Abstract 355: Heart Failure Impairs Bone Marrow Mesenchymal Stem Cell Renewing Capacity and Migration

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Victoria Florea ◽  
Cristina Sanina ◽  
Darcy Difede ◽  
Krystalenia Valasaki ◽  
Aisha Khan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Stem Cells ◽  
Bone Marrow ◽  
Growth Rate ◽  
Clinical Trials ◽  
Stem Cell ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Healthy Donors

Background: Clinical trials have shown a sustained beneficial effect of bone marrow mesenchymal stem cells (MSCs) as a therapy for acute and chronic heart failure (HF). Clinical grade cell manufacturing of autologous and allogeneic MSCs is becoming a standard procedure. This study investigates the differences of bone marrow MSC isolation and expansion in favorable in vitro conditions. We compared MSC production from both healthy young donors and chronic HF patients. Methods: We analyzed MSC manufacturing records from five clinical trials: TAC-HFT (Ischemic cardiomyopathy (CMP), patient and donors), POSEIDON (Ischemic CMP, donors), POSEIDON DCM (Dilated CMP, donors), TRIDENT (Ischemic CMP, donors), and CRATUS (Frailty, donors). Results: All cells expressed CD105, CD90 and lacked hematopoietic marker CD45. The age of healthy donors (25.5 ± 0.7 y.o., N=24) and HF patients (56.1 ± 2.5, y.o., N=23), was significantly different (P<0.0001). Collectively, the number of mononuclear cells (MNCs) isolated from bone marrow (volume range 58-125ml) didn’t differ between the groups. However, plated MNCs from healthy adults generated more MSCs than MNCs from HF patients (p0: 5.9x10^6±0.5x10^6, N=23 vs 3.8x10^6±0.4x10^6, N=24, respectively, P=0.003 and p1: 15.4x10^6±2.5x10^6, N=23 vs 10.8x10^6±1.1x10^6, N=24, respectively, P=0.036). No correlation was found between stem cell growth and age (35 to 78y.o.). Left ventricular ejection fraction (LVEF) in patients with HF had a direct correlation with MSC growth rate (P=0.03), particularly, in patients with severely depressed LVEF (<30%), which had a tendency to generate less MSCs overall. Moreover, MSCs from HF patients demonstrated less migration compared to MSCs from healthy donors at 6, 10 and 24 hours (h) relative to baseline (6 h: 9.5±3.0% vs 30.7±2.1%; 10 h: 19.9±13.7% vs 53.1±2.5% and 24 h: 41.5±15.8% vs 88.9±1.6%, N=4, respectively. P=0.03). Conclusions: Despite equivalent numbers of MNCs, healthy young donors generate significantly more MSCs than HF patients, due to increased growth rate and higher number of resident stromal bone marrow stem cells. MSC migration was impaired in HF patients compared to healthy donors. HF appears to be an independent factor for MSC renewal capacity and culture phenotype.

scholarly journals Stem cell therapy in patients with nonischemic heart failure

2021 ◽  
Vol 20 (Supplement_1) ◽  
Author(s):  
Z Tomsic ◽  
V Androcec
Keyword(s):  
Heart Failure ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Treatment Options ◽  
Left Ventricular ◽  
Advanced Heart Failure ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction

Abstract Funding Acknowledgements None Background Advanced chronic heart failure, characterized by a functional NYHA class III/IV, low LVEF, elevated B-type natriuretic peptides and other criteria’s is a big epidemiological problem, and its prevalence is increasing every year. There are many treatment options for patients with chronic and advanced heart failure. Treatment options include optimal medical therapy, treatment with cardiac resynchronization devices, left ventricular assist devices, heart transplantation and from 2006 treatment with CD 34 + stem cells. Method Patient inclusion criteria for stem cell therapy include dilated cardiomyopathy with no valve disease, hypertension or substance abuse, with optimal medical management for 6 months and a decreased left ventricular ejection fraction of &lt;40%. Patients are treated with autologous pluripotent CD 34+ cells, which are mobilized in the blood stream with a bone marrow stimulant Filgrastim, administered subcutaneously for 5 days. The patients are educated by the nurses to do administer the injections at home, and have a contact number of our department in case of side effects. On the day of the procedure, stem cells are collected using the apheresis technique and then delivered transendocardialy in the catheterisation laboratory using the system for electromechanical mapping. If no complications develop, the patients can go home the next day. Results During follow-up visits patients treated with stem cells have an increased left ventricular ejection fraction, lower levels of NT-proBNP, increased distance of 6-minute walk test and increased survival compared with the control group. They also report better physical performance.  Conclusion  Stem cell therapy is thus a viable option and could become a mainstream therapy for the treatment of advanced heart failure in the future.

A Systematic Review and Meta-analysis : Safety and Efficacy of Mesenchymal stem Cells Therapy for Heart Failure

2020 ◽  
Vol 15 ◽  
Author(s):  
Tiantian Shen ◽  
Lin Xia ◽  
Wenliang Dong ◽  
Jiaxue Wang ◽  
Feng Su ◽  
...  
Keyword(s):  
Heart Failure ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Safety And Efficacy ◽  
Systolic Volume ◽  
End Diastolic Volume ◽  
End Systolic Volume

Background: Preclinical and clinical evidence suggests that mesenchymal stem cells (MSCs) may be beneficial in treating heart failure (HF). However, the effects of stem cell therapy in patients with heart failure is an ongoing debate and the safety and efficacy of MSCs therapy is not well-known. We conducted a systematic review of clinical trials that evaluated the safety and efficacy of MSCs for HF. This study aimed to assess the safety and efficacy of MSCs therapy compared to the placebo in heart failure patients. Methods: We searched PubMed, Embase, Cochrane library systematically, with no language restrictions. Randomized controlled trials(RCTs) assessing the influence of MSCs treatment function controlled with placebo in heart failure were included in this analysis. We included RCTs with data on safety and efficacy in patients with heart failure after mesenchymal stem cell transplantation. Two investigators independently searched the articles, extracted data, and assessed the quality of the included studies. Pooled data was performed using the fixed-effect model or random-effect model when it appropriate by use of Review Manager 5.3. The Cochrane risk of bias tool was used to assess bias of included studies. The primary outcome was safety assessed by death and rehospitalization and the secondary outcome was efficacy which was assessed by six-minute walk distance and left ventricular ejection fraction (LVEF)，left ventricular end-systolic volume（LVESV），left ventricular end-diastolic volume（LVEDV） and brain natriuretic peptide（BNP） Results: A total of twelve studies were included, involving 823 patients who underwent MSCs or placebo treatment. The overall rate of death showed a trend of reduction of 27% (RR [CI]=0.73 [0.49, 1.09], p=0.12) in the MSCs treatment group. The incidence of rehospitalization was reduced by 47% (RR [CI]=0.53[0.38, 0.75], p=0.0004). The patients in the MSCs treatment group realised an average of 117.01m (MD [95% CI]=117.01m [94.87, 139.14], p<0.00001) improvement in 6MWT.MSCs transplantation significantly improved left ventricular ejection fraction (LVEF) by 5.66 % (MD [95% CI]=5.66 [4.39, 6.92], p<0.00001), decreased left ventricular end-systolic volume (LVESV) by 14.75 ml (MD [95% CI]=-14.75 [-16.18, -12.83], p<0.00001 ) and left ventricular end-diastolic volume (LVEDV) by 5.78 ml (MD [95% CI]=-5.78[-12.00, 0.43], p=0.07 ) ,in the MSCs group , BNP was decreased by 133.51 pg/ml MD [95% CI]= -133.51 [-228.17,-38.85], p=0.54, I2= 0.0%) than did in the placebo group. Conclusions: Our results suggested that mesenchymal stem cells as a regenerative therapeutic approach for heart failure is safe and effective by virtue of their self-renewal potential, vast differentiation capacity and immune modulating properties. Allogenic MSCs have superior therapeutic effects and intracoronary injection is the optimum delivery approach. In the tissue origin, patients who received treatment with umbilical cord MSCs seem more effective than bone marrow MSCs. As to dosage injected, (1-10)*10^8 cells were of better effect.

scholarly journals The continuous heart failure spectrum: moving beyond an ejection fraction classification

2019 ◽  
Vol 40 (26) ◽  
pp. 2155-2163 ◽  
Author(s):  
Filippos Triposkiadis ◽  
Javed Butler ◽  
Francois M Abboud ◽  
Paul W Armstrong ◽  
Stamatis Adamopoulos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Clinical Trials ◽  
Ejection Fraction ◽  
Statistical Power ◽  
Structural Changes ◽  
Randomized Clinical Trials ◽  
New Technologies ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction

Abstract Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as ‘HFrEF’ (HF with reduced LVEF), ‘HFpEF’ (HF with preserved LVEF), and more recently ‘HFmrEF’ (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone.

scholarly journals Cardiac Cell Therapies for the Treatment of Acute Myocardial Infarction: A Meta-Analysis from Mouse Studies

2017 ◽  
Vol 42 (1) ◽  
pp. 254-268 ◽  
Author(s):  
Cajetan Immanuel Lang ◽  
Markus Wolfien ◽  
Anne Langenbach ◽  
Paula Müller ◽  
Olaf Wolkenhauer ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Stem Cell ◽  
Mouse Model ◽  
Left Ventricular ◽  
Phase Iii ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Cell Therapies ◽  
Positive Effects ◽  
Advanced Therapies

Aims: Stem cell-based regenerative therapies for the treatment of ischemic myocardium are currently a subject of intensive investigation. A variety of cell populations have been demonstrated to be safe and to exert some positive effects in human Phase I and II clinical trials, however conclusive evidence of efficacy is still lacking. While the relevance of animal models for appropriate pre-clinical safety and efficacy testing with regard to application in Phase III studies continues to increase, concerns have been expressed regarding the validity of the mouse model to predict clinical results. Against the background that hundreds of preclinical studies have assessed the efficacy of numerous kinds of cell preparations - including pluripotent stem cells - for cardiac repair, we undertook a systematic re-evaluation of data from the mouse model, which initially paved the way for the first clinical trials in this field. Methods and Results: A systematic literature screen was performed to identify publications reporting results of cardiac stem cell therapies for the treatment of myocardial ischemia in the mouse model. Only peer-reviewed and placebo-controlled studies using magnet resonance imaging (MRI) for left ventricular ejection fraction (LVEF) assessment were included. Experimental data from 21 studies involving 583 animals demonstrate a significant improvement in LVEF of 8.59%+/- 2.36; p=.012 (95% CI, 3.7–13.8) compared with control animals. Conclusion: The mouse is a valid model to evaluate the efficacy of cell-based advanced therapies for the treatment of ischemic myocardial damage. Further studies are required to understand the mechanisms underlying stem cell based improvement of cardiac function after ischemia.

scholarly journals Paracrine Effects of the Pluripotent Stem Cell-Derived Cardiac Myocytes Salvage the Injured Myocardium

2017 ◽  
Vol 121 (6) ◽  
Author(s):  
Atsushi Tachibana ◽  
Michelle R. Santoso ◽  
Morteza Mahmoudi ◽  
Praveen Shukla ◽  
Lei Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Left Ventricular Ejection Fraction ◽  
Cardiac Myocytes ◽  
Pluripotent Stem Cells ◽  
Pluripotent Stem Cell ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Paracrine Effects

Rationale: Cardiac myocytes derived from pluripotent stem cells have demonstrated the potential to mitigate damage of the infarcted myocardium and improve left ventricular ejection fraction. However, the mechanism underlying the functional benefit is unclear. Objective: To evaluate whether the transplantation of cardiac-lineage differentiated derivatives enhance myocardial viability and restore left ventricular ejection fraction more effectively than undifferentiated pluripotent stem cells after a myocardial injury. Herein, we utilize novel multimodality evaluation of human embryonic stem cells (hESCs), hESC-derived cardiac myocytes (hCMs), human induced pluripotent stem cells (iPSCs), and iPSC-derived cardiac myocytes (iCMs) in a murine myocardial injury model. Methods and Results: Permanent ligation of the left anterior descending coronary artery was induced in immunosuppressed mice. Intramyocardial injection was performed with (1) hESCs (n=9), (2) iPSCs (n=8), (3) hCMs (n=9), (4) iCMs (n=14), and (5) PBS control (n=10). Left ventricular ejection fraction and myocardial viability, measured by cardiac magnetic resonance imaging and manganese-enhanced magnetic resonance imaging, respectively, was significantly improved in hCM- and iCM-treated mice compared with pluripotent stem cell- or control-treated mice. Bioluminescence imaging revealed limited cell engraftment in all treated groups, suggesting that the cell secretions may underlie the repair mechanism. To determine the paracrine effects of the transplanted cells, cytokines from supernatants from all groups were assessed in vitro. Gene expression and immunohistochemistry analyses of the murine myocardium demonstrated significant upregulation of the promigratory, proangiogenic, and antiapoptotic targets in groups treated with cardiac lineage cells compared with pluripotent stem cell and control groups. Conclusions: This study demonstrates that the cardiac phenotype of hCMs and iCMs salvages the injured myocardium effectively than undifferentiated stem cells through their differential paracrine effects.

scholarly journals Circular RNA Expression for Dilated Cardiomyopathy in Hearts and Pluripotent Stem Cell–Derived Cardiomyocytes

2021 ◽  
Vol 9 ◽  
Author(s):  
Yiyu Zhang ◽  
Guoqing Huang ◽  
Zhaohu Yuan ◽  
Yonggang Zhang ◽  
Rong Chang
Keyword(s):  
Heart Failure ◽  
Stem Cell ◽  
Dilated Cardiomyopathy ◽  
Pluripotent Stem Cell ◽  
Single Gene ◽  
Scientific Progress ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Circular Rnas ◽  
Ventricular Ejection Fraction

Dilated cardiomyopathy (DCM) is a type of heart disease delimited by enlargement and dilation of one or both of the ventricles along with damaged contractility, which is often accompanied by the left ventricular ejection fraction (LVEF) less than 40%. DCM is progressive and always leads to heart failure. Circular RNAs (circRNAs) are unique species of noncoding RNAs featuring high cell-type specificity and long-lasting conservation, which normally are involved in the regulation of heart failure and DCM recently. So far, a landscape of various single gene or polygene mutations, which can cause complex human cardiac disorders, has been investigated by human-induced pluripotent stem cell (hiPSC) technology. Furthermore, DCM has been modeled as well, providing new perspectives on the disease study at a cellular level. In addition, current genome editing methods can not only repair defects of some genes, but also rescue the disease phenotype in patient-derived iPSCs, even introduce pathological-related mutations into wild-type strains. In this review, we gather up the aspects of the circRNA expression and mechanism in the DCM disease scenario, facilitating understanding in DCM development and pathophysiology in the molecular level. Also, we offer an update on the most relevant scientific progress in iPSC modeling of gene mutation–induced DCM.

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