G-CSF therapy and infusion of PBSCs into the IRA are associated with a significant increase in global LVEF and regional systolic wall motion after 6 months. To be able to attribute improvement of myocardial contractility to PBSC transplantation, only patients with a long duration of chest pain (median 6 hours) before primary PCI and sufficient mobilization of PBSCs after G-CSF therapy were included. Previous studies on revascularization in AMI have demonstrated that moderate LVEF improvement can only be achieved, if unimpeded blood flow in the IRA can be reestablished within the first 4 hours after onset of symptoms.9,11,15-17 After ischemia, gradual recovery of stunned myocardium makes the interpretation of improvement in LVEF difficult.18 To achieve accurate information on the dimension of destroyed myocardium, we performed baseline ventriculography not immediately after primary PCI but 5 to 7 days later. At this time, left ventricular dysfunction caused by postischemic stunning is likely to be less pronounced.15,16,18 Our results of stress echocardiography support the assumption that improvement in left ventricular function was beyond the effects of recovery from myocardial stunning. The resting WMSI decreased significantly from baseline to 6-month follow-up, whereas the index difference between resting and dobutamine stress remained stable. We interpret these findings to be caused by the presence of newly generated viable myocardium. Simple recovery from stunning would

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most likely result in an additional decrease in the index difference between resting and stress motion values.19 The reduction in nonperfused myocardium detected by thallium-201 SPECT provides additional evidence that the infarcted myocardium and its border zone are positively influenced by PBSC transplantation. For therapeutic progenitor cell transplantation after myocardial infarction, harvest of hematopoietic stem cells by bone marrow aspiration as well as by processing venous blood has been described.8,9,11 Assmus et al9 elegantly demonstrated that blood-derived progenitor cells are equal to cells gained by bone marrow aspiration in improving contractile function. We planned to harvest PBSCs from venous blood. In contrast to other groups, we did not process venous blood after a single collection, but aimed to gain a maximum of PBSCs by means of G-CSF–induced propagation and subsequent apheresis.8,9,11 Our results demonstrate that mobilization and extraction of sufficient numbers of CD34+ cells after stimulation with G-CSF are possible in many patients after AMI (in 95% of our patient cohort). Following our protocol for G-CSF administration guided by repeated monitoring of CD34+ cell proliferation, we obtained a mean number of transplantated CD34+ cells about 4 to 10 times higher than the numbers obtained by other groups.8,10,11 Experience in the use of G-CSF in patients with coronary artery disease is limited. Hill et al20 reported 2 cases of AMI, one of them fatal, during G-CSF therapy in 16 patients with intractable angina, and Zbinden et al21 observed 2 acute coronary occlusions in 14 patients treated with granulocyte–macrophage colony-stimulating factor before elective PCI. However, 2 other recently published trials did not report thrombotic or arrhythmogenic events after sole application of G-CSF after primary stenting for AMI.22,23 We performed a combination of G-CSF therapy and transcoronary cell transplantation after recent primary stent implantation for AMI. In our series, there were no acute thrombotic complications after G-CSF therapy or cell transplantation. Although experimental data suggest that G-CSF induces recruitment of neutrophil granulocytes at sites of tissue injury that may activate coagulatory or proliferative processes,24 we did not find any angiographic or enzyme-kinetic evidence of acute microcirculatory thrombosis or inflammation after G-CSF therapy. Our experience is confirmed by the findings of Kang et al10 who demonstrated unimpeded coronary circulation after G-CSF application and intracoronary cell infusion by performing serial coronary flow reserve measurements. On the other hand, we observed an unexpected high ISR rate of 40% at 6-month follow-up. Although we did not find a significant correlation between the number of transplanted PBSCs and in-stent plaque volume, the PBSCs or mediators delivered by them might play an

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important role in the promotion of intimal hyperplasia. As Sata et al25 showed, hematopoietic stem cells can differentiate into smooth muscle cells and thus participate in pathological vascular remodeling. However, the clinical impact of transcoronary cell transplantation on the development of ISR is reported controversially and seems to depend on the particular cellular composition of the infused suspension. Bartunek et al26 observed a significantly increased ISR rate of 37% after transcoronary transplantation of CD133+-enriched bone marrow progenitor cells compared to an ISR rate of 25% in the control group. In contrast, Wollert et al11 reported no significant difference in ISR rate after transcoronary transfer of CD34+ bone marrow progenitor cells between cell and control group (23% vs 13%). Sole G-CSF therapy without cell transplantation after primary stenting for AMI has been shown not to be associated with an increased ISR rate after 4 to 6 months.22,23 Regarding our results, the combination of G-CSF therapy and transcoronary transplantation of CD34+ cells after recent stent implantation for AMI seems to imply a high risk for the development of ISR. Additional unknown long-term effects of G-CSF therapy triggered by the mechanical damage inflicted by the balloon inflations during PBSC transplantation may have led to the unexpected high ISR rate of 40%. It is of particular interest that we observed no significant ISR in the 4 patients with drug-eluting stents. These stents have been shown to exert potent antiproliferative effects on smooth muscle cells resulting in a decreased rate of restenosis. Whether these effects can be extended to G-CSF–related stenosis clearly needs accurate further assessment. Despite the fact that drugeluting stents are increasingly implanted in the setting of AMI, no systematic data on a reduced rate of ISR effected by them are available in the setting of additional G-CSF therapy or stem cell transplantation. However, in view of the observed high rate of ISR in bare metal stents in our series, implantation of drug-eluting stents should be considered during primary PCI for AMI when subsequent G-CSF therapy and transcoronary cell transfer are planned.

Conclusions Transcoronary transplantation of G-CSF–mobilized PBSCs shortly after primary stent implantation for AMI can be performed without periprocedural adverse events. However, significant ISR or myocardial reinfarction seems to occur frequently during the following 6 months. These observations warrant a cautious approach to the combination of G-CSF and transcoronary transplantation of PBSCs, although improvements in LVEF were similar to that observed after transplantation of bone marrow–derived cells in other studies.

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