Therapy For Ischemic Heart Disease Research Articles

Mesenchymal Stem Cell Therapy for Ischemic Heart Disease: Advances and Challenges.

Ischemic Heart Disease (IHD) has been recognized as the main cause of mortality in the modern world. Application of cell therapy technologies for the IHD treatment has been actively studied from the beginning of 2000s. The review is dedicated to the use of mesenchymal stem cells (MSC) in the therapy of IHD. The strategies of the MSC modification in vitro for improvement of their regenerative potential are extensively discussed, including preconditioning to enhance the cell survival, boosting their paracrine effect and manipulating their cardiomyogenic differentiation. The optimization of the MSC delivery and opportunities related to the use of biomaterials as cell carriers are also discussed. The results of the most important clinical studies on the MSC-based IHD therapy are presented, including those completed and published in the literature and the ongoing clinical trials registered at clinicaltrials.gov by June 2018.

Overexpression of miR-210 promotes the potential of cardiac stem cells against hypoxia

Objective. To evaluate the effects of miR-210 on cardiac stem cells (CSCs) against hypoxia-induced injury. Methods. CSCs were isolated from rat ventricular wall and cultured until passage 4. After exposure to hypoxia for 6 h, the expression of miR-210 was determined. Thereafter, transfection of miR-210 mimic and inhibitor was carried out. 1 week later, in vitro experiments were performed to measure the expression of caspase-8-associated protein 2 (Casp8ap2), Caspase 8, protein tyrosine phosphatase, non-receptor type 2 (PTPN2) and CXC chemokine receptor 4 (CXCR4), as well as migration and apoptosis of CSCs under hypoxic condition. Results. Hypoxia induced a significant up-regulation of miR-210 expression in CSCs. Notably, the expression of Casp8ap2, Caspase8, PTPN2 was dramatically inhibited by overexpression of miR-210 in CSCsmiR-210 Group (P < .05), but no changes in CXCR4 (P > .05), compared with the control. Additionally, a decreased apoptosis of CSCs was detected in CSCsmiR-210 Group (26.22 ± 1.15%, P < .001), compared with Control Group (34.97 ± 0.63%). Moreover, the migration of CSCs was significantly promoted in CSCsmiR-210 Group (45.73 ± 2.4, P < .001), compared with Control Group (19.6 ± 1.11). Meanwhile, down-regulation of miR-210 reversed these results (P < .05). Conclusions. miR-210 was a hypoxia responsive element in CSCs, and its up-regulation inhibited apoptosis of CSCs and promoted their migration under hypoxic condition, through regulating its target genes Casp8ap2/Caspase 8 and PTPN2, which may provide a new strategy for cell therapy of ischemic heart disease.

Evaluation of the effect of taurine on the course of coronary artery disease associated with diabetes of the 2nd type, in patients undergoing coronary revascularization

The aimwas to study the effect of taurine in the complex therapy of patients with coronary artery disease associated with type 2 diabetes mellitus (DM2) who underwent coronary revascularization.Material and methods. Examined 53 patients with coronary artery disease associated with type 2 diabetes, after undergoing endovascular revascularization of the myocardium, which were distributed in 2 groups. The 1st group included 30 patients who received, in addition to basic therapy, taurine at a dose of 500 mg 2 times a day. In group 2 (n = 23) – patients who received only basic therapy of ischemic heart disease and diabetes. Body mass index, waist and hip volume, as well as physical tolerance by means of Bicycle ergometry and 6-minute walk test were evaluated. Indicators of carbohydrate and lipid metabolism wer e determined, insulin resistance index was calculated.Results. At the end of 16-week therapy, physical tolerance according toVEM in group 1 increased by 29.67% (p&lt;0.01), in group 2-by 9.14% (p&gt;0.05). The distance during the 6-minute walk test was significantly increased in both groups: by 34.37% and by 25.80%, respectively. Patients of group 1 had a significant decrease in BMI by 11.52%, postprandial glucose level by 19.38% (p = 0.018), insulin by 18.90%, glyca ted hemoglobin (HbA1c) by 13.21%, insulin resistance index by 17.65%, triglyceride by 14.14% (p&lt;0.05), low density lipoprotein cholesterol by 16.05% (p&lt;0.01).), aspartate aminotransferases and alanine aminotransferases – by 27.75% and 16.52%, respectively.Conclusion. Sup plement taurine standard therapy of coronary heart disease associated with type 2 diabetes mellitus, in patients who have undergone endovascular myocardial revascularization, has a positive effect on the performance of carbohydrate and lipid metabolism, reduces body weight, improves physical performance.

Safety and Efficacy of Adult Stem Cell Therapy for Acute Myocardial Infarction and Ischemic Heart Failure (SafeCell Heart): A Systematic Review and Meta-Analysis.

Preclinical and clinical evidence suggests that mesenchymal stem cells (MSCs) may be beneficial in treating both acute myocardial infarction (AMI) and ischemic heart failure (IHF). However, the safety profile and efficacy of MSC therapy is not well‐known. We conducted a systematic review of clinical trials that evaluated the safety or efficacy of MSCs for AMI or IHF. Embase, PubMed/Medline, and Cochrane Central Register of Controlled Trials were searched from inception to September 27, 2017. Studies that examined the use of MSCs administered to adults with AMI or IHF were eligible. The Cochrane risk of bias tool was used to assess bias of included studies. The primary outcome was safety assessed by adverse events and the secondary outcome was efficacy which was assessed by mortality and left ventricular ejection fraction (LVEF). A total of 668 citations were reviewed and 23 studies met eligibility criteria. Of these, 11 studies evaluated AMI and 12 studies evaluated IHF. There was no association between MSCs and acute adverse events. There was a significant improvement in overall LVEF in patients who received MSCs (SMD 0.73, 95% CI 0.24–1.21). No significant difference in mortality was noted (Peto OR 0.68, 95% CI 0.38–1.22). Results from our systematic review suggest that MSC therapy for ischemic heart disease appears to be safe. There is a need for a well‐designed adequately powered randomized control trial (with rigorous adverse event reporting and evaluations of cardiac function) to further establish a clear risk‐benefit profile of MSCs. Stem Cells Translational Medicine 2018;7:857–866

Apheresis on aged patients/donors with complicated backgrounds like ischemic heart disease, arrhythmia, and others

Peripheral blood stem cells (PBSCs) are currently one of the most important stem cell sources for hematopoietic stem cell transplantation as well as cell therapy for ischemic heart disease or critical limb ischemia. Thus, it is sometimes necessary to collect autologous PBSCs from donors who have comorbidities.In terms yield, a sufficient number of PBSCs can be collected from donors with comorbidities for performing cell therapy if their age is < 60 years or up to a maximum of 70 years, although the number of PBSCs collected from older donors would probably be lower than that obtained from younger donors. On the other hand, granulocyte colony-stimulating factor (G-CSF) administration sometimes results in severe adverse events (AEs), such as ischemic heart disease and vascular thrombosis. Therefore, it is very important to perform strict medical check-ups according to the standards for donor operations in each country before apheresis. The apheresis procedure and G-CSF administration should be performed after administering the appropriate treatment. There is very less information available regarding AEs related to citrate administration during apheresis in aged donors with complicated medical histories. Medical staff should have knowledge of the electrocardiogram (ECG) QTc prolongation that occurs during apheresis owing to hypocalcemia caused by citrate administration, necessitating electrocardiographic monitoring of patients. Calcium should be administered during apheresis to prevent citrate related symptoms.

Study of efficacy of ischemia reversal program (IRP) in ischemic heart disease (IHD) patients with VO2max and Duke’s treadmill score

Background: Number of people dying from IHD has increased from 0.61 million in 1990 to 1.13 million in 2010, which is a disturbing fact. According to report by World Health Organization, India would be spending a whopping 237 billion US dollars, owing to direct spending on health care and indirectly due to loss of productivity due to IHD. Ischemia Reversal Program (IRP) is a combination of Panchakarma and allied therapy. This study was conducted to evaluate the effect of IRP on VO2max, Duke’s treadmill score, systolic blood pressure (SBP), diastolic blood pressure (DBP), and dependency on conventional therapy in IHD patients.Methods: This observational study was conducted in January 2017, wherein the data of IHD patients (inducible ischemia on stress testing) who attended out-patient departments (OPDs) at Madhavbaug clinics in Maharashtra, India were identified. Data of patients who were administered IRP (60-75 minutes) with minimum 7 sittings over 90 days (±15 days) were considered. Variables were compared between day 1 and day 90 of the IRP.Results: Out of 38 enrolled patients, 25 were males while 13 females. There was significant improvement in Duke’s score with subjects at moderate (50%) and high (31.6%) risk at baseline were significantly decreased to low (52.6%) and moderate (47.4%) after the 90th day of therapy. IRP also showed significant improvement in VO2max by 9.11 (from 20.29±6.72 to 29.40±6.71; p&lt;0.001), SBP by 5.78 (from 128.78±17.40 to 123±12.23, p&lt;0.03), DBP by 4.76 (from 80.53±8.10 to 75.76±6.85, p&lt;0.005). Dependency on concomitant medicines was reduced.Conclusions: IRP was effective in IHD; it had dual benefits, i.e. anti-ischemic effect, as well as reducing the dependency on allopathic medicines.

Intramyocardial autologous CD34+ cell therapy for refractory angina: A meta-analysis of randomized controlled trials.

Previous studies have demonstrated that intramyocardial human CD34+ cells may relieve symptoms and improve clinical outcomes in chronic refractory angina unresponsive to optimal medical therapy or not amenable to revascularization. We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the impact of human CD34+ cells compared with placebo in chronic refractory angina. Primary efficacy outcomes in our analysis were angina frequency and exercise time. Primary safety outcomes included major adverse cardiovascular events such as myocardial infarction (MI), stroke and death. Three eligible randomized trials including 269 patients (placebo = 90, CD34+ = 179) were included. Dose of auto-CD34+ cells ranged from 5 × 104 to 5 × 105 cells/kg. Follow-up ranged from 6 to 24 months. In a pooled analysis, administration of CD34+ cells decreased the risk of all-cause mortality [OR 0.24, 95% CI (0.08-0.73), p = 0.01], reduced angina frequency [mean difference -2.91, 95% CI (-4.57 to -1.25), p = 0.0006] and improved exercise time [mean difference 58.62 s, 95% CI (21.19 to 96.06), p = 0.02] compared with control group. However, there was no significant difference in the risk of myocardial infarction (MI) and stroke between groups. In a meta-analysis, intra-myocardial CD34+ cell therapy was superior to placebo in improving risk of all - cause mortality, angina frequency with an increase in exercise time, without a significant increase in adverse events. This analysis supports further trials of CD34+ cell therapy for ischemic heart disease.

Sulfiredoxin-1 enhances cardiac progenitor cell survival against oxidative stress via the upregulation of the ERK/NRF2 signal pathway

Cardiac stem/progenitor cells (CPCs) have recently emerged as a potentially transformative regenerative medicine to repair the infarcted heart. However, the limited survival of donor cells is one of the major challenges for CPC therapy. Our recent research effort on preconditioning human CPCs (hCPCs) with cobalt protoporphyrin (CoPP) indicated that sulfiredoxin-1 (SRXN1) is upregulated upon preconditioning aldehyde dehydrogenase bright hCPCs (ALDHbr-hCPCs) with CoPP. Further studies demonstrated that overexpressing SRXN1 enhanced the survival capacity for ALDHbr-hCPCs. This was associated with the up-regulation of anti-apoptotic factors, including BCL2 and BCL-xL. Meanwhile, overexpressing SRXN1 decreased the ROS generation and mitochondrial membrane potential, concomitant with the up-regulated primary antioxidant systems, such as PRDX1, PRDX3, TXNRD1, Catalase and SOD2. It was also observed that overexpressing SRXN1 increased the migration, proliferation, and cardiac differentiation of ALDHbr-hCPCs. Interestingly, SRXN1 activated the ERK/NRF2 cell survival signaling pathway, which may be the underlying mechanism through which overexpressing SRXN1 lead to protection of hCPCs against oxidative stress-induced apoptosis. Taken together, these results provide a rationale for the exploration of SRXN1 as a novel molecular target that can be used to enhance the effectiveness of cardiac stem/progenitor cell therapy for ischemic heart disease.

Cost Effectiveness of Ventricular Tachycardia Ablation Versus Escalation of Antiarrhythmic Drug Therapy: The VANISH Trial.

This analysis uses the data from the randomized controlled trial to assess the cost effectiveness of catheter ablation (n= 132) versus escalated antiarrhythmic therapy (n= 127). For survivors of myocardial infarction with implantable cardioverter-defibrillator shocks despite antiarrhythmicdrugs, the VANISH (Ventricular Tachycardia Ablation Versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease) trial demonstrated improved clinical outcomes with catheter ablation compared with more aggressive antiarrhythmic pharmacotherapy. Health care resource use and quality-of-life data were used to determine the cost effectiveness of catheter ablation. Published references were used to estimate costs (in 2015 Canadian dollars). The analysis was over 3 years, with a 5% discount rate. Adjustment was made for censoring and baseline utilities. Ablation resulted in greater quality-adjusted life-years (QALYs) than escalated drug therapy did (1.63 vs. 1.49; difference: 0.14; 95% confidence interval [CI]: -0.20 to 0.46) and higher cost ($65,126 vs. $60,269; difference: $4,857; 95% CI: -$19,757 to $27,106); with an incremental cost per QALY gained for ablation versus escalated drug therapy of $34,057 primarily due to the initial costs of ablation, which were partially offset by the costs of subsequent ablations and adverse outcomes in the escalated drug therapy arm. For patients with amiodarone-refractory ventricular tachycardia, ablation dominated escalated drug therapy, with greater QALYs (1.48 vs. 1.26; difference: 0.22; 95% CI: -0.19 to 0.59) and lower costs ($67,614 vs. $68,383; difference: -$769; 95% CI: -$35,330 to $27,092). For those with sotalol-refractory ventricular tachycardia, ablation resulted in similar QALYs (1.90 vs. 1.90; difference: -0.00; 95% CI: -0.59 to 0.62) andhigher costs ($60,455 vs. $45,033; difference: $15,422; 95% CI: -$10,968 to $48,555). For the total trial population, results are suggestive that ablation is cost effective compared with escalation of drug therapy. This result was only manifest for the subgroup of patients whose qualifying arrhythmia occurred despite amiodarone.

Concise Review: Is Cardiac Cell Therapy Dead? Embarrassing Trial Outcomes and New Directions for the Future.

Stem cell therapy is a promising strategy for tissue regeneration. The therapeutic benefits of cell therapy are mediated by both direct and indirect mechanisms. However, the application of stem cell therapy in the clinic is hampered by several limitations. This concise review provides a brief introduction into stem cell therapies for ischemic heart disease. It summarizes cell‐based and cell‐free paradigms, their limitations, and the benefits of using them to target disease. stem cells translational medicine 2018;7:354–359

Cell therapy for heart disease: current status and future directions.

Treatment of ischemic heart disease has evolved considerably over time, seeing a technological impetus in recent times. Prompt diagnosis and progressively earlier reperfusion of the infarct artery have become the cornerstone of the early myocardial ischemia management. However, treatment of post-infarction sequelae resulting from ischemic damage sustained within the myocardium remains a considerable challenge. In this setting, stem cell therapy has emerged as an exciting regenerative modality with a promise to arrest or even reverse the pathological myocardial remodeling. Multiple preclinical and clinical studies have thereafter reported use of various types of stem cells delivered through varying routes. While most of these studies reported positive results, some appropriate concerns were raised in others. This has resulted in considerable uncertainty regarding cell therapy and an inability to formulate therapeutic recommendations. Though there has been a considerable improvement in our understanding of stem cell properties, there is a need to identify specific mechanisms of actions in order to maximize the benefits of stem cell therapy in ischemic heart disease. With this review, we attempt to highlight some of the salient features of stem cell research, focusing on understanding the predominant types of stem cells, proposed mechanisms of action, routes of administration, and application of this exciting and innovative regenerative therapy offered by stem cells.

Effect of Baseline Antiarrhythmic Drug on Outcomes With Ablation in Ischemic Ventricular Tachycardia: A VANISH Substudy (Ventricular Tachycardia Ablation Versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease).

The VANISH trial (Ventricular Tachycardia Ablation Versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease) compared the effectiveness of escalated antiarrhythmic drug therapy to catheter ablation in patients with prior myocardial infarction, an implanted defibrillator, and ventricular tachycardia (VT). The effectiveness of these interventions in patients on sotalol versus amiodarone was compared. Analysis was conducted based on whether patients had recurrent VT, despite amiodarone (amio-refractory) or nonamiodarone drugs (sotalol-refractory). Outcomes included death, VT storm, appropriate implantable cardioverter defibrillator shock, and any ventricular arrhythmia. At baseline, 169 (65.2%) were amio-refractory, and 90 (34.7%) were sotalol-refractory (1 patient on procainamide rather than sotalol). Amio-refractory patients had more renal insufficiency (23.7% versus 10%; P=0.0008), worse New York Heart Association class (82.3% II/III versus 65.5%; P=0.0003), and lower ejection fraction (29±9.7% versus 35.2±11%; P<0.0001). Within the amio-refractory group, ablation resulted in reduction of any ventricular arrhythmia compared with escalated drug therapy (hazard ratio, 0.53; 95% confidence interval, 0.31-0.9), P=0.020). Sotalol-refractory patients had trends toward higher mortality and VT storm with ablation, with no effect on implantable cardioverter defibrillator shocks. Within the escalated drug therapy arm, amio-refractory patients had a higher rate of the composite outcome (hazard ratio, 1.94; 95% confidence interval, 1.14-3.29; P=0.0144) and a trend to higher mortality (hazard ratio, 2.40; 95% confidence interval, 0.93-6.22; P=0.07), whereas mortality was not different between amio- and sotalol-refractory patients within the ablation treatment group. Patients with amio-refractory VT have a higher rate of ventricular arrhythmia and mortality than those with sotalol-refractory VT and derive greater benefit of catheter ablation than for patients with sotalol-refractory VT who are switched to amiodarone. URL: https://clinicaltrials.gov. Unique identifier: NCT00905853.

Up to 15-Year Survival of Men and Women after Percutaneous Coronary Intervention Paid by the Brazilian Public Healthcare System in the State of Rio de Janeiro, 1999-2010.

BackgroundPercutaneous coronary intervention (PCI) is the most frequently used invasive therapy for ischemic heart disease (IHD). Studies able to provide information about PCI's effectiveness should be conducted in a population of real-world patients.Objectives To assess the survival rate of IHD patients treated with PCI in the state of Rio de Janeiro (RJ).MethodsAdministrative (1999-2010) and death (1999-2014) databases of dwellers aged ≥ 20 years old in the state of RJ submitted to one single PCI paid by the Brazilian public healthcare system (SUS) between 1999 and 2010 were linked. Patients were grouped as follows: 20-49 years old, 50-69 years old and ≥ 70 years old, and PCI in primary PCI, with stent and without stent placement (bare metal stent). Survival probabilities in 30 days, one year and 15 years were estimated by using the Kaplan-Meier method. Cox hazards regression models were used to compare risks among sex, age groups and types of PCI. Test results with a p-value < 0.05 were deemed statistically significant.ResultsData of 19,263 patients (61 ± 11 years old, 63.6% men) were analyzed. Survival rates of men vs. women in 30 days, one year and 15 years were: 97.3% (97.0-97.6%) vs. 97.1% (96.6-97.4%), 93.6% (93.2-94.1%) vs. 93.4% (92.8-94.0%), and 55.7% (54.0-57.4%) vs. 58.1% (55.8-60.3%), respectively. The oldest age group was associated with lower survival rates in all periods. PCI with stent placement had higher survival rates than those without stent placement during a two-year follow-up. After that, both procedures had similar survival rates (HR 0.91, 95% CI 0.82-1.00).ConclusionsIn a population of real-world patients, women had a higher survival rate than men within 15 years after PCI. Moreover, using a bare-metal stent failed to improve survival rates after a two-year follow-up compared to simple balloon angioplasty.

Cytoglobin Promotes Cardiac Progenitor Cell Survival against Oxidative Stress via the Upregulation of the NF\u03baB/iNOS Signal Pathway and Nitric Oxide Production

Human cardiac stem/progenitor cells (hCPCs) may serve in regenerative medicine to repair the infarcted heart. However, this approach is severely limited by the poor survival of donor cells. Recent studies suggest that the mammalian globin cytoglobin (CYGB) regulates nitric oxide (NO) metabolism and cell death. In the present study, we found that CYGB is expressed in hCPCs. Through molecular approaches aimed at increasing or decreasing CYGB expression in hCPCs, we found that CYGB functions as a pro-survival factor in response to oxidative stress. This was associated with the upregulation of primary antioxidant systems such as peroxiredoxins-1, heme oxygenase-1, and anti-apoptotic factors, including BCL2, BCL-XL, and MCL1. Most significantly, we established that CYGB increased the expression of NFкB-dependent genes including iNOS, and that iNOS-dependent NO production was required for a feedforward loop that maintains CYGB expression. Our study delineates for the first time a role for a globin in regulating hCPC survival and establishes mechanistic insights in the function of CYGB. It provides a rationale for the exploration of the CYGB pathway as a molecular target that can be used to enhance the effectiveness of cardiac stem/progenitor cell therapy for ischemic heart disease.

Abstract 337: Cytoglobin Promotes Cardiac Stem Cell Survival Against Oxidative Stress via the Upregulation of the NFkB/iNOS Signal Pathway and Nitric Oxide Production

Cardiac stem cells may serve in regenerative medicine to repair the infarcted heart. However, this approach is severely limited by the poor survival of donor cells. We previously showed that preconditioning human cardiac stem cells (hCSCs) with a nitric oxide (NO) donor enhanced cell survival through activation of survival signaling pathways. Recent studies suggest that the mammalian globin cytoglobin (CYGB) regulates NO metabolism and may regulate cell death. Therefore, the goal of the present study was to test the hypothesis that CYGB may serve important pro-survival functions in hCSCs. We found that CYGB is expressed in hCSCs, in the absence of any significant expression of myoglobin (MB), the primary hemoglobin expressed in adult cardiomyocytes. Through molecular approaches aimed at increasing or decreasing CYGB expression in hCSCs, we found that CYGB functions as a pro-survival factor in response to oxidative stress. This was associated with the upregulation of primary antioxidant systems such as peroxiredoxin 1 (PRDX1) and heme oxygenase-1 and anti-apoptotic factors, including BCL2, BCL-XL, and MCL1. Most significantly, we established that CYGB increased the expression of NFкB-dependent genes including iNOS (NOS2) and that iNOS-dependent NO production was required for a feedforward loop that maintains CYGB expression. Our study delineates for the first time a role for a globin in regulating hCSC survival and establishes novel mechanistic insights in the functional role of CYGB. It provides a rationale for the exploration of the CYGB pathway as a novel molecular target that can be used to enhance the effectiveness of stem cell therapy for ischemic heart disease.

Lentiviral vector-mediated co-overexpression of VEGF and Bcl-2 improves mesenchymal stem cell survival and enhances paracrine effects in vitro

Mesenchymal stem cell (MSC) transplantation has emerged as a promising therapy for ischemic heart disease; however, the low survival rate of transplanted cells limits their therapeutic efficacy. The aim of this study was to investigate whether the dual genetic modification of vascular endothelial growth factor (VEGF) and B-cell lymphoma-2 (Bcl-2) confers a higher expression level of the target genes, better survival and a stronger paracrine effect in MSCs in an adverse environment than the modification of the individual genes. For this purpse, a lentiviral vector was constructed by using a self-cleaving T2A peptide sequence to link and achieve the co-overexpression of VEGF and Bcl-2. Rat MSCs were transfected to obtain cell lines that exhibited a stable overexpression. An in vitro model of oxygen glucose deprivation (OGD) was applied to mimic the ischemic microenvironment, and cell apoptosis, autophagy and the paracrine effects were then determined. Compared with the MSCs in which individual genes were modified and the control MSCs, the MSCs which were subjected to dual genetic modification had a higher expression level of the target genes, a more rapid proliferation, reduced apoptosis, decreased autophagy and an enhanced paracrine effect. Furthermore, the suppression of autophagy was found to contribute to the inhibition of apoptosis in this in vitro OGD model. On the whole, these data indicate that the co-overexpression of VEGF and Bcl-2 protects MSCs in an ischemic environment by inhibiting apoptosis, suppressing autophagy and enhancing the paracrine effects.

Intramyocardially Transplanted Neonatal Cardiomyocytes (NCMs) Show Structural and Electrophysiological Maturation and Integration and Dose-Dependently Stabilize Function of Infarcted Rat Hearts

Cardiac cell replacement therapy is a promising therapy to improve cardiac function in heart failure. Persistence, structural and functional maturation, and integration of transplanted cardiomyocytes into recipients' hearts are crucial for a safe and efficient replacement of lost cells. We studied histology, electrophysiology, and quantity of intramyocardially transplanted rat neonatal cardiomyocytes (NCMs) and performed a detailed functional study with repeated invasive (pressure–volume catheter) and noninvasive (echocardiography) analyses of infarcted female rat hearts including pharmacological stress before and 3 weeks after intramyocardial injection of 5 × 106 (low NCM) or 25 × 106 (high NCM) syngeneic male NCMs or medium as placebo (Ctrl). Quantitative real-time polymerase chain reaction (PCR) for Y-chromosome confirmed a fivefold higher persisting male cell number in high NCM versus low NCM after 3 weeks. Sharp electrode measurements within viable slices of recipient hearts demonstrated that transplanted NCMs integrate into host myocardium and mature to an almost adult phenotype, which might be facilitated through gap junctions between host myocardium and transplanted NCMs as indicated by connexin43 in histology. Ejection fraction of recipient hearts was severely impaired after ligation of left anterior descending (LAD; pressure–volume catheter: 39.2 ± 3.6%, echocardiography: 39.9 ± 1.4%). Repeated analyses revealed a significant further decline within 3 weeks in Ctrl and a dose-dependent stabilization in cell-treated groups. Consistently, stabilized cardiac function/morphology in cell-treated groups was seen in stroke volume, cardiac output, ventricle length, and wall thickness. Our findings confirm that cardiac cell replacement is a promising therapy for ischemic heart disease since immature cardiomyocytes persist, integrate, and mature after intramyocardial transplantation, and they dose-dependently stabilize cardiac function after myocardial infarction.

Insights for Oxidative Stress and mTOR Signaling in Myocardial Ischemia/Reperfusion Injury under Diabetes.

Diabetes mellitus (DM) displays a high morbidity. The diabetic heart is susceptible to myocardial ischemia/reperfusion (MI/R) injury. Impaired activation of prosurvival pathways, endoplasmic reticulum (ER) stress, increased basal oxidative state, and decreased antioxidant defense and autophagy may render diabetic hearts more vulnerable to MI/R injury. Oxidative stress and mTOR signaling crucially regulate cardiometabolism, affecting MI/R injury under diabetes. Producing reactive oxygen species (ROS) and reactive nitrogen species (RNS), uncoupling nitric oxide synthase (NOS), and disturbing the mitochondrial quality control may be three major mechanisms of oxidative stress. mTOR signaling presents both cardioprotective and cardiotoxic effects on the diabetic heart, which interplays with oxidative stress directly or indirectly. Antihyperglycemic agent metformin and newly found free radicals scavengers, Sirt1 and CTRP9, may serve as promising pharmacological therapeutic targets. In this review, we will focus on the role of oxidative stress and mTOR signaling in the pathophysiology of MI/R injury in diabetes and discuss potential mechanisms and their interactions in an effort to provide some evidence for cardiometabolic targeted therapies for ischemic heart disease (IHD).

Optimizing stem cells for cardiac repair: Current status and new frontiers in regenerative cardiology.

Cell therapy has the potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function. The tremendous hope and potential of stem cell therapy is well understood, yet recent trials involving cell therapy for cardiovascular diseases have yielded mixed results with inconsistent data thereby readdressing controversies and unresolved questions regarding stem cell efficacy for ischemic cardiac disease treatment. These controversies are believed to arise by the lack of uniformity of the clinical trial methodologies, uncertainty regarding the underlying reparative mechanisms of stem cells, questions concerning the most appropriate cell population to use, the proper delivery method and timing in relation to the moment of infarction, as well as the poor stem cell survival and engraftment especially in a diseased microenvironment which is collectively acknowledged as a major hindrance to any form of cell therapy. Indeed, the microenvironment of the failing heart exhibits pathological hypoxic, oxidative and inflammatory stressors impairing the survival of transplanted cells. Therefore, in order to observe any significant therapeutic benefit there is a need to increase resilience of stem cells to death in the transplant microenvironment while preserving or better yet improving their reparative functionality. Although stem cell differentiation into cardiomyocytes has been observed in some instance, the prevailing reparative benefits are afforded through paracrine mechanisms that promote angiogenesis, cell survival, transdifferentiate host cells and modulate immune responses. Therefore, to maximize their reparative functionality, ex vivo manipulation of stem cells through physical, genetic and pharmacological means have shown promise to enable cells to thrive in the post-ischemic transplant microenvironment. In the present work, we will overview the current status of stem cell therapy for ischemic heart disease, discuss the most recurring cell populations employed, the mechanisms by which stem cells deliver a therapeutic benefit and strategies that have been used to optimize and increase survival and functionality of stem cells including ex vivo preconditioning with drugs and a novel “pharmaco-optimizer” as well as genetic modifications.

Exosomes from MiR-126-Overexpressing Adscs Are Therapeutic in Relieving Acute Myocardial Ischaemic Injury

Background/Aims: Recent studies have indicated that exosomes play an important role in adipose-derived stem cell (ADSC) transplant-mediated ischaemic heart disease therapy. However, the treatment effect is not obvious. The aim of this study is to investigate whether ADSC-derived exosomes enriched with microRNA (miR)-126 have a more protective effect on acute myocardial infarction (AMI). Methods: Exosomes were characterized by transmission electron microscopy, and the exosome particles were further examined using nanoparticle tracking analyses. A rat model of myocardial infarction and in vitro model of hypoxia-induced H9c2 myocardial cell injury were established to study the protective mechanism of exosomes from miR-126-overexpressing ADSCs. Results: The in vitro results showed that exosomes derived from miR-126-overexpressing ADSCs decreased H9c2 myocardial cell injury by reducing inflammation factor expression during hypoxia induction. The miR-126-enriched exosomes also decreased the expression of fibrosis-related proteins of H9c2 cells under hypoxic conditions. Matrigel® and Transwell® assays showed that miR-126-enriched exosomes significantly promoted microvascular generation and migration, respectively. In vivo studies confirmed that exosomes derived from ADSCs significantly decreased the myocardial injury area of infarction, especially after miR-126-enriched exosome treatment. Cardiac fibrosis and inflammatory cytokine expression were also decreased after treatment with miR-126-enriched exosomes. However, blood vessel formation was promoted in the infarction region of AMI rats. Conclusions: The results suggested that the expression of miR-126-enhanced ADSC-derived exosomes prevented myocardial damage by protecting myocardial cells from apoptosis, inflammation, fibrosis, and increased angiogenesis.