VIEWPOINT
Promise of Blood- and Bone Marrow-Derived Stem Cell Transplantation for Functional Cardiac RepairPutting It in Perspective With Existing Therapy
Thorsten Reffelmann, MD*, , ,*,
Stephanie Könemann, MD* and
Robert A. Kloner, MD, PhD, FACC,
* Klinik und Poliklinik für Innere Medizin B, Universitätsklinikum der Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany
The Heart Institute, Good Samaritan Hospital, Los Angeles, California
Division of Cardiology, Keck School of Medicine, University of Southern California, Los Angeles, California
Manuscript received June 20, 2008;
revised manuscript received October 9, 2008,
accepted October 13, 2008.
* Reprint requests and correspondence: Dr. Thorsten Reffelmann, Klinik und Poliklinik für Innere Medizin B, Universitätsklinikum der Ernst-Moritz-Arndt-Universität Greifswald, Friedrich-Löffler Str. 23 a, 17475 Greifswald, Germany (Email: ThorstenReffelmann{at}web.de).
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Abstract
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Intracoronary transplantation of peripheral blood- or bone marrow-derived cells, as tested in several recent trials, is associated with moderate increases in left ventricular (LV) ejection fraction (EF) and a small reduction of LV end-systolic volumes. Substantial variability exists between trials, and most of them are based on a small number of patients. Meta-analyses estimated an increase in EF of 3% to 4% more in comparison with control patients. In this review, the effects are put into perspective with established treatment options for acute myocardial infarction (AMI), such as thrombolysis and acute percutaneous interventions or pharmacotherapy aimed at favorably influencing the cardiac remodeling process. Changes in functional and morphometric parameters of LV performance after cell therapy appear to be in the range of effects observed with reperfusion therapy, pharmacotherapeutic interventions influencing the renin-angiotensin-aldosterone pathway, and beta-blockers after AMI.
Key Words: cell transplantation • acute myocardial infarction • remodeling • thrombolysis • immediate coronary angioplasty
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Abbreviations and Acronyms
| | AMI = acute myocardial infarction | | EF = ejection fraction | | LV = left ventricular | | MI = myocardial infarction |
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After the comprehensive scientific validation of reperfusion therapy for the treatment of acute myocardial infarction (AMI) and the seminal advances in pharmacotherapy targeting left ventricular (LV) remodeling after a cardiac insult that were accomplished in the second half of the 20th century, any innovative therapy for AMI and its consequences will be compared with the progress made in the past. Many of the early landmark trials demonstrated convincing benefit in terms of clinical end points (1–4). Some of the initial studies were accompanied by parallel analyses in which functional and morphometric parameters were used as correlates for clinical end points.
In the majority of clinical trials investigating the effects of intracoronary cell transplantation, the primary end point comprises changes in LV volumes and EF in comparison with a control group over time (5–7). In the following discussion, the effects of intracoronary transplantation of bone marrow- and blood-derived stem cells in AMI on functional and morphometric LV parameters are put into the context of established therapy, such as reperfusion therapy and adjunctive pharmacotherapy.
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Current State of Clinical Work on Transplantation of Bone Marrow- and Peripheral Blood-Derived Stem Cells
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Table 1
(8–20) summarizes LV ejection fraction (EF) at baseline and latest available follow-up in the control group and transplantation group in 13 trials of intracoronary transplantation performed in AMI (8–20).
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Table 1 Changes in LVEF in the Control Groups and Transplantation Groups in 13 Trials of Intracoronary Injection of Blood- or Bone Marrow-Derived Cells in Acute Myocardial Infarction
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A meta-analysis by Lipinski et al. (5) included 10 of these trials (7 randomized, 3 cohort studies) on intracoronary cell injection (within the first 14 days after infarction), yielding 698 patients, of which 659 were available at follow-up (median follow-up of 6 months). In 2 trials (n = 126), peripheral blood cells were used for intracoronary infusion and in 8 investigations bone marrow-derived cells were used. For the pooled population, Lipinski et al. (5) found a significantly superior improvement in LVEF of 3.0% (95% confidence interval: 1.9% to 4.1%, p < 0.00001) for subjects receiving bone marrow transplantation in comparison with control subjects. Similarly, LV end-systolic volumes were reduced in patients receiving cell therapy by –7.4 ml (95% confidence interval: –12.2 to –2.7 ml, p < 0.002) compared with control subjects. Changes in end-diastolic volumes were not significantly different between groups in this meta-analysis.
Clinical end points, such as death, target vessel revascularization, and rehospitalization for heart failure, did not significantly differ between groups of the pooled population except for the incidence of recurrent myocardial infarction (MI). The reduction of reinfarction in the cell transplantation group was based mainly on the effects reported in the REPAIR-AMI (Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction) study (17,21). Study size in the remaining studies was too small for adequate end point analysis.
Notably, the findings of the meta-analysis by Lipinski et al. (5) correspond well with another meta-analysis by Abdel-Latif et al. (6) (in part an overlapping, but more heterogeneous set of trials), which calculated a mean increase in EF of 3.66% more in comparison with control subjects.
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How Do Improvements in EF With Cell Therapy Compare With Other Established Treatment Options for AMI?
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Thrombolysis for AMI.
The authors of the ISAM (Intravenous Streptokinase in Acute Myocardial Infarction) trial evaluated the effect of intravenous streptokinase application within 6 h after onset of AMI on clinical end points, infarct size, and EF (22). LVEF at 3 to 4 weeks was 56.8 ± 0.7% in the streptokinase group (n = 428) but 53.9 ± 0.7% in control patients (n = 420). A pooled analysis of 10 randomized trials of intracoronary and intravenous application of streptokinase by Patel et al. (4) (total of 14,355 patients) demonstrated a reduction in mortality within the first 6 weeks by thrombolysis, whereas data on LV function remained inconclusive. Only by analyzing patients with successful reperfusion and without reperfusion separately, a clear effect toward improvement of LVEF could be demonstrated for patients with successful reperfusion.
Immediate coronary angioplasty for AMI.
As an alternative approach to coronary reperfusion, acute percutaneous angioplasty was developed in the early 1990s. In a landmark trial by Zijlstra et al. (23), angioplasty (without stenting) was associated with a greater coronary patency rate and less residual stenosis compared with intravenous streptokinase. LVEF, as assessed by radionuclide scanning before hospital discharge, amounted to 45 ± 12% in patients treated with streptokinase (n = 72, time to start of streptokinase infusion: 30 ± 15 min) and 51 ± 11% (p < 0.004) in patients with immediate angioplasty (n = 70, time to first balloon inflation 61 ± 22 min).
In a multicenter trial in which the authors compared tissue plasminogen activator (n = 200) and immediate angioplasty (n = 195) within 12 h of onset of MI, the authors found a lower incidence of death or reinfarction within 6 months for patients with acute angioplasty (16.8% vs. 8.5%, p < 0.02) (24). Nonetheless, EF at 6 weeks was similar (53 ± 13% vs. 53 ± 13%).
In 1998, Ribichini et al. (25) published a randomized study in which they compared thrombolysis using tissue plasminogen activator with "liberal stenting" (n = 55, 58% of patients with stent implantation) in patients with acute inferior MI. At 1 year, the combined incidence of death, reinfarction, and target vessel revascularization was 52.7% in the thrombolysis group and 11.0% in the angioplasty group (p < 0.0001). Parallel to clinical end points, EF was 55.2 ± 9.5% in the percutaneous coronary angioplasty group and 48.2 ± 9.9% in patients treated with plasminogen activator (p < 0.0001).
Angiotensin-converting enzyme inhibition and angiotensin receptor blockade after MI.
In the SAVE (Survival And Ventricular Enlargement) study, in which researchers investigated captopril treatment compared with placebo in survivors of AMI, a significant reduction in cardiovascular events was demonstrated with the use of captopril. The echocardiographic SAVE substudy (n = 785 initially) illustrated less increase in end-diastolic and -systolic volumes as well as less reduction in change in LV areas, as a measure of EF, over 1 year (Fig. 1) (26).
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Figure 1 Changes in Left Ventricular Echocardiographic Ejection Fraction From Baseline to Follow-Up
Changes in left ventricular echocardiographic ejection fraction from baseline to follow-up in the echocardiographic subgroups of the SAVE (Survival and Ventricular Enlargement) study (26), in the HEART (Healing and Early Afterload Reducing Therapy) study (2), in the VALIANT (Valsartin in Acute Myocardial Infarction Trial) study (3), and in the CAPRICORN (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction) trial (27). (In the SAVE study, an echocardiographic parameter calculated from changes in measured areas was used [here also termed ejection fraction].)
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In the HEART (Healing and Early Afterload Reducing Therapy) trial, 352 patients with anterior MI received either ramipril titrated to a dose of 10 mg from day 1 after MI within the first 14 days (full dose), 0.625 mg of ramipril from day 1 (low dose), or placebo (2). A significantly greater improvement in EF and less increase in LV diastolic dimensions over the course of 14 days (echocardiography) were observed with ramipril in a dose-dependent manner (Fig. 1). Importantly, benefit from ramipril treatment appeared to be greatest in subjects with the lowest baseline EF.
An echocardiographic substudy of the VALIANT (Valsartan in Acute Myocardial Infarction Trial), in which valsartan treatment and treatment with captopril resulted in a comparable incidence of cardiovascular events after AMI over a median of 24.7 months of follow-up, demonstrated similar effects of captopril and valsartan on changes in cardiac functional parameters over time (Fig. 1) (3).
Beta-blockers after AMI.
The CAPRICORN (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction) study was a randomized, controlled trial (n = 1,959) in which researchers investigated the application of the beta-blocker carvedilol in addition to optimal medical treatment in patients with LV dysfunction (EF  40%) after AMI (27). All-cause mortality was significantly lower in the carvedilol group (12%) in comparison with the placebo group (15%, p < 0.03). In an echocardiographic substudy, including 127 patients from the CAPRICORN trial, LV end-systolic volumes decreased significantly more in the carvedilol group (–4.8 ± 4.9 ml vs. +4.5 ± 2.8 ml at 6 months, carvedilol vs. placebo: p < 0.023), and EF increased significantly more in the carvedilol group (+5.0 ± 1.1% vs. +1.0 ± 1.2%, carvedilol vs. placebo: p < 0.015) (Fig. 1).
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Conclusions
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Many of the treatment options for AMI, as validated in several large-scale investigations in the past, are associated with a moderate increase in EF that is accompanied by a small reduction of LV dimensions. Putting these effects in perspective with achievements by transplantation of peripheral blood- or bone marrow-derived cells, as summarized in Table 1, demonstrates a very similar variability among trials, emphasizes the extreme importance of adequately considering changes in LV parameters over time within the respective control group, and reveals that improvements in EF achieved by cell transplantation are within an intriguingly similar range compared with established therapeutic strategies.
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References
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Abstract
Current State of Clinical...