|Year : 2020 | Volume
| Issue : 3 | Page : 739-743
Stem cell therapy for dilated cardiomyopathy: systematic review of the existing data and ongoing trials
Abdalla M Kamal1, Waleed A Ibrahim1, Ehsan S Sarhan2
1 Department of Cardiology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Cardiology, Ministry of Health, Tanta, Egypt
|Date of Submission||31-Dec-2018|
|Date of Decision||24-Mar-2019|
|Date of Acceptance||30-Mar-2019|
|Date of Web Publication||30-Sep-2020|
Ehsan S Sarhan
Tanta, Gharbia 31511
Source of Support: None, Conflict of Interest: None
The aim of this review is to preview recent advances in clinical applications of stem cell therapy in nonischemic dilated cardiomyopathy (DCM).
PubMed and OVID Library were searched. There was no restriction on the publication year. Articles in English language only were reviewed. Clinicaltrials.gov was searched also to find ongoing and unpublished trials.
Studies that included adult DCM patients injected with any type of stem cells were selected. Data extraction: in this review, data from published studies were manually extracted and summarized.
In this review, the data revealed that stem cell therapy can change the course of the disease through improving Left Ventricular Ejection Fraction (LVEF), New York Heart Association (NYHA) functional class, exercise tolerance, and quality of life of the patients.
The results of clinical trials in this field are encouraging, so DCM may be a more attractive target for stem cell therapy than chronic ischemic heart failure, where studies up till now failed to demonstrate a standardized result of treatment with stem cells on myocardial performance.
Stem cells have been considered in the treatment of DCM to improve myocardial performance, functional capacity, and neurohumoral activation; this may pave the way for more prevalent clinical use in DCM treatment. Future stem cell methods ought to aim for additional individual therapeutic approach by establishing the optimum stem cell type or their combination, dose, and delivery technique for each patient adjusted for the patient's age and stage of the disease.
Keywords: clinical trials, dilated cardiomyopathy, stem cells
|How to cite this article:|
Kamal AM, Ibrahim WA, Sarhan ES. Stem cell therapy for dilated cardiomyopathy: systematic review of the existing data and ongoing trials. Menoufia Med J 2020;33:739-43
|How to cite this URL:|
Kamal AM, Ibrahim WA, Sarhan ES. Stem cell therapy for dilated cardiomyopathy: systematic review of the existing data and ongoing trials. Menoufia Med J [serial online] 2020 [cited 2021 Mar 5];33:739-43. Available from: http://www.mmj.eg.net/text.asp?2020/33/3/739/296685
| Introduction|| |
In spite of recent improvements in medical and device therapy, dilated cardiomyopathy (DCM) appears to be a widespread disease that costs the world a lot. The different treatment modalities for DCM aim to reduce hospital admissions due to heart failure, improve its symptoms and signs, and importantly improve patients' survival, but no therapeutic modality dealt with the repair of the diseased myocardium .
The first published successful experiment in the use of stem cells was done on mice. Bone marrow stem cells were transplanted in the infarcted myocardium of the mice to test whether the infarcted myocardium could be restored or not . Another experiment on a rat model of DCM showed improved function of the cardiac muscle after transplantation of pluripotent mesenchymal stem cells (MSCs) . Stem cell therapy in DCM has not the same growing steps as in chronic ischemic heart failure. Few clinical studies were performed to examine the effect of stem cells in DCM patients. In this review, we discuss the recent advances in stem cell treatment in DCM, with a concentration on how to select the patient, type of stem cells, delivery route, and the effect of the treatment clinically and functionally. The aim of this review is to preview recent advances in clinical applications of stem cell therapy in nonischemic DCM.
| Materials and Methods|| |
The full search strategy is provided in the Preferred Reporting Items for Systematic reviews and meta-analyses statement.
The searched databases were PubMed and OVID libraries. The searched key words were DCM and stem cells. Articles in English language only were reviewed. We used articles published any year without restriction. Another search was done in clinicaltrials.gov to find ongoing and unpublished trials with the same criteria.
Clinical, prospective, randomized trials with DCM adult patients (18 years or older) received any type of stem cells assessing the clinical and functional improvement of the patients with any follow-up period. Ongoing trials that were withdrawn or terminated before the enrollment were excluded. Papers selected for retrieval were assessed by an independent reviewer for methodological validity prior to inclusion in the review using standardized critical appraisal. Any disagreements that ascended between the reviewers were resolved through discussion.
Quantitative data were extracted from papers included in the review manually. The data extracted included explicit information about the types of stem cells, methods of delivery, and clinical and functional improvement.
Qualitative research findings were pooled to measure the clinical and functional improvement in DCM patients through the changes occurring in left ventricular (LV) function, NYHA functional class, 6-min walk test (6MWT), quality of life (QOL), NT-proBNP, and major adverse cardiac event (MACE).
| Results|| |
Thirteen published trials that met our inclusion criteria were identified in our search and are analyzed in [Table 1]. The results of most trials revealed improvement in LVEF, exercise capacity, and functional status, which positively affects the lifestyle of the patients. These encouraging results make stem cell therapy an attractive line of treatment for patients with DCM, but needs more research as DCM has heterogeneous etiology. Stem cells have to be more specified in the type of cell, dose, and mode of cell delivery to each patient to guarantee effective and safe treatment.
|Table 1: Results of clinical trials of stem cell therapy in dilated cardiomyopathy|
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The data from the unpublished ongoing trials are collected and analyzed in [Table 2]. The future results of these trials will offer more illustration of the role of stem cell therapy in this category of patients.
| Discussion|| |
This review aims to clarify the actual role of stem cell therapy in DCM patients. We focused in our review on parameters that are important in disease management. We emphasized on cell types and doses, patient selection, delivery methods, the change in NYHA functional classification, 6MWT (exercise capacity), QOL, and MACE. According to the published data, previous reviews mostly focused on LVEF and mortality end points only.
Stem cells have the ability to differentiate into several types of cells if moved out to other tissues. Bone marrow-derived stem cells [bone marrow mononuclear cells (BMMC)] are the most preferred for stem cell therapy studies as they are easily harvested. In both the ABCD trial  and the Bocchi et al.  study, intracoronary infusion of BMMC caused improvement in LVEF, NYHA functional class, and QOL. On the other hand, in IMPACT-DCM and Catheter-DCM studies (NCT00765518, NCT01020968), there was no significant improvement in DCM patients .
In more recent trials, REGENERATE-DCM (NCT01302171)  and INTRACELL trial (NCT00743639) , BMMC transplantation caused improvement in both clinical and functional status of the patients, while in the DCM arm of the Mi Heart study (NCT00333827) there were no considerable differences in the changes in LV function .
The DCM-SUPPORT study (NCT 03572660) is an active-phase II study that aims to test the effect of autologous BMMC and G-CSF on DCM. LVEF will be measured by computed tomography at 3 and 12 months. The change of NYHA functional class, exercise capacity, and MACE will be also assessed at 3 and 12 months. In another ongoing phase IIb clinical trial in Spain (NCT02033278), patients are randomized to receive IC injection of BMMC or placebo. During the 24 month follow-up period, LV function should be assessed by echocardiography and the change in NYHA functional class, NB-proBNP, and exercise tolerance.
By gathering these data, the results of these trials are found to be conflicting and this difference may be due to the various delivery methods, variation in BMMC dose, multiple methods of LV function assessment, or low statistical power.
MSCs can differentiate into cardiomyocytes and endothelial cells in vitro. The most characteristic feature of MSC is that they do not cause activation of the immune response. Clinical trials of MSC have shown more encouraging results in DCM patients than BMMC ,. Other trials also compared allogeneic-MSC and autologous-MSC . Many strategies have been constructed to control the problem of the immune response as the use of immunosuppressant, HLA matching, genetic cell manipulation, and use of chemical or biomaterials for reducing the risk of immune recognition . Currently active, ongoing phase III trial DREAM-HF (NCT02032004) tests the efficacy of transendocardial delivery of allogeneic-MSCs (Rexlemestrocel-L) on heart failure patients by evaluating the changes in LV function, 6MWT, and MACE.
Hematopoietic stem cells (HSCs) are a good base for tissue neovascularization because they have the potential to differentiate into endothelial cells and are positive for the CD34+ surface marker. The procurement of HSC is more complex and has higher cost and so are not widely used in trials. The first clinical trial estimated the outcome of HSC in DCM was done by Vrtovec et al.. After a 1-year follow up, the treated group showed increases in LVEF by 5%, an improvement in 6MWD and NT-proBNP levels and more importantly less 1-year mortality and heart transplantation. After that, the authors published the results of the long-term 5-year follow-up of patients who received CD34+ cell therapy. The improvement observed in the 1-year follow-up was persisted and confirmed in the 5-year follow-up period . Then another paper was published comparing between transendocardial and intracoronary CD34+ transplantation in DCM patients and its results clarified that the transendocardial route is associated with more improvement in LV function, exercise tolerance, and NT-proBNP than the intracoronary route .
Recently, the REMEIUM trial  (NCT02248532) evaluated the effect of repetitive transendocardial CD34+ injection in DCM, but the two groups did not show significant differences in change in LVEF or other physical or chemical parameters. More clinical trials are needed to prove this result or reject it.
Cardiosphere-derived cells (CDC) are obtained from the myocardial tissue. CDC can differentiate into cardiomyocytes in vitro but not tested in vivo in a complete clinical study yet. The DYNAMIC trial (NCT02293603) is an active, ongoing phase I clinical study that aims to test the safety and efficacy of IC allogeneic human CDC. Forty-two patients receive IC infusion of CAP-1002 or placebo. The treated group will receive multiple IC injections of CAP-1002. This study is done in the United States and is anticipated to end in April 2020 and its primary endpoint is unexpected death and MACE.
This review proves that stem cell therapy can be an attractive line of treatment in DCM as it causes improvement in both clinical and functional status of the patients and this is reflected in the lifestyle and care of the patients. Although autologous BMMC were the most used type in DCM clinical trials, the more differentiated types of cells showed more encouraging results. Research should be continued to determine which cell type is the most appropriate for cardiac regeneration in this category of patients after adequate testing in vitro and in preclinical studies. More studies with longer follow-up periods, more participants, more specified stem cell types, and better selection of the patients, according to the stage and etiology of the disease are needed.
| Conclusion|| |
The currently published clinical trials in the issue of stem cell therapy in DCM offer encouraging data about this treatment. The results of these clinical trials showed improvements in LV function, exercise capacity, functional status, and MACE. Larger clinical trials in this field with longer follow-up periods are mandatory to confirm the results of the previous trials, and to cover up the weakness points considering more personalized stem cell therapy for each patient according to clinical status, stage of the disease, and preexisting comorbidities.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJ, et al
. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur Heart J 2016; 18
Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et al
. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410
Nagaya N, Kangawa K, Itoh T, Iwase T, Murakami S, Miyahara Y, et al
. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation 2005; 112
Seth S, Bhargava B, Narang R, Ray R, Mohanty S, Gulati G, et al
. The ABCD (autologous bone marrow cells in dilated cardiomyopathy) trial a long-term follow-up study. J Am Coll Cardiol 2010; 55
Bocchi EA, Bacal F, Guimarães G, Mendroni A, Mocelin A, Filho AE, et al
. Granulocyte-colony stimulating factor or granulocyte-colony stimulating factor associated to stem cell intracoronary infusion effects in non-ischemic refractory heart failure. Int J Cardiol 2010; 138
Vrtovec B, Poglajen G, Sever M, Lezaic L, Domanovic D, Cernelc P, et al
. Effects of intracoronary stem cell transplantation in patients with dilated cardiomyopathy. J Card Fail 2011; 17
Vrtovec B, Poglajen G, Lezaic L, Sever M, Domanovic D, Cernelc P, et al
. Effects of intracoronary CD34+stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up. Circ Res 2013; 112
Vrtovec B, Poglajen G, Lezaic L, Sever M, Domanovic D, Cernelc P, et al
. Comparison of transendocardial and intracoronary CD34+cell transplantation in patients with nonischemic dilated cardiomyopathy. Circulation 2013; 128
Henry TD, Traverse JH, Hammon BL, East CA, Bruckner B, Remmers AE, et al
. Safety and efficacy of ixmyelocel-T: an expanded, autologous multicellular therapy, in dilated cardiomyopathy. Circ Res 2014; 115
Hamshere S, Arnous S, Choudhury T, Choudry F, Mozid A, Yeo C, et al
. Randomized trial of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with nonischemic dilated cardiomyopathy: the REGENERATE-DCM trial. Eur Heart J 2015; 36
Sant'Anna RT, Fracasso J, Valle FH, Castro I, Nardi NB, Sant'Anna JR, et al
. Direct intramyocardial transthoracic transplantation of bone marrow mononuclear cells for non-ischemic dilated cardiomyopathy: INTRACELL trial. Rev Bras Cir Cardiovasc 2014; 29
Martino H, Brofman P, Greco O, Bueno R, Bodanese L, Clausell N, et al
. Dilated Cardiomyopathy Arm of the MiHeart Study Investigators. Multi-center, randomized, double-blind trial of intracoronary autologous mononuclear bone marrow cell injection in non-ischemic dilated cardiomyopathy (the dilated cardiomyopathy arm of the MiHeart study). Eur Heart J 2015; 36
Butler J, Epstein SE, Greene SJ, Quyyumi AA, Sikora S, Kim RJ, et al
. Intravenous allogeneic mesenchymal stem cells for nonischemic cardiomyopathy: safety and efficacy results of a phase II: a randomized trial. Circ Res 2017; 120
Hare JM, DiFede DL, Castellanos AM, Florea V, Landin AM, El-Khorazaty J, et al
. Randomized comparison of allogeneic versus autologous mesenchymal stem cells for nonischemic dilated cardiomyopathy: POSEIDONDCM trial. J Am Coll Cardiol 2017; 69
Bartolucci J, Verdugo FJ, González PL, Larrea RE, Abarzua E, Goset C, et al
. Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure: a phase 1/2 randomized controlled trial (RIMECARD Trial). Circ Res 2017; 121
Vrtovec B, Poglajen G, Sever M, Zemljic G, Frljak S, Cerar A, et al
. Effects of repetitive transendocardial CD34+cell transplantation in patients with nonischemic dilated cardiomyopathy. Circ Res 2018; 123
Nigro P, Bassetti B, Cavallotti L, Catto V, Carbucicchio C, Pompilio G. Cell therapy for heart disease after 15 years: unmet expectations. Pharmacol Res 2018; 127:77–91.
[Table 1], [Table 2]