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Since both myocardium and vasculature in the heart are excessively damaged following myocardial infarction (MI), therapeutic strategies for treating MI hearts should concurrently target both so as to achieve true cardiac repair. Here we demonstrate a concomitant method that exploits the advantages of cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) and human mesenchymal stem cell-loaded patch (hMSC-PA) to amplify cardiac repair in a rat MI model. Epicardially implanted hMSC-PA provide a complimentary microenvironment which enhances vascular regeneration through prolonged secretion of paracrine factors, but more importantly it significantly improves the retention and engraftment of intramyocardially injected hiPSC-CMs which ultimately restore the cardiac function. Notably, the majority of injected hiPSC-CMs display adult CMs like morphology suggesting that the secretomic milieu of hMSC-PA constitutes pleiotropic effects in vivo. We provide compelling evidence that this dual approach can be a promising means to enhance cardiac repair on MI hearts. Myocardial infarction causes damage to the myocardium and vasculature. Here the authors show in a rat model of myocardial infarction that cardiomyocytes derived from human induced pluripotent stem cells combined with a human mesenchymal stem cell-loaded patch lead to improved cardiac function and promote vessel formation.

Accumulation of lipids and their metabolites induces lipotoxicity in diabetic cardiomyopathy. Lowering ceramide concentration could reduce the impact of metabolic damage to target organs. Adiponectin improves lipotoxicity through its receptors (AdiopRs), which have sequence homology with ceramidase enzymes. Therefore, cardioprotective role of AdipoR agonism by AdipoRon was investigated. Sixteen-week-old male db/m and db/db mice were fed a diet containing AdipoRon for four weeks. Phenotypic and metabolic profiles with associated cellular signaling pathways involved in lipid metabolism were investigated in the mice heart and human cardiomyocytes to establish treatment effect of AdipoRon. AdipoRon ameliorated insulin resistance, fibrosis, M1-dominant inflammation, and apoptosis in association with reduced accumulations of free fatty acid, triglycerides, and TLR4-related ceramide in the heart. This resulted in overall reduction in the level of oxidative stress which ameliorated cardiac hypertrophy and its function. AdipoRon increased the expression of AdipoR1 and AdipoR2 via pAMPK/FoxO1-induced Akt phosphorylation resulting from a decrease in PP2A level. It also increased acid ceramidase activity which reduced ceramide and increased sphingosine-1 phosphate levels in the heart of db/db mice and cultured human cardiomyocytes. Consistent upregulation of AdipoRs and their downstream regulatory pathways involving pAMPK/PPARα/PGC-1α levels led to lipid metabolism enhancement, thereby improving lipotoxicity-induced peroxisome biogenesis and oxidative stress. AdipoRon might control oxidative stress, inflammation, and apoptosis in the heart through increased AdipoR expression, acid ceramidase activity, and activation of AMPK-PPARα/PGC-1α and related downstream pathways, collectively improving cardiac lipid metabolism, hypertrophy, and functional parameters.

Engineered human cardiac tissues have been utilized for various biomedical applications, including drug testing, disease modeling, and regenerative medicine. However, the applications of cardiac tissues derived from human pluripotent stem cells are often limited due to their immaturity and lack of functionality. Therefore, in this study, we establish a perfusable culture system based on in vivo-like heart microenvironments to improve human cardiac tissue fabrication. The integrated culture platform of a microfluidic chip and a three-dimensional heart extracellular matrix enhances human cardiac tissue development and their structural and functional maturation. These tissues are comprised of cardiovascular lineage cells, including cardiomyocytes and cardiac fibroblasts derived from human induced pluripotent stem cells, as well as vascular endothelial cells. The resultant macroscale human cardiac tissues exhibit improved efficacy in drug testing (small molecules with various levels of arrhythmia risk), disease modeling (Long QT Syndrome and cardiac fibrosis), and regenerative therapy (myocardial infarction treatment). Therefore, our culture system can serve as a highly effective tissue-engineering platform to provide human cardiac tissues for versatile biomedical applications. The application of engineered cardiac tissues is limited due to their immaturity and lack of functionality. Here, the authors develop an integrated culture platform featuring heart extracellular matrix cultured in a microfluidic chip to facilitate cardiac tissue development for versatile biomedical applications.

Neutrophils are critical mediators of both the initiation and resolution of inflammation after myocardial infarction (MI). Overexuberant neutrophil signaling after MI exacerbates cardiomyocyte apoptosis and cardiac remodeling while neutrophil apoptosis at the injury site promotes macrophage polarization toward a pro-resolving phenotype. Here, we describe a nanoparticle that provides spatiotemporal control over neutrophil fate to both stymie MI pathogenesis and promote healing. Intravenous injection of roscovitine/catalase-loaded poly(lactic-co-glycolic acid) nanoparticles after MI leads to nanoparticle uptake by circulating neutrophils migrating to the infarcted heart. Activated neutrophils at the infarcted heart generate reactive oxygen species, triggering intracellular release of roscovitine, a cyclin-dependent kinase inhibitor, from the nanoparticles, thereby inducing neutrophil apoptosis. Timely apoptosis of activated neutrophils at the infarcted heart limits neutrophil-driven inflammation, promotes macrophage polarization toward a pro-resolving phenotype, and preserves heart function. Modulating neutrophil fate to tune both inflammatory and reparatory processes may be an effective strategy to treat MI. Neutrophils are involved in both the initiation and resolution of cardiac inflammation post myocardial infarction (MI). Here, the authors show that intravenously injected nanoparticles can modulate cardiac neutrophils to inhibit inflammation and promote repair for MI therapy.

Intravascular microrobots have emerged as a promising tool for vascular diseases. They can be wirelessly and precisely manipulated with a high degree of freedom. Previous studies have evaluated their drilling performance and locomotion, and showed the feasibility of using microrobots for biomedical applications in two-dimensional space. However, it is critical to validate micro-drillers in a three-dimensional (3D) environment because gravity plays an important role in a 3D environment and significantly affects the performance of the micro-drillers in vascular networks. In this work, we fabricated magnetic drilling actuators (MDAs) and characterized their locomotion and drilling performance in vascular network-mimicking fluidic channels. The MDAs were precisely manipulated in the fluidic channel network in both horizontal and vertical planes, selecting and moving through the desired path via the junctions of multiple channels. The MDAs also accurately navigated an artificial thrombosis in an artificial 3D vascular network and successfully drilled through it. The results obtained here confirmed the precise manipulation and drilling performance of the developed MDAs in 3D. We think that the MDAs presented in this paper have great potential as intravascular drillers for precise thrombus treatment.

BackgroundIntravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) has been shown to improve outcomes in complex coronary artery disease compared with angiography-guided PCI. However, long-term comparisons between IVUS-guided PCI and coronary artery bypass grafting (CABG) for multivessel disease (MVD) remain limited.MethodsThis post hoc analysis of the Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment Extended Follow-up study included 880 patients with MVD, excluding 15 patients who received medical therapy. Patients were categorised into IVUS-guided PCI (n=333), angiography-guided PCI (n=131) and CABG (n=401). The primary endpoint was the composite of death, myocardial infarction (MI) or target-vessel revascularisation over a median follow-up of 11.8 years.ResultsThe IVUS-guided PCI group showed no difference in the primary endpoint compared with CABG (adjusted HR 1.013; 95% CI 0.747 to 1.374; p=0.93). In contrast, angiography-guided PCI was associated with a higher risk of clinical events (adjusted HR 2.231; 95% CI 1.582 to 3.145; p<0.001). The safety endpoint (composite of death, MI and stroke) did not differ between IVUS-guided PCI and CABG (adjusted HR 0.845; 95% CI 0.605 to 1.181; p=0.324), while angiography-guided PCI was associated with a higher risk (adjusted HR 2.016; 95% CI 1.405 to 2.895; p<0.001). Both PCI groups had higher rates of repeat revascularisation compared with CABG.ConclusionsIVUS-guided PCI demonstrated comparable long-term outcomes to CABG in terms of mortality and safety endpoints, supporting its use in the treatment of MVD. These findings highlight the potential benefits of IVUS guidance in complex PCI procedures.Trial registration numbers NCT05125367 and NCT00997828.

Ischemia–reperfusion (I/R) injury accelerates the cardiomyocytes (CMs) death by oxidative stress, and thereby deteriorates cardiac function. There has been a paradigm shift in the therapeutic perspective more towards the prevention or amelioration of damage caused by reperfusion. Cardiac microvascular endothelial cells (CMECs) are more vulnerable to reperfusion injury and play the crucial roles more than CMs in the pathological process of early I/R injury. In this study, we investigate that CU06-1004, as a vascular leakage blocker, can improve cardiac function by inhibiting CMEC’s hyperpermeability and subsequently reducing the neutrophil’s plugging and infiltration in infarcted hearts. CU06-1004 was delivered intravenously 5 min before reperfusion and the rats were randomly divided into three groups: (1) vehicle, (2) low-CU06-1004 (1 mg/kg, twice at 24 h intervals), and (3) high-CU06-1004 (5 mg/kg, once before reperfusion). CU06-1004 treatment reduced necrotic size and cardiac edema by enhancing vascular integrity, as demonstrated by the presence of intact junction proteins on CMECs and surrounding pericytes in early I/R injury. It also decreased the expression of vascular cell adhesion molecule 1 (VCAM-1) on CMECs, resulting in reduced infiltration of neutrophils and macrophages. Echocardiography showed that the CU06-1004 treatment significantly improved cardiac function compared with the vehicle group. Interestingly, single high-dose treatment with CU06-1004 provided a greater functional improvement than repetitive low-dose treatment until 8 weeks post I/R. These findings demonstrate that CU06-1004 enhances vascular integrity and improves cardiac function by preventing lethal myocardial I/R injury. It can provide a promising therapeutic option, as potential adjunctive therapy to current reperfusion strategies. Heart attack: Drug boosts survival of heart cells during treatment A drug that can block excess inflammation and leakage from blood vessels shows promise in boosting the survival of heart cells following treatment for heart attack. Reperfusion therapy aims to restore blood flow around or through blocked arteries after a heart attack. However, in some cases the treatment can trigger the overproduction of reactive oxygen species, damaging the endothelium (lining of blood vessels) and further injuring heart muscle cells. Hun-Jun Park (Catholic University) and Young-Guen Kwon (Yonsei University), both in Seoul, South Korea, and co-workers, have demonstrated that the drug CU06-1004, used successfully in animal trials for other conditions, can enhance cardiac integrity and function following reperfusion in rats. A single high dose of CU06-1004 inhibited leakage from heart microvascular endothelial cells, reducing the build-up of fluid in tissues and limiting tissue death.

Despite recent progress in medical and endovascular therapy, the prognosis for patients with critical limb ischemia (CLI) remains poor. In response, various stem cells and growth factors have been assessed for use in therapeutic neovascularization and limb salvage in CLI patients. However, the clinical outcomes of cell-based therapeutic angiogenesis have not provided the promised benefits, reinforcing the need for novel cell-based therapeutic angiogenic strategies to cure untreatable CLI. In the present study, we investigated genetically engineered mesenchymal stem cells (MSCs) derived from human bone marrow that continuously secrete stromal-derived factor-1α (SDF1α-eMSCs) and demonstrated that intramuscular injection of SDF1α-eMSCs can provide long-term paracrine effects in limb ischemia and effectively contribute to vascular regeneration as well as skeletal muscle repair through increased phosphorylation of ERK and Akt within the SDF1α/CXCR4 axis. These results provide compelling evidence that genetically engineered MSCs with SDF-1α can be an effective strategy for successful limb salvage in limb ischemia. Breakthrough in limb ischemia: the power of genetically modified MSCs Researchers have developed a strategy using SDF1α-engineered mesenchymal stem cells (SDF1α-eMSCs) to simultaneously regenerate blood vessels and skeletal muscles in limbs experiencing ischemia. In a mouse model of hindlimb ischemia, intramuscular injection of SDF1α-eMSCs improved blood perfusion, preserved limb function, and prevented amputation. In vitro result showed that SDF1α-eMSCs not only amplified the angiogenic potential and survival of endothelial cells, but also demonstrated enhanced survival and migration abilities in myoblasts. The study suggests that SDF1α-eMSCs can be considered an effective therapeutic strategy for limb salvage in patients with critical limb ischemia.

Implantable medical devices (IMDs) enable patients to monitor their health anytime and receive treatment anywhere. However, due to the limited capacity of a battery, their functionalities are restricted, and the devices may not achieve their intended potential fully. The most promising way to solve this limited capacity problem is wireless power transfer (WPT) technology. In this study, a WPT based implantable electrocardiogram (ECG) monitoring device that continuously records ECG data has been proposed, and its effectiveness is verified through an animal experiment using a rat model. Our proposed device is designed to be of size 24 × 27 × 8 mm, and it is small enough to be implanted in the rat. The device transmits data continuously using a low power Bluetooth Low Energy (BLE) communication technology. To charge the battery wirelessly, transmitting (Tx) and receiving (Rx) antennas were designed and fabricated. The animal experiment results clearly showed that our WPT system enables the device to monitor the ECG of a heart in various conditions continuously, while transmitting all ECG data in real-time.

Background Myocardial infarction (MI), a representative form of ischemic heart disease, remains a huge burden worldwide. This study aimed to explore whether extracellular vesicles (EVs) secreted from hyaluronic acid (HA)-primed induced mesenchymal stem cells (HA-iMSC-EVs) could enhance the cardiac repair after MI. Results HA-iMSC-EVs showed typical characteristics for EVs such as morphology, size, and marker proteins expression. Compared with iMSC-EVs, HA-iMSC-EVs showed enhanced tube formation and survival against oxidative stress in endothelial cells, while reduced reactive oxygen species (ROS) generation in cardiomyocytes. In THP-1 macrophages, both types of EVs markedly reduced the expression of pro-inflammatory signaling players, whereas HA-iMSC-EVs were more potent in augmenting anti-inflammatory markers. A significant decrease of inflammasome proteins was observed in HA-iMSC-EV-treated THP-1. Further, phospho-SMAD2 as well as fibrosis markers in TGF-β1-stimulated cardiomyocytes were reduced in HA-iMSC-EVs treatment. Proteomic data showed that HA-iMSC-EVs were enriched with multiple pathways including immunity, extracellular matrix organization, angiogenesis, and cell cycle. The localization of HA-iMSC-EVs in myocardium was confirmed after delivery by either intravenous or intramyocardial route, with the latter increased intensity. Echocardiography revealed that intramyocardial HA-iMSC-EVs injections improved cardiac function and reduced adverse cardiac remodeling and necrotic size in MI heart. Histologically, MI hearts receiving HA-iMSC-EVs had increased capillary density and viable myocardium, while showed reduced fibrosis. Conclusions Our results suggest that HA-iMSC-EVs improve cardiac function by augmenting vessel growth, while reducing ROS generation, inflammation, and fibrosis in MI heart. Graphical Abstract