Abstract
Importance
Whether culture expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy (ICM) remains controversial.
Objective
To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and whole bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy.
Design, Setting and Patients
A phase 1 and 2 randomized blinded placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than50%(September 1, 2009-July 12, 2013). The study compared injection of MSCs (N=19) and placebo (N=11) or BMCs (N=19) with placebo (N=10) with 1-year of follow up.
Interventions
Injections into 10 LV sites with an infusion catheter.
Main Outcomes and Measures
Treatment-emergent 30 day serious adverse event rate defined as composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade or sustained ventricular arrhythmias.
Results
No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6% (95% CI, 12.6%-56.6%) for MSCs, 31.6% (95% CI, 12.6%-56.6%) for BMCs, and 38.1% (95% CI, 18.1%-61.6%) for placebo. Over 1-year the Minnesota Living with Heart Failure (MLHF) score improved with MSCs (repeated measures ANOVA P= .02) and BMCs (P= .005) but not placebo (P= .38), and 6-minute walk distance increased with MSCs only (repeated measures model P= .03). Infarct size as a percentage of LV Mass was reduced by MSCs (-18.9%; 95% CI, -30.4 to -7.4; within-group P= .004) but not by BMCs (-7.0%; 95% CI, -15.7%-1.7%; within-group P= .11) or placebo (-5.2; 95% CI, -16.8%-6.5%; within-group P=.36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95% CI, -13.3-3.5; within-group repeated measures P=.03) but not BMCs (-2.1; 95% CI -5.5-1.3; P=.21) or placebo (-0.03; 95% CI, -1.9-1.9; P=.14). Left ventricular chamber volume and ejection fraction did not change.
Conclusions and Relevance
Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach.
Introduction
Recent preclinical studies and clinical trials suggest that bone-marrow derived cell preparations, including mononuclear bone marrow cells1-6 and mesenchymal stem cells,7,8 ameliorate left ventricular (LV) remodeling with acute4,7 myocardial infarction (MI) and chronic1-3,5,8,9 ischemic cardiomyopathy. An effective anti-remodeling, pro-regenerative treatment for ICM would address a major unmet need for many patients. By virtue of their greater differentiation potential10, the culture expanded mesenchymal stem cells constituent of bone marrow is speculated to have potential for forming ectopic tissue11 or stimulating tumors,12 but could also have greater anti-fibrotic and pro-regenerative effects than BMCs.13 An unresolved issue is whether mesenchymal stem cells have similar safety and possibly greater efficacy than BMCs.8
To address these issues, we performed a phase 1 and 2 randomized, double-blind, placebo-controlled study of autologous culture-expanded mesenchymal stem cells vs. autologous BMCs delivered by transendocardial stem cell injection (TESI) in patients with ICM.14 The findings of The Transendocardial Autologous Cells in Ischemic Heart Failure Trial (TAC-HFT) have implications for the development of cell-based therapies for ICM, and possibly for other organs and diseases.
Methods
Study Design and Enrollment
The TAC-HFT study protocol, a phase 1 and 2, randomized, double-blind, placebo-controlled study of the safety and efficacy of the procedure, was conducted under the Investigational National Drug Application from the US Food and Drug Administration. The primary objective was to demonstrate the safety of mesenchymal stem cells and bone marrow mononuclear cells administered by TESI in patients with chronic MI and LV dysfunction. The secondary objective was to demonstrate the efficacy of autologous mesenchymal stem cells and bone marrow mononuclear cells in this context. Efficacy domains included myocardial scar size: regional function; LV size; viable tissue mass, shape, and global function; and patient quality of life and exercise capacity. A detailed description of the trial design was published.14
Patients were randomized at the University of Miami starting on September 1, 2009, with follow-up completed on July 12, 2013. This study had institutional review board approval from the University of Miami Miller School of Medicine, and all patients gave written informed consent. Sixty-five patients were randomized in a 1:1 ratio between the mesenchymal stem cell group and the bone marrow mononuclear cell group. Randomization between mesenchymal stem cell and bone marrow mononuclear cell groups was unblinded to preserve the advantage of a bone marrow mononuclear cell strategy, which allows use on the day of aspiration. Preparation14 of mesenchymal stem cells took 4-6 weeks after bone marrow aspiration,8 whereas the preparation of bone marrow mononuclear cells took 4 hours. To maintain a blinded assessment of cells vs placebo, patients were further randomized in a 2:1 ratio of cell therapy vs placebo. Preparation and administration of the study product was blinded to patients and investigators outside the cell-processing laboratory. An electronic data entry system was used for randomization and data collection.
An independent data and safety monitoring board was responsible for safety oversight.
Patient Population
Patients included in the study were aged 21 to 90 years and had ischemic cardiomyopathy with LV dysfunction resulting from chronic MI, as documented by confirmed coronary artery disease with a corresponding area of myocardial akinesis, dyskinesis, or severe hypokinesis and had LV ejection fraction of less than 50% within 6 months of screening while taking maximally tolerated doses of β-adrenergic blocking and angiotensin converting enzyme or angiotensin II receptor blocking drugs and not during or recently after an ischemic event. Patients were eligible for TESI catheterization within 5 to 10 weeks of screening. Patients were excluded for noncardiac conditions limiting life expectancy to less than 1 year, glomerular filtration rate of less than 45 mL/min per 1.73 m2, serious radiographic contrast allergy, clinical requirement for coronary revascularization, a life-threatening arrhythmia in the absence of an implanted defibrillator, or a malignancy within 5 years of screening.
Study Procedures and Timeline
Baseline studies included chemistry and hematology laboratory tests, echocardiography, and computed tomography (CT) scans of chest, abdomen, and pelvis. Demographic and clinical variables were acquired by interview. Race and ethnicity were recorded as self-described. Cardiac imaging was done with magnetic resonance imaging (MRI) when possible; patients with an implanted device that precluded MRI underwent cardiac CT imaging instead15. Most implanted pacemaker and defibrillator devices were not considered as contraindicating MRI, and these studies were performed as previously described.16 All patients underwent bone marrow aspiration from the iliac crest; mesenchymal stem cellswere prepared in culture from the marrow aspirate, as described.8,17 bone marrow mononuclear cells were prepared by centrifugation of whole bone marrow against a low-density gradient using Ficoll-Paque Premium (d = 1.077) according to the manufacturer's protocol. Cells were collected at the interface.
Cells or vehicle placebo were delivered to 10 LV sites by TESI during retrograde left heart catheterization using the Helical Infusion Catheter (Biocardia). 2,14 Injections were targeted to encircle the border zone of a chronically infarcted myocardial territory, as delineated by MRI or CT imaging, echocardiography, and well-opacified biplane left ventriculography. Following TESI, patients were hospitalized for a minimum of 4 days, and were seen at two weeks, monthly thereafter for six months and at 12 months for safety assessments including clinical interview and physical examination for adverse events (AEs), CT of the chest, abdomen, and pelvis, and for efficacy assessments including cardiac MRI or CT, exercise peak VO2, a 6-minute walk test (6MWT), New York Heart Association (NYHA) Class, and the Minnesota Living with Heart Failure questionnaire.
Study End Points
The primary end point was the incidence of any treatment emergent serious adverse events 1month after TESI, defined as the composite of death, nonfatal MI, stroke, hospitalization for worsening heart failure, cardiac perforation, pericardial tamponade, or sustained ventricular arrhythmias (>15 seconds or causing hemodynamic compromise).Additional safety assessments included clinical monitoring for adverse and serious adverse events and major adverse cardiac events (defined as the composite incidence of death, hospitalization for worsening heart failure, or nonfatal recurrent myocardial infarction), and surveillance testing including serial troponin and CK-MB; CT scans of the chest, abdomen, and pelvis to identify ectopic tissue formation; and 48-hour ambulatory electrocardiography, hematology, chemistry, urinalysis, spirometry, and serial echocardiography.
Prespecified secondary cardiac imaging end points were infarct size, regionalwall motion at the sites of study agent injection, and measures of global LV size and function. 8,14 Other prespecified secondary efficacy assessments included exercise peak VO2, a 6MWT, NYHA Class, and the Living With Heart Failure score.
MRI and CT Imaging
Cardiac MRI (General Electric, 1.5T) with gadolinium contrast was performed at baseline, 3, 6 and 12 months,8 to measure global cardiac function (cine), regional function (tagged cine to measure peak negative Eulerian circumferential strain, Ecc, a measure of local cardiac contraction8,18), and infarct size (delayed myocardial gadolinium enhancement using 0.2mmol/kg Magnevist, Bayer Healthcare), as previously described,8 and analyzed with Qmass MR 7.2 (Medis Inc) and Diagnosoft 2.71 (Diagnosoft Inc). Contrast-enhanced CT was performed at screening and at 12-month (128 slice Siemens AS+, Siemens Medical Solutions).18,19 Images were analyzed for global LV volumes, function, sphericity,20 and infarct scar size19 (iNtuition software ver.4.4.7.47; TeraRecon, Inc). For CT assessment, early-enhanced viability imaging19 employed prospective ECG-gating22,23 at 70-90% of the R-R interval and low tube voltage (100 kV) to minimize radiation exposure.
Statistical Analysis
The study was designed to estimate the confidence intervals of treatment-emergent serious adverse events at 30 days after undergoing TESI among both treatment groups vs placebo. The underlying rate of 30-day treatment-emergent adverse events was assumed to be 25% in each group. In this setting, the binomial 95% confidence interval is 6% to 44%. Rates of treatment-emergent, adverse, and serious adverse events were compared using the Fisher exact test at 30 days and at 12months. For continuous measures, normality of data was tested using the Shapiro-Wilk test, and the t test or nonparametric tests for differences between groups. Normally distributed efficacy parameters were tested with a repeated measures analysis of variance model using the entire data set including between-group comparisons as well as time and group × time interaction terms. Bonferroni correction was applied post hoc to test for within-group differences when the main effect was statistically significant. A 2-sided P value <.05 was considered statistically significant21. For the prespecified secondary efficacy parameters, 6-minute walk test, Minnesota Living With Heart Failure score, and MI size, the data are presented with the placebo groups pooled together when no significant differences in baseline characteristics were detected between placebo groups. Analyses were conducted using the SAS System, version 9.3 (SAS Institute Inc), and conformed to the prespecified objectives of the trial. Imaging analyses combined MRI and CT data unless otherwise specified.
Results
Patient population
A total of 65 patients were randomized. The 6 patients who did not receive TESI for protocol-specified reasons were not followed up once they were replaced by protocol-defined contingencies. Three patients who received the study intervention but did not complete the 1-year follow-up were evaluated for the 30-day safety assessment (Figure 1). The study population was predominantly male and white with a significant proportion of Hispanic participants (Table 1).Most patients had mild to moderate heart failure symptoms and impaired 6-minute walk test and Minnesota Living With Heart Failure scores.
Figure 1.
Study Flow Chart.
Table 1. Baseline Characteristics.
| Group: MSC/Placebo | Group: BMC/Placebo | |||
|---|---|---|---|---|
| MSCs (N=19) | Placebo (N=11) | BMCs (N=19) | Placebo (N=10) | |
| Male sex | 18 (94.7%) | 10 (90.9%) | 17 (89.5%) | 10 (100.0%) |
| Hispanic or Latino ethnicity | 7 (36.8%) | 4 (36.4%) | 10 (45.5%) | 5 (50.0%) |
| White race | 16 (84.2%) | 10 (90.9%) | 10 (52.6%) | 10 (100.0%) |
| Age (years) | 57.1 (10.6) | 60.0 (12.0) | 61.1 (8.4) | 61.3 (9.0) |
| Qualifying ejection fraction (%) | 35.8 (8.5) | 31.6 (10.0) | 36.3 (11.1) | 34.4 (9.5) |
| History of Coronary Interventions | 19 (100.0%) | 10 (90.9%) | 18 (94.7%) | 10 (100.0%) |
| History of Atrial/Ventricular Arrhythmia | 5 (26.3%) | 3 (27.3%) | 4 (21.1%) | 3 (20.0%) |
| History of Hypertension | 12 (63.2%) | 6 (54.5%) | 12 (63.2%) | 10 (100.0%) |
| History of Diabetes | 3 (15.8%) | 3 (27.3%) | 4 (21.1%) | 4 (40.0%) |
| History of Congestive Heart Failure | 11 (57.9%) | 7 (63.6%) | 16 (84.2%) | 9 (90.9%) |
| History of Smoking | 14 (73.7%) | 9 (81.8%) | 10 (52.6%) | 7 (70.0%) |
| New York Heart Association class | ||||
| Class I | 5 (26.3%) | 2 (20.0%) | 5 (26.3%) | 2 (25.0%) |
| Class II | 12 (63.2%) | 5(50.0%) | 10 (52.6%) | 5 (62.5%) |
| Class III | 2 (10.5%) | 3 (30.0%) | 4 (21.1%) | 1 (12.5%) |
| Six Minute Walk Test (meters) | 415.3 (67.9) | 388.5 (69.0) | 399.6 (95.0) | 387.8 (47.8) |
| Peak VO2 (mL/kg/min) | 18.8 (3.8) | 14.5 (4.5) | 17.3 (4.4) | 14.6 (7.0) |
| % Predicted FEV1 | 86.2 (15.7) | 77.0 (14.2) | 83.2 (23.2) | 81.4 (25.8) |
| MLHFQ Total Score | 28.4 (22.8) | 18.9 (15.0) | 29.5 (25.8) | 44.9 (24.9) |
| Device | ||||
| AICD | 10 (52.6%) | 4 (36.4%) | 10 (52.6%) | 4 (40.0%) |
| BiV | 1 (5.3%) | 2 (18.2%) | 1 (5.3%) | 1 (10.0%) |
| None | 8 (42.1%) | 5 (42.5%) | 8 (42.1%) | 5 (50.0%) |
| Imaging Modality | ||||
| MRI | 13 (68.4%) | 8 (72.7%) | 13 (68.4%) | 7 (70.0%) |
| CT | 6 (31.6%) | 3 (27.3%) | 6 (31.6%) | 3 (30.0%) |
| Time since first MI (years) | 10.0 (10.1) | 9.9 (7.9) | 7.7 (7.2) | 15.1 (8.6) |
| Cardiac Imaging Parameters | ||||
| LV ejection fraction, % | 35.7 (9.0) | 28.1 (9.8) | 35.9 (8.2) | 36.2 (7.4) |
| End-diastolic volume, mL | 283.2 (85.1) | 261.0 (87.5) | 254.9 (107.5) | 237.6 (65.1) |
| End-systolic volume, mL | 186.9 (75.6) | 189.9 (75.6) | 170.3 (92.5) | 153.9 (52.6) |
| Stroke volume, mL | 96.4 (18.9) | 71.1 (24.9) | 84.6 (19.1) | 83.8 (21.5) |
| End-diastolic sphericity index | 0.49 (0.08) | 0.49 (0.11) | 0.45 (0.10) | 0.46 (0.08) |
| Scar Mass, g | 26.6 (16.1) | 23.2 (14.3) | 23.5 (16.7) | 22.7 (14.6) |
| Scar size as % of LV mass, % | 25.9 (11.3) | 27.5 (16.5) | 25.5 (8.4) | 23.0 (9.2) |
| Viable Tissue Mass, g | 145.1 (78.3) | 123.6 (62.9) | 143.6 (76.0) | 146.3 (80.6) |
| Medications Pre-Injection | ||||
| ACE-1 | 11 (57.9%) | 8 (72.7%) | 11 (57.9%) | 6 (60.0%) |
| Angiotensin 2 Blockers | 4 (21.1%) | 0 (0.0%) | 6 (31.6%) | 2 (20.0%) |
| Beta Blockers | 17 (89.5%) | 11 (100.0%) | 17 (89.5%) | 9 (90.0%) |
| Diuretic | 12 (63.2%) | 6 (54.5%) | 14 (73.7%) | 6 (60.0%) |
Notes: Values presented as n, n (%) or mean (standard deviation); FEV1=Forced Expiratory Volume in 1 second; MSCs=mesenchymal stem cells; BMC=mononuclear bone marrow cells; MLHF=Minnesota living with Heart Failure Questionnaire: AICD=Automatic Implanted Cardioverter Defibrillator; BiV=Biventricular Pacing. No statistically significant differences between groups with the exception of stroke volume (P=.03).
Safety
There were no treatment-emergent serious adverse events among any of the patients who underwent TESI in any of the cell groups; corresponding 95%CIs ranged from0.0%to 17.7% (Table 2). Furthermore, the 30-day adverse event rate did not significantly differ by group: 31.6% (95% CI, 12.6%-56.6%) among those in the mesenchymal stem cell group vs 27.3%(95% CI, 6.0%-61.0%) in the respective placebo group and 36.8% (95%CI, 16.3%-61.6%) in the bone marrow group vs 30.0%(95% CI, 6.7%-65.3%) in the respective placebo group (Table 2). Serious adverse events were similarly infrequent among all patients who received TESI resulting in an overall incidence at 30 days of 11.9% (95% CI, 4.9%-22.9%).
Table 2. Safety Summary by 30-Days Post-TESI.
| Group: MSC/Placebo | Group: BMC/Placebo | |||
|---|---|---|---|---|
| MSCs (N=19) | Placebo (N=11) | BMCs (N=19) | Placebo (N=10) | |
| Primary Endpoint: Incidence of TE-SAE, n (%; 95% CI) | 0 (0.0%; 0.0-17.7) | 0 (0.0%; 0.0-28.5) | 0 (0.0%; 0.0-17.7) | 0 (0.0%; 0.0-30.9) |
| # of AEs | 8 | 4 | 10 | 4 |
| # of AEs/Patient, median (range) | 0 (0-2) | 0 (0-2) | 0 (0-2) | 0 (0-2) |
| Incidence of AE, n (%; 95% CI) | 6 (31.6%; 12.6-56.6) | 3 (27.3%; 6.0-61.0) | 7 (36.8%; 16.3-61.6) | 3 (30.0%; 6.7-65.3) |
| Incidence of AEs by SOC, n (%; 95% CI) | ||||
| Cardiac disorders | 2 (10.5%; 1.3-33.1) | 2 (18.2%; 2.3-51.8) | 1 (5.3%; 0.1-26.0) | 1 (10.0%; 0.3-44.5) |
| Gastrointestinal disorders | 1 (5.3%; 0.1-26.0) | --- | --- | --- |
| General disorders and administration site conditions | 3 (15.8%; 3.4-39.6) | 1 (9.1%; 0.2-41.2) | 2 (10.5%; 1.3-33.1) | --- |
| Infections and infestations | --- | --- | 1 (5.3%; 0.1-26.0) | 1 (10.0%; 0.3-44.5) |
| Injury, poisoning and procedural complications | --- | --- | --- | --- |
| Investigations | --- | --- | --- | 1 (10.0%; 0.3-44.5) |
| Musculoskeletal and connective tissue disorders | --- | --- | 1 (5.3%; 0.1-26.0) | --- |
| Nervous system disorders | --- | --- | 3 (15.8%; 3.4-39.6) | 1 (10.0%; 0.3-44.5) |
| Respiratory, thoracic and mediastinal disorders | --- | 1 (9.1%; 0.2-41.2) | --- | --- |
| Skin and subcutaneous tissue disorders | 2 (10.5%; 1.3-33.1) | --- | 1 (5.3%; 0.1-26.0) | --- |
| # of SAEs | 2 | 2 | 2 | 1 |
| # of SAEs/Patient, median (range) | 0 (0-1) | 0 (0-1) | 0 (0-1) | 0 (0-1) |
| Incidence of SAE, n (%; 95% CI) | 2 (10.5%; 1.3-33.1) | 2 (18.2%; 2.3-51.8) | 2 (10.5%; 1.3-33.1) | 1 (10.0%; 0.3-44.5) |
| Incidence of SAE by SOC, n (%; 95% CI) | ||||
| Cardiac disorders | 2 (10.5%; 1.3-33.1) | 2 (18.2%; 2.3-51.8) | --- | 1 (10.0%; 0.3-44.5) |
| General disorders and administration site conditions | --- | --- | 1 (5.3%; 0.1-26.0) | --- |
| Musculoskeletal and connective tissue disorders | --- | --- | 1 (5.3%; 0.1-26.0) | --- |
| Major Adverse Cardiac Event, n (%; 95% CI) | --- | --- | --- | --- |
| Deaths, n (%; 95% CI) | --- | --- | --- | --- |
| Ectopic Tissue Formation | --- | --- | --- | --- |
| Creatine kinase MB, ng/mL | ||||
| Baseline | 1.61 (1.21-2.02) | 1.32 (0.94-1.71) | 1.36 (0.80-1.91) | 1.96 (1.04-2.87) |
| 12 hour | 3.75 (2.70-4.80) | 2.85 (1.54-4.15) | 2.98 (2.17-3.79) | 6.14 (1.80-10.48) |
| 24 hour | 2.19 (1.64-2.74) | 2.08 (0.88-3.28) | 1.73 (1.23-2.24) | 3.78 (0.62-6.94) |
| 36 hour | 1.38 (1.11-1.66) | 1.19 (0.73-1.65) | 1.28 (0.98-1.59) | 2.11 (0.90-3.32) |
| 48 hour | 1.05 (0.84-1.27) | 0.87 (0.62-1.12) | 1.03 (0.79-1.26) | 1.91 (0.79-3.04) |
| Serum Troponin I, ng/mL | ||||
| Baseline | 0.06 (0.02-0.10) | 0.04 (0.03-0.05) | 0.06 (0.02-0.11) | 0.17 (-0.13-0.48) |
| 12 hour | 0.82 (0.47-1.17) | 0.66 (0.21-1.12) | 1.03 (0.06-1.99) | 1.33 (0.36-2.29) |
| 24 hour | 0.60 (0.29-0.91) | 0.34 (0.05-0.63) | 0.45 (0.04-0.86) | 0.52 (0.03-1.00) |
| 36 hour | 0.39 (0.16-0.62) | 0.25 (0.03-0.46) | 0.29 (0.01-0.57) | 0.38 (0.04-0.72) |
| 48 hour | 0.31 (0.08-0.54) | 0.11 (0.02-0.20) | 0.25 (0.01-0.49) | 0.34 (0.00-0.68) |
Values are presented as n or n (%; 95% CI) unless otherwise noted; 95% confidence interval was estimated using the exact binomial proportion; Zero events are denoted as (---); AE=Adverse Event, SAE=Serious Adverse Event, TE-SAE=Treatment Emergent SAE, MACE=Major Adverse Cardiac Event (defined as the composite incidence of (1) death, (2) hospitalization for worsening HF, or (3) non-fatal recurrent MI; SAEs/AEs are categorized according to MedDRA by System Organ Class (SOC). Cardiac enzymes are presented as mean and 95% CI. No statistically significant difference was noted among any parameter.
The TESI procedure was technically successful in all patients. No patient had significant postprocedural pericardial effusion. The myocardial biomarkers (CK-MB and serum troponin I) showed small transient increases (Table 2). Patients with implanted cardiac rhythm devices experienced no complications related to MRI.
Long Term Adverse Events
Two patients in the mesenchymal stem cell/placebo group died of cardiac events during the study period: the first died 239days after receiving transendocardial stem cell injection and the second, 115 days after receiving placebo. The 12-month adverse and serious adverse event incidence was similar among all groups (eTable 1 in the Supplement).
Rehospitalization and Major Cardiac Adverse Events
Six patients (31.6%; 95% CI, 12.6%-56.6%) in the mesenchymal stem cell group were rehospitalized during the 12-month study period, 5 (26.3%; 95% CI, 9.2%-51.2%) in the bone marrow group, and 5 (23.8%; 95% CI, 8.2%-47.2%) in the placebo groups (P = .85). The 12-month incidence of major adverse cardiac events was 1 (5.3%; 95% CI, 0.0%-26.0%) in the mesenchymal stem cell group, 0 (0.0%; 95% CI, 0.0%-17.7%) in the bone marrow group, and 2 (9.5%; 95% CI, 1.2%-3 0.4%) in the placebo groups (P = .77; eTable 1 in the Supplement).
Ectopic Tissue Formation
All patients underwent 12 month CT scans of chest, abdomen and pelvis; no ectopic tissue formation was detected.
Functional Status, Quality of Life, and Pulmonary Function
Patient functional status and quality of life were monitored serially. In a repeated measures model, the 6-minute walk test increased in the mesenchymal stem cell group but not in the bone marrow or placebo groups (P = .03; Figure 2). The mean change from baseline in distance walked in the mesenchymal stem cell group at 6 months was 28.2 m (95% CI, 10.8 to 45.5 m; P = .005) and at 12 months, 32.6m(95% CI, −4.6 to 69.7; P = .12). Among the bone marrow mononuclear cell group, the mean change from baseline in distance walked at 6 months was −25.7 m (95% CI, −74.1 to 22.6 m; P = .21) and at 12 months, 16.9 m (95% CI, −14.2 to 48.0 m; P = .30), whereas the placebo group mean change from baseline at 6 months was 21.6 m (95% CI, 1.4 to 41.8 m; P = .02) and at 12 months, 6.3 m (95% CI, −31.4 to 44.0 m; P = .70). When changes in 6-minute walk test were evaluated relative to changes in their respective placebo group at 12 months, the distance walked in 6 minutes did not differ in the mesenchymal stem cell group (−5.24 m; 95% CI, −62.68 to 52.21; P = .85) or in the bone marrow group (45.55 m; 95% CI, −11.0 to 102.1; P = .11). Neither peak oxygen consumption nor spirometric forced expiration volume in the first second of expiration changed with cell therapy.
Figure 2. Impact of Transendocardial Stem Cell Injection of Mesenchymal Stem Cells, Bone Marrow Cells, or Placebo on the 6-MinuteWalk Distance.
Patients in the mesenchymal stem cell group exhibited a significant increase in 6-minute walk distance when 6-month and 12-month time points were compared to baseline in a repeated measures model (P = .03). No significant difference was observed for patients in the bone marrow cell group (P = .73) or in the placebo group (P = .25). Data markers represent means; error bars, 95% CIs. Analysis of variance (ANOVA) was conducted with repeated measures.
a Within group, P<.05.
b Within group, P<.01.
The NYHA class improved at 12 months compared with baseline in 6 patients (35.3%) in the mesenchymal stem cell group, 9 patients (52.9%) in the bone marrow group, and 7 patients (43.8%) in the placebo group or did not change in 7 patients (41.2%) in the mesenchymal stem cell group, 6 patients (35.3%) in the bone marrow group, and 8 patients (50.0%) in the placebo group. Four patients in the mesenchymal stem cell group, 2 in the bone marrow group, and 1 in the placebo group had worsened NYHA class scores at 12months compared with baseline (P = .47).
The mean (SD) Minnesota Living With Heart Failure score at baselinewas28.4(22.8) for the mesenchymal stem cell group, 29.5 (25.8) for the bone marrow group, and 33.3 (24.5) for the placebo group. The score improved in both treatment groups but not in the placebo group (Figure 3). The improved score was greatest at 5 months, with amean reduction of 11.6 (95% CI, −23.7 to 0.5; P = .006) in the mesenchymal stem cell group and 15.80 (95%CI, −28.6 to −3.0; P = .04) in the bone marrow group, whereas the reduction in the placebo groupwas4.6(95% CI, −20.1 to 10.7; P = .69). When evaluating the changes in the Minnesota Living With Heart Failure score against the respective placebo group at 6 months, the mean difference between the mesenchymal stem cell group and the placebo group was −14.55 (95%CI, −31.1 to 2.01; P = .08) and the mean difference between the bone marrow group and the placebo group was 6.63 (95% CI, −15.68 to 28.95; P = .54). Over 1 year, the mesenchymal stem cell group score improved from baseline in a repeated measures analysis of variance model (−6.3;95%CI,−15.0 to 2.4; P = .02) as did the bone marrow cell group score (−8.2; 95% CI, −17.4 to 0.97; P = .005), but the placebo group score did not improve (0.4; 95%CI, −9.45 to 10.25; P = .38; Figure 3).
Figure 3. Impact of Transendocardial Stem Cell Injection of Mesenchymal Stem Cells, Bone Marrow Cells, or Placebo on Minnesota Living With Heart Failure Score.
Minnesota Living With Heart Failure questionnaire score improved in a repeated measures analysis of variance compared with baseline for the mesenchymal stem cell group (P = .02) and the bone marrow group (P = .005) but not the placebo group (P = .38). Repeated measures analyses of variance for model P values: treatment group, P = .29; time, P = .01; treatment group × time, P = .71. Data markers represent means; error bars, 95%CIs. Analysis of variance (ANOVA) was conducted with repeated measures.
a Within group, P<.05.
b Within group, P<.01.
Myocardial Infarct Size, Regional and Global Function
Infarct scar was assessed by cardiac MRI or CT18,22 and was expressed as ‘absolute values of myocardial scar mass’ and as ‘percentage of LV mass’ (scar size/LV mass). Both mesenchymal stem cells and bone marrow mononuclear cells reduced absolute scar mass but only mesenchymal stem cells reduced scar size as a percentage of LV mass. Scar mass/LV mass decreased 18.9% (95% CI, -30.4 to -7.4; within group P=.004; Figure 3A) 12 months after MSCs while remaining unchanged with bone marrow mononuclear cells (-7.0%; 95% CI, -15.7, 1.7; within group P=.11) and placebo (-5.2; 95% CI, -16.8, 6.5; within group P=.36). The change in scar mass as a fraction of LV mass relative to their respective placebo was -17.67% (95% CI, -35.85 to 0.51; P= .056) in MSCs and 2.1% (95% CI, -15.44 to 19.63 P=.8) in the bone marrow group.
Furthermore at 12-months, viable tissue mass significantly increased only with mesenchymal stem cell group (eFigure 1 in the Supplement) with a mean change of 8.4% (95% CI, 3.1, 13.7; within group P=.005) but not with bone marrow mononuclear cells (3.4; 95% CI, -1.5, 8.3; within group P=.16) or placebo (-1.1; 95% CI, -8.0, 5.8; within group P=.73). In an exploratory comparison analysis, the increase in viable tissue mass with mesenchymal stem cells differed significantly from the change in placebo (9.4; 95% CI, -0.4, 19.3; P=.05; eFigure 1) but there was no difference between bone marrow mononuclear cells and placebo (1.87; 95% CI, -3.64, 12.73; P=.26). When considering patients studied with serial cardiac MRI, patients in the mesenchymal stem cell group exhibited a progressive, time-dependent decrease in scar mass as a fraction of LV mass (p<0.001, Figure 5 and Figure 6).
Figure 5. Impact of Transendocardial Stem Cell Injection of Mesenchymal Stem Cells, Bone Marrow Cells, or Placebo on the Scar Size.
Significant reduction in scar size as the percentage of left ventricular mass for patients treated with mesenchymal stem cells (MSCs) and those in the placebo group who underwent serial magnetic resonance imaging. Repeated measures of analysis of variance model P values: treatment group, P=.99; time, P=.007; treatment group Å∼ time, P=.22. Data markers represent means; error bars, 95%CIs. Analysis of variance (ANOVA)was conductedwith repeated measures.
a Within group, P<.05 vs baseline.
b Within group, P<.01 vs baseline.
Figure 6. Cardiac Magnetic Resonance Images From a Representative Patient Before and 12 Months After Mesenchymal Stem Cell Injection.
A, Short-axis views of the basal area of a patient's heart, with delayed tissue enhancement delineated at the septal wall. Delayed tissue enhancement corresponds to scarred tissue and is depicted brighter than the nonscarred tissue (automatically detected and delineated with red using the full width at half maximum technique). The red, green, and white lines demarcating the endocardial, epicardial contours, and borders of the segments, respectively, were drawn manually. Twelve months after injection ofmesenchymal stem cells, scar mass was reduced from 30.85 g at baseline to 21.17 g at 12 months. B, Long-axis 2-chamber views of the same heart with delayed tissue enhancement delineated at the anterior and inferior wall, as well as the entire apex. At baseline and at 12 months after injection of mesenchymal stem cells, the delayed tissue enhancement receded in the midinferior and basal anterior walls (see Interactive of representative cardiac MRI cine sequences).
The mean absolute mass of myocardial scar before injection was 26.6 g (95% CI, 18.6-34.6 g) at baseline and 14.0 g (95% CI, 9.9-18.1 g) at 12 months, corresponding to a 32.9% reduction (95% CI, −44.9% to −20.9%; P < .001) in the mesenchymal stem cell group. Scar mass also decreased 23.1% in the bone marrow group (95% CI, −36.4% to −9.7%; P = .002) and 15.3% in the placebo group (95% CI, −29.3% to −1.27%; P = .04). Scar mass differed significantly at 12 months relative to their respective placebo cohort in the mesenchymal stem cell group (−29.98 g; 95% CI, −48.35 to −11.13 g; P = .003) but not in the bone marrow group (4.58 g; 95% CI, −18.43 to 27.58 g; P = .68). End-diastolic volume, end-systolic volume, LV ejection fraction, or end-diastolic sphericity index did not significantly change in within group or between-group comparisons (eFigure 1 in the Supplement).
Regional Function
Regional myocardial function measured as peak Eulerian circumferential strain at the site of injection (Interactive of representative cardiac MRI cine sequences)was improved by mesenchymal stem cells with a mean absolute change from baseline at 12 months −4.9 (95% CI, −13.3 to 3.5; within-group repeated measures P = .03) for the mesenchymal stem cell group, −2.1 (95% CI, −5.5 to 1.3; within-group repeated measures P = .21) for the bone marrow group and −0.03 (95%CI, −1.9 to 1.9; within-group repeated measures P = .14) for the placebo group (eFigure 2 in the Supplement).
Discussion
Cell therapy offers promise for treating for chronic ischemic heart disease1-3,5,7,13,23-27 but safety and efficacy remain uncertain. The TAC-HFT study was designed to provide a rigorous placebo-controlled and double-blinded safety assessment employing two leading candidates for cell therapy, bone marrow derived mesenchymal stem cells and fresh bone marrow mononuclear cells.14 Transendocardial injection of both cell types was not associated with an increased risk of adverse side effects, nor was ectopic tissue formation detected although the sample precludes any definitive statement about safety. We also show that mesenchymal stem cells exert regenerative and anti-fibrotic effects within the myocardium, and that these effects are associated with improved functional capacity and quality of life. Ongoing exploration of cell-based therapy for ICM is warranted.
While cell therapy for acute MI has been extensively studied, the challenges for treating chronic infarction are mechanistically distinct. In acute MI, anti-inflammatory and other healing influences could be invoked, whereas in chronic infarction regenerative and anti-fibrotic potential of stem cells may be required. Consistent with preclinical mechanistic studies18,28-33 and previous clinical studies, our data indicate biological activity of these cells in vivo after TESI. Dose and delivery are critical determinants of outcome. In the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis Pilot Study (POSEIDON) clinical trial of patients with ICM, mesenchymal stem cells (both autologous and allogeneic) produced significant scar size reductions, with an inverse dose response; the impact of 20 million MSCs exceeded that of 200 million.19 Other studies have indicated that infarct size reduction may be the predominant outcome of cell-based therapy.23,25,26,32,34
Exploratory analyses of TAC-HFT data suggest that the efficacy of MSCs exceed that of bone marrow mononuclear cells in most measures. bone marrow mononuclear cells reduced absolute scar mass and improved the Minnesota Living With Heart Failure score, suggesting a possibility of efficacy. Interestingly, patients receiving placebo injections showed some evidence of scar reduction at three months, which did not further change over time; however, in neither bone marrow mononuclear cell nor placebo groups did the scar as a percentage of LV mass decrease, suggesting that mechanisms other than myocardial regeneration may explain the improvements in these groups. MSCs were associated with decreasing scar fraction and increasing viable myocardial mass, suggesting true myocardial regeneration. We detected a trend correlating scar reduction with improved Minnesota Living With Heart Failure functional status, and this was particularly evident in the MSC group (eFigure 3A and 3B in the Supplement).
Although ejection fraction improvements have not been consistently shown in clinical trials of cell therapy,35 it is important to note that scar size is highly predictive of ventricular arrhythmias, LV remodeling, heart failure, and mortality. 36,37 Although our study was not powered for mortality outcomes, infarct size reductions of a magnitude that might have the potential of a mortality benefit. Efficacy findings were detected in several clinical outcome measures, but definitive demonstration of the value of TESI remains for future trials, including in the sickest patients for whom cell therapy might answer an urgent unmet need.
Mechanistically, mesenchymal stem cells reduce tissue fibrosis by releasing anti-fibrotic matrix metaloproteases,13 and stimulate neovascularization13,30,38,39 and cardiomyocyte regeneration both primarily and by promoting endogenous stem cell proliferation40. The findings of the TAC-HFT trial are consistent with observations from animal models and support that these mechanisms are operative in the human heart.
This study used both cardiac MRI and multi-detector CT scanning to evaluate heart function and infarct size. The sophisticated cardiac phenotyping of MRI can be repeated without accumulating radiation exposure, and can be used in many patients with implanted devices16 although artifact from intracardiac defibrillating leads may obscure parts of the heart. Computed tomography also allows measurement of cardiac function and infarct size.18,41 Either cardiac MRI or CT were both performed at baseline and at 12 months; patients studied by MRI also had LV assessment at 3 and 6 months.13 With MRI, myocardial scar was determined from delayed enhanced images. With CT we analyzed the early enhancement defect as was done in the POSEIDON trial19; this may detect infarction as well as severe resting ischemia42, but by excluding individuals with active ischemia, early enhancement defects in TAC-HFT reasonably measure scar size. Three-dimensional echocardiography could have offered a unified approach to measuring LV dimension in all patients, but may not discern changes in infarct scar size43.
Future refinements in cell-based therapy may lead to greater effectiveness of the approach. Cardiac stem cells exerted highly favorable effects in the Cardiac Stem Cell Infusion in Patients With Ischemic Cardiomyopathy (SCIPIO) trial23; tissue-derived cells and cell combinations33 are both under development in patients with ischemic cardiomyopathy, and both autologous and allogeneic options are being evaluated27. This study and the POSEIDON19 trial highlight the importance of carefully delineating optimal delivery and dosing.
Limitations
Within-group efficacy improvementswere detected by analyses of several outcome measures for mesenchymal stem cell and a few for bone marrow mononuclear cells, but these differences were not significant in most cases when compared across groupwith placebo. This in part reflects that the study was not powered to drawdefinitive efficacy comparisons between cell types.Multiple comparisonswere conducted, further limiting the conclusions.21 Although, this and other studies support the safety of delivering cell-therapy by transendocardial injection, the sample size limits the strength of the conclusion, so larger studies are warranted (eFigure 3 in the Supplement).
Conclusions
In this preliminary study, TESI with autologous mesenchymal stem cells or bone marrowmononuclear cells appeared to be safe in patientswith chronic ischemic cardiomyopathy and LVdysfunction. These results provide the basis for larger studies to provide definitive assessment of safety and to assess efficacy of this new therapeutic approach.
Supplementary Material
Figure 4. Percent Change in Scar Size as a Percentage of Left Ventricular Mass.
The 14 patients treated with mesenchymal stem cells (MSCs) exhibited a significant reduction in scar size (P = .004) as a percentage of left ventricular mass with no differences for the 15 patients treated with bone marrow cells or the 16 patients in the placebo group. The overall analysis of variance was P=.13. Data markers represent means; error bars, 95%CIs.
a Within group, P<.01.
Acknowledgments
This study was funded in part by the Interdisciplinary Stem Cell Institute, Miller School of Medicine, Biocardia, and the NHLBI Specialized Center for Cell Therapy U54HL081028-01, Helical Infusion Catheters were provided by Biocardia, Inc. Dr. Hare is supported by NIH grants: RO1 HL094849, P20 HL101443, RO1 HL084275, RO1 HL107110, RO1 HL110737 and UM1HL113460.
Role of the Sponsor: The Sponsor, Bicoardia, was involved in the design of the protocol of the study. It had no role in data collection or analysis. Biocardia employees reviewed the final draft and are included in the authors list.
We wish to thank the TAC-HFT DSMB, the patients who participated in this trial, and staff of the cardiac catheterization laboratory at the University of Miami Hospital.
Footnotes
Drs. Hare and Heldman had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Drs. Hare and Heldman are listed on a patent application for cardiac cell-based therapy, receive research support from Biocardia, and report an equity interest in Vestion, Inc.
Dr. Hare is a consultant to Kardia. Drs. Altman, Rouy and Wong Po Foo are employees of Biocardia, and E. Anderson and A. Mendizabal are employees of The EMMES Corporation.
The other authors report no conflict of interest relevant to this work.
References
- 1.Assmus B, Honold J, Schachinger V, et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med. 2006;355(12):1222–1232. doi: 10.1056/NEJMoa051779. [DOI] [PubMed] [Google Scholar]
- 2.de la Fuente LM, Stertzer SH, Argentieri J, et al. Transendocardial autologous bone marrow in chronic myocardial infarction using a helical needle catheter: 1-year follow-up in an open-label, nonrandomized, single-center pilot study (the TABMMI study) Am Heart J. 2007;154(1):79–77. doi: 10.1016/j.ahj.2007.04.051. [DOI] [PubMed] [Google Scholar]
- 3.Hendrikx M, Hensen K, Clijsters C, et al. Recovery of regional but not global contractile function by the direct intramyocardial autologous bone marrow transplantation: results from a randomized controlled clinical trial. Circulation. 2006;114(1 Suppl):I101–I107. doi: 10.1161/CIRCULATIONAHA.105.000505. [DOI] [PubMed] [Google Scholar]
- 4.Leistner DM, Fischer-Rasokat U, Honold J, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCAREAMI): final 5-year results suggest long-term safety and efficacy. Clin Res Cardiol. 2011;100(10):925–934. doi: 10.1007/s00392-011-0327-y. [DOI] [PubMed] [Google Scholar]
- 5.Perin EC, Willerson JT, Pepine CJ, et al. Effect of Transendocardial Delivery of Autologous Bone Marrow Mononuclear Cells on Functional Capacity, Left Ventricular Function, and Perfusion in Chronic Heart Failure: The FOCUS-CCTRN Trial. JAMA. 2012;307(16):1717–1726. doi: 10.1001/jama.2012.418. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet. 2004;364(9429):141–148. doi: 10.1016/S0140-6736(04)16626-9. [DOI] [PubMed] [Google Scholar]
- 7.Hare JM, Traverse JH, Henry TD, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol. 2009;54(24):2277–2286. doi: 10.1016/j.jacc.2009.06.055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Williams AR, Trachtenberg B, Velazquez DL, et al. Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling. Circ Res. 2011;108(7):792–796. doi: 10.1161/CIRCRESAHA.111.242610. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Losordo DW, Henry TD, Davidson C, et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res. 2011;109(4):428–436. doi: 10.1161/CIRCRESAHA.111.245993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–147. doi: 10.1126/science.284.5411.143. [DOI] [PubMed] [Google Scholar]
- 11.von Bahr L, Batsis I, Moll G, et al. Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells. 2012;30(7):1575–1578. doi: 10.1002/stem.1118. [DOI] [PubMed] [Google Scholar]
- 12.Hatzistergos KE, Blum A, Ince T, Grichnik JM, Hare JM. What is the oncologic risk of stem cell treatment for heart disease? Circ Res. 2011;108(11):1300–1303. doi: 10.1161/CIRCRESAHA.111.246611. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Williams AR, Hare JM. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res. 2011;109(8):923–940. doi: 10.1161/CIRCRESAHA.111.243147. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Trachtenberg B, Velazquez DL, Williams AR, et al. Rationale and design of the Transendocardial Injection of Autologous Human Cells (bone marrow or mesenchymal) in Chronic Ischemic Left Ventricular Dysfunction and Heart Failure Secondary to Myocardial Infarction (TAC-HFT) trial: A randomized, double-blind, placebo-controlled study of safety and efficacy. Am Heart J. 2011;161(3):487–493. doi: 10.1016/j.ahj.2010.11.024. [DOI] [PubMed] [Google Scholar]
- 15.Mak GS, Truong QA. Cardiac CT: Imaging of and Through Cardiac Devices. Curr Cardiovasc Imaging Rep. 2012;5(5):328–336. doi: 10.1007/s12410-012-9150-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Junttila MJ, Fishman JE, Lopera GA, et al. Safety of serial MRI in patients with implantable cardioverter defibrillators. Heart. 2011;97(22):1852–1856. doi: 10.1136/heartjnl-2011-300153. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Da Silva JS, Hare JM. Cell-Based Therapies for Myocardial Repair: Emerging Role for Bone Marrow-Derived Mesenchymal Stem Cells (MSCs) in the Treatment of the Chronically Injured Heart. Methods Mol Biol. 2013;1037:145–163. doi: 10.1007/978-1-62703-505-7_8. [DOI] [PubMed] [Google Scholar]
- 18.Amado LC, Schuleri KH, Saliaris AP, et al. Multimodality noninvasive imaging demonstrates in vivo cardiac regeneration after mesenchymal stem cell therapy. J Am Coll Cardiol. 2006;48(10):2116–2124. doi: 10.1016/j.jacc.2006.06.073. [DOI] [PubMed] [Google Scholar]
- 19.Hare JM, Fishman JE, Gerstenblith G, et al. Comparison of Allogeneic vs. Autologous Bone Marrow Derived Mesenchymal Stem Cells Delivered by Transendocardial Injection in Patients with Ischemic Cardiomyopathy: The POSEIDON Randomized Trial. JAMA. 2012;308(22):2369–2379. doi: 10.1001/jama.2012.25321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Lamas GA, Vaughan DE, Parisi AF, Pfeffer MA. Effects of left ventricular shape and captopril therapy on exercise capacity after anterior wall acute myocardial infarction. Am J Cardiol. 1989;63(17):1167–1173. doi: 10.1016/0002-9149(89)90173-2. [DOI] [PubMed] [Google Scholar]
- 21.Hare JM, Bolli R, Cooke JP, et al. Phase II clinical research design in cardiology: learning the right lessons too well: observations and recommendations from the Cardiovascular Cell Therapy Research Network (CCTRN) Circulation. 2013;127(15):1630–1635. doi: 10.1161/CIRCULATIONAHA.112.000779. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Choi SI, George RT, Schuleri KH, Chun EJ, Lima JA, Lardo AC. Recent developments in wide-detector cardiac computed tomography. Int J Cardiovasc Imaging. 2009;25(Suppl 1):23–29. doi: 10.1007/s10554-009-9443-4. [DOI] [PubMed] [Google Scholar]
- 23.Bolli R, Chugh AR, D'Amario D, et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet. 2011;378(9806):1847–1857. doi: 10.1016/S0140-6736(11)61590-0. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- 24.Kinkaid HY, Huang XP, Li RK, Weisel RD. What's new in cardiac cell therapy? Allogeneic bone marrow stromal cells as “universal donor cells”. J Card Surg. 2010;25(3):359–366. doi: 10.1111/j.1540-8191.2009.00984.x. [DOI] [PubMed] [Google Scholar]
- 25.Menasche P. Cardiac cell therapy: lessons from clinical trials. J Mol Cell Cardiol. 2011;50(2):258–265. doi: 10.1016/j.yjmcc.2010.06.010. [DOI] [PubMed] [Google Scholar]
- 26.Suncion VY, Schulman IH, Hare JM. The Role of Clinical Trials in Deciphering Mechanisms of Action of Cardiac Cell-Based Therapy. Stem Cells-Transl Med. 2012;1(2):29–35. doi: 10.5966/sctm.2011-0014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Telukuntla KS, Suncion VY, Schulman IH, Hare JM. The advancing field of cell-based therapy: insights and lessons from clinical trials. J Am Heart Assoc. 2013;2(5):e000338. doi: 10.1161/JAHA.113.000338. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Hamamoto H, Gorman JH, 3rd, Ryan LP, et al. Allogeneic mesenchymal precursor cell therapy to limit remodeling after myocardial infarction: the effect of cell dosage. Ann Thorac Surg. 2009;87(3):794–801. doi: 10.1016/j.athoracsur.2008.11.057. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Lee ST, White AJ, Matsushita S, et al. Intramyocardial injection of autologous cardiospheres or cardiosphere-derived cells preserves function and minimizes adverse ventricular remodeling in pigs with heart failure post-myocardial infarction. J Am Coll Cardiol. 2011;57(4):455–465. doi: 10.1016/j.jacc.2010.07.049. [DOI] [PubMed] [Google Scholar]
- 30.Quevedo HC, Hatzistergos KE, Oskouei BN, et al. Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proc Natl Acad Sci U S A. 2009;106(33):14022–14027. doi: 10.1073/pnas.0903201106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Schuleri KH, Amado LC, Boyle AJ, et al. Early improvement in cardiac tissue perfusion due to mesenchymal stem cells. Am J Physiol Heart Circ Physiol. 2008;294(5):H2002–H2011. doi: 10.1152/ajpheart.00762.2007. [DOI] [PubMed] [Google Scholar]
- 32.Williams AR, Suncion VY, McCall F, et al. Durable scar size reduction due to allogeneic mesenchymal stem cell therapy regulates whole-chamber remodeling. J Am Heart Assoc. 2013;2(3):e000140. doi: 10.1161/JAHA.113.000140. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Williams AR, Hatzistergos KE, Addicott B, et al. Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation. 2013;127(2):213–223. doi: 10.1161/CIRCULATIONAHA.112.131110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Karantalis V, Balkan W, Schulman IH, Hatzistergos K, Hare JM. Cell-Based Therapy for Prevention and Reversal of Myocardial Remodeling. Am J Physiol Heart Circ Physiol. 2012;303(1):H256–270. doi: 10.1152/ajpheart.00221.2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Janssens S, Dubois C, Bogaert J, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet. 2006;367(9505):113–121. doi: 10.1016/S0140-6736(05)67861-0. [DOI] [PubMed] [Google Scholar]
- 36.Bello D, Einhorn A, Kaushal R, et al. Cardiac magnetic resonance imaging: infarct size is an independent predictor of mortality in patients with coronary artery disease. Magn Reson Imaging. 2011;29(1):50–56. doi: 10.1016/j.mri.2010.03.031. [DOI] [PubMed] [Google Scholar]
- 37.Perin EC, Dohmann HF, Borojevic R, et al. Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation. 2004;110(11 Suppl 1):II213–218. doi: 10.1161/01.CIR.0000138398.77550.62. [DOI] [PubMed] [Google Scholar]
- 38.Silva GV, Litovsky S, Assad JA, et al. Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation. 2005;111(2):150–156. doi: 10.1161/01.CIR.0000151812.86142.45. [DOI] [PubMed] [Google Scholar]
- 39.Zhou Y, Wang S, Yu Z, Hoyt RF, Jr, Qu X, Horvath KA. Marrow stromal cells differentiate into vasculature after allogeneic transplantation into ischemic myocardium. Ann Thorac Surg. 2011;91(4):1206–1212. doi: 10.1016/j.athoracsur.2011.01.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Hatzistergos KE, Quevedo H, Oskouei BN, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res. 2010;107(7):913–922. doi: 10.1161/CIRCRESAHA.110.222703. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Schuleri KH, Centola M, Choi SH, et al. CT for evaluation of myocardial cell therapy in heart failure: a comparison with CMR imaging. JACC Cardiovasc Imaging. 2011;4(12):1284–1293. doi: 10.1016/j.jcmg.2011.09.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Mahnken AH, Koos R, Katoh M, et al. Assessment of myocardial viability in reperfused acute myocardial infarction using 16-slice computed tomography in comparison to magnetic resonance imaging. J Am Coll Cardiol. 2005;45(12):2042–2047. doi: 10.1016/j.jacc.2005.03.035. [DOI] [PubMed] [Google Scholar]
- 43.Nihoyannopoulos P, Vanoverschelde JL. Myocardial ischaemia and viability: the pivotal role of echocardiography. Eur Heart J. 2011;32(7):810–819. doi: 10.1093/eurheartj/ehr002. [DOI] [PubMed] [Google Scholar]
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