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(Circulation. 2003;107:2294.)
© 2003 American Heart Association, Inc.
Clinical Investigation and Reports |
From the Texas Heart Institute at St Lukes Episcopal Hospital, Houston, Tex (E.C.P., G.V.S., Y.J.G., W.K.V., J.T.W.); Hospital Procardiaco, Rio de Janeiro, Brazil (H.F.R.D., S.A.S., A.L.S.S., C.T.M., H.J.F.D., L.B., R.V., F.O.D.R., R.E., J.A.R.A., E.T.M.); Federal University, Rio de Janeiro, Brazil (R.B., M.I.D.R., A.C.C., H.S.D.); and Brazilian Millennium Institute for Tissue Bioengineering (H.F.R.D., R.B., A.C.C.).
Correspondence to Emerson C. Perin, MD, 6624 Fannin, Suite 2220, Houston, TX 77030 (e-mail eperin{at}crescentb.net), and Hans F.R. Dohmann, MD, Rua General Polidoro, 192, CEP 22080-000Botafogo, Rio de Janeiro, Brazil (e-mail hemodinamica@procardiaco.com.br).
| Abstract |
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Methods and Results Twenty-one patients were enrolled in this prospective, nonrandomized, open-label study (first 14 patients, treatment; last 7 patients, control). Baseline evaluations included complete clinical and laboratory evaluations, exercise stress (ramp treadmill), 2D Doppler echocardiogram, single-photon emission computed tomography perfusion scan, and 24-hour Holter monitoring. Bone marrow mononuclear cells were harvested, isolated, washed, and resuspended in saline for injection by NOGA catheter (15 injections of 0.2 cc). Electromechanical mapping was used to identify viable myocardium (unipolar voltage
6.9 mV) for treatment. Treated and control patients underwent 2-month noninvasive follow-up, and treated patients alone underwent a 4-month invasive follow-up according to standard protocols and with the same procedures used as at baseline. Patient population demographics and exercise test variables did not differ significantly between the treatment and control groups; only serum creatinine and brain natriuretic peptide levels varied in laboratory evaluations at follow-up, being relatively higher in control patients. At 2 months, there was a significant reduction in total reversible defect and improvement in global left ventricular function within the treatment group and between the treatment and control groups (P=0.02) on quantitative single-photon emission computed tomography analysis. At 4 months, there was improvement in ejection fraction from a baseline of 20% to 29% (P=0.003) and a reduction in end-systolic volume (P=0.03) in the treated patients. Electromechanical mapping revealed significant mechanical improvement of the injected segments (P<0.0005) at 4 months after treatment.
Conclusions Thus, the present study demonstrates the relative safety of intramyocardial injections of bone marrowderived stem cells in humans with severe heart failure and the potential for improving myocardial blood flow with associated enhancement of regional and global left ventricular function.
Key Words: cells heart failure ischemia revascularization gene therapy
| Introduction |
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The understanding that vasculogenesis can occur in the adult has led to intense investigation into stem cell therapy. Several recent experimental studies have confirmed the potential of pluripotential cells in differentiating into cardiomyocytes and endothelial cells.1,2 Further evidence from animal models has confirmed that pluripotential cells from bone marrow improve myocardial function and perfusion in the setting of ischemic heart disease.3,4 In addition, recent publications5,6 have described beneficial effects of intracoronary infusion of autologous, mononuclear bone marrow in the immediate postinfarction period in humans. A recent report by Tse et al7 described improvement in myocardial perfusion and segmental contractility (as assessed by cardiac magnetic resonance imaging) in ischemic myocardial segments treated with catheter-based delivery.
The present study addresses primarily the safety of endocardial bone marrow mononuclear cell (BMMNC) injections and secondarily the hypothesis that endocardial injections of autologous BMMNCs (ABMMNCs) in patients with end-stage ischemic heart disease may promote neovascularization and may overcome the failure of the natural myocardial healing process.
| Methods |
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The ethics committee of Pro-Cardiaco Hospital (Rio de Janeiro) and the Brazilian National Research Ethics Council approved the study protocol.
Baseline Evaluation
Baseline evaluation in the treatment group included a complete clinical evaluation (history and physical), laboratory evaluation (complete blood count, blood chemistry, C-reactive protein [CRP], brain natriuretic peptide [BNP], creatine kinase [CK]-MB and troponin serum levels), exercise stress test with ramp treadmill protocol,8 2D Doppler echocardiogram, dipyridamole SPECT perfusion scan, and 24-hour Holter monitoring.
The control group underwent the above-mentioned baseline evaluation except for 24-hour Holter monitoring, CK-MB, and troponin serum levels.
Periprocedural Evaluation
Patients in the treatment group had serum CRP, complete blood count, CK, troponin, and BNP (only 9 patients) levels measured and an ECG performed just before the procedure. Immediately after the procedure, another ECG and 2D Doppler echocardiogram were performed, and 24-hour Holter monitoring was begun. Serum CRP, CK, and troponin levels were also assessed at 24 hours. Patients were monitored in the cardiac intensive care unit for 48 hours after the injection procedure.
Bone Marrow Aspiration and Isolation of Mononuclear Cells
Approximately 4 hours before the cell injection procedure, bone marrow (50 mL) was aspirated under local anesthesia from the posterior iliac crest. BMMNCs were isolated by density gradient on Ficoll-Paque Plus (Amersham Biosciences). Mononuclear cells were exhaustively washed with heparinized saline containing 5% human serum albumin and filtered through 100-µm nylon mesh to remove cell aggregates. The cells were finally resuspended in saline with 5% human serum albumin for injection. A small fraction of the cell suspension was used for cell counting and viability testing with trypan blue exclusion. Cell viability was shown to be >90% (96.2±4.9%), assuring the quality of the cell suspension. Post-hoc characterization of leukocyte differentiation markers by flow cytometry and functional assays was done on another fraction of cells. The clonogenic capacity of hematopoietic progenitors was evaluated by colony-forming assays (granulocyte-macrophage colony-forming unit) as previously described.9
A high correlation between granulocyte-macrophage colony-forming units and CD45loCD34+ cells was seen (Spearman r=0.77, P=0.0012). Fibroblast colony-forming assay was done as previously described10 to determine the presence of putative progenitor mesenchymal lineages. Bacterial and fungal cultures of the clinically used cell preparations were performed and proved negative.
Antibodies and Staining Procedure for Fluorescence-Activated Cell Sorter Analysis
The following antibodies were either biotinylated or conjugated with fluorescein isothiocyanate (Pharmingen), phycoerythrin (PE), or PerCP: anti-CD45 as a pan-leukocyte marker (clone HI30), anti-CD34 as a hematopoietic progenitor marker (clone HPCA-II), anti-CD3 as a panT-cell marker (clone SK7), anti-CD4 as a T-cell subpopulation marker (clone SK3), and anti-CD8 as a T-cell subpopulation marker (clone SK1) from Becton Dickinson; anti-CD14 as a monocyte marker (clone TUK4), anti-CD19 as a panB-cell marker (clone SJ25-C1), and anti-CD56 as an NK-cell marker (clone NKI nbl-1), from Caltag Laboratories (Burlingame, Calif); and anti-HLADR (MHC-II, clone B8.12.2) from Beckman-Coulter. The biotinylated antibodies were revealed with Streptavidin PECy7 (Caltag Laboratories). Three-color immunofluorescence analysis was used for the identification of leukocyte populations in total nucleated bone marrow cell suspensions. After staining, erythrocytes were lysed with the Becton Dickinson lysis buffer solution according to the manufacturers instructions, and CD45 antibody was used to assess the percentages of leukocytes in each sample. Data acquisition and analyses were performed on a fluorescence-activated cell sorter Calibur with CellQuest 3.1 software (Becton Dickinson).
Transendocardial Delivery of ABMMNCs
In the cell-injection treatment group, patients were taken to the cardiac catheterization laboratory
1 hour before the anticipated arrival of the bone marrow cells from the laboratory. Left heart catheterization with biplane LV angiography was performed. Subsequently, electromechanical mapping (EMM) of the left ventricle was performed as previously described.11 The general region for treatment was selected by matching the area identified as ischemic by previous SPECT perfusion imaging. The electromechanical map was then used to target the specific treatment area by identifying viable myocardium (unipolar voltage
6.9 mV)12 within that region. Areas associated with decreased mechanical activity (local linear shortening <12%, indicating hibernating myocardium) were preferred.
The NOGA injection catheter (Figure 1) was prepared by adjusting the needle extension at 0° and 90° flex and by placing 0.1 cc of ABMMNCs to fill the needle dead space. The injection catheter tip was placed across the aortic valve and into the target area, and each injection site was carefully evaluated before the cells were injected. Before every injection of cells into the LV wall, the following criteria had to be met: (1) perpendicular position of the catheter to the LV wall; (2) excellent loop stability (<4 mm); (3) underlying voltage >6.9 mV; and (4) presence of a premature ventricular contraction on extension of the needle into the myocardium. Fifteen injections of 0.2 cc (mean of 25.5±6.3x106 cells/patient) were delivered (Figure 2).
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Two-Month Noninvasive Follow-Up Evaluation
All patients, both treated and control, underwent noninvasive follow-up evaluations at 2 months, which consisted of a clinical evaluation, ramp treadmill protocol, 2D Doppler echocardiogram, and dipyridamole SPECT perfusion scan. Patients in the treatment group had repeat 24-hour Holter monitoring. The ramp treadmill protocol was selected because it is better than standard incremental protocols in estimating functional capacity in these severely ill patients.8
The predicted ·VO2max was used to tailor the patient workload. Treadmill speed was initially 0.5 mph, and inclination was 0% to 10% with a planned duration of 10 minutes of exercise.13,14 The echocardiographic data were analyzed by 2 independent, blinded, experienced observers. Images were stored digitally and analyzed offline. If a discrepancy between the readings of >5% was noted, a third blinded observer was called and a consensus achieved. The end-systolic volume (ESV), end-diastolic volume (EDV), and EF were measured according to standard protocols.
Dipyridamole stress and resting SPECT imaging were performed with the same stress procedure at baseline and at follow-up. Studies were read by a blinded, experienced observer. Approximately 740 MBq of technetium-99m sestamibi was injected at rest and after stress, with dipyridamole infusion at a rate of 142 µg/kg of body weight per minute infused for 4 minutes. One hour later, SPECT imaging was initiated, using a 15% window centered over the 140-keV photopeak. Acquisitions were performed with a 1-detector gamma camera (Ecam, Siemens), acquiring 32 projections over 180° (right anterior oblique 45° to left posterior oblique 45°) (low-energy, high-resolution collimation; 64x64 matrixes; and 35 seconds per projection). Short-axis and vertical and horizontal long-axis tomograms of the left ventricle were extracted from the reconstructed transaxial tomograms by performing coordinate transformation with appropriate interpolation. No attenuation or scatter correction was applied. Quantitative SPECT analysis was performed on an ICON workstation computer (Siemens). The analysis was performed with the use of a completely automated software package, with the exception of a quality-control check to verify the maximum count circumferential profiles. The methods for quantitative analysis have been previously described.15,16 In brief, processing parameters, including the apical and most basal tomographic short-axis slices, the central axis of the LV chamber, and a limiting radius for myocardial count search, were automatically derived. Short-axis tomograms were then sampled by using a maximum-count circumferential profile sampling technique with a cylindrical approach for sampling the body of the left ventricle and a spherical approach for sampling the LV apex. Comparisons were made to sex-matched normal limits.16 Polar map displays and quantitative values were then generated to indicate stress myocardial perfusion defect extent and severity.16,17
Four-Month Invasive Follow-Up Evaluation
Patients in the control group did not undergo NOGA mapping or repeat LV angiograms at late follow-up (because of ethics committee recommendations).
Patients in the treatment group had 4-month invasive follow-up evaluations consisting of LV angiograms and EMM. LV angiography was performed through the femoral approach with the use of a 5F pigtail catheter. All angiograms were obtained in 2 planesa 30° right anterior oblique view and a 60° left anterior oblique viewduring a period of stable sinus rhythm. Ventricular volume was not measured during or after a premature beat. A 40-mm sphere was used as calibration device. LV EDV, ESV, and EF were calculated by 2 blinded, experienced observers who used the area-length method.18
EMM was performed according to established criteria11 with a fill threshold of 15 mm. After the acquisition of points, postprocessing analysis was performed with a series of filters (moderate setting) to eliminate inner points, points that do not fit the standard stability criteria (location stability <4 mm, loop stability <6 mm, and cycle length variation <10%), points acquired during ST-segment elevation, and points not related to the left ventricle (eg, those in the atrium). A blinded, expert observer used a 12-segment bulls-eye to compare electromechanical values (unipolar voltage and local linear shortening) of injected segments at baseline and follow-up.
Statistical Analyses
Univariate differences in demographic characteristics (Table 1) between the control and treated groups were assessed with
2/Fishers exact test and t tests for discrete and continuous variables, respectively. Multivariable logistic regression was also used to determine the independent relationship between each demographic variable and treatment group. No statistically significant differences between the 2 groups were found. Because each patient in both groups was used as his or her own control, changes between baseline and 8 weeks in the control and treated groups were assessed with paired t tests. Logistic regression analysis was utilized to compare medications (Table 2) at baseline, 8 weeks, and 16 weeks within the control and treatment groups and between the control and treatment groups.
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Comparisons of the changes from baseline to 8 weeks in the control and treatment groups were made with repeated-measures ANOVA. The ANOVA model included the control versus treatment and baseline versus 8 weeks as factors and also included the interaction between the 2 factors. A probability value <0.05 was considered statistically significant.
| Results |
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Procedural Data
The total procedural time for mapping and injection was 81±19 minutes. Electromechanical maps comprised an average of 92±16 points. Patients received an average of 15±2 cell injections in a mean of 2±0.7 segments (6 inferior, 14 lateral, 2 anterior, and 5 septal). Each injection of 2 million cells was delivered in a volume of 0.2 cc. The cell population comprised a mean of 2.44±1.33% CD45loCD34+ cells (Table 3).
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Safety Data
One patient in the control group died 2 weeks after enrollment in the study and was not included in the analysis. A patient in the treatment group died at 14 weeks, presumably of sudden cardiac death. This patient had onset of severe angina and was found to be in asystole by emergency medical personnel. The patient had persistent improvement in cardiac function, as assessed by echocardiography. Baseline EF was 30% by echocardiography and increased to 57% at 2-month follow-up, demonstrating a similar response as the rest of the treatment group with regard to increased contractile function. In both cases, the families refused postmortem exams.
There were no major periprocedural complications. One patient had a transient episode of pulmonary edema that was easily reversed with loop diuretics after the procedure. No sustained arrhythmias were associated with the injection procedures, nor did any significant arrhythmias occur while the patients were hospitalized. There were no sustained ventricular arrhythmias found on 24-hour Holter monitoring at baseline or when repeated after the injection procedure and no significant differences in the number or percentage of premature ventricular contractions. No postprocedural pericardial effusions were seen on 2D Doppler echocardiograms. All patients were discharged on the third hospital day as per protocol.
Two-Month Noninvasive Follow-Up Evaluations
Of all baseline and follow-up laboratory values (Table 4), only serum creatinine and BNP levels varied between the control and treatment groups at follow-up. Follow-up serum creatinine levels were significantly elevated in the control group as compared with the treatment group (P=0.03). The levels of CRP at baseline and follow-up were not significantly different between the two groups (Table 4). There was a trend toward increased difference of BNP levels at follow-up between the two groups, with higher levels in the control group (P=0.06).
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Patients in the treatment group experienced less heart failure and fewer anginal symptoms at the 2-month follow-up when compared with the control group, by both New York Heart Association (NYHA) and Canadian Cardiovascular Society Angina Score (CCSAS) distribution (Table 5). Baseline exercise test variables (METs and ·VO2max) were similar for the 2 groups. There was a significant increase, however, in METs and ·VO2max at follow-up in the treatment group (P=0.0085 and 0.01, respectively). There was a trend toward improvement when these variables were compared with the control group (P=0.08 for both variables).
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Baseline comparison of ESV, EDV, and LVEF between the treatment and control groups revealed significant differences: The control group had smaller LV volumes (P<0.001) and a trend (P=0.054) toward higher baseline EF. Cardiac function (measured by EF on echocardiograms) had an absolute increase of 6% over the 2-month follow-up period in the cell-treated group. In contrast, the mean EF decreased, although not significantly, in the control group. In addition, when the 2 groups were compared, the treatment group showed a significant improvement in EF after 2 months (P=0.03). Cardiac geometry, as assessed by ESV, also improved. A significant fall in ESV (P=0.03) and a trend toward reduction in EDV (P=0.07) were noted in the treatment group. Volumes remained unchanged within the control group. When the two groups were compared at follow-up, a significant reduction in ESV was seen in the treated patients (P=0.04).
Nuclear perfusion imaging studies were similar at baseline for the amount of total reversible defect and percent of rest defect with 50% activity (scar). Within the control group, there was no significant change in these two variables at follow-up. Within the treatment group, there was no significant change in rest defect, with 50% activity at 2-month follow-up, but there was a significant 73% reduction in total reversible defect (P=0.022; from 15.15±14.99% to 4.53±10.61%). A typical example of resolution of inferolateral ischemia (baseline to follow-up) in a cell-treated patient is shown in Figure 3A.
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Four-Month Invasive Follow-Up Evaluations
Results from LV angiography at baseline and 4-month follow-up are shown in Table 6. There was a sustained improvement in LVEF from baseline, an increase from 20% to 29% at 4 months (31% relative increase) (P=0.0003) in the treated patients. There was also a continued reduction in ESV (P=0.03) at 4 months. EDV remained unchanged (P=0.1). Control group patients did not have repeat LV angiograms.
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On EMM, segmental analysis revealed a significant mechanical improvement of the injected segments (P<0.0005) (Table 6). Significant improvement in mechanical function at the injection site is illustrated by EMM in Figure 3B. Unipolar voltage values did not change from baseline to follow-up.
| Discussion |
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Wound healing is a multifaceted process that involves complex interactions between inflammatory cells, cytokines, and a number of extracellular matrix proteins, and the development of new capillaries. Because the normal reparative mechanisms seem to be overwhelmed when clinically significant myocardial injury occurs, a logical next step would be to amplify one part of this response artificially by applying stem cells locally in the setting of ischemia or infarction when a large amount of heart muscle has been injured.
In experimental animals, bone marrowderived cells have been shown to regenerate areas of infarcted myocardium and coronary capillaries,1 thus limiting functional impairment after myocardial infarction. Transendocardial injection of ABMMNCs has been shown to increase myocardial contractility and perfusion in swine.4 Various cell lineages have been used to generate evidence that bone marrow stem cells differentiate into cardiomyocytes, endothelium, and smooth muscle cells.19 Bone marrow hemangioblasts add to the development of new vessels, and mesenchymal stem cells can transdifferentiate into functional cardiomyocytes.20 Recently, bone marrowderived cardiomyocytes were demonstrated in hearts of women who received gender-mismatched bone marrow transplantation.21 Moreover, bone marrow cellular components secrete a range of cytokines, fibroblast growth factor, and vascular endothelial growth factor,22 which are involved in the natural process of angiogenesis. Endothelial progenitor cells have been implicated in neovascularization associated with postnatal vasculogenesis and are mobilized to peripheral circulation after acute ischemic events.23
In the present study, there is preliminary evidence that in humans, bone marrowderived mononuclear cells are capable of enhancing perfusion, as shown by significant reductions in reversible stress defects on SPECT (P=0.02). Bone marrowderived cells were purposefully injected into areas of hibernating myocardium. In hibernating areas, the underlying physiological state allows for restoration of myocardial function if myocardial perfusion is improved. We hypothesize that angiogenesis is the mechanism that allowed improvement in myocardial function in the patients in our study. Furthermore, we may speculate that an orchestrated sequence of events that includes not only the presence of the transplanted cells but also the action of cytokines and growth factors and intricate cell-to-cell interactions may all contribute to angiogenesis as an end result. Therefore, the resultant localized increase in contractility at cell injection sites, as seen by a significant increase in mechanical function on EMM, likely occurred as a consequence of an underlying improvement in perfusion. However, we cannot exclude the possibility that the injections themselves stimulated new blood vessel growth and enhanced function through the induction of angiogenic and important growth factors.
The homing process, which results in cell engraftment, may also play a key role in the success of cell therapy. After acute events, serum vascular endothelial growth factor levels rise significantly,23 and it is likely that homing signals may be more intense in acute and subacute ischemic syndromes. In our patients, all of whom had chronic disease, we opted to perform transendocardial cell-therapy delivery because we believe that homing signaling may not be as intense and, therefore, might not be optimal for cell engraftment. It is also likely that a smaller number of cells is required to achieve the desired effect.
EMM technology has been widely confirmed to be accurate for delineating and identifying scarred and viable myocardium and for differentiating degrees of infarct transmurality.11,12,24 EMM thus offers a theoretical benefit over surgical or intracoronary approaches because viability of the site can be determined before each injection. Injections would then be performed only to targeted, viable areas of hibernating myocardium. Many treated sites targeted in this study were in areas of totally occluded epicardial vascular beds, making intracoronary delivery impossible. Furthermore, potential ischemia provoked by coronary manipulation is avoided. This approved procedure seemed safer for these chronically ill, high-risk patients because it avoided associated surgical morbidity and mortality.
Tse et al7 recently demonstrated improvement in myocardial perfusion and segmental contractility after ABMMNC transendocardial injections. Those results are somewhat similar to results of the present study, although Tse and colleagues did not see improvement in global EF. The main difference between the studies is the significant baseline LV dysfunction present in our group (mean EF, 20%) as compared with a normal mean EF (56.9%) in the Tse study.7 The preliminary data of Tse and colleagues also suggest the relative safety of the procedure.
The use of transendocardial delivery proved to be safe in our study, as cellular therapy was successfully delivered in every case without any major periprocedural events (eg, death, myocardial infarction, ventricular arrhythmias, cardiac perforation, pericardial effusion, or development of intramyocardial tumor). Troponin levels increased by a small but significant amount, consistent with delivery via intramuscular injection (Table 4), but the absolute rise was relatively small biologically. The stability between levels of CRP in the treatment and control groups suggests that we did not initiate a significant inflammatory reaction with cell injection.
The major limitations of this study are the small number of patients enrolled and the study design, which limits conclusions about efficacy. Because of ethics committee concerns, the control group was not enrolled concurrently with treated patients, did not receive a placebo injection, and did not undergo invasive follow-up. However, treatment and control groups had similar follow-up up to 2 months. The benefits seen in this study with cell therapy could be attributable to the placebo effect seen in phase 1 trials. Potential biases include selection bias (eg, tertiary hospital population) and investigator bias when assessing symptoms at follow-up (CCSAS and NYHA class) although echocardiographic, angiographic, and SPECT studies were read blindly. In addition, smaller LV volumes and a trend toward higher EFs were present in the control group. However, both groups were matched in terms of demographics, medication use, baseline laboratory values, functional status classification, treadmill workload, and ·VO2max. More importantly, similar baseline reversible and fixed ischemic defects were present in both groups, as one of the most important end points assessed in this study was the amount of reversible perfusion defect at follow-up. The end point of contractility is more difficult to evaluate in light of the differences between the groups at baseline; however, changes in opposite directions occurred at follow-up. In addition, the slightly better LVEFs and smaller hearts should logically have biased results against the cell-treated group.
Although the mechanisms by which cell therapy confers clinical benefit are not well understood, correlation between cell phenotype subpopulation analysis and long-term clinical outcomes is beyond the scope of the present study. Future analyses will be performed in this regard when longer-term follow-up is available.
The treatment of patients with heart failure has become increasingly important given the growing number of cases and their economic impact on the healthcare system.25,26 More aggressive and widespread therapy in patients with chronic, ischemic heart failure will ultimately lead to a population harboring more advanced disease with a potential yearly mortality rate as high as 50%.27 For these patients, therapeutic options remain limited. The very high-risk nature of the patient population represented in our study cohort is underscored by the fact that there was a death in both the control and the treatment groups. However, the significant improvement in LVEF noted in the treatment group on angiographic follow-up at 4 months (from 20% to 29%) may imply an improved clinical state and, it is hoped, provide some reduction in risks for the future.28
| Conclusion |
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| Acknowledgments |
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We thank Rita Weiler, Ana Cristina Reis, RN, and Patricia Souza, RN, for their enthusiastic support and coordination of the study patients; Cristine Rutherford for the psychological assessment and support of the patients; David R. Buskohl, Mark Martin, and Jacqueline Grant for their outstanding technical support; and Marianne Mallia, ELS, for editorial assistance in the preparation of the manuscript.
| Footnotes |
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Guest editor for this article was Valentin Fuster, MD, PhD, Mount Sinai School of Medicine, NY.
This article originally appeared Online on April 21, 2003 (Circulation. 2003;107:r75r83).
Received March 7, 2003; revision received March 25, 2003; accepted March 26, 2003.
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