Author + information
- Received October 11, 2016
- Revision received October 26, 2016
- Accepted November 1, 2016
- Published online January 30, 2017.
- Joshua M. Hare, MDa,b,∗ (, )
- Darcy L. DiFede, RN, BSNa,
- Angela C. Rieger, MD, MSca,
- Victoria Florea, MDa,
- Ana M. Landin, PhDa,
- Jill El-Khorazaty, MScc,
- Aisha Khan, MSc, MBAa,
- Muzammil Mushtaq, MDb,
- Maureen H. Lowery, MDb,
- John J. Byrnes, MDb,
- Robert C. Hendel, MDb,
- Mauricio G. Cohen, MDb,
- Carlos E. Alfonso, MDb,
- Krystalenia Valasaki, MSca,
- Marietsy V. Pujol, MBAa,
- Samuel Golpanian, MDd,
- Eduard Ghersin, MDe,
- Joel E. Fishman, MD, PhDe,
- Pradip Pattany, PhDe,
- Samirah A. Gomes, MD, PhDa,
- Cindy Delgado, MAa,
- Roberto Miki, MDb,
- Fouad Abuzeid, MDa,
- Mayra Vidro-Casiano, MPHa,
- Courtney Premer, BSca,
- Audrey Medina, BSca,
- Valeria Porras, BSca,
- Konstantinos E. Hatzistergos, PhDa,
- Erica Anderson, MScc,
- Adam Mendizabal, PhDc,
- Raul Mitrani, MDb and
- Alan W. Heldman, MDb
- aInterdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida
- bDepartment of Medicine, University of Miami Miller School of Medicine, Miami, Florida
- cThe Emmes Corporation, Rockville, Maryland
- dDepartment of Surgery, University of Miami Miller School of Medicine, Miami, Florida
- eDepartment of Radiology, University of Miami Miller School of Medicine, Miami, Florida
- ↵∗Address for correspondence:
Dr. Joshua M. Hare, Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 Northwest 10th Avenue, 9th Floor, Miami, Florida 33136.
Background Although human mesenchymal stem cells (hMSCs) have been tested in ischemic cardiomyopathy, few studies exist in chronic nonischemic dilated cardiomyopathy (NIDCM).
Objectives The authors conducted a randomized comparison of safety and efficacy of autologous (auto) versus allogeneic (allo) bone marrow-derived hMSCs in NIDCM.
Methods Thirty-seven patients were randomized to either allo- or auto-hMSCs in a 1:1 ratio. Patients were recruited between December 2011 and July 2015 at the University of Miami Hospital. Patients received hMSCs (100 million) by transendocardial stem cell injection in 10 left ventricular sites. Treated patients were evaluated at baseline, 30 days, and 3-, 6-, and 12-months for safety (serious adverse events [SAE]), and efficacy endpoints: ejection fraction, Minnesota Living with Heart Failure Questionnaire, 6-min walk test, major adverse cardiac events, and immune biomarkers.
Results There were no 30-day treatment-emergent SAEs. Twelve-month SAE incidence was 28.2% with allo-hMSCs versus 63.5% with auto-hMSCs (p = 0.1004 for the comparison). One allo-hMSC patient developed an elevated (>80) donor-specific calculated panel reactive antibody level. The ejection fraction increased in allo-hMSC patients by 8.0 percentage points (p = 0.004) compared with 5.4 with auto-hMSCs (p = 0.116; allo vs. auto p = 0.4887). The 6-min walk test increased with allo-hMSCs by 37.0 m (p = 0.04), but not auto-hMSCs at 7.3 m (p = 0.71; auto vs. allo p = 0.0168). MLHFQ score decreased in allo-hMSC (p = 0.0022) and auto-hMSC patients (p = 0.463; auto vs. allo p = 0.172). The major adverse cardiac event rate was lower, too, in the allo group (p = 0.0186 vs. auto). Tumor necrosis factor-α decreased (p = 0.0001 for each), to a greater extent with allo-hMSCs versus auto-hMSCs at 6 months (p = 0.05).
Conclusions These findings demonstrated safety and clinically meaningful efficacy of allo-hMSC versus auto-hMSC in NIDCM patients. Pivotal trials of allo-hMSCs are warranted based on these results. (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy [PoseidonDCM]; NCT01392625)
Nonischemic dilated cardiomyopathy (NIDCM) is a progressive disorder with no current cure, often culminating in heart transplantation (1,2). Cell-based therapy for heart disease is a promising new treatment strategy undergoing evaluation (3–8), with a major challenge and opportunity in developing allogeneic (allo) therapy (9). Bone marrow-derived human mesenchymal stem cells (hMSCs) may be a viable source of allo-cells, because they lack major histocompatibility class II and costimulatory molecules, rendering them immune-evasive (8,10). Allo-hMSCs also have immunomodulatory effects (8), which could have therapeutic importance in NIDCM, a disorder with a major component of immune dysregulation as an underlying etiology (11,12). Although allo-hMSCs offer a major opportunity as an off-the-shelf therapeutic, they may lack the efficacy of autologous (auto)-hMSC therapy because some preclinical data indicated a higher risk of immunological clearance (13).
Compared with auto-hMSCs, allo-hMSC therapy has great potential for developing readily available, disease-free cell products in a cost-effective manner, an important issue for disorders with high incidence. In the field of heart failure (HF), hMSCs exert antifibrotic and proregenerative effects leading to improved ventricular function and architecture in patients with antecedent myocardial infarction (6,8,9). Because MSCs have powerful and sustained anti-inflammatory effects (8,14) and stimulate restoration of endothelial health (15), they could be of substantial therapeutic importance in conditions such as NIDCM.
The POSEIDON-DCM (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy) trial was a randomized trial testing the hypothesis that allo-hMSCs represent a safe and efficacious alternative to auto-hMSCs in patients with NIDCM. The study design was previously published (16).
Patients provided written informed consent. All patients were recruited between December 2011 and July 2015 at the University of Miami Hospital (Figure 1). Thirty-seven patients were randomized to either auto- or allo-hMSCs in a 1:1 ratio. Following cardiac catheterization and cell injections, patients remained hospitalized for a minimum of 2 days, with in-clinic follow-up at 2 weeks post-catheterization, and in-person/in-clinic follow-up at 2, 3, 6, and 12 months for safety and efficacy assessments. An electronic data entry system was used for randomization and data collection. Although this was an open-label study, all data analysis was masked to those assessing all study endpoints, and statistical analysis was performed by a third party for unmasking. Detailed methods are explained in the Online Appendix. The National Heart, Lung, and Blood Institute Gene and Cell Therapy Data and Safety Monitoring Board provided safety oversight of the trial.
Patients, procedures, and cells used
Patient eligibility was determined after confirmation of NIDCM diagnosis with an ejection fraction (EF) <40% and either a left ventricular (LV) end-diastolic diameter >5.9 cm in male subjects or >5.6 cm in female subjects, or an LV end-diastolic volume index >125 ml/m2, as previously described (16).
Baseline assessments included chemistry and hematology laboratory tests and echocardiography, plus chest, abdominal, and pelvic computed tomography scans. Cardiac computerized tomography (CT) or magnetic resonance imaging (MRI) was performed (9).
All allo-hMSCs and auto-hMSCs were manufactured at the University of Miami Interdisciplinary Stem Cell Institute (8,16). Allo-hMSCs were derived from Caucasian male donors, mean age 25.4 ± 3.3 years, and the samples were 80% to 90% viable at time of transendocardial stem cell injection (TESI). The auto-hMSCs were from 11 men with a mean age of 58.0 ± 9.9 years and 6 women with a mean age of 55.0 ± 12.4 years.
Injection sites were selected to prioritize TESI safety and to distribute sites throughout the accessible myocardial territories. Considerations for site selection included avoidance of the ventricular apex and optimization of catheter stability before needle extension.
The primary safety endpoint was the incidence of any treatment-emergent serious adverse events (TE-SAEs) occurring within 30 days after treatment (16). Secondary safety endpoints included other adverse events, ectopic tissue formation, and forced expiratory volume in 1 s (FEV1). Secondary efficacy endpoints included incidence of major adverse cardiac events (MACE), LV structure and function, patient quality of life (QOL) measured by New York Heart Association (NYHA) functional class and Minnesota Living with Heart Failure Questionnaire (MLHFQ), 6-min walk test (6MWT), maximal oxygen consumption (Vo2), endothelial function, and immunologic status.
Endothelial function was assessed at baseline and 3 months post–allo-hMSC or auto-hMSC. Endothelial progenitor cell colony forming units (EPC-CFUs) from peripheral blood samples and flow-mediated vasodilation (FMD) brachial artery diameter measurements and percent of FMD were performed. A subset of patient results for endothelial function was previously described (15).
Calculated panel reactive antibodies (cPRA) were measured at baseline and at 6 months. Serum tumor necrosis factor (TNF)-α was measured using a human TNF-α enzyme-linked immunoadsorbent assay high-sensitivity kit. Lymphocytes were stained for T-cell markers of activation, late/exhausted T cells, B cell subsets (switched memory and late/exhausted B cells) and TNF-α by B cells. All samples were acquired using the LSR-Fortessa-HTS analyzer (BD Biosciences Pharmigen, San Diego, California) and analyzed with FlowJo version 10 software (FlowJo, Ashland, Oregon).
The sample size of 18 per treatment arm was chosen to be appropriate for a phase I/II study; if the true TE-SAE event rate was 25%, the probability of observing at least 1 event per treatment arm would be 99%. All patients who received study injection were included in analysis.
Continuous variables were summarized using the following descriptive statistics: n (nonmissing sample size), mean ± SD (or median and interquartile range [IQR] as appropriate), maximum, and minimum. The frequency and percentages (based on the nonmissing sample size) of observed levels were reported for all categorical measures. Outcomes, which were collected at multiple follow-up visits, were analyzed using a mixed model for repeated measures to compare treatment groups, with treatment group considered an effect as well as a group-by-time interaction.
Within-group effects were described using model-estimated contrasts. Outcomes that were highly skewed were analyzed using ranked analysis of covariance adjusting for baseline at each follow-up assessment, and within-group effects were described using a Wilcoxon signed rank test. Categorical variables were compared between groups using Fisher exact tests. Analysis of time-to-event data was done using a 2-sided log-rank test, censoring those who did not experience an event at their last known follow-up day. All statistical tests were performed at α = 0.05 using 2-sided tests. All data analyses and statistical computations were conducted with SAS version 9.3 (SAS Institute, Cary, North Carolina).
Of the 37 patients randomized to either auto- or allo-hMSCs, 34 received study injection of either auto- (n = 16) or allo-hMSCs (n = 18). Three patients did not receive the study injection: 1 withdrew consent before treatment; 1 was recruited, but did not receive treatment due to automatic implantable cardioverter-defibrillator placement; and 1 died before treatment.
The mean age of injected participants was 55.8 ± 11.2 years, 29% were female, and 35% were Hispanic (Table 1). The mean years of NIDCM diagnosis before TESI was 6.1 ± 6.2 years for allo and 6.9 ± 7.3 years for auto hMSCs patients (p = 0.5 between groups). Fifty percent of patients had NYHA functional class II symptoms, mean baseline global EF was 26.5 ± 9.64%, mean 6MWT was 422 ± 86.8 m, and median baseline MLHFQ score was 36 (IQR: 18.0 to 64.0).
Safety and long-term adverse events
TESI was technically successful in 33 (97.05%) patients. One patient experienced ventricular tachycardia after the ninth injection, and did not receive the last injection. No patients experienced significant post-procedural pericardial effusion. The intervention was safe in all TESI recipients, with no TE-SAEs within 30 days. Furthermore, the incidence of AEs by 30 days did not significantly differ by cell type (p = 0.6117) (Table 2). Moreover, SAE rates were infrequent through day 30 and similar in both groups (p = 0.6238) (Table 2). Accordingly, the study met the primary safety endpoint, documenting the safety of TESI in patients with NIDCM.
The 12-month post-TESI SAE incidence was 28.2% (95% confidence interval [CI]: 12.8 to 55.1) in allo-hMSC and 63.5% (95% CI: 40.8 to 85.7; p = 0.1004) in auto-hMSC patients. Post-TESI, 2 auto-hMSCs patients and 1 allo-hMSCs patient underwent heart transplantation; similarly, LV assist devices were implanted in 1 patient in each group. Two deaths occurred post-injection in the auto-hMSCs group: a fatal subdural hematoma due to trauma on day 152 post-injection and a death due to NIDCM 291 days post-injection. Both events were considered unrelated to study treatment.
The 12-month all-cause rehospitalization rate was lower in the allo- versus the auto-hMSCs recipients: 28.2% (95% CI: 12.8% to 55.1%) versus 70.0% (95% CI: 47.0% to 89.8%), respectively (p = 0.0447). Similarly, MACE over 12 months was lower in the allo-hMSCs group: 20.3% (95% CI: 6.8% to 52.1%) compared with 57.1% (95% CI: 34.9% to 81.2%) in the auto-hMSCs group (p = 0.0186). No ectopic tissue formation was identified in either group at 1-year follow-up by computed tomography of the chest, abdomen and pelvis.
LV function and other testing results
At baseline, the average EF was 26.5 ± 9.6%, and median LV end-diastolic diameter was 70.4 mm (IQR: 64.1 to 80.0). EF increased significantly in the allo-hMSCs group by 8.0 percentage points (95% CI: 2.8 to 13.2 percentage points; p = 0.004), but not in the auto-hMSCs cohort (5.4; 95% CI: −1.4 to 12.1; p = 0.116) at 12 months (p = 0.49 between group) (Figures 2A and 3). This resulted in the EF rising above 40% in 46.7% of the allo-hMSC patients (Figure 3) versus 22.2% of the auto-hMSCs patients. Stroke volume (Figure 2B), end-diastolic volume (EDV) (Figure 2C), and end-systolic volume (Figure 2D) did not significantly decrease from baseline. End-diastolic long-axis diameter decreased 3.5 mm (95% CI: −6.4 mm to −0.6 mm; p = 0.04) from baseline to 12 months in the allo-hMSCs group compared with 1.7 mm (95% CI: −7.3 mm to 3.9 mm) in the auto-hMSCs arm (p = 0.73) (Figure 2E). Neither sphericity index, end-diastolic diameter, nor end-systolic diameter changed from baseline to 12 months in either group (data not shown).
The 6MWT distance significantly increased in patients receiving allo-hMSCs by 37.0 m (95% CI: 2.0 m to 72.0 m; p = 0.04) at 12 months compared with baseline, but did not significantly change in the auto-hMSCs group (7.3 m; 95% CI: −47.8 m to 33.3 m; p = 0.71) (Central Illustration, part A). The between-group difference was 67.7 m (95% CI: 16.4 m to 118.9 m; p = 0.0116) and 46.53 m (95% CI: −5.5 m to 98.5 m; p = 0.0770) at 6 and 12 months, respectively (overall comparison between allo and auto p = 0.0168). At 12 months, allo-hMSC patients was associated with a 66.7% improvement in NYHA functional class, whereas only 27.3% of auto-hMSC patients improved in NYHA functional class (between group change in NYHA functional class p = 0.0527). Two patients receiving auto-hMSCs worsened by 12 months (Central Illustration, part B). There were no significant differences in the maximal Vo2 at 6 or 12 months compared with baseline in either group (data not shown). FEV1 improved in allo-hMSCs patients by 3.7% (95% CI: −0.08% to 0.30%; p = 0.2423) compared with a decrease of 3.8% (95% CI: −0.36% to 0.06%; p = 0.16) among the auto-hMSCs group at 12 months. However, the between-group difference at 12 months was 0.29 l (95% CI: 0.01 l to 0.56 l; p = 0.0430) (Figure 4A).
Functional capacity and QOL showed greater improvement with allo- compared with auto-hMSCs use. The median MLHFQ score at baseline was 38 (IQR: 23 to 54) in the allo-hMSC cohort versus 30.5 (IQR: 16.5 to 60.5) with auto-hMSCs. The MLHFQ improved in both groups (Figure 4B) over 12 months (allo p = 0.0022; auto p = 0.1719). Unlike with auto-hMSCs, EPC-CFU significantly increased with allo-hMSCs (p = 0.0107) (Figure 4C) as did percentage of FMD at 3 months (p = 0.09). The percent of FMD increased from baseline to 3 months in the allo-group, from 4.5% (IQR: 2.9% to 7.4%) to 6.4% (IQR: 5.1% to 12.3%) (p = 0.0005), compared with no significant change in the auto-cohort, from 6.4% (IQR: 3.7% to 10.0%) to 5.8% (IQR: 4.4% to 10.0%) (p = 0.8457) (Figure 4D).
The cPRA results showed that two-thirds of allo- and nearly all auto-hMSCs recipients had no reaction to low cPRA (0% to 20% cPRA), with only 1 allo-hMSC subject displaying a high cPRA response (+80% cPRA) (Table 3).
Elevated levels of TNF-α decreased from baseline to 6 months in both groups (allo −10.6 ± 1.6 pg/ml; p < 0.0001; auto −6.8 ± 1.4 pg/ml; p < 0.0001; between-group p = 0.05) (Table 4). Terminally differentiated effector memory CD45RA+ (TEMRA) T cells (exhausted T-cell phenotype) also were reduced in both groups with a greater decrease in allo-hMSC (−15.9 ± 5.4%; p < 0.0001) than auto-hMSC (9.3 ± 3.3%; p < 0.0001; between-group p = 0.0111) (Table 4). Suppressed percent switch memory B cells (a predictive biomarker for antibody response) at baseline were significantly increased at 6 months in both groups but more so with allo- (10.2 ± 4.9%; p < 0.0001) versus auto-hMSCs (4.3 ± 3.9%; p = 0.0014; between-group p < 0.0001) (Table 4).
Finally, intracellular TNF-α expression in B cells was also decreased at 6 months relative to baseline in both groups (between-group p = 0.174) (Table 4). By contrast, late/exhausted B cells decreased significantly in both groups, whereas early T-cell activation decreased to similar degrees in both groups (Table 4). However, late/chronic T-cell activation did not significantly decrease in either group (allo −2.3 ± 1.3%; p = 0.4; auto −3.4 ± 2.7%; p = 0.7).
The POSEIDON-DCM study was a randomized comparison of allo-hMSCs versus auto-hMSCs in patients with NIDCM (16). Results supported the safety and feasibility of TESI for both types of cells, and neither were associated with any ectopic tissue formation. Importantly, allo-hMSCs produced a constellation of clinically meaningful effects of greater magnitude than auto-hMSCs, including significant improvement in EF, 6MWT, and MLHFQ scores. Endothelial function was improved, but only in the allo group. Similarly, TNF-α suppression was greater with allo-hMSCs, and these cells were also associated with evidence of clinical efficacy, including improved NYHA functional class, lower MACE, and lower hospitalization rates at 1 year. Together, these findings show a substantial magnitude of clinical responsiveness in patients with NIDCM, a group with major unmet medical needs.
The findings here provide evidence of a clinically relevant effect that was substantially larger than previous trials of cell therapy in patients with ischemic cardiomyopathy (4–7,17). Whereas cell therapy in ischemic cardiomyopathy produces a reduction in infarct scar size (6,9), increased EF has been difficult to show in this population (6,17). In the present study, EF increased by 8 percentage points in the allo-hMSC group, with nearly one-half of these patients increasing EF to levels above 40% (Figure 3 and Figures 5A and 5B⇓), an accepted cutoff for the diagnosis of NIDCM (1,18). HF with recovered EF is a recognized syndrome that carries an improved prognosis relative to HF with persistently low EF (19). As such, if the present results are replicated in a larger trial, they represent a major clinical advance for NIDCM, a condition affecting individuals of all ages and accounting for approximately one-half of all heart transplants (2,20).
In this study, 2 pathophysiological features were identified that could underlie the effects of allo-hMSCs. First, hMSCs exerted a significant restoration of endothelial dysfunction, implicated as an underlying contributor to the failing circulation in ischemic cardiomyopathy and NIDCM (15,21). Second, hMSCs reduced the elevated TNF-α levels in the study population. Elevated levels of TNF-α, a crucial proinflammatory cytokine, are tied to heart disease progression and are implicated in modulating both cardiac contractility and peripheral resistance (22,23).
The use of entanercept to inhibit TNF-α in HF did not improve mortality and hospitalization rates (24); however, hMSC therapy has the advantage of reducing several proinflammatory cytokines, favoring an anti-inflammatory profile. In our trial, TNF-α levels were significantly reduced at 6 months post-TESI by both cell types, but allo-hMSCs were more effective.
Several reasons might account for allogeneic MSCs providing greater efficacy relative to auto-hMSCs. These include age of the donors (mean age in the allo-hMSC group was roughly one-half that of the auto-hMSC group) and possible adverse impact of the disease milieu (e.g., the proinflammatory phenotype) (25). Alternatively, preferential response of allo- versus auto-hMSCs might reflect enhanced endogenous repair, an important mechanism underlying hMSC cardio-repair (26). Further studies to delineate potency differences between auto and allo hMSCs in NIDCM are underway.
In addition, our present findings included a detailed evaluation of humoral lymphocytes following hMSC therapy. These cells favorably altered several immunologic markers typically elevated in chronic inflammation, such as TEMRA T cells (exhausted phenotype) and late/exhausted B cells (27,28). As with TNF-α, hMSCs reversed the exhausted immune phenotype (TEMRA T cells and late/exhausted memory B cells) (29). In contrast to previous studies, we showed the important finding that hMSC therapy (allo-cells in particular) increased switched memory B cells (a predictive biomarker for a protective antibody response) (28). Restoration of immune competence may have clinical relevance in these patients who are of higher risk for comorbid infectious disease.
The cPRA yielded mostly no-to-low response with very few moderate responses for either allo or auto-hMSCs. Only 1 patient in the allo group mounted an elevated cPRA response that included donor-specific antibodies. This incidence was similar to 2 previous studies employing allo MSCs or mesenchymal precursor cells (9,30). This cPRA response did not cause clinical immunologic rejection in the patient. Ongoing immunologic monitoring is warranted during larger pivotal trials.
There are limited previous cell-based therapy trials in NIDCM showing improved cardiac function and/or QOL. TOPCARE-DCM (Transplantation of Progenitor Cells and Functional Regeneration Enhancement Pilot Trial in Patients With Nonischemic Dilated Cardiomyopathy) showed that intracoronary delivery of auto bone marrow cells improved LV EF 3 months after cell administration (31). Similarly, another study demonstrated an increased EF and sustained improvement in QOL 3 years post-treatment with auto bone marrow cells (32,33). Although several other groups have shown that cell-based therapy appears to reduce the incidence of heart transplantation and/or mortality in NIDCM, there is variability in the selected cells used for therapy and their distinct cell surface markers, such as CD34+ (34). Perin et al. (32), in a study including both ischemic cardiomyopathy and NIDCM patients, delivered bone marrow-derived mesenchymal precursor cells, characterized by surface antigen expression of STRO-1, STRO-3, CC-9, and HLA class I and II antigens. This study, however, did not address differences in responses between ischemic cardiomyopathy and NIDCM.
To date, no previous study to our knowledge has compared bone marrow-derived allo-hMSC and auto-hMSC in patients with NIDCM. In the POSEIDON pilot study, we showed that allo- and auto-hMSCs were safe and did not increase SAEs or immunologic reactions with allo-hMSCs therapy. Furthermore, we showed reverse remodeling of the LV chamber dimension (shown by reduction of the long axis diameter), decreased scar size, improved EDV and sphericity index, and increased EF with low-dose allo-hMSC (9).
The limitations of our study include the lack of a placebo group, which was by trial design. Another limitation is the loss of patients due to withdrawal of consent or loss to follow-up. This trial also was limited by small sample size, which was prospectively determined based upon a pre-set threshold for 30-day TE-SAE rate. The sample size limits interpretation of efficacy results; nevertheless, the findings are of significant value in designing and determining sample size for future pivotal trials. Future phase II/III studies will incorporate a placebo-controlled, double-blind design.
This study tested the safety and efficacy of allo- versus auto-hMSCs in NIDCM patients. This study revealed a highly acceptable safety profile at 30 days in both groups, similar to previously published trials using TESI (6,9,32). Importantly, several lines of evidence supported superiority for allo-hMSCs versus auto-hMSCs in regard to efficacy, including EF, 6MWT, MLHFQ, and endothelial function. In addition, the proinflammatory/exhausted immune phenotype in patients receiving allo-hMSCs for NIDCM had a dramatic remodeling of the immune cells toward a less inflammatory or exhausted phenotype. These data provided important and clinically relevant insights into the therapeutic basis and effects of allo-hMSCs and auto-hMSCs for NIDCM patients. Clinical benefits of the magnitude shown here support the development of allo-hMSCs for treating NIDCM.
COMPETENCY IN MEDICAL KNOWLEDGE: In a pilot study involving patients with NIDCM, transendocardial injections of bone marrow-derived allogeneic hMSCs were well tolerated and associated with favorable effects on the immune system and myocardial and endothelial function.
TRANSLATIONAL OUTLOOK: Additional studies in larger cohorts comparing allogenic with autologous mesenchymal stem cells are needed to assess the relative risks and benefits of these therapeutic strategies in patients with NIDCM.
The authors thank Dr. Huw S. Kruger Gray and Patricia Guevara, MS, at the University of Miami, Sylvester Comprehensive Cancer Center Flow Cytometric Core, for their assistance. Alina Gutierrez, BS, MT, and Dr. Phillip Ruiz from the University of Miami Transplant Department for cPRA assay and interpretation.
For an expanded Methods section, please see the online version of this article.
This study was funded by the National Heart, Lung, and Blood Institute with grant number RO1 HL RO110737. Dr. Hare is a board member, a consultant, and holds equity in Vestion Inc.; and is a board member, a consultant, and holds equity in Longeveron. Ms. DiFede is a consultant for Biologics Delivery Systems and Longeveron. Dr. Landin and Ms. Khan are consultants for Longeveron LLC. Dr. Hendel is a consultant for Astellas Pharma. Drs. Hatzistergos and Valasaki hold equity in Vestion Inc. Dr. Heldman has received research support from Biosense Webster Biologics Delivery Systems; and is a board member, a consultant, and holds equity in Vestion Inc. Longeveron LLC and Vestion Inc. did not fund this study. The other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- 6-min walk test
- confidence interval
- calculated panel reactive antibody
- end-diastolic volume
- ejection fraction
- endothelial progenitor cell colony forming unit
- flow-mediated vasodilation
- heart failure
- human mesenchymal stem cell
- interquartile range
- left ventricular
- major adverse cardiac event(s)
- Minnesota Living with Heart Failure Questionnaire
- nonischemic dilated cardiomyopathy
- New York Heart Association
- quality of life
- serious adverse event
- terminally differentiated effector memory CD45RA+
- treatment-emergent serious adverse event
- transendocardial stem cell injection
- tumor necrosis factor-α
- Received October 11, 2016.
- Revision received October 26, 2016.
- Accepted November 1, 2016.
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