Animal Models Of Myocardial Ischemia Research Articles

Diabetic state of human coronary artery endothelial cells results in altered effects of bone mesenchymal stem cell-derived extracellular vesicles.

Human bone mesenchymal stem cell-derived extracellular vesicles (HBMSC-EV) have been used successfully in animal models of myocardial ischemia, yet have dampened effects in metabolic syndrome through unknown mechanisms. This study demonstrates the basal differences between non-diabetic human coronary artery endothelial cells (HCAEC) and diabetic HCAEC (DM-HCAEC), and how these cells respond to the treatment of HBMSC-EV. HCAEC and DM-HCAEC were treated with HBMSC-EV for 6 h. Proteomics, western blot analysis, and tube formation assays were performed. Key metabolic, growth, and stress/starvation cellular responses were significantly altered in DM-HCAEC in comparison to that of HCAEC at baseline. Proteomics demonstrated increased phosphorus metabolic process and immune pathways and decreased RNA processing and biosynthetic pathways in DM-HCAEC. Similar to previous invivo findings, HCAEC responded to the HBMSC-EV with regenerative and anti-inflammatory effects through the upregulation of multiple RNA pathways and downregulation of immune cell activation pathways. In contrast, DM-HCAEC had a significantly diminished response to HBMSC-EV, likely due to the baseline abnormalities in DM-HCAEC. To achieve the full benefits of HBMSC-EV and for a successful transition of this potential therapeutic agent to clinical studies, the abnormalities found in DM-HCAEC will need to be further studied.

Proteomic Assessment of Hypoxia-Pre-Conditioned Human Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Vesicles Demonstrates Promise in the Treatment of Cardiovascular Disease.

Human bone marrow mesenchymal stem cell derived-extracellular vesicles (HBMSC-EV) are known for their regenerative and anti-inflammatory effects in animal models of myocardial ischemia. However, it is not known whether the efficacy of the EVs can be modulated by pre-conditioning of HBMSC by exposing them to either starvation or hypoxia prior to EV collection. HBMSC-EVs were isolated following normoxia starvation (NS), normoxia non-starvation (NNS), hypoxia starvation (HS), or hypoxia non-starvation (HNS) pre-conditioning. The HBMSC-EVs were characterized by nanoparticle tracking analysis, electron microscopy, Western blot, and proteomic analysis. Comparative proteomic profiling revealed that starvation pre-conditioning led to a smaller variety of proteins expressed, with the associated lesser effect of normoxia versus hypoxia pre-conditioning. In the absence of starvation, normoxia and hypoxia pre-conditioning led to disparate HBMSC-EV proteomic profiles. HNS HBMSC-EV was found to have the greatest variety of proteins overall, with 74 unique proteins, the greatest number of redox proteins, and pathway analysis suggestive of improved angiogenic properties. Future HBMSC-EV studies in the treatment of cardiovascular disease may achieve the most therapeutic benefits from hypoxia non-starved pre-conditioned HBMSC. This study was limited by the lack of functional and animal models of cardiovascular disease and transcriptomic studies.

Myocardial protection with glucose-insulin potassium in patients with acute coronary syndromes requiring coronary artery bypass grafting: A case series

Emergent cardiac surgery in patients with acute coronary syndrome (ACS) is always a challenging task for surgeons, anesthesiologists and patients. As “time is muscle,” early revascularization by percutaneous coronary intervention (PCI) has been largely advocated to salvage myocardial ischemic cells. In cases judged not suitable for PCI, on-pump coronary artery bypass grafting (CABG) is indicated with cardioplegic arrest and eventually anesthetic preconditioning to enhance myocardial protection. In these high-risk emergent procedures, adjuvant interventions to cardioplegic arrest are aimed to maximize the chance of cardiac functional recovery. Although the infusion of glucose-insulin-potassium (GIK) has demonstrated interesting cardioprotective effects in animal models of myocardial ischemia and in patients undergoing elective cardiac surgery, this cardioprotective strategy has not yet been adopted largely and has been ignored so far in emergent myocardial revascularization procedures. In this case series, we describe the effects of GIK on left ventricular performance assessed by transesophageal echocardiography in four patients with ACS who required emergent CABG surgery. The GIK solution of 20 g glucose, 20 UI insulin and 10 mEq potassium chloride was infused twice over 30 min, first after anesthesia induction and later after aortic unclamping. The systolic performance was assessed after anesthesia induction and after each GIK infusion using the 3D left ventricular ejection fraction, as well as the global longitudinal and circumferential strain. The diastolic function was assessed based on mitral inflow patterns (E-and A-waves) as well as flow propagation velocity.

Meta-analysis reveals inhibition of the inflammatory cytokine IL-6 affords limited protection post-myocardial ischemia/infarction

BackgroundProinflammatory cytokine cascades play crucial roles in the onset and progression of myocardial ischemia and infarction. Clinically, elevated serum levels of pro-inflammatory cytokine interleukin-6 is a poor prognostic indicator for future cardiac events and cardiac morbidity. Despite several reports, there is no clear evidence of cardiac benefits of inhibiting IL-6 in pre-clinical and clinical settings. ObjectiveTo analyze the available data systematically and perform a meta-analysis to show the evidence of effects of IL-6 inhibition on cardiac remodeling and mortality in ischemic animal models. MethodsWe used PICO framework and the quality of the studies was assessed using SYRCLE's risk of bias tool. Studies with interventions i.e., genetic deletion or pharmacological inhibition of IL-6/IL-6R were included for the meta-analysis. Systematic review was synthesized by including pre-clinical as well as randomized clinical trials involving myocardial infarction patients treated with IL-6 inhibitors. The effect size of the pooled data was determined using standard mean difference and 95% confidence intervals. ResultsA total of 12 pre-clinical studies were included in the review for analysis. Most of the studies showed an unclear risk of bias as the selection and reporting criteria were poorly described. We observed high heterogeneity in the included studies due to the varying duration of myocardial infarction and the dosage of IL-6 antibodies used in the studies. Overall inhibition of IL-6 significantly increased area at risk [p = 0.001, SMD = 0.49 (95% CI: -0.36, 1.35)] and significantly reduced ejection fraction [p = 0.001, SMD = -0.19 (95% CI: -1.39, 1.01)] and end-diastolic diameter [p = 0.02, SMD = -0.25 (95% CI: -0.87, 0.36)] of left ventricle post-MI, but no effects on infarct size [p < 0.01, SMD = 0.00; 95% CI: -1.34, 0.58). In randomized clinical trials, the overall effect on C-reactive protein remains significantly unchanged on CRP levels (SMD = -0.38; 95% CI: -1.94, 0.55) post-treatment with IL-6R inhibitor tocilizumab. The meta-regression demonstrates a significant positive correlation (p = 0.058) between the increase in ischemic area and duration of ischemia post-surgery in the absence of IL-6. This meta-analysis indicates mixed effect of IL-6 inhibition on cardiac remodeling post-MI, particularly in protecting the myocardium viability from damaging acute inflammation but not significant on cardiac function of ischemic animal models. ConclusionDespite the well-established pro-inflammatory nature of IL-6 in myocardial ischemia, our meta-analysis reports a limited contribution of IL-6 in the cardiac remodeling of hearts in animal models of myocardial ischemia. Moreover, genetically deleted IL-6 murine models produced contrasting results. Additional pre-clinical studies exploring the pharmacological inhibition of IL-6R are required to determine the beneficial effects of IL-6 inhibitors in regulating cardiac remodeling. The findings from IL-6R inhibition have better clinical relevance compared to genetically inhibited IL-6.

Shengmai Yin alleviated plaque vulnerability and ischemic myocardial damage in diesel exhaust particle-aggravated atherosclerosis with myocardial ischemia

Exposure to diesel exhaust particles (DEP) increases the risk of ischemic heart disease, especially heart attacks and ischemic/thrombotic strokes. Shengmai Yin (SMY) is a traditional Chinese medicine used to treat coronary heart disease. The aim of this study was to determine the protective role of SMY and the mechanism by which SMY affects DEP-induced cardiovascular injury. This study is expected to provide the basis for the development of an adaptive signature of SMY in the prevention of atherosclerotic cardiovascular disease and premature death from global air pollution exposure. We developed animal models of myocardial ischemia and atherosclerosis (AS) in response to DEP exposure. After SMY treatment, serum lipids returned to normal. Aortic plaque area and MMP9 expression were significantly reduced and collagen fiber expression increased after SMY treatment compared to DEP exposure alone. Thus, the risk of plaque formation and vulnerability is reduced. In addition, SMY improved left ventricular structure, morphology, function, blood flow, infarct area, myocardial damage, and ROS accumulation to varying degrees in ApoE-/- mice. These results indicate that the use of SMY is effective, to varying degrees, for the treatment of dyslipidemia, atherosclerosis, myocardial ischemia, and oxidative stress in ApoE-/- mice. SMY has a potential protective effect in DEP-aggravated AS in people with myocardial ischemia.

Protective effect of quercetin against myocardial ischemia as a Ca2+ channel inhibitor: involvement of inhibiting contractility and Ca2+ influx via L-type Ca2+ channels.

Many studies describe the stimulating effect of quercetin on Ca2+ channels and the treatment of cardiovascular diseases such as myocardial ischemia and hypertension. However, these studies are scattered and contradictory. The aim of this study is to elucidate the protective effects of quercetin against isoproterenol (ISO)-induced myocardial ischemia and verify the cellular mechanisms based on the L-type Ca2+ channel (LTCC), Ca2+ transients, and myocardial contractility. An animal model of myocardial ischemia was established by subcutaneous injection of ISO for 2days. Quercetin significantly reduced J-point elevation, heart rate, reactive oxygen species, serum levels of myocardial enzymes, superoxide dismutase, catalase, glutathione, glutathione peroxidase, glutathione S-transferase and improved heart pathologic morphology. L-type Ca2+ current (ICa-L) was tested in an experiment with isolated rat myocardial cells by using the whole-cell patch-clamp recording technique and IonOptix Myocam detection system. Quercetin reduced ICa-L in a concentration-dependent fashion with a half-maximal inhibitory concentration of 4.67 × 10-4M. Quercetin also shifted the current-voltage curve upwards, moved the activation and inactivation curves to the left and inhibited the amplitude of the cell shortening and Ca2+ transients. The results showed that quercetin acts as a LTCC inhibitor and exerts a cardioprotective effect by inhibiting Ca2+ influx and contractility in rats.

Protective effects of rimeporide on left ventricular function in golden retriever muscular dystrophy dogs

BackgroundAlterations in intracellular Na+ and Ca2+ have been observed in patients with Duchenne muscular dystrophy (DMD) and in animal models of DMD, and inhibition of Na+-H+ exchanger 1 (NHE1) by rimeporide has previously demonstrated cardioprotective effects in animal models of myocardial ischemia and heart failure. Since heart failure is becoming a predominant cause of death in DMD patients, this study aimed to demonstrate a cardioprotective effect of chronic administration of rimeporide in a canine model of DMD. MethodsGolden retriever muscular dystrophy (GRMD) dogs were randomized to orally receive rimeporide (10 mg/kg, twice a day) or placebo from 2 months to 1 year of age. Left ventricular (LV) function was assessed by conventional and advanced echocardiography. ResultsCompared with placebo-treated GRMD, LV function deterioration with age was limited in rimeporide-treated GRMD dogs as indicated by the preservation of LV ejection fraction as well as overall cardiac parameters different from placebo-treated dogs, as revealed by composite cardiac scores and principal component analysis. In addition, principal component analysis clustered rimeporide-treated GRMD dogs close to healthy control dogs. ConclusionsChronic administration of the NHE1 inhibitor rimeporide exerted a protective effect against LV function decline in GRMD dogs. This study provides proof of concept to explore the cardiac effects of rimeporide in DMD patients.

Multi-phase catheter-injectable hydrogel enables dual-stage protein-engineered cytokine release to mitigate adverse left ventricular remodeling following myocardial infarction in a small animal model and a large animal model

Although ischemic heart disease is the leading cause of death worldwide, mainstay treatments ultimately fail because they do not adequately address disease pathophysiology. Restoring the microvascular perfusion deficit remains a significant unmet need and may be addressed via delivery of pro-angiogenic cytokines. The therapeutic effect of cytokines can be enhanced by encapsulation within hydrogels, but current hydrogels do not offer sufficient clinical translatability due to unfavorable viscoelastic mechanical behavior which directly impacts the ability for minimally-invasive catheter delivery. In this report, we examine the therapeutic implications of dual-stage cytokine release from a novel, highly shear-thinning biocompatible catheter-deliverable hydrogel. We chose to encapsulate two protein-engineered cytokines, namely dimeric fragment of hepatocyte growth factor (HGFdf) and engineered stromal cell-derived factor 1α (ESA), which target distinct disease pathways. The controlled release of HGFdf and ESA from separate phases of the hyaluronic acid-based hydrogel allows extended and pronounced beneficial effects due to the precise timing of release. We evaluated the therapeutic efficacy of this treatment strategy in a small animal model of myocardial ischemia and observed a significant benefit in biological and functional parameters. Given the encouraging results from the small animal experiment, we translated this treatment to a large animal preclinical model and observed a reduction in scar size, indicating this strategy could serve as a potential adjunct therapy for the millions of people suffering from ischemic heart disease.

Preconditioning and postconditioning with netrin-1 in acute myocardial infarction model of rat improves systolic and diastolic left ventricular dysfunction

Introduction To evaluate the improvement of systolic and diastolic left ventricular(LV) dysfunction by preconditioning and postconditioning with netrin-1 after acute myocardial infarction(MI) in rat model, we examined the changes of echocardiographic parameters and compared with them before and after MI. Methods Male, 8-to 9-week-old, Spraque-Dawley rats with a mean body weight of 277.40 ±9.48 g were anesthesized with intraperitoneal injection of pentobarbital at a dose of 65 mg / kg, followed by intubation and positive pressure ventilation for 15 minutes as a stabilizing period. The acute MI model had the ligation of left coronary artery under heart exposure through 4-5th intercostal space then closed. After 30 minutes under mechanical ventilation, the left anterior descending artery (LAD) of the rat was ligated for 30 minutes And reperfusion for 2 hours to produce an ischemic / perfusion animal model of myocardial ischemia. After 30 minutes of ischemia, netrin-1(5mcg/kg) was slowly injected into MI group but vehicle(normal saline) into another MI group via tail vein. Netrin-1 preconditioning was administered intravenously 3 minutes before the induction of ischemia and 3 minutes after the induction of ischemia. Netrin-1 postconditioning was administered intravenously 5 minutes before the end of ischemic induction for 3 minutes and pentobarbital 35 mg / kg after 2 hours of reperfusion. And the echocardiographic evaluation was performed. Using Vevo2100, Echocardiographic studies were performed before surgery and After 120 minutes of reperfusion. Results Fractional shortening values were significantly increased in the pre-isch, pre-netrin, post-isch and post-netrin groups compared to the vehicle group. The EF (ejection fraction), And in the post-netrin group, the left ventricular systolic function was improved. E'(initial diastolic velocity) values were significantly higher in the post-iso, post-isch, and post-netrin groups than in the vehicle group. E / E', Post-isch, post-isch, and post-netrin, respectively. Discussion Preconditioning and postconditioning with netrin-1 makes meaningful improvemet of systolic dysfunction with significant increase with FS and EF after acute MI. Also it helps E’ recovery for LV diastolic function and E/E’ ratio for left atrial pressure.

Effects of rotigotine and rotigotine extended-release microsphere therapy on myocardial ischemic injury in mice

Rotigotine is a dopamine receptor agonist that can improve motor function in Parkinson's disease (PD) patients. Rotigotine extended-release microsphere (RoMS) is an extended-release intramuscular formulation that exhibits a sustained release of rotigotine over a 14-day period. The clinical trials of RoMS has been carried out in USA and China. The purpose of this study is to observe the effects of RoMS therapy on myocardial ischemic injury in mice, to know whether RoMS alleviate or deteriorate the myocardial ischemic injury while PD patient has onset of myocardial ischemia concurrent after administered with RoMS. A mouse model of myocardial ischemia was established using isoproterenol, and mice were pretreated with rotigotine or RoMS before inducing myocardial ischemic injury. The effects of rotigotine or RoMS therapy on the degree of myocardial ischemic injury were studied by evaluating troponin I level, creatine kinase-MB (CK-MB) activity, and histopathological changes in cardiomyocytes. The dopamine receptor blocker chlorpromazine was used to further investigate the effects of rotigotine or RoMS on myocardial ischemic injury. Furthermore, serum rotigotine concentrations were also assayed. When myocardial ischemia occurred during rotigotine or RoMS administration, troponin I level and CK-MB activity were decreased, and ischemia-induced histopathological changes in cardiomyocytes were alleviated. The effects of rotigotine were maintained only 12 h and after that no protective effect was observed. RoMS releases continuously into the circulation after intramuscular injection. The cardioprotective effects of RoMS were maintained 14 days after a single RoMS administration. When combined with chlorpromazine, the protective effects of rotigotine on myocardial ischemic injury were eliminated, and the protective effects of RoMS were also partially abolished. In the animal model of myocardial ischemia, pretreatment with rotigotine or RoMS does not deteriorate, but can alleviate cardiomyocyte injury. Furthermore, RoMS pretreatment show long-term and continuous protective effects on cardiomyocyte injury. RoMS therapy in PD patients at high risk for cardiovascular diseases may attenuate the degree of cardiomyocyte injury caused by ischemia.

Impact of different anesthetic states on acupuncture-mediated modulation of autonomic nervous system in animal studies

Acupuncture therapy has a positive role in the prevention and treatment of some related diseases by regulating autonomic nervous function. But it has been found in experimental researches that the modulatory effects of acupuncture on autonomic nervous system are not always consistent with each other. Because in the animal studies on the mechanism of acupuncture intervention, the anesthetic agent has to be used and definitely affects the activities of the autonomic nervous system while playing its pharmacological effects. Hence, it is very significant to explore the rational application of anesthetic agents and minimize their unfavorable impacts on the research outcomes. In the present paper, we make a retrospective analysis on (1) the effect of acupuncture intervention on activities of the autonomic nerve in animal models of myocardial ischemia, gastrointestinal mobility, and urinary system; (2) the effect of anesthetics as isoflurane, urethane, pentobarbital sodium, ketamine, α-chloralose, propofolum, etc. on activities of the autonomic nerve system. In terms of different anesthetic modes and various depths of anesthesia by using isoflurane inhalation, mixed solution of urethane and chloralose, etc., some approaches for assessing the state of anesthesia in accordance with the pupillary reflex, righting reflex, footboard reflex, swallowing reflex, heart rate, blood pressure, body temperature, respiration frequency, ventilation volume, oxygen saturation, partial pressure of carbon dioxide, neuromuscular blo-ckade, etc. in combination with the indexes directly and indirectly reflecting functions of the sympathetic and vagus nerves are proposed to analyze the impact of different anesthetic states on the therapeutic effect of acupuncture in various models of dysfunction of the autonomic nerve system. Under the circumstances, it is possible to provide a reference for rational use of anesthetic agents and dosages in the acupuncture research of autonomic nerve regulation.

Tobacco smoking and psychotropic drugs

Rotigotine is a dopamine receptor agonist that can improve motor function in Parkinson's disease (PD) patients. Rotigotine extended-release microsphere (RoMS) is an extended-release intramuscular formulation that exhibits a sustained release of rotigotine over a 14-day period. The clinical trials of RoMS has been carried out in USA and China. The purpose of this study is to observe the effects of RoMS therapy on myocardial ischemic injury in mice, to know whether RoMS alleviate or deteriorate the myocardial ischemic injury while PD patient has onset of myocardial ischemia concurrent after administered with RoMS. A mouse model of myocardial ischemia was established using isoproterenol, and mice were pretreated with rotigotine or RoMS before inducing myocardial ischemic injury. The effects of rotigotine or RoMS therapy on the degree of myocardial ischemic injury were studied by evaluating troponin I level, creatine kinase-MB (CK-MB) activity, and histopathological changes in cardiomyocytes. The dopamine receptor blocker chlorpromazine was used to further investigate the effects of rotigotine or RoMS on myocardial ischemic injury. Furthermore, serum rotigotine concentrations were also assayed. When myocardial ischemia occurred during rotigotine or RoMS administration, troponin I level and CK-MB activity were decreased, and ischemia-induced histopathological changes in cardiomyocytes were alleviated. The effects of rotigotine were maintained only 12 h and after that no protective effect was observed. RoMS releases continuously into the circulation after intramuscular injection. The cardioprotective effects of RoMS were maintained 14 days after a single RoMS administration. When combined with chlorpromazine, the protective effects of rotigotine on myocardial ischemic injury were eliminated, and the protective effects of RoMS were also partially abolished. In the animal model of myocardial ischemia, pretreatment with rotigotine or RoMS does not deteriorate, but can alleviate cardiomyocyte injury. Furthermore, RoMS pretreatment show long-term and continuous protective effects on cardiomyocyte injury. RoMS therapy in PD patients at high risk for cardiovascular diseases may attenuate the degree of cardiomyocyte injury caused by ischemia.

MicroRNA-1 and Circulating Microvesicles Mediate the Protective Effects of Dantonic in Acute Myocardial Infarction Rat Models.

Aim: To investigate the protective effect of dantonic in ischemic myocardial damage by evaluating the expression of circulating microvesicles (MVs) and microRNA-1 (miR-1) in two animal models.Methods: Two animal models of myocardial ischemia were established that were isoproterenol-induced myocardial ischemia (ISO-AMI) rat model and the acute myocardial infarction rat model induced by ligation of the left anterior descending coronary artery (LAD-AMI) of rat. To investigate the protective effect of dantonic, we observed the myocardial infarction size, creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) activities, cardiac troponin I (cTnI) level in serum, and the plasma levels of miR-1 and MVs.Results: The results showed that pretreatment with dantonic significantly attenuated the LAD-AMI induced myocardial damage by decreasing the size of myocardial infarction, CK, LDH, AST activities, and cTnI level in serum. High dose dantonic treatment could significantly abrogate the increased plasma levels of miR-1 and MVs as compared to the LAD rat model. In addition, pretreatment with dantonic also showed a significant myocardial protective effect through reducing the expression levels of CK, LDH, and AST as compared to the ISO-AMI model. Whereas the cTnI level was no significant difference between model group and control group, suggesting that the model caused less myocardial damage. In the ISO-induced myocardial ischemia model, there is no significant difference between the model group with the control group of MVs and miR-1 levels. This may be that miR-1 is reported as a biomarker of acute myocardial infarction. The pathological changes of IOS-induced acute myocardial ischemia model are also different from those of acute myocardial infarction.Conclusion: Dantonic showed the protective effect in these two ischemic myocardial injury rat models, whereas the circulating miR-1 and MVs levels were only ameliorated in the LAD rat model.

Abstract 553: Inhibition of Microrna-21 Prevents Myocardial Remodelling and Dysfunction in a Pig Model of Ischemia/reperfusion Injury

Background: Upregulation of microRNA-21 (miR-21) has been associated with myocardial disease and its systemic inhibition was effective in reducing cardiac fibrosis and dysfunction in rodent models. However, the translation to human disease is challenging, as systemic application of miR inhibitors does not achieve adequate delivery in most organs including the heart. Here, we sought to test the applicability and therapeutic efficacy of local, catheter-based delivery of antimiR-21 in a large animal model of heart failure. Methods and results: Pigs underwent percutaneous occlusion of the left coronary artery for 60 minutes and were followed up for 33 days. A synthetic inhibitor against miR-21 (LNA-antimiR-21, 10 mg per application) was applied locally by intracoronary infusion at days 5 and 19 after the injury. AntimiR-21 effectively suppressed the I/R-induced increase of miR-21. At 33 days after I/R, LNA-21-treated hearts exhibited reduced cardiac fibrosis and hypertrophy, and improved cardiac function (ejection fraction: I/R control 22±1% vs. I/R LNA-21 33±2%). RNA sequencing of ischemic myocardium revealed a significant enrichment for miR-21 targets in anti-miR-21 treated hearts. Mechanistically, antimiR-21 interfered with a number of signalling pathways involved in myocardial remodelling including the MAPK-ERK signalling cascade. Conclusion: Taken together, our study provides the first evidence for the feasibility and therapeutic efficacy of miR-21 inhibition in a large animal model of myocardial ischemia. AntimiR-21 prevented the structural and functional consequences of ischemic myocardial damage.

Concise Review: The Regenerative Journey of Pericytes Toward Clinical Translation.

Coronary artery disease (CAD) is the single leading cause of death worldwide. Advances in treatment and management have significantly improved patient outcomes. On the other hand, although mortality rates have decreased, more people are left with sequelae that require additional treatment and hospitalization. Moreover, patients with severe nonrevascularizable CAD remain with only the option of heart transplantation, which is limited by the shortage of suitable donors. In recent years, cell‐based regenerative therapy has emerged as a possible alternative treatment, with several regenerative medicinal products already in the clinical phase of development and others emerging as competitive preclinical solutions. Recent evidence indicates that pericytes, the mural cells of blood microvessels, represent a promising therapeutic candidate. Pericytes are abundant in the human body, play an active role in angiogenesis, vessel stabilization and blood flow regulation, and possess the capacity to differentiate into multiple cells of the mesenchymal lineage. Moreover, early studies suggest a robustness to hypoxic insult, making them uniquely equipped to withstand the ischemic microenvironment. This review summarizes the rationale behind pericyte‐based cell therapy and the progress that has been made toward its clinical application. We present the different sources of pericytes and the case for harvesting them from tissue leftovers of cardiovascular surgery. We also discuss the healing potential of pericytes in preclinical animal models of myocardial ischemia (MI) and current practices to upgrade the production protocol for translation to the clinic. Standardization of these procedures is of utmost importance, as lack of uniformity in cell manufacturing may influence clinical outcome. Stem Cells 2018;36:1295–1310

Endothelial progenitor cells for cellular angiogenesis and repair: lessons learned from experimental animal models.

Stem/progenitor cell-based therapy has been extensively studied for angiomyogenic repair of the ischemic heart by regeneration of the damaged myocytes and neovascularization of the ischemic tissue through biological bypassing. Given their inherent ability to assume functionally competent endothelial phenotype and release of broad array of proangiogenic cytokines, endothelial progenitor cells (EPCs)-based therapy is deemed as most appropriate for vaculogenesis in the ischemic heart. Emulating the natural repair process that encompasses mobilization and homing-in of the bone marrow and peripheral blood EPCs, their reparability has been extensively studied in the animal models of myocardial ischemia with encouraging results. Our literature review is a compilation of the lessons learned from the use of EPCs in experimental animal models with emphasis on the in vitro manipulation and delivery strategies to enhance their retention, survival and functioning post-engraftment in the heart.

Cardiovascular Actions and Clinical Outcomes With Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors.

Potentiation of glucagon-like peptide-1 (GLP-1) action through selective GLP-1 receptor (GLP-1R) agonism or by prevention of enzymatic degradation by inhibition of dipeptidyl peptidase-4 (DPP-4) promotes glycemic reduction for the treatment of type 2 diabetes mellitus by glucose-dependent control of insulin and glucagon secretion. GLP-1R agonists also decelerate gastric emptying, reduce body weight by reduction of food intake and lower circulating lipoproteins, inflammation, and systolic blood pressure. Preclinical studies demonstrate that both GLP-1R agonists and DPP-4 inhibitors exhibit cardioprotective actions in animal models of myocardial ischemia and ventricular dysfunction through incompletely characterized mechanisms. The results of cardiovascular outcome trials in human subjects with type 2 diabetes mellitus and increased cardiovascular risk have demonstrated a cardiovascular benefit (significant reduction in time to first major adverse cardiovascular event) with the GLP-1R agonists liraglutide (LEADER trial [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Ourcome Results], -13%) and semaglutide (SUSTAIN-6 trial [Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide], -24%). In contrast, cardiovascular outcome trials examining the safety of the shorter-acting GLP-1R agonist lixisenatide (ELIXA trial [Evaluation of Lixisenatide in Acute Coronary Syndrom]) and the DPP-4 inhibitors saxagliptin (SAVOR-TIMI 53 trial [Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53]), alogliptin (EXAMINE trial [Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome]), and sitagliptin (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin]) found that these agents neither increased nor decreased cardiovascular events. Here we review the cardiovascular actions of GLP-1R agonists and DPP-4 inhibitors, with a focus on the translation of mechanisms derived from preclinical studies to complementary findings in clinical studies. We highlight areas of uncertainty requiring more careful scrutiny in ongoing basic science and clinical studies. As newer more potent GLP-1R agonists and coagonists are being developed for the treatment of type 2 diabetes mellitus, obesity, and nonalcoholic steatohepatitis, the delineation of the potential mechanisms that underlie the cardiovascular benefit and safety of these agents have immediate relevance for the prevention and treatment of cardiovascular disease.

A systematic review of the mechanisms of acupuncture for myocardial ischemia on central nervous system

Based on the systematic review on acupuncture improving the mechanism of central nervous system in animal model of myocardial ischemia in recent years, we analyzed the effects of acupuncture on medulla oblongata rVLM zone, hippocampus, hypothalamus, spinal cord segment and automalic to the mechanism of positively regulating myocardial ischemic, which provided a new way for the clinical treatment of myocardial ischemia and cardiovascular diseases. Key words: Acupuncture; Myocardial ischemia; Disease models, animal; Central nervous system; Review

Human Placenta-Derived Multipotent Cells (hPDMCs) Modulate Cardiac Injury: From Bench to Small and Large Animal Myocardial Ischemia Studies

Cardiovascular disease is the leading cause of death globally, and stem cell therapy remains one of the most promising strategies for regeneration or repair of the damaged heart. We report that human placenta-derived multipotent cells (hPDMCs) can modulate cardiac injury in small and large animal models of myocardial ischemia (MI) and elucidate the mechanisms involved. We found that hPDMCs can undergo in vitro cardiomyogenic differentiation when cocultured with mouse neonatal cardiomyocytes. Moreover, hPDMCs exert strong proangiogenic responses in vitro toward human endothelial cells mediated by secretion of hepatocyte growth factor, growth-regulated oncogene-α, and interleukin-8. To test the in vivo relevance of these results, small and large animal models of acute MI were induced in mice and minipigs, respectively, by permanent left anterior descending (LAD) artery ligation, followed by hPDMC or culture medium-only implantation with follow-up for up to 8 weeks. Transplantation of hPDMCs into mouse heart post-acute MI induction improved left ventricular function, with significantly enhanced vascularity in the cell-treated group. Furthermore, in minipigs post-acute MI induction, hPDMC transplantation significantly improved myocardial contractility compared to the control group (p = 0.016) at 8 weeks postinjury. In addition, tissue analysis confirmed that hPDMC transplantation induced increased vascularity, cardiomyogenic differentiation, and antiapoptotic effects. Our findings offer evidence that hPDMCs can modulate cardiac injury in both small and large animal models, possibly through proangiogenesis, cardiomyogenesis, and suppression of cardiomyocyte apoptosis. Our study offers mechanistic insights and preclinical evidence on using hPDMCs as a therapeutic strategy to treat severe cardiovascular diseases.

Pathophysiology of ST-segment elevation myocardial infarction: novel mechanisms and treatments.

Despite major advances in mechanical and pharmacological reperfusion strategies to improve acute myocardial infarction (MI) injury, substantial mortality, morbidity, and socioeconomic burden still exists. To further reduce infarct size and thus ameliorate clinical outcome, the focus has also shifted towards early detection of MI with high-sensitive troponin assays, imaging, cardioprotection against pathophysiological targets of myocardial reperfusion injury with mechanical (ischaemic post-conditioning, remote ischaemic pre-conditioning, therapeutic hypothermia, and hypoxemia) and newer pharmacological interventions (atrial natriuretic peptide, cyclosporine A, and exenatide). Evidence from animal models of myocardial ischaemia and reperfusion also demonstrated promising results on more selective anti-inflammatory compounds that require additional validation in humans. Cardiac stem cell treatment also hold promise to reduce infarct size and negative remodelling of the left ventricle that may further improves symptoms and prognosis in these patients. This review focuses on the pathophysiology, detection, and reperfusion strategies of ST-segment elevation MI as well as current and future challenges to reduce ischaemia/reperfusion injury and infarct size that may result in a further improved outcome in these patients.