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Objective: Coronary artery disease remains a leading cause of morbidity and mortality worldwide. Patients with advanced coronary artery disease who are not eligible for endovascular or surgical revascularization have limited options. Extracellular vesicles have shown potential to improve myocardial function in preclinical models. Extracellular vesicles can be conditioned to modify their components. Hypoxia-conditioned extracellular vesicles have demonstrated the ability to reduce infarct size and apoptosis in small animals. Our objective is to assess the potential benefits of hypoxia-conditioned extracellular vesicles in a large animal model of coronary artery disease. Methods: Coronary artery disease was induced in 14 Yorkshire swine by ameroid constriction of the left circumflex coronary artery. Two weeks postsurgery, swine underwent a repeat left thoracotomy for injections of hypoxia-conditioned extracellular vesicles (n = 7) or saline (control, n = 7). Five weeks later, all animals underwent terminal harvest for perfusion measurements and myocardial sectioning. Results: Myocardial perfusion analysis demonstrated a trend toward increase at rest and a significant increase during rapid pacing (P = .09, P

Lipid nanoparticle (LNP)-coated-modified RNA(modRNA) has been developed for enhancing the stability of modRNA, but it tends to accumulate in liver. The current study aimed to optimize strategy for increasing cardiac expression efficiency of modRNA. We synthesized Luciferase (Luc)-modRNA, and also developed 122Luc modRNA, a liver silencing Luc modRNA. Intramyocardial injection of naked Luc modRNA induced high bioluminescence signal in heart, but very low in other organs including liver. Luc modRNA-LNP injection showed the signal was increased by 5 folds in the heart and by 15,000 folds in the liver, compared to naked Luc modRNA group. In comparison with Luc modRNA-LNP group, the liver signal was decreased to 0.17%, while cardiac signal showed a slight drop by intramyocardial injection of 122Luc-modRNA-LNP. Our data revealed that intramyocardial injection of naked modRNA could effectively induced cardiac-specific expression. For cardiac delivery of Luc modRNA-LNP, 122modRNA-LNP enhances specificity of cardiac expression by abolishing liver signal. [ABSTRACT FROM AUTHOR]

Abstract Background Human umbilical cord-derived mesenchymal stem cells (HucMSCs) have been recognized as a promising cell for treating myocardial infarction (MI). Inflammatory response post MI is critical in determining the cardiac function and subsequent adverse left ventricular remodeling. However, the local inflammatory effect of HucMSCs after intramyocardial injection in murine remains unclear. Methods HucMSCs were cultured and transplanted into the mice after MI surgery. Cardiac function of mice were analyzed among MI-N.S, MI-HucMSC and MI-HucMSC-C–C Motif Chemokine receptor 5 (CCR5) antagonist groups, and angiogenesis, fibrosis and hypertrophy, and immune cells infiltration of murine hearts were evaluated between MI-N.S and MI-HucMSC groups. We detected the expression of inflammatory cytokines and their effects on CD4+ T cells migration. Results HucMSCs treatment can significantly improve the cardiac function and some cells can survive at least 28 days after MI. Intramyocardial administration of HucMSCs also improved angiogenesis and alleviated cardiac fibrosis and hypertrophy. Moreover, we found the much higher numbers of CD4+ T cells and CD4+FoxP3+ regulatory T cells (Tregs) in the heart with HucMSCs than that with N.S treatment on day 7 post MI. In addition, the protein level of C–C Motif Chemokine Ligand 5 (CCL5) greatly increased in HucMSCs treated heart compared to MI-N.S group. In vitro, HucMSCs inhibited CD4+ T cells migration and addition of CCL5 antibody or CCR5 antagonist significantly reversed this effect. In vivo results further showed that addition of CCR5 antagonist can reduce the cardioprotective effect of HucMSCs administration on day 7 post MI injury. Conclusion These findings indicated that HucMSCs contributed to cardiac functional recovery and attenuated cardiac remodeling post MI. Intramyocardial injection of HucMSCs upregulated the CD4+FoxP3+ Tregs and contributed to the migration of CD4+ T cells into the injured heart via CCL5/CCR5 pathway.

Background: Human umbilical cord-derived mesenchymal stem cells (HucMSCs) have been recognized as a promising cell for treating myocardial infarction (MI). Inflammatory response post MI is critical in determining the cardiac function and subsequent adverse left ventricular remodeling. However, the local inflammatory effect of HucMSCs after intramyocardial injection in murine remains unclear. Methods: HucMSCs were cultured and transplanted into the mice after MI surgery. Cardiac function of mice were analyzed among MI-N.S, MI-HucMSC and MI-HucMSC-C–C Motif Chemokine receptor 5 (CCR5) antagonist groups, and angiogenesis, fibrosis and hypertrophy, and immune cells infiltration of murine hearts were evaluated between MI-N.S and MI-HucMSC groups. We detected the expression of inflammatory cytokines and their effects on CD4+ T cells migration. Results: HucMSCs treatment can significantly improve the cardiac function and some cells can survive at least 28 days after MI. Intramyocardial administration of HucMSCs also improved angiogenesis and alleviated cardiac fibrosis and hypertrophy. Moreover, we found the much higher numbers of CD4+ T cells and CD4+FoxP3+ regulatory T cells (Tregs) in the heart with HucMSCs than that with N.S treatment on day 7 post MI. In addition, the protein level of C–C Motif Chemokine Ligand 5 (CCL5) greatly increased in HucMSCs treated heart compared to MI-N.S group. In vitro, HucMSCs inhibited CD4+ T cells migration and addition of CCL5 antibody or CCR5 antagonist significantly reversed this effect. In vivo results further showed that addition of CCR5 antagonist can reduce the cardioprotective effect of HucMSCs administration on day 7 post MI injury. Conclusion: These findings indicated that HucMSCs contributed to cardiac functional recovery and attenuated cardiac remodeling post MI. Intramyocardial injection of HucMSCs upregulated the CD4+FoxP3+ Tregs and contributed to the migration of CD4+ T cells into the injured heart via CCL5/CCR5 pathway. [ABSTRACT FROM AUTHOR]

Objective(s): Existing studies have demonstrated that intravenous and intramyocardial-administrated mesenchymal stem cells (MSCs) lead to tissue repair after cardiac disorders. We compared the efficiency of both administration methods.Materials and Methods: A rat model of isoproterenol-induced heart failure (ISO-HF) was established to compare the effects of intravenous and intramyocardial-administrated MSCs on cardiac fibrosis and function. The animals were randomly assigned into six groups: i) control or normal, ii) ISO-HF (HF) iii) ISO-HF rats treated with intramyocardial administration of culture medium (HF+IM/CM), iv) ISO-HF rats treated with intravenous administration of culture medium ( HF+IV/CM), v) ISO-HF rats treated with intravenous administration of MSCs (HF+IV/MSCs), vi) ISO-HF rats treated with intramyocardial administration of MSCs ( HF+IM/MSCs). Cultured MSCs and culture medium were administrated at 4 weeks after final injection of ISO. Heart function, identification of MSCs, osteogenic differentiation, adipogenic differentiation, cardiac fibrosis and tissue damage were evaluated by echocardiography, flow-cytometery, von Kossa, oil red O, Masson’s trichrome and H & E staining, respectively. Results: Both intravenous and intramyocardial MSCs therapy significantly improved heart function and reduced cardiac fibrosis and tissue damage (PConclusion: In sum, our results confirm the validity of both administration methods in recovery of HF, but more future research is required.

Introduction. Despite resounding success in treatment of patients with coronary heart disease (CHD), researchers are yet unable to significantly reduce mortality in this disease. With this in mind, there are ongoing studies everywhere, which are aimed at investigating new techniques in order to boost the efficiency of existing standards. One of such promising techniques is cell/regenerative therapy with autologous bone marrow mononuclear cells (ABMMCs). However, even though ABMMCs have been studied for more than 10 years, there are no unambiguous data yet on several issues. Objective: to evaluate the outcome of ABMMC transplantation during coronary artery bypass grafting (CABG) surgery in combined treatment of CHD. Materials and methods. The data of 408 patients admitted to the clinic from 2013 to 2016 for planned surgical treatment of CHD were analyzed. The work included 117 people based on the design of the study. Patients were randomized in 3 groups: Group 0 (control group) – CABG surgery and intramyocardial injection of 0.9% NaCl solution, Group 1 – CABG surgery and intramyocardial injection of ABMMCs, Group 2 – CABG surgery, intramyocardial and intra-graft injection of ABMMCs. The dynamics was assessed 12 months later – functional class of angina pectoris and heart failure, echocardiography, speckle tracking (assessment of the degree of myocardial deformation), treadmill test, 6-minute walk test, daily ECG monitoring, quality of life questionnaires, coronary angiography. Qualitative indicators were calculated using the Pearson’s chi-squared test and Fisher criteria. Quantitative indicators were calculated using the Kruskal–Wallis and Wilcoxon tests. Factor analysis was used to identify certain severity factors and to study data homogeneity. Discriminant analysis was performed to investigate the leading characteristics that determine differentiation between the groups. For analysis of variance, taking into account various factors, the model of variance analysis for dependent samples – Repeated Measures ANOVA – was used. Results. In the observation groups, an improvement in both systolic and diastolic myocardial function was universally noted. A six-minute walk test showed statistically significant increase in Groups 1 and 2 compared with the control Group 0 – 315.06 ± 17.6 (433.54 ± 20.6), Group 1 – 319.8 ± 24.5 (524.4 ± 28.7), Group 2 – 329.9 ± 25.3 (452.7 ± 29.7) meters. A significant decrease in the functional class of exertional angina pectoris in Groups 1 and 2 was noted unlike in the control group. The percentage of functioning coronary shunts after a 12-month follow-up period was 87.6% in Group 0. In Groups 1 and 2, this ratio was 96.2% and 97.3%, respectively. Predictors of overall effectiveness were identified: smoking, initial diastolic myocardial dysfunction, left ventricular ejection fraction. Conclusion. In addition to surgical treatment of coronary heart disease, ABMMC transplantation can improve myocardial contractility, boost exercise tolerance, and increase the duration of the functioning of coronary shunts at the follow-up period of 12 months. The study showed the need for stage-by-stage analytical calculations with the aim of possible correction of further work.

Objective: We investigated the potency of cardiac repair based on echocardiography-guided multiple percutaneous left ventricular intramyocardial injection of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) after myocardial infarction (MI).Methods: Mice with surgically induced MI were randomly divided into three groups (n = 8 in each group) and subjected to echocardiography-guided percutaneous left ventricular infarcted border injection of hiPSC-CMs (single dose; 10 μl 3 × 105 cells) or repeated injections of hiPSC-CMs at post-MI weeks 1 and 2 (multiple doses). The sham group of animals underwent all surgical procedures necessary for MI induction except for ligation. Then 4 weeks after MI, heart function was measured with transthoracic echocardiography. Engraftment was evaluated through the detection of human-specific cardiac troponin T. Infarct size and collagen volume were calculated with Sirius Red/Fast Green staining. Angiogenesis was evaluated with isolectin B4 staining. Cardiac remodeling was evaluated from the cardiomyocyte minimal fiber diameter in the infarcted border zone. Apoptosis was detected via TdT-mediated dUTP Nick-End Labeling (TUNEL) staining in cardiomyocytes from the infarcted border zone.Results: No mice died after echocardiography-guided percutaneous left ventricular intramyocardial injection. hiPSC-CMs were about nine-fold higher in the multiple-dose group at week 4 compared to the single-dose group. Multiple-dose transplantation was associated with significant improvement in left ventricular function, infarct size, angiogenesis, cardiac remodeling, and cardiomyocyte apoptosis.Conclusion: Echocardiography-guided multiple percutaneous left ventricular intramyocardial injection is a feasible, satisfactory, repeatable, relatively less invasive, and effective method of delivering cell therapy. The delivery of hiPSC-CMs indicates a novel therapy for MI.

Objective(s): Existing studies have demonstrated that intravenous and intramyocardial-administrated mesenchymal stem cells (MSCs) lead to tissue repair after cardiac disorders. We compared the efficiency of both administration methods. Materials and Methods: A rat model of isoproterenol-induced heart failure (ISO-HF) was established to compare the effects of intravenous and intramyocardial-administrated MSCs on cardiac fibrosis and function. The animals were randomly assigned into six groups: i) control or normal, ii) ISO-HF (HF) iii) ISO-HF rats treated with intramyocardial administration of culture medium (HF+IM/CM), iv) ISO-HF rats treated with intravenous administration of culture medium ( HF+IV/CM), v) ISO-HF rats treated with intravenous administration of MSCs (HF+IV/MSCs), vi) ISO-HF rats treated with intramyocardial administration of MSCs ( HF+IM/MSCs). Cultured MSCs and culture medium were administrated at 4 weeks after final injection of ISO. Heart function, identification of MSCs, osteogenic differentiation, adipogenic differentiation, cardiac fibrosis and tissue damage were evaluated by echocardiography, flow-cytometery, von Kossa, oil red O, Masson's trichrome and H & E staining, respectively. Results: Both intravenous and intramyocardial MSCs therapy significantly improved heart function and reduced cardiac fibrosis and tissue damage (P<0.05), whereas the cultured medium had no beneficial effects. Conclusion: In sum, our results confirm the validity of both administration methods in recovery of HF, but more future research is required. [ABSTRACT FROM AUTHOR]

The distribution of intramyocardially injected rabbit MSCs, labeled with the near-infrared dye 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbo-cyanine-iodide (DiR) using hybrid Fluorescence Molecular Tomography-X-ray Computed Tomography (FMT-XCT) and Multispectral Optoacoustic Tomography (MSOT) imaging technologies, was investigated. Viability and induction of apoptosis of DiR labeled MSCs were assessed by XTT- and Caspase-3/-7-testing in vitro. 2 × 106, 2 × 105 and 2 × 104 MSCs labeled with 5 and 10 μg DiR/ml were injected into fresh frozen rabbit hearts. FMT-XCT, MSOT and fluorescence cryosection imaging were performed. Concentrations up to 10 μg DiR/ml did not cause apoptosis in vitro (p > 0.05). FMT and MSOT imaging of labeled MSCs led to a strong signal. The imaging modalities highlighted a difference in cell distribution and concentration correlated to the number of injected cells. Ex-vivo cryosectioning confirmed the molecular fluorescence signal. FMT and MSOT are sensitive imaging techniques offering high-anatomic resolution in terms of detection and distribution of intramyocardially injected stem cells in a rabbit model.

Background and Aims Intramyocardial autologous bone marrow-derived stem cells injection (IM-BMCs) has been used in patients with ischemic heart disease (IHD) who are ineligible for revascularization; however, the procedure has yielded mixed results. The objective of this meta-analysis was to evaluate the safety and therapeutic benefits of this treatment on a relatively large scale. Methods PubMed, EMBASE, and Cochrane Library databases through September 2014 were searched for randomized clinical trials (RCTs) of IM-BMCs to treat IHD. Outcome measures were defined as mortality after treatment, change in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV). Weighted mean differences for the changes were estimated with a random-effects model. Results Nine RCTs were eligible for inclusion. IM-BMCs significantly reduced the risk of mortality (RR, 0.33; 95% CI, 0.17–0.65; p = 0.001). IM-BMCs significantly improved LVEF by 2.57% (95% CI, 0.34–4.80%; p = 0.02) and reduced LVESV by 9.67 mL (95% CI, −16.43 mL to −2.91 mL; p = 0.005). No significant improvement in LVEDV (WMD = 4.73 mL; 95% CI, −7.22 mL to 16.68 mL; p = 0.44) was detected in patients who received IM-BMC therapy. Conclusions IM-BMC therapy showed clinical safety while being used as stand-alone treatment in IHD with no option of revascularization. The therapeutic efficacy requires further confirmation in large well-powered trials with long-term follow-up. [ABSTRACT FROM AUTHOR]

Aim: To determine the differences in improvement in cardiac function by intramyocardial (IM) vs . intravenous (IV) injection of human bone mesenchymal stem cell-derived extracellular vesicles (HBMSC-EV) after acute MI., Methods: FVB mice underwent acute MI via left anterior descending coronary artery ligation and subsequent injection of: (1) IM saline control; (2) IM HBMSC-EV; (3) IV saline control; and (4) IV HBMSC-EV. Cardiac function was evaluated with weekly postoperative echocardiography. On postoperative day 28, the mice were euthanized, and the heart, lungs, liver, spleen, and kidneys were harvested. Given previous studies showing HBMSC-EV hepatic uptake after IV injection, the liver was evaluated for changes in inflammation, fibrosis, and proliferation., Results: On postoperative day 28, there were no significant differences in left ventricular ejection fraction ( P = 0.6151), fractional shortening ( P = 0.1135), or anterior border zone fibrosis ( P = 0.6333) in any of the experimental groups. Interestingly, there was a strong trend demonstrating improvement in infarct size on fibrosis staining, which did not reach significance ( P = 0.05620). There were no differences in hepatic inflammation, fibrosis, and proliferation., Conclusions: Although there was a trend in the improvement in infarct size, a single-dose administration of neither IM nor IV injection of HBMSC-EV resulted in significant improvement in post-MI cardiac function. A major limitation of this study is the lack of trials determining the optimal dose of HBMSC-EV needed in this model. However, the current study demonstrates that future studies are required to either optimize administration or bioengineer HBMSC-EV with cardiac-homing properties., Competing Interests: Conflicts of interest All authors declared that there are no conflicts of interest.

A decade ago, stem or progenitor cells held the promise of tissue regeneration in human myocardium, with the expectation that these therapies could rescue ischemic myocyte damage, enhance vascular density and rebuild injured myocardium. The accumulated evidence in 2014 indicates, however, that the therapeutic success of these cells is modest and the tissue regeneration involves much more complex processes than cell-related biologics. As the quest for the ideal cell or combination of cells continues, alternative cell types, such as resident cardiac cells, adipose-derived or phenotypic modified stem or progenitor cells have also been applied, with the objective of increasing both the number and the retention of the reparative cells in the myocardium. Two main delivery routes (intracoronary and percutaneous intramyocardial) of stem cells are currently used preferably for patients with recent acute myocardial infarction or ischemic cardiomyopathy. Other delivery modes, such as surgical or intravenous via peripheral veins or coronary sinus have also been utilized with less success. Due to the difficult recruitment of patients within conceivable timeframe into cardiac regenerative trials, meta-analyses of human cardiac cell-based studies have tried to gather sufficient number of subjects to present a statistical compelling statement, reporting modest success with a mean increase of 0.9-6.1% in left ventricular global ejection fraction. Additionally, nearly half of the long-term studies reported the disappearance of the initial benefit of this treatment. Beside further extensive efforts to increase the efficacy of currently available methods, pre-clinical experiments using new techniques such as tissue engineering or exploiting paracrine effect hold promise to regenerate injured human cardiac tissue. [ABSTRACT FROM AUTHOR]

Background We previously showed that intramyocardial bone marrow cell (BMC) injection in patients with refractory angina and chronic myocardial ischemia improves myocardial perfusion, cardiac function and disease-related complaints. Treatment effect varied between patients, but the predictors of response remain to be identified. Therefore, the aim of the present study was to assess whether patient characteristics, procedural data and baseline measurements influence the response to intramyocardial BMC treatment in a large cohort of refractory angina patients. Methods and results In 120 patients (64 ± 9 years, 88% men) with refractory angina, 97 ± 13 × 10 6 BMCs were injected intramyocardially in regions with stress-inducible ischemia as assessed by single photon emission computed tomography (SPECT). Canadian Cardiovascular Society angina (CCS) class, quality-of-life score, exercise testing, SPECT and magnetic resonance imaging were performed at baseline and at 3 months follow-up demonstrating significant improvements in CCS class, quality-of-life, exercise capacity, myocardial perfusion and left ventricular function (all variables P < 0.001). Multivariate analysis was performed to evaluate the influence of patient characteristics, procedural data and baseline measurements on BMC treatment response. Based on the improvement of myocardial perfusion at stress, diabetes and a large number of ischemic segments at baseline were shown to be independently associated with a large response to BMC therapy. Conclusion The present study demonstrates that diabetes and a large number of ischemic segments are predictors of a large response to intramyocardial BMC injection in refractory angina and chronic ischemia. Furthermore, the safety and efficacy results of previous trials are now confirmed in a larger study population. [ABSTRACT FROM AUTHOR]

In experimental studies, mesenchymal stem cell (MSC) transplantation in acute myocardial infarction (AMI) models has been associated with enhanced neovascularization and myogenesis. Clinical data however, are scarce. Therefore, the present study evaluates the safety and feasibility of intramyocardial MSC injection in nine patients, shortly after AMI during short-term and 5-year follow-up. Periprocedural safety analysis demonstrated one transient ischemic attack. No other adverse events related to MSC treatment were observed during 5-year follow-up. Clinical events were compared to a nonrandomized control group comprising 45 matched controls. A 5-year event-free survival after MSC-treatment was comparable to controls (89 vs. 91 %, P = 0.87). Echocardiographic imaging for evaluation of left ventricular function demonstrated improvements up to 5 years after MSC treatment. These findings were not significantly different when compared to controls. The present safety and feasibility study suggest that intramyocardial injection of MSC in patients shortly after AMI is feasible and safe up to 5-year follow-up. [ABSTRACT FROM AUTHOR]

Abstract: Background: Clinical application of skeletal myoblast transplantation has been curtailed due to arrhythmogenicity and inconsistent therapeutic benefits observed in previous studies. However, these issues may be solved by the use of a new cell-delivery mode. It is now possible to generate “cell-sheets” using temperature-responsive dishes without artificial scaffolds. This study aimed to validate the safety and efficacy of epicardial placement of myoblast-sheets (myoblast-sheet therapy) in treating heart failure. Methods and results: After coronary artery ligation in rats, the same numbers of syngeneic myoblasts were transplanted by intramyocardial injection or cell-sheet placement. Continuous radio-telemetry monitoring detected increased ventricular arrhythmias, including ventricular tachycardia, after intramyocardial injection compared to the sham-control, while these were abolished in myoblast-sheet therapy. This effect was conjunct with avoidance of islet-like cell-cluster formation that disrupts electrical conduction, and with prevention of increased arrhythmogenic substrates due to exaggerated inflammation. Persistent ectopic donor cells were found in the lung only after intramyocardial injection, strengthening the improved safety of myoblast-sheet therapy. In addition, myoblast-sheet therapy enhanced cardiac function, corresponding to a 9.2-fold increase in donor cell survival, compared to intramyocardial injection. Both methods achieved reduced infarct size, decreased fibrosis, attenuated cardiomyocyte hypertrophy, and increased neovascular formation, in association with myocardial upregulation of a group of relevant molecules. The pattern of these beneficial changes was similar between two methods, but the degree was more substantial after myoblast-sheet therapy. Conclusion: The cell-sheet technique enhanced safety and therapeutic efficacy of myoblast-based therapy, compared to the current method, thereby paving the way for clinical application. [Copyright &y& Elsevier]

Abstract: Tissue-specific elasticity arises in part from developmental changes in extracellular matrix over time, e.g. ∼10-fold myocardial stiffening in the chicken embryo. When this time-dependent stiffening has been mimicked in vitro with thiolated hyaluronic acid (HA-SH) hydrogels, improved cardiomyocyte maturation has been observed. However, host interactions, matrix polymerization, and the stiffening kinetics remain uncertain in vivo, and each plays a critical role in therapeutic applications using HA-SH. Hematological and histological analysis of subcutaneously injected HA-SH hydrogels showed minimal systemic immune response and host cell infiltration. Most importantly, subcutaneously injected HA-SH hydrogels exhibited time-dependent porosity and stiffness changes at a rate similar to hydrogels polymerized in vitro. When injected intramyocardially host cells begin to actively degrade HA-SH hydrogels within 1week post-injection, continuing this process while producing matrix to nearly replace the hydrogel within 1month post-injection. While non-thiolated HA did not degrade after injection into the myocardium, it also did not elicit an immune response, unlike HA-SH, where visible granulomas and macrophage infiltration were present 1month post-injection, likely due to reactive thiol groups. Altogether these data suggest that the HA-SH hydrogel responds appropriately in a less vascularized niche and stiffens as had been demonstrated in vitro, but in more vascularized tissues, in vivo applicability appears limited. [Copyright &y& Elsevier]

An important factor to determine the success of stem cell therapy to the heart is the choice of cell delivery route. This will affect the fate of donor cells and subsequently influence the outcome of treatment; however, there is currently no optimum cell delivery route appropriate for every disease condition or every donor cell type. This review summarises currently available approaches for administering cells to the heart, with a particular focus on cell retention/survival and the therapeutic benefits seen in preclinical and clinical studies. Two major approaches are intracoronary and intramyocardial injection, which have been widely used for the delivery of various types of cells. Although there are advantages to both approaches, donor cell retention and survival are poor using these methods, potentially limiting therapeutic effects. Various attempts to improve current approaches, along with the development of emerging new approaches, are also described and discussed in this review. [ABSTRACT FROM AUTHOR]

This study presents a novel method that direct intramyocardial injection of low-dose plasmid DNA and microbubbles combined with insonation could further augment gene expression in normal and ischemic canine myocardium. Plasmids encoding enhanced green fluorescent protein (pEGFP) and hepatocyte growth factor (pHGF) (500 μg) were individually mixed with 0.5 ml of microbubble solution (MB) and injected into the normal or acute ischemic canine myocardium. The dogs in the plasmid + MB/US group underwent insonation (US). Other dogs were randomly divided into three treatment groups: plasmid and insonation, plasmid and MB injection, and plasmid injection only. The EGFP and HGF mRNA expressions were assessed in the myocardium at the injection site and at sites 0.5 and 1 cm remote from the injection site. Compared to plasmid transfer alone, a mean 13.4-fold enhancement of gene expression was achieved in the EGFP + MB/US group at 48 h ( p < 0.01). HGF mRNA expression in ischemic zones was markedly elevated after 28 days, with a mean 9.0-fold enhancement in the HGF + MB/US group ( p < 0.01). EGFP protein expression was detected in the normal myocardium at 1 cm remote from the injection site in the EGFP + MB/US group. Similarly, HGF protein expression was detected in the ischemic myocardium at 0.5 cm remote from the injection site in the HGF + MB/US group. These findings indicate that the radius of gene expression was partly extended in the two plasmid + MB/US groups. The capillary density increased from 20.9 ± 5.3/mm in control myocardial infarction dogs without treatment to 126.7 ± 38.2/mm in the HGF + MB/US group ( p < 0.01). Taken together, the present data demonstrate that direct intramyocardial injection of an angiogenic gene and microbubbles combined with insonation can augment gene expression and angiogenesis. Consequently, this strategy may be a useful tool for gene therapy of ischemic heart disease. [ABSTRACT FROM AUTHOR]

Background aims. Mesenchymal stromal cells (MSC) may improve cardiac function following myocardial infarction. MSC can differentiate into cardiomyocytes and endothelial cells while exerting additional paracrine effects. There is limited information regarding the efficacy of route for MSC treatment of severe dilated cardiomyopathy (DCM). The aim of this study was to demonstrate the clinical safety, feasibility and efficacy of direct intramyocardial and intracoronary administration of autologous bone marrow-derived MSC treatment for no-option patients with chronic severe refractory DCM. Methods. Ten symptomatic patients with DCM and refractory cardiac function, despite maximum medical therapy, were selected. Five had ischemic DCM deemed unlikely to benefit from revascularization alone and underwent bypass operations with concurrent intramyocardial MSC injection (group A). Two patients had previous revascularization and three had non-ischemic DCM and received intracoronary MSC injection (group B). Results. Group A and B patients received 0.5-1.0 × 106 and 2.0-3.0 × 106 MSC/kg body weight, respectively. All patients remained alive at 1 year. There were significant improvements from baseline to 6 and 12 months in left ventricular ejection fraction and other left ventricular parameters. Scar reduction was noted in six patients by 12 months. Conclusions. Autologous bone marrow MSC treatment is safe and feasible for treating chronic severe refractory DCM effectively, via intracoronary or direct intramyocardial administration at prescribed doses. [ABSTRACT FROM AUTHOR]

Abstract: Background: Bone marrow cell treatment has been proposed as a therapy for myocardial infarction, but the optimal timing and number of injections remain unknown. Methods: Myocardial infarction was induced in mice followed by ultrasound-guided injection of mouse bone marrow cells at different time points post myocardial infarction (Days 3, 7, and 14) as monotherapy and at Days 3+7 as “double” therapy and at Days 3+7+14 as “triple” therapy. Controls received saline injections at Day 3 and Days 3+7+14. Left ventricular ejection fraction was evaluated post myocardial infarction prior to any therapy and at Day 28. Hearts were analyzed at Day 28 for infarct size and survival of donor cells. Results: Left ventricular ejection fraction decreased from 55.3±0.9% to 37.6±0.6% (P<.001) 2 days post myocardial infarction in all groups. Injection of bone marrow cells at Day 3 post myocardial infarction resulted in smaller infarct size (17.8±3.6% vs. 36.6±7.1%; P=.05) and improved LV function (left ventricular ejection fraction 40.3±2.0% vs. 31.1±8.3%; P<.05) compared to control. However, delayed therapy at Day 7 or 14 did not. Multiple injections of bone marrow cells, either double therapy or triple therapy, did not result in reduction in infarct size, but led to improvements in left ventricular ejection fraction at Day 28 compared to control (39.9±3.6% and 38.8±5.5% vs. 34.8±5.3%; all P<.05). The number of donor cells surviving at Day 28 did not correlate with improvement in left ventricular ejection fraction. Conclusions: Injection of bone marrow cells at Day 3 reduced infarct size and improved left ventricular function. Multiple injections of bone marrow cells had no additive effect. Delaying cell therapy post myocardial infarction resulted in no functional benefit at all. These results will help inform future clinical trials. [Copyright &y& Elsevier]

Intramyocardial bone marrow cell injection is currently being investigated as a new therapeutic option for the treatment of chronic myocardial ischemia. Experimental studies and early phase clinical trials established a favorable safety profile of this approach and suggested that bone marrow cell injection was associated with clinical and functional improvements. Recently, a randomized, double-blind, placebo-controlled trial demonstrated that intramyocardial bone marrow cell injection was associated with beneficial effects on myocardial perfusion and anginal symptoms. However, the mechanisms by which bone marrow cells may improve myocardial perfusion are only partially understood, and several issues remain to be addressed. This review aims to provide a summary of the current experience with bone marrow cell therapy as a novel treatment option for patients with chronic myocardial ischemia. Therefore, the most frequently used cell types will be reviewed along with the mechanisms through which bone marrow cells may improve myocardial perfusion and function. In addition, possible routes of delivery are compared, and the results of currently available experimental and clinical studies are discussed. [ABSTRACT FROM AUTHOR]

Background: Cellular cardiomyoplasty is emerging as a potentially novel therapeutic option for heart failure and typically involves direct intramyocardial injection of donor cells into a beating heart. Yet, limited rates of cell engraftment remain an obstacle to be overcome before cell therapy is fully recognized. Mechanical and biological mechanisms may account for observed donor cell loss. This study examines acute mechanical loss during intramyocardial injections in beating and arrested hearts. Materials and methods: A porcine cardiopulmonary bypass model was used. Animals underwent either beating (n = 5) or arrested (n = 5) intramyocardial injections into the left ventricle. Fluorescent microspheres were used in lieu of cells because they are biologically inert. Thirty minutes after delivery, animals were euthanized. Microspheres in cardiac and peripheral tissues were quantified using flow cytometry. Results: Approximately 10% of microspheres were retained within the site of injection in both groups. There was no statistical difference between microsphere retention rates in either the beating or the arrested heart group. Microspheres were found in peripheral organs, pericardial fluid, and the delivery device. Conclusions: The majority of microspheres injected intramyocardially are lost in both beating and arrested hearts. Cardiac standstill does not enhance microsphere retention. Possible mechanisms include leakage from the injection site and washout via the cardiac venous/lymphatic system. Delivery strategy will need to be modified if more cells are to be retained within the target organ. [Copyright &y& Elsevier]

Background: Intravenous (IV) ultrasound-targeted microbubble destruction (UTMD) has made distinct but limited progress in gene transfected therapy. Intramyocardial (IM) injection also has some effect. In this study, IM injection could be performed under the guidance of transthoracic ultrasound without thoracotomy. We aimed to evaluate the effect of combination transthoracic ultrasound-guided percutaneous IM injection and UTMD for mediating the angiogenin 1 (Ang1) gene therapy in myocardial infarction (MI) canines., Methods: Forty-two canines were divided into four groups: IM-UTMD group (intramyocardial injection of the negative control plasmid with UTMD as the sham group); IM-Ang1 group (intramyocardial injection of the Ang1 plasmid without UTMD); IM-Ang1-UTMD group (intramyocardial injection of the Ang1 plasmid with UTMD); and IV-Ang1-UTMD group (intravenous injection of the Ang1 plasmid with UTMD). The FITC green fluorescence and Ang1 protein in myocardial tissue were used for the distribution of Ang1 gene. Left ventricular dimension and systolic function were observed by echocardiography. The Masson's and Sirius Red's staining were used for evaluating the collagen fiber. The immunohistochemistry for CD31 and alpha-smooth muscle actin (α-SMA) were as the indicators of microvasculature. Myocardial contrast echocardiography was used to reflect the microvascular perfusion., Results: More FITC-labeled plasmid was observed in the three IM injection groups than in the IV-Ang1-UTMD group, and the Ang1 protein expression was higher in the IM-Ang1-UTMD group. One month later, no significant differences in survival rate and complications were observed among all four groups. Although there were no differences in the left ventricular end-diastolic diameter among the 4 groups, the left ventricular end-systolic diameter was lower in the IM-Ang1-UTMD group than in the other groups. Then, the left ventricular ejection fraction was increased in the IM-Ang1-UTMD group, with lower collagen fiber percentage, higher blood vessel density and myocardial reperfusion intensity than those in the other groups (P<0.05)., Conclusions: Transthoracic ultrasound-guided percutaneous IM injection combined with UTMD is a safe and effective method for mediating Ang1 plasmid therapy in MI canines., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/cdt-21-364). The authors have no conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Myocardial infarction, or heart attack, is the leading cause of mortality globally. Although the treatment of myocardial infarct has improved significantly, scar tissue that persists can often lead to increased stress and adverse remodeling of surrounding tissue and ultimately to heart failure. Intra‐myocardial injection of biomaterials represents a potential treatment to attenuate remodeling, mitigate degeneration, and reverse the disease process in the tissue. In vivo experiments on animal models have shown functional benefits of this therapeutic strategy. However, a poor understanding of the optimal injection pattern, volume, and material properties has acted as a barrier to its widespread clinical adoption. In this study, we developed two quasistatic finite element simulations of the left ventricle to investigate the mechanical effect of intra‐myocardial injection. The first model employed an idealized left ventricular geometry with rule‐based cardiomyocyte orientation. The second model employed a subject‐specific left ventricular geometry with cardiomyocyte orientation from diffusion tensor magnetic resonance imaging. Both models predicted cardiac parameters including ejection fraction, systolic wall thickening, and ventricular twist that matched experimentally reported values. All injection simulations showed cardiomyocyte stress attenuation, offering an explanation for the mechanical reinforcement benefit associated with injection. The study also enabled a comparison of injection location and the corresponding effect on cardiac performance at different stages of the cardiac cycle. While the idealized model has lower fidelity, it predicts cardiac function and differentiates the effects of injection location. Both models represent versatile in silico tools to guide optimal strategy in terms of injection number, volume, site, and material properties. [ABSTRACT FROM AUTHOR]

Ischemic cardiomyopathy is becoming a leading cause of morbidity and mortality in the whole world. Stem cell-based therapy is emerging as a promising option for treatment of ischemic cardiomyopathy. Several stem cell types, including cardiac-derived stem cells, bone marrow-derived stem cells, mesenchymal stem cells, skeletal myoblasts, CD34+ and CD133+ stem cells have been used in clinical trials. Clinical effects mostly depend on transdifferentiation and paracrine factors. One important issue is that a low survival and residential rate of transferred stem cells blocks the effective advances in cardiac improvement. Many other factors associated with the efficacy of cell replacement therapy for ischemic cardiomyopathy mainly including the route of delivery, the type and number of stem cell infusion, the timing of injection, patient's physical conditions, the particular microenvironment onto which the cells are delivered, and clinical conditions remain to be addressed. Here we provide an overview of modern methods of stem cell delivery, types of stem cells and discuss the current state of their therapeutic potential.

Ischemic cardiomyopathy is becoming a leading cause of morbidity and mortality in the whole world. Stem cell-based therapy is emerging as a promising option for treatment of ischemic cardiomyopathy. Several stem cell types, including cardiac-derived stem cells, bone marrow-derived stem cells, mesenchymal stem cells, skeletal myoblasts, CD34+ and CD133+ stem cells have been used in clinical trials. Clinical effects mostly depend on transdifferentiation and paracrine factors. One important issue is that a low survival and residential rate of transferred stem cells blocks the effective advances in cardiac improvement. Many other factors associated with the efficacy of cell replacement therapy for ischemic cardiomyopathy mainly including the route of delivery, the type and number of stem cell infusion, the timing of injection, patient's physical conditions, the particular microenvironment onto which the cells are delivered, and clinical conditions remain to be addressed. Here we provide an overview of modern methods of stem cell delivery, types of stem cells and discuss the current state of their therapeutic potential.