Therapy For Ischemic Heart Disease Research Articles

Finding the right balance on the challenging path to clinical translation of anti-inflammatory therapies for ischemic heart disease

Finding the right balance on the challenging path to clinical translation of anti-inflammatory therapies for ischemic heart disease

The Current State of Extracellular Matrix Therapy for Ischemic Heart Disease.

The extracellular matrix (ECM) is a three-dimensional, acellular network of diverse structural and nonstructural proteins embedded within a gel-like ground substance composed of glycosaminoglycans and proteoglycans. The ECM serves numerous roles that vary according to the tissue in which it is situated. In the myocardium, the ECM acts as a collagen-based scaffold that mediates the transmission of contractile signals, provides means for paracrine signaling, and maintains nutritional and immunologic homeostasis. Given this spectrum, it is unsurprising that both the composition and role of the ECM has been found to be modulated in the context of cardiac pathology. Myocardial infarction (MI) provides a familiar example of this; the ECM changes in a way that is characteristic of the progressive phases of post-infarction healing. In recent years, this involvement in infarct pathophysiology has prompted a search for therapeutic targets: if ECM components facilitate healing, then their manipulation may accelerate recovery, or even reverse pre-existing damage. This possibility has been the subject of numerous efforts involving the integration of ECM-based therapies, either derived directly from biologic sources or bioengineered sources, into models of myocardial disease. In this paper, we provide a thorough review of the published literature on the use of the ECM as a novel therapy for ischemic heart disease, with a focus on biologically derived models, of both the whole ECM and the components thereof.

Induced Pluripotent Stem Cell-Derived Cardiomyocytes Therapy for Ischemic Heart Disease in Animal Model: A Meta-Analysis.

Ischemic heart disease (IHD) poses a significant challenge in cardiovascular health, with current treatments showing limited success. Induced pluripotent derived-cardiomyocyte (iPSC-CM) therapy within regenerative medicine offers potential for IHD patients, although its clinical impacts remain uncertain. This study utilizes meta-analysis to assess iPSC-CM outcomes in terms of efficacy and safety in IHD animal model studies. A meta-analysis encompassing PUBMED, ScienceDirect, Web of Science, and the Cochrane Library databases, from inception until October 2023, investigated iPSC therapy effects on cardiac function and safety outcomes. Among 51 eligible studies involving 1012 animals, despite substantial heterogeneity, the iPSC-CM transplantation improved left ventricular ejection fraction (LVEF) by 8.23% (95% CI, 7.15 to 9.32%; p < 0.001) compared to control groups. Additionally, cell-based treatment reduced the left ventricle fibrosis area and showed a tendency to reduce left ventricular end-systolic volume (LVESV) and end-diastolic volume (LVEDV). No significant differences emerged in mortality and arrhythmia risk between iPSC-CM treatment and control groups. In conclusion, this meta-analysis indicates iPSC-CM therapy's promise as a safe and beneficial intervention for enhancing heart function in IHD. However, due to observed heterogeneity, the efficacy of this treatment must be further explored through large randomized controlled trials based on rigorous research design.

Role of long non-coding RNA Zeb2os in protection of the injured heart

Abstract Heart failure due to ischemic heart disease is one of the leading causes of death worldwide. Terminated vasculature and cardiomyocyte apoptosis due to myocardial infarction are critical events in infarct healing. Therefore, identifying factors that can enhance cardiac repair by restoring the capillary network and inhibiting cardiomyocyte death is of great significance. Accumulating evidence implies that long non-coding RNAs (lncRNAs) are potent regulators of cardiac development and disease. Our preliminary data show the potential cardioprotective function of the long non-coding RNA Zeb2 opposite strand (Zeb2os). This lncRNA overlaps and is antisense to ZEB2 at the 5' splice site of an intron within the 5' UTR. Zeb2os was shown to prevent splicing of the intron containing an internal ribosome entry site (IRES) that increases translation of the ZEB2 transcript. In line with the known function of ZEB2, Zeb2os has pro-angiogenic and anti-apoptotic functions in different organs. However, its role in the heart still has to be determined. Our results show that Zeb2os expression is decreased in cultured cardiomyocytes subjected to H2O2-mediated oxidative stress, which correlates with increased apoptosis and reduced antioxidant defence of cardiac muscle cells. AAV6-mediated overexpression of Zeb2os in hiPSC-derived cardiomyocytes protects from H2O2-induced apoptosis, suggesting it may have cardioprotective activity, possibly through regulating Zeb2 translation. Additionally, systemic AAV9-mediated delivery of Zeb2os to the mouse heart enhanced angiogenesis by increasing the number of proliferating endothelial cells. Moreover, RNA-sequencing of Zeb2os overexpressing hearts at baseline implicated Zeb2os in the regulation of numerous genes related to response to hypoxia. In conclusion, we uncovered/identified Zeb2os as a new potential cardioprotective factor with pro-angiogenic and anti-apoptotic properties. We are currently investigating the effect of AAV9-mediated delivery of Zeb2os in a mouse model of cardiac ischemia to understand further its protective role in the injured heart, which is an essential step towards the development of improved therapies for ischemic heart disease.

Abstract 18313: Sex Disparities in Optimal Medical Therapy for Ischemic Heart Disease

Background: Despite secondary prevention guidelines recommending optimal medical therapy (OMT) forischemic heart disease (IHD), which includes antiplatelets, statins, renal-angiotensin aldosterone inhibitors (RAASi), and β-blockers, significant sex disparities in OMT utilization have been observed. However, theimpact of national efforts on narrowing this gap in contemporary cohorts remains uncertain. Methods: Using data from the National Health and Nutrition Examination Survey cycles 2011-2020, we examined the distribution and trends of OMT medication classes and combinations used in the preceding 30 days (verified through containers in most cases) among adult men and women with self-reported IHD (myocardial infarction or coronary artery disease). Results: Among 1905 adults included (40.6% women, mean age 65.4years), women had significantlylower proportions of OMT use across all medication classes- antiplatelets (68% vs. 77.7%), statins (57.2% vs. 73.9%), RAASi (45.6% vs. 59.0%), and β-blockers (51.2% vs. 61.1%); as well as combinations such as aspirin+statins (47.4% vs. 64.1%) and all four medications (17.5% vs. 32.5%). After adjusting forsociodemographic and clinical factors, the odds of using antiplatelets (OR 0.71 95%CI 0.52-0.94), statins (OR 0.62, 0.40-0.96), and RAASi (OR 0.56, 0.38-0.84) were significantly lower among women than men,whereas β-blocker use was comparable. Moreover, between 2011 to 2020, fewer women consistentlyreported using statins, RAASi, β-blockers, antiplatelets+statins, and all four medications in each survey cycle. Conclusion: This nationally representative study reveals persistent sex disparities in OMT utilization forIHD, with women receiving suboptimal treatment compared to men. These findings emphasize the urgentneed for novel targeted interventions to address and mitigate the sex disparities in OMT utilization foreffective IHD prevention.

Prediction of therapy for ischemic heart disease from PPG signals using fuzzy GRU network

BackgroundCardiac morbidity like ischemic heart disease (IHD) causes global mortality. Diagnosis of IHD requires coronary angiograms — an invasive, sophisticated, and expensive procedure. However, non-invasive methods could not gain much confidence in swift diagnosis of IHD patients. These potential issues provided the research motivation for diagnosing IHD priorly in this pilot study. ObjectiveA computer-aided technique, as an alternate method to fasten and ease IHD detection and categorization, has been suggested in this cohort study. Here, the classification was conducted by a sandwich model of GRU and fuzzy logic in a deep GRU Fuzzy network. MethodsIn this work, photoplethysmography (PPG) signals were acquired from 355 IHD patients. Gabor–Winger transform was used to derive signal features using statistical identities. Analysis was done with a Fuzzy GRU Network comprising GRU and BiGRU layers with fuzzy layers. An algorithm was designed with a Rete network and three membership functions to deduce fuzzy inference. Then, Choquet Integral was used for defuzzification. ResultsThe proposed network predicted results with 0.85 accuracy, 0.86 recall, 0.84 precision, 0.86 sensitivity, 0.78 Micro-averaged F1-score, and 0.84 specificity. The network architecture was validated using ablation and comparative studies. The PRC and ROC curves gave the highest values of 0.91 AP and 0.90 AUC, respectively for this network. A state-of-the-art study was done to show the superiority of the technique. ConclusionThis computer-aided model using PPG might become a tool in predicting the type of therapy for IHD patients which will provide a non-invasive, inexpensive, and fast mode of diagnosis.

Cardiac Stem Cell–Derived Treatment for Ischemic Heart Disease: A Review

Current first-line pharmacologic therapies for ischemic heart disease (ISD) have proven largely ineffective, leading to the exploration of alternative treatments. Various stem cell–like/progenitor cell lineages have been studied, especially c-kit+ cardiac stem cells (CSCs) due to their true stem cell origin and differentiation capabilities. These CSCs reside in the heart after birth and possess regenerative potential, providing a means of maintaining and repairing myocardial tissue. Previous studies have demonstrated the therapeutic potential of CSCs for patients with ISD. However, counterarguments have focused on the inflammatory state present in diseased hearts, which may limit the benefits of c-kit+ CSCs. Nonetheless, we argue that a thorough examination of the literature supports the potential of c-kit+ CSCs as a safe and effective therapeutic approach for restoring lost cardiac tissue and function in patients with ISD. Though promising, we believe further scientific inquiry is necessary to discern the exact mechanisms by which c-kit+ CSCs function, which could pay dividends in the approach to treating ISD.

572 Pseudoaneurysm of Profunda Femoris Artery in a Patient Post Dynamic Hip Screw Fixation for a Neck of Femur Fracture: A Case Report

Abstract Background Profunda femoris artery (PFA) pseudoaneurysm as a complication of hip fracture is rare [1]. The majority of recorded cases of PFA pseudoaneurysm are caused by femur fractures, surgical operations, and penetrating trauma [2]. We present a case of PFA pseudoaneurysm following surgical fixation for neck of femur fracture with dynamic hip screw (DHS) and canulated cancellous screw. Case Presentation The patient sustained a fractured neck of femur fracture following a fall and was on long term antiplatelet therapy for ischaemic heart disease. Thery underwent surgical fixation with DHS and canulated cancellous screw but developed an unexpected drop in their haemoglobin post-op. Initial thigh ultrasound indicated a large, localised hematoma. Further investigation with CT angiography however demonstrated pseudoaneurysm of the branch of the profunda femoris artery. The patient was treated with coil embolization and was able to fully weight bear with support. Discussion Vascular injuries following hip fractures are becoming more common complications [2-4]. Pseudoaneurysms of the profunda femoris artery are an unusual but well-recognized consequence of proximal femoral fractures. When post-operative pain is unexplained, or the haemoglobin level drops, there should be a high index of suspicion for vascular injury. Ultrasound and CT angiography are useful investigations. Conclusions We present a case of pseudoaneurysm of the PFA in a patient following DHS for fractured neck of femur. This is a rare yet recognised complication of femur fractures and should be suspected where pain is increased or there is a sudden decrease in haemoglobin.

A review of stem cell therapy in ischemic heart disease, where are we now?

Background: Regenerative therapies to rejuvenate the heart have a significant appeal for researchers. Preliminary findings from pre-clinical studies suggest that bone marrow cells may have reparative and regenerative effects on heart muscles, creating a ripe area for research. Many generations of stem cells used in pre-clinical and early clinical studies have shown promising but variable results. Objective: The current review article discusses the dilemmas in applying stem cell therapy to cardiovascular diseases and possible strategies to make it feasible. Methods: The field of regenerative therapies continued to progress with second-generation cells, third-generation cells, combination cell therapy, and the use of cell products alone. Research showed promising positive results in multiple randomized phases 1, 2, and 3 clinical trials in addition to numerous meta-analyses. The gaps in knowledge included stem-cell sources, their delivery routes, dosing, types of cells, and the indicated cardiac conditions. Results: The results from the latest randomized clinical trials, namely the Dream-HF, showed improved left ventricle function, symptoms, and overall survival. Studied patient populations include post-myocardial infarction (MI), ischemic/non-ischemic cardiomyopathy, intractable/microvascular angina, and cardiac surgery for congenital and valvular heart disease. The phase 3 DREAM-HF trial did not meet the primary heart failure endpoint of reducing hospital admission. Still, it showed a clinically significant reduction in major adverse cardiovascular events (MACE), including recurrent MI and stroke, by 60%. A 60% reduction in cardiovascular mortality and a 79% reduction in cardiovascular mortality in patients with evidence of inflammation (high CRP). The latter finding suggests a more anti-inflammatory effect. This effect was much higher than that observed in the PARADIGM-HF trial, which showed a 20% relative risk reduction in cardiovascular mortality. By combining the results of the DREAM-HF trial with MSC-HF, ixCELL-DCM, CONCERT-HF, and REGENERATE-DCM, the potential for clinical applications of cell therapy is promising. Conclusion: There is a promising role for cell therapy in the management of cardiovascular diseases. Results of trials in the setting of heart failure are more encouraging in both ischemic and non-ischemic cardiomyopathy. This is in contrast with acute myocardial infarction, where the results have been variable. Amongst all the various cell types tested MSCs show the most significant promise for treating HF.

Associations of systemic oxidative stress with functional outcomes after ST-segment elevation myocardial infarction

BackgroundIschemia-reperfusion is accompanied by oxidative stress. Serum free thiols (FTs; sulfhydryl groups) reliably reflect systemic oxidative stress. This study evaluates longitudinal changes in FTs and their associations with outcomes after ST-segment elevation myocardial infarction (STEMI). MethodsFTs were detected in archived serum samples from 378 participants of a neutral randomized trial on metformin therapy after STEMI. FT levels were determined at presentation with STEMI and at 24 h, 2 weeks, 4 months and 1 year thereafter. Outcomes included infarct size and left ventricular ejection fraction (LVEF), both determined with cardiac magnetic resonance imaging after 4 months, and 5-year major adverse cardiovascular events (MACE). ResultsSerum FT concentrations at presentation and at 24 h were 356 ± 91 and 353 ± 76 μmol/L, respectively. The change in FTs between presentation and 24 h (ΔFTs) was associated with outcomes in age- and sex-adjusted analysis (per 100 μmol/L FT increase, β = −0.87 for infarct size, 95% confidence interval (CI): −1.75 to −0.001, P = 0.050; β = 1.31, 95% CI: 0.37 to 2.25 for LVEF, P = 0.007). Associations between ΔFTs and LVEF were markedly stronger in patients with Thrombolysis in Myocardial Infarction flow of 0 or 1 before percutaneous coronary intervention (PCI)(β = 2.73, 95% CI: 0.68 to 4.77, P = 0.009). Declining FTs during the first 24 h might be associated with higher incidence of 5-year MACE (P = 0.09). ConclusionsChanges in oxidative stress early post-PCI may predict functional outcomes after STEMI. Our findings warrant validation in larger cohorts, and then may be used as rationale for development of thiol-targeted therapy in ischemic heart disease.

Targeting Endothelial HIF2α/ARNT Expression for Ischemic Heart Disease Therapy.

Ischemic heart disease (IHD) is a major cause of mortality and morbidity worldwide, with novel therapeutic strategies urgently needed. Endothelial dysfunction is a hallmark of IHD, contributing to its development and progression. Hypoxia-inducible factors (HIFs) are transcription factors activated in response to low oxygen levels, playing crucial roles in various pathophysiological processes related to cardiovascular diseases. Among the HIF isoforms, HIF2α is predominantly expressed in cardiac vascular endothelial cells and has a key role in cardiovascular diseases. HIFβ, also known as ARNT, is the obligate binding partner of HIFα subunits and is necessary for HIFα's transcriptional activity. ARNT itself plays an essential role in the development of the cardiovascular system, regulating angiogenesis, limiting inflammatory cytokine production, and protecting against cardiomyopathy. This review provides an overview of the current understanding of HIF2α and ARNT signaling in endothelial cell function and dysfunction and their involvement in IHD pathogenesis. We highlight their roles in inflammation and maintaining the integrity of the endothelial barrier, as well as their potential as therapeutic targets for IHD.

Ventricular Tachycardia and ICD Therapy Burden With Catheter Ablation Versus Escalated Antiarrhythmic Drug Therapy

BackgroundCatheter ablation improves ventricular tachycardia (VT) event-free (time to event) survival in patients with antiarrhythmic drug (AAD)-refractory VT and previous myocardial infarction (MI). The effects of ablation on recurrent VT and implantable cardioverter-defibrillator (ICD) therapy (burden) have yet to be investigated. ObjectivesThis study sought to compare the VT and ICD therapy burden following treatment with either ablation or escalated AAD therapy among patients with VT and previous MI in the VANISH (Ventricular tachycardia AblatioN versus escalated antiarrhythmic drug therapy in ISchemic Heart disease) trial. MethodsThe VANISH trial randomized patients with previous MI and VT despite initial AAD therapy to either escalated AAD treatment or catheter ablation. VT burden was defined as the total number of VT events treated with ≥1 appropriate ICD therapy. Appropriate ICD therapy burden was defined as the total number of appropriate shocks or antitachycardia pacing therapies (ATPs) delivered. The Anderson-Gill recurrent event model was used to compare burden between the treatment arms. ResultsOf the 259 enrolled patients (median age, 69.8 years; 7.0% women), 132 patients were randomized to ablation and 129 patients were randomized to escalated AAD therapy. Over 23.4 months of follow-up, ablation-treated patients had a 40% lower shock-treated VT event burden and a 39% lower appropriate shock burden compared with patients who received escalated AAD therapy (P <0.05 for all). A reduction in VT burden, ATP-treated VT event burden, and appropriate ATP burden among ablation patients was only demonstrated in the stratum of patients with amiodarone-refractory VT (P <0.05 for all). ConclusionsAmong patients with AAD-refractory VT and a previous MI, catheter ablation reduced shock-treated VT event burden and appropriate shock burden compared with escalated AAD therapy. There was also lower VT burden, ATP-treated VT event burden, and appropriate ATP burden among ablation-treated patients; however, the effect was limited to patients with amiodarone-refractory VT.

Transfer of Cardiac Mitochondria Improves the Therapeutic Efficacy of Mesenchymal Stem Cells in a Preclinical Model of Ischemic Heart Disease.

The use of mesenchymal stem cells (MSCs) appears to be a promising therapeutic approach for cardiac repair after myocardial infarction. However, clinical trials have revealed the need to improve their therapeutic efficacy. Recent evidence demonstrated that mitochondria undergo spontaneous transfer from damaged cells to MSCs, resulting in the activation of the cytoprotective and pro-angiogenic functions of recipient MSCs. Based on these observations, we investigated whether the preconditioning of MSCs with mitochondria could optimize their therapeutic potential for ischemic heart disease. Human MSCs were exposed to mitochondria isolated from human fetal cardiomyocytes. After 24 h, the effects of mitochondria preconditioning on the MSCs' function were analyzed both in vitro and in vivo. We found that cardiac mitochondria-preconditioning improved the proliferation and repair properties of MSCs in vitro. Mechanistically, cardiac mitochondria mediate their stimulatory effects through the production of reactive oxygen species, which trigger their own degradation in recipient MSCs. These effects were further confirmed in vivo, as the mitochondria preconditioning of MSCs potentiated their therapeutic efficacy on cardiac function following their engraftment into infarcted mouse hearts. The preconditioning of MSCs with the artificial transfer of cardiac mitochondria appears to be promising strategy to improve the efficacy of MSC-based cell therapy in ischemic heart disease.

Stem cell therapies for ischemic heart disease: clinical trial outcomes and futures

Ischemic heart disease carries high morbidity and mortality despite modern pharmaceutical treatment and revascularization procedures. Biologic stem cell therapy offers the potential to revolutionize clinical outcomes for ischemic heart disease by reducing scarring and improving cardiac function. Several small randomized clinical trials have been done utilizing various methodologies, different types of stem cells and doses, and measuring different clinical outcomes. The findings of these individual studies, as well as larger meta-analyses, have been inconsistent likely due to the significant heterogeneity within the methods used. In this review, we provide a more structured approach by comparing the recent studies by type of disease, stem cells, dose, delivery method, and outcome in an effort to draw attention to the similarities and differences in these studies and the need for a standardized approach in larger trials. We show that out of all the current stem cell therapies that have been tried, Adult stem cells, primarily mesenchymal stem cells are currently the most promising for post-myocardial infarction and heart failure while granulocyte colony-stimulating factor and bone marrow mononuclear treatment show efficacy in treating ischemic cardiomyopathy. Lastly, we discuss the potential future directions of stem cell therapy for clinical application in ischemic heart disease.

Abstract 11483: Rationale and Design of Randomized Controlled Trial Evaluating an Atrial Appendage Micrograft Transplantation in Conjunction With Coronary Artery Bypass Surgery

Introduction: In addition to the revascularization therapies for ischemic heart disease (IHD), such as coronary artery bypass grafting (CABG), tissue-engineered cell therapies can help further improve myocardial repair. First clinical results on autologous right atrial appendage-derived micrograft (AAM) transplantation have demonstrated excellent safety and feasibility profiles and suggested a therapeutic effect on myocardial viability. This randomized clinical trial aims to extend the evaluation of efficacy of AAMs transplantation when combined with CABG surgery. Methods and objectives: This double-blinded randomized controlled AAMS2 trial will assess the benefits, safety, and feasibility of the perioperatively assembled and epicardially transplanted AAMs-patch in conjunction with CABG. The trial recruits a total of 50 patients, half of which are randomized to receive the AAMs-patch (CABG+AAMs) and the other half to undergo a standard CABG. Prior to surgery, cardiac structure and function are assessed with late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMRI), electrocardiogram, and transthoracic echocardiography (TTE). LGE-CMRI, electrocardiogram, and TTE are repeated at 6-month follow-up for structural and functional comparisons to baseline. The primary endpoints focus on the efficacy of the AAMs patch as evaluated by LGE-CMRI and TTE as well as changes in health-related quality of life assessments, 6-minute walk test or N-terminal-pro-BNP levels. The secondary endpoints centre on feasibility and safety. For molecular and especially RNA-level analysis of the response to therapy in blood, RNA-stabilized whole blood and plasma samples are collected. Conclusions: The AAMS2 trial is expected to provide further feasibility and safety data as well as insights for efficacy of epicardial AAMs-patch transplantation when administered during CABG surgery.

Anti-ischemic effect of Tamarindus indica L. seed extract against myocardial hypoxic injury.

Background: Ischemic heart disease is a leading cause of death in patients with cardiovascular disease. Natural products containing high antioxidant activity have been used as an alternative therapy to improve the living conditions of patients. In this study, we examine the protective effect of tamarind seed (TS) on myocardial hypoxic injury. Methods: The hypoxia model was mimicked by mineral oil overlayed on H9c2 cardiomyoblasts for 4 h. TS extract was pretreated and administered during the hypoxic condition. Radical scavenging activity of TS extract was measured and exhibited very potent antioxidant activities on 2,2-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) assays. Results: TS extract at a concentration of 10 µg/ml significantly reversed the effect of hypoxia-induced cell death and intracellular reactive oxygen species (ROS) production. We also observed hypoxia-induced over-expression of both inflammatory cytokine mRNA and activation of cellular apoptosis. Pretreatment of TS extract significantly reduced hypoxia-induced HIF-1a and pro-inflammatory cytokine production, IL-1b and IL-6. The Western blot analysis for apoptotic regulatory molecules, caspase 3, caspase 8 and Bax proteins, also showed hypoxia injury reversal by TS extract treatment. Conclusions: The results suggest that the anti-ischemic effect of TS extract protects against hypoxia-induced injury and has potential to be an effective alternative therapy for ischemic heart disease and oxidative-damage related disease.

Ginsenoside Rb1 promotes angiogenesis potentially by activating the JAK-STAT3 signalling pathway

Conventional revascularization strategies for ischemic heart disease (IHD) are designed to prompt reperfusion of the coronary artery to the salvaged cardiomyocytes. However, these strategies may cause myocardial reperfusion injuries. Therefore, a safe and effective strategy needs to be developed to improve the conventional strategies. Here, we investigated the pro-angiogenic effect of Ginsenoside Rb1 (Rb1) to provide the experimental basis for angiogenesis-mediated drug therapy of IHD. Thus, Human umbilical vein endothelial cells (HUVECs) were treated with either a vehicle or Rb1 at 4, 8, 12 or 16 μM for 24 h. A model of hindlimb ischemia was established using C57BL/6J mice. In sham-operated mice, only the femoral artery was isolated without ligation whereas the other operations and supplementation control group were consistent. The mice in the supplementation group were injected with Rb1 (50 mg/kg body wt./day) for 7 days. The results indicated that Rb1 promotes cell proliferation, adhesion, migration and tube formation in the HUVECs in a dose-dependent manner. The ED50 of Rb1 to improve cell adhesion is 8 μM. In mice, Rb1 promoted angiogenesis after the ligation of the femoral artery and ameliorated the ischemic conditions. Intriguingly, more blood flow recovery was observed in the Rb1 supplemented mice than in the vehicle-treated mice (0.85 ± 0.05 vs. 0.71±0.10 on day 3; 0.94±0.10 vs. 0.75±0.08 on day 7). In HUVECs, Rb1 increased the phosphorylation of STAT3 and JAK, which may be the mechanism through which Rb1 mitigates IHD. Moreover, our results confirmed that Rb1mitigates IHD potentially by activating the JAK-STAT3 pathway. Further clinical trials are warranted to verify the clinical implications of Rb1.

Pioglitazone-incorporated microspheres alleviates cardiac dysfunction through macrophage polarization in a rat myocardial infarction model

Abstract   Inflammatory processes are essential for the repair processes after myocardial infarction. Among inflammatory cells involved in this process, macrophages play a critical role through polarization in pro-inflammatory M1 or reparative M2 subtype. Pioglitazone, known as a treatment drug for diabetes mellitus, is reported to regulate macrophage polarization toward reparative M2 subtype. Poly L-lactic-co-glycolic acid (PLGA) has been widely accepted as the delivery carrier in drug delivery system (DDS). Here, we aimed to validate the therapeutic effects and investigate the mechanisms of DDS-based treatment using pioglitazone to left ventricular remodeling after myocardial infarction. Pioglitazone-incorporated PLGA microspheres (PGZ-MS) were prepared and the drug release profile was evaluated. The concentration of interleukin-10 secreted from murine bone marrow derived macrophages incubated with PGZ-MS was quantified in the culture supernatant. To validate the therapeutic potential of PGZ-MS in vivo, Sprague-Dawley rats were subjected to permanent left coronary artery ligation to induce myocardial infarction. Mock-MS (100 μg) or PGZ-MS (100 μg) was injected to the infarct region just after induction (n=9–11/group). Cardiac function and left ventricular size were assessed by echocardiography. At 28-day after surgery, rats were sacrificed, and excised hearts were evaluated histologically. PGZ-MS released 1.8±0.3% of incorporated PGZ within 24 hours and 29.5±1.2% within 14 days indicating sustained release of PGZ in vitro. PGZ-MS augmented Interleukin-10 release from bone marrow derived macrophages, indicating polarization toward reparative M2 subtype. PGZ-MS significantly ameliorated cardiac function after myocardial infarction (fractional shortening: MI vs MI+Mock-MS vs MI+PGZ-MS, 24.4±1.1 vs 24.3±1.6 vs 32.2±1.4%; P=0.0035) with reverse remodeling (wall thickness: MI vs MI+Mock-MS vs MI+PGZ-MS, 0.69±0.12 vs 0.71±0.13 vs 1.06±0.09; P=0.03). Immunohistochemical analyses revealed that PGZ-MS enhanced macrophage polarization toward reparative M2 subtype (ratio of reparative M2 macrophages: 0.39±0.03 vs 0.42±0.02 vs 0.54±0.02; P=0.0004) and attenuated apoptosis of cardiomyocytes in the ischemic border zone (MI vs MI+Mock-MS vs MI+PGZ-MS, 2.6±0.2 vs 1.9±0.2 vs 1.2±0.2 cells/field; P=0.002). In the present study, we confirmed that PGZ-MS could realize sustained release of pioglitazone which resulted in sustained effect of macrophage polarization and attenuated left ventricular remodeling accompanied with the amelioration of cardiac dysfunction and cardiomyocytes apoptosis. The strategy of DDS-based macrophage polarization might serve as a promising strategy in cardiac regenerative therapy for ischemic heart disease in the future. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan

Cross talk of vasopressin conditioned cell therapy in ischemic heart disease: Role of oxidative stress markers.

Objective(s):Background: Impaired coronary blood flow causes cardiac ischemia. Cellular therapy is a new approach to the treatment of myocardial ischemia. This study aimed to investigate the effect of adipose tissue-derived mesenchymal stem cells (AD-MSCs) conditioned with vasopressin on oxidative stress, perivascular collagen, and angiogenesis caused by myocardial infarction (MI) in rats. Materials and Methods:We divided 40 male albino Wistar rats into 4 groups; Control group; No intervention; in experimental groups, after it generated induced MI on models, it divided into three groups: Vehicle group (150 μl of cell-free culture medium received); ASC-MI group (6× 106 AD-MSC received) and AVP-ASC-MI group (received 6 × 106 AD-MSC conditioned with 10 nM vasopressin). Then, histologic parameters and anti-oxidant enzymes were evaluated 7 days post-MI cell injection. Results:Arterial muscle diameter improved and collagen deposition around the coronary arteries decreased in cell-received groups compared with the vehicle group. Malondialdehyde (MDA), catalase (CAT), (GSH) Glutathione, and Total Anti-oxidant Capacity (TAC) parameters were not significantly different between the cells received groups compared with the vehicle group. But the Catalase (CAT) parameter in the ASC-MI group had a significant increase from the control group. Conclusion:We prepared direct evidence that intramyocardial injection of AD-MSCs reveals the positive cardiac remodeling post-MI in rats, and these useful effects can be more enhanced by administrating injection of conditioned ADSCs with vasopressin.

Pioglitazone-incorporated microspheres targeting macrophage polarization alleviates cardiac dysfunction after myocardial infarction.

Excessive and chronic inflammation after a myocardial infarction (MI) is associated with left ventricular remodelling and impaired cardiac function. Among inflammatory cells, macrophages play a critical role in polarizing proinflammatory M1 or the reparative M2 subtype. Pioglitazone (PGZ) is reported to regulate macrophage polarization to the M2 subtype. Our goal was to validate the therapeutic effects and the mechanisms of PGZ utilizing a drug delivery system. Poly L-lactic-co-glycolic acid microspheres (MS) incorporating PGZ were prepared. To validate the therapeutic potential of PGZ-MS, Sprague-Dawley rats were subjected to permanent left coronary artery ligation to induce an MI. Placebo-MS (100 μg) or PGZ-MS (100 μg) was injected to the infarct region just after induction. Cardiac function and size were assessed by echocardiography. At 28 days after surgery, the rats were sacrificed, and the excised hearts were evaluated histologically. Sustained release of PGZ from the PGZ-MS was confirmed in vitro. PGZ-MS significantly rehabilitated cardiac dysfunction after an MI (fractional shortening: MI vs MI+placebo-MS vs MI+PGZ-MS, 24.4 ± 1.1 vs 24.3 ± 1.6 vs 32.2 ± 1.4%; P = 0.0035) with reverse remodelling. Immunohistochemical analyses revealed that PGZ-MS enhanced macrophage polarization (ratio of M2 subtype: 0.39 ± 0.03 vs 0.42 ± 0.02 vs 0.54 ± 0.02; P = 0.0004) and attenuated apoptosis of cardiomyocytes in the ischaemic border zone. We confirmed macrophage polarization by sustained release of PGZ, which resulted in amelioration of adverse left ventricular remodelling and cardiac dysfunction. Drug delivery system-based macrophage polarization might serve as a promising strategy in cardiac regenerative therapy for ischaemic heart disease. (241 words).