Abnormal circadian rhythms exacerbate dilated cardiomyopathy by reducing the ventricular mechanical strength.

AIMS: Dilated cardiomyopathy (DCM) has etiological and pathophysiological heterogeneity. Abnormal circadian rhythm (ACR) is related to the development of DCM in animal models, but exploration based on clinical samples is lacking. Sleep apnea (SA) is the most common disease related to ACR, and we chose SA as the study object to explore ACR-DCM. METHODS AND RESULTS: We included a derivation cohort (n =105) and a validation cohort (n = 65). DCM patients were divided into SA and without SA group. RT-qPCR was used to determine the change of rhythm gene expression pattern of heart samples from different timepoints. We used single-nucleus RNA sequencing (snRNA-seq) to explore the abnormal transcriptional patterns in the ACR group, and we verified the findings by pathological staining, atomic force microscopy (AFM), and Rev-erbα/ß knockout (KO) mice analysis. DCM patients with SA showed decreased amplitude of rhythm gene expression. SA group showed more severe dilation of left heart chambers. From snRNA-seq, ACR-DCM lost the morning transcriptional patterns, detailly, actin cytoskeleton organization of cardiomyocytes (CMs) disrupted and hypertrophy aggravated, and the proportion of activated fibroblasts (Fibs) decreased with the reduction of fibrotic area ratio. The results of pathological staining, mechanical experiments, and transcriptional feature of Rev-erbα/ß KO mice supported the above findings. CONCLUSION: Compared with the non-SA group, left ventricular (LV) wall dilation was more severe and the structural strength was lower in DCM patients with SA, and phenotypic changes in CM and Fib were involved in this process. ACR-DCM was histopathologically characterized by a structurally weak ventricular wall.

Estrogen Oppositely Regulates Pulmonary Hypertension via METTL3/PFKFB3 Under Normoxia and Hypoxia.

Despite extensive investigation into estrogen's role in pulmonary hypertension (PH) development, its effects-whether beneficial or detrimental-remains contentious. This study aimed to elucidate estrogen's potential role in PH under normoxic and hypoxic conditions. Utilizing norfenfluramine- and hypoxia-induced rat models of PH, the study evaluated the impact of 17ß-estradiol (E2) on PH progression. E2 promoted PH development under normoxia while providing protection under hypoxia. Mechanistically, under normoxia, E2 upregulated methyltransferase-like 3 (METTL3) gene transcription and protein via an estrogen response element-dependent pathway, which in turn elevated the m6A methylation and translational efficiency of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3) mRNA, leading to increased PFKFB3 protein levels and enhanced proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Conversely, under hypoxia, E2 downregulated METTL3 transcription through a hypoxia response element-dependent mechanism, driven by elevated hypoxia-induced factor 1α (HIF-1α) levels, resulting in reduced PFKFB3 protein expression and diminished PASMCs proliferation and migration. Both METTL3 and PFKFB3 proteins are upregulated in the pulmonary arteries of patients with PAH. Collectively, these findings suggest that E2 exerts differential effects on PH progression via dual regulation of the METTL3/PFKFB3 protein under normoxic and hypoxic conditions, positioning the METTL3/PFKFB3 protein as a potential therapeutic target for PH treatment.

Cardiovascular adaptations and pathological changes induced by spaceflight: from cellular mechanisms to organ-level impacts.

The advancement in extraterrestrial exploration has highlighted the crucial need for studying how the human cardiovascular system adapts to space conditions. Human development occurs under the influence of gravity, shielded from space radiation by Earth's magnetic field, and within an environment characterized by 24-hour day-night cycles resulting from Earth's rotation, thus deviating from these conditions necessitates adaptive responses for survival. With upcoming manned lunar and Martian missions approaching rapidly, it is essential to understand the impact of various stressors induced by outer-space environments on cardiovascular health. This comprehensive review integrates insights from both actual space missions and simulated experiments on Earth, to analyze how microgravity, space radiation, and disrupted circadian affect cardiovascular well-being. Prolonged exposure to microgravity induces myocardial atrophy and endothelial dysfunction, which may be exacerbated by space radiation. Mitochondrial dysfunction and oxidative stress emerge as key underlying mechanisms along with disturbances in ion channel perturbations, cytoskeletal damage, and myofibril changes. Disruptions in circadian rhythms caused by factors such as microgravity, light exposure, and irregular work schedules, could further exacerbate cardiovascular issues. However, current research tends to predominantly focus on disruptions in the core clock gene, overlooking the multifactorial nature of circadian rhythm disturbances in space. Future space missions should prioritize targeted prevention strategies and early detection methods for identifying cardiovascular risks, to preserve astronaut health and ensure mission success.

o8G-miR-6513-5p/BCL2L13 Axis Regulates Mitophagy during Oxidative Stress in the Human Saphenous Vein Endothelial Cells.

Venous graft decay (VGD) occurs in coronary artery bypass grafting (CABG), and ischemia-reperfusion oxidative stress injury during the operation is involved in VGD. To explore the cellular phenotypic changes during this process, a stable oxidative stress model of human saphenous vein endothelial cells (HSVECs) is constructed. Through proteomics and cell experiments, it is found that the expression of BCL2L13 is upregulated during oxidative stress of HSVECs, and BCL2L13 regulated mitophagy through receptor-mediated interaction with LC3 and plays a role in cell protection. During oxidative stress, intracellular o8G epigenetic modification occurs, and the o8G modification of miR-6513-5p causes this molecule to lose its targeted regulation of BCL2L13 and participates in the upregulation of BCL2L13. There is a regulatory pathway of o8G modification-BCL2L13-LC3-mitophagy when oxidative stress occurs in HSVECs.

Strategies for arterial graft optimization at the single-cell level.

Common arterial grafts used in coronary artery bypass grafting include internal thoracic artery (ITA), radial artery (RA) and right gastroepiploic artery (RGA) grafts; of these, the ITA has the best clinical outcome. Here, by analyzing the single-cell transcriptome of different arterial grafts, we suggest optimization strategies for the RA and RGA based on the ITA as a reference. Compared with the ITA, the RA had more lipid-handling-related CD36+ endothelial cells. Vascular smooth muscle cells from the RGA were more susceptible to spasm, followed by those from the RA; comparison with the ITA suggested that potassium channel openers may counteract vasospasm. Fibroblasts from the RA and RGA highly expressed GDF10 and CREB5, respectively; both GDF10 and CREB5 are associated with extracellular matrix deposition. Cell-cell communication analysis revealed high levels of macrophage migration inhibitory factor signaling in the RA. Administration of macrophage migration inhibitory factor inhibitor to mice with partial carotid artery ligation blocked neointimal hyperplasia induced by disturbed flow. Modulation of identified targets may have protective effects on arterial grafts.

Progress of organoid platform in cardiovascular research.

Cardiovascular disease is a significant cause of death in humans. Various models are necessary for the study of cardiovascular diseases, but once cellular and animal models have some defects, such as insufficient fidelity. As a new technology, organoid has certain advantages and has been used in many applications in the study of cardiovascular diseases. This article aims to summarize the application of organoid platforms in cardiovascular diseases, including organoid construction schemes, modeling, and application of cardiovascular organoids. Advances in cardiovascular organoid research have provided many models for different cardiovascular diseases in a variety of areas, including myocardium, blood vessels, and valves. Physiological and pathological models of different diseases, drug research models, and methods for evaluating and promoting the maturation of different kinds of organ tissues are provided for various cardiovascular diseases, including cardiomyopathy, myocardial infarction, and atherosclerosis. This article provides a comprehensive overview of the latest research progress in cardiovascular organ tissues, including construction protocols for cardiovascular organoid tissues and their evaluation system, different types of disease models, and applications of cardiovascular organoid models in various studies. The problems and possible solutions in organoid development are summarized.

Suppression of RCAN1 alleviated lipid accumulation and mitochondrial fission in diabetic cardiomyopathy.

BACKGROUND: Although metabolic disturbance is a characteristic of diabetic cardiomyopathy (DbCM), the detailed pathogenesis of DbCM remains unknown. METHODS: We used a heart transplantation (HTx) cohort to explore the effect of diabetes mellitus on heart failure (HF) progression dependent of myocardium. Microscopic and ultramicroscopic pathology were used to depict the pathological features of human myocardium of DbCM. We performed targeted metabolomics to characterize the metabolic phenotype of human DbCM. Transcriptomics data were analyzed and weighted gene co-expression network analysis was performed to explore the potential upstream regulator for metabolic remodeling of DbCM. In vivo and in vitro experiments were further conducted to demonstrate the therapeutic effects and molecular mechanisms. RESULTS: DbCM promoted the progression of HF and increased death or HF-rehospitalization after HTx. Lipid accumulation and mitochondrial fission were the obvious pathological features of DbCM myocardium. The concentrations of C14:0-CoA and C16:1-CoA were significantly increased in the myocardium, and they were positively correlated with the accelerated HF progression and RCAN1 expression in DbCM patients. Knockdown of RCAN1 improved cardiac dysfunction, lipid accumulation, and mitochondrial fission in db/db mice. In vitro studies showed that RCAN1 knockdown improved mitochondrial dysfunction in DbCM cardiomyocytes via the RCAN1-p-Drp1 Ser616 axis. CONCLUSIONS: Diabetes is associated with faster progression of HF and causes poor prognosis after HTx, accompanied by metabolic remodeling in the myocardium. Accumulation of long chain acyl-CoA in the myocardium is the metabolic hallmark of human DbCM and is associated with more rapid disease progression for DbCM patients. Upregulation of RCAN1 in the myocardium is associated with the metabolic signatures of DbCM and RCAN1 is a potential therapeutic target for DbCM.

Single-Cell RNA Sequencing Deconstructs the Distribution of Immune Cells Within Abdominal Aortic Aneurysms in Mice.

BACKGROUND: Inflammation is a key component in the development of abdominal aortic aneurysm (AAA), yet insights into the roles of immune cells and their interactions in this process are limited. METHODS: Using single-cell RNA transcriptomic analysis, we deconstructed the CD45+ cell population in elastase-induced murine AAA at the single-cell level. We isolated each group of immune cells from murine AAA tissue at different time points and divided them into several subtypes, listed the remarkable differentially expressed genes, explored the developmental trajectories of immune cells, and demonstrated the interactions among them. RESULTS: Our findings reveal significant differences in several immune cell subsets, including macrophages, dendritic cells, and T cells, within the AAA microenvironment compared with the normal aorta. Especially, conventional dendritic cell type 1 exclusively existed in the AAA tissue rather than the normal aortas. Via CellChat analysis, we identified several intercellular communication pathways like visfatin, which targets monocyte differentiation and neutrophil extracellular trap-mediated interaction between neutrophils and dendritic cells, which might contribute to AAA development. Some of these pathways were validated in human AAA. CONCLUSIONS: Despite the absence of external pathogenic stimuli, AAA tissues develop a complex inflammatory microenvironment involving numerous immune cells. In-depth studies of the inflammatory network shall provide new strategies for patients with AAA.

On-surface conversion reaction realizes advanced red phosphorus/carbon anode for high-performance lithium-ion batteries.

Red phosphorus (RP), the one of the most prospective anodes in lithium-ion batteries (LIBs), has been severely limited due to the intrinsic defects of massive volume expansion and low electronic conductivity. The vaporization-condensation-conversion (VCC), which confines RP nanoparticles into carbon host, is the most widely used method to address the above drawbacks and prepare RP/C nanostructured composites. However, the volume effect-dominated RP caused by the inevitably deposition of RP vapor on the surface of carbon material suffers from the massive volume change and unstable solid electrolyte interface (SEI) film. Herein, we propose a simple interfacial modification method to eliminate the superficial RP and yield stable surface composed of ion-conducting Li3PS4 solid electrolyte, endowing RP/AC composites excellent cycling performance and ultrafast reaction kinetics. Therefore, the RP/AC@S composites exhibit 926 mAh/g after 320 cycles at 0.2 A/g (running over 181 days), with 81.6 % capacity retention and a corresponding capacity decay rate of as low as 0.059 %. When coupled with LiFePO4 cathode, the full cells present superior cycling performance (62.1 mAh/g after 500 cycles at 1 A/g) and excellent rate capability (81.1 mAh/g at 1.0 A/g).

Genetic variations in PTPN11 lead to a recurrent left ventricular outflow tract obstruction phenotype in childhood hypertrophic cardiomyopathy.

OBJECTIVE: Left ventricular septal myotomy provides a favorable prognosis for children with hypertrophic obstructive cardiomyopathy (HOCM). However, some children still suffer from recurrent left ventricular outflow tract obstruction (LVOTO) after surgery. Poor prognosis exists for HOCM caused by PTPN11 mutation. Therefore, the aim of this study was to determine the clinical features of recurrent obstruction in children with HOCM caused by pathogenic mutations in the PTPN11 gene. METHODS: Fifty-six children who were diagnosed with HOCM underwent septal myectomies. Whole-exome sequencing of 49 pediatric cardiomyopathy-associated genes (including PTPN11) was performed. We performed hematoxylin-eosin, Masson, and wheat germ agglutinin staining of those tissues positive and negative for PTPN11. RESULTS: Whole-exome sequencing results showed 11 children with the PTPN11 mutation (19.6%). In long-term follow-up (median 37 months, maximum 9 years), children with the PTPN11 mutation had 6 (54.5%) recurrent LVOTOs compared with other groups (P = .015) but similar survival rates (P = .514). The mean postoperative time to recurrent obstruction was 22 ± 7 months. Children with PTPN11 mutation were 9-fold more likely to experience the risk associated with recurrent obstruction (95% confidence interval, 1.77-45.81, P < .001). Hematoxylin-eosin, Masson, and wheat germ agglutinin staining also revealed more cardiomyocyte hypertrophy in tissues with the PTPN11 mutation. CONCLUSIONS: Children with PTPN11 mutation-associated hypertrophic cardiomyopathy have a greater risk of recurrent LVOTO.

PICALM Regulating the Generation of Amyloid ß-Peptide to Promote Anthracycline-Induced Cardiotoxicity.

Anthracyclines are chemotherapeutic drugs used to treat solid and hematologic malignancies. However, life-threatening cardiotoxicity, with cardiac dilation and heart failure, is a drawback. A combination of in vivo for single cell/nucleus RNA sequencing and in vitro approaches is used to elucidate the underlying mechanism. Genetic depletion and pharmacological blocking peptides on phosphatidylinositol binding clathrin assembly (PICALM) are used to evaluate the role of PICALM in doxorubicin-induced cardiotoxicity in vivo. Human heart tissue samples are used for verification. Patients with end-stage heart failure and chemotherapy-induced cardiotoxicity have thinner cell membranes compared to healthy controls do. Using the doxorubicin-induced cardiotoxicity mice model, it is possible to replicate the corresponding phenotype in patients. Cellular changes in doxorubicin-induced cardiotoxicity in mice, especially in cardiomyocytes, are identified using single cell/nucleus RNA sequencing. Picalm expression is upregulated only in cardiomyocytes with doxorubicin-induced cardiotoxicity. Amyloid ß-peptide production is also increased after doxorubicin treatment, which leads to a greater increase in the membrane permeability of cardiomyocytes. Genetic depletion and pharmacological blocking peptides on Picalm reduce the generation of amyloid ß-peptide. This alleviates the doxorubicin-induced cardiotoxicity in vitro and in vivo. In human heart tissue samples of patients with chemotherapy-induced cardiotoxicity, PICALM, and amyloid ß-peptide are elevated as well.

New insights gained from cellular landscape changes in myocarditis and inflammatory cardiomyopathy.

Advances in the etiological classification of myocarditis and inflammatory cardiomyopathy (ICM) have reached a consensus. However, the mechanism of myocarditis/ICM remains unclear, which affects the development of treatment and the improvement of outcome. Cellular transcription and metabolic reprogramming, and the interactions between cardiomyocytes and non-cardiomyocytes, such as the immune cells, contribute to the process of myocarditis/ICM. Recent efforts have been made by multi-omics techniques, particularly in single-cell RNA sequencing, to gain a better understanding of the cellular landscape alteration occurring in disease during the progression. This article aims to provide a comprehensive overview of the latest studies in myocarditis/ICM, particularly as revealed by single-cell sequencing.

Left ventricular posterior wall hypertrophy leads to poor prognosis of hypertrophic obstructive cardiomyopathy in children - a cohort study.

OBJECTIVE: The modified Morrow operation for hypertrophic obstructive cardiomyopathy (HOCM) in children has a favorable outcome, but some children still have a poor prognosis after the procedure. In this study, we aimed to investigate the application of cardiac computed tomography (CCT) to construct a three-dimensional(3D) model of the left ventricle (LV) and analyze the association between hypertrophy in different parts of the LV and poor prognosis. METHODS: We retrospectively analyzed 57 children with HOCM from April 2015 to October 2022, among whom 16 underwent preoperative CCT examination. All children underwent the modified Morrow surgery in our center. We defined heart failure (HF), malignant ventricular arrhythmia, and recurrent left ventricular outflow tract obstruction (LVOTO) as adverse events. We performed a retrospective Cox analysis and conducted genetic testing. A 3D model of the LV was built through the standard 17-segment method and analyzing the high-risk factors. RESULTS: 17 (29.8%) had adverse events during follow-up. Multivariate Cox analysis revealed that genetic mutation (HR:5.634, 95%CI:1.663-19.086, P=0.005), Noonan syndrome (HR:3.770, 95%CI:1.245-11.419, P=0.019), preoperational systolic anterior motion (SAM)(HR:4.596, 95%CI:1.532-13.792, P=0.007)and mid-ventricular obstruction (HR:4.763, 95%CI:1.538-14.754, P=0.007) were high-risk factors, suggesting that the degree of hypertrophy in the left ventricle is associated with poor prognosis. By analyzing the CCT with 3D model, children with poor prognosis have more hypertrophy in basal-inferior (P=0.014), mid-inferoseptal(P=0.044), mid-inferior(P=0.017). It suggests that a more hypertrophied posterior left ventricular wall portends a worse prognosis. CONCLUSION: Even after modified Morrow surgery, the prognostic impact of genetic mutation remains significant. Moreover, the degree of hypertrophy of the posterior wall in the LV was also related to the postoperative prognosis through CCT combined with 3D technology. It provides surgeons guiding to evaluate the overall prognosis and the treatment plan before surgery.

Evolution of the network structure and voltage loss of anode electrode with the polymeric dispersion in PEM water electrolyzer.

Exploring the intrinsic relationship between the network structure and the performance of catalyst layer (CL) by rational design its structure is of paramount importance for proton exchange membrane (PEM) electrolyzers. This study reveals the relative effect of polymeric dispersion evolution on oxygen evolution reaction (OER) performance and cell voltage loss and linked to CL network structure. The results show that although the dispersed particle size of the ionomer and ink increases with increasing the solubility parameter (δ) difference between the mixed solvent and the ionomer, MeOH-cat (ink from MeOH aqueous solution) has the largest ionomer and ink particle size resulting in the poorest stability, but has comparable OER overpotential to that of IPA-cat (249 mV@10 mA cm-2), which has the smallest dispersed size. While at 100 mA cm-2, the overpotential of the ink rises as the particle size increases, suggesting that the electrode structure becomes more influential as the current density increases. Quantitatively analyzed the electrolyzers' voltage losses and determined that the CL from MeOH-cat has the lowest kinetic overpotential. However, its performance is the worst because of the insufficient network structure of CL, resulting in an output of 1.96 V at 1.5 A cm-2. Comparatively, the CL from IPA-cat has the highest kinetic overpotential yet can achieve the greatest performance of 1.76 V at 2 A cm-2 due to its homogeneous network structure and optimal mass transport. Furthermore, the performance variation becomes more pronounced as current density rises. Hence, this study highlights the significant impact of CL structure on electrolyzer's performance. To improve performance in PEM water electrolysis technology, especially for large work current density, it is crucial to enhance the CL's network structure.

Overexpression of ATP5F1A in Cardiomyocytes Promotes Cardiac Reverse Remodeling.

BACKGROUND: The mechanism of cardiac reverse remodeling (CRR) mediated by the left ventricular assist device remains unclear. This study aims to identify the specific cell type responsible for CRR and develop the therapeutic target that promotes CRR. METHODS: The nuclei were extracted from the left ventricular tissue of 4 normal controls, 4 CRR patients, and 4 no cardiac reverse remodeling patients and then subjected to single-nucleus RNA sequencing for identifying key cell types responsible for CRR. Gene overexpression in transverse aortic constriction and dilated cardiomyopathy heart failure mouse model (C57BL/6J background) and pathological staining were performed to validate the results of single-nucleus RNA sequencing. RESULTS: Ten cell types were identified among 126 156 nuclei. Cardiomyocytes in CRR patients expressed higher levels of ATP5F1A than the other 2 groups. The macrophages in CRR patients expressed more anti-inflammatory genes and functioned in angiogenesis. Endothelial cells that elevated in no cardiac reverse remodeling patients were involved in the inflammatory response. Echocardiography showed that overexpressing ATP5F1A through cardiomyocyte-specific adeno-associated virus 9 demonstrated an ability to improve heart function and morphology. Pathological staining showed that overexpressing ATP5F1A could reduce fibrosis and cardiomyocyte size in the heart failure mouse model. CONCLUSIONS: The present results of single-nucleus RNA sequencing and heart failure mouse model indicated that ATP5F1A could mediate CRR and supported the development of therapeutics for overexpressing ATP5F1A in promoting CRR.

Inhibition of fatty acid uptake by TGR5 prevents diabetic cardiomyopathy.

Diabetic cardiomyopathy is characterized by myocardial lipid accumulation and cardiac dysfunction. Bile acid metabolism is known to play a crucial role in cardiovascular and metabolic diseases. Takeda G-protein-coupled receptor 5 (TGR5), a major bile acid receptor, has been implicated in metabolic regulation and myocardial protection. However, the precise involvement of the bile acid-TGR5 pathway in maintaining cardiometabolic homeostasis remains unclear. Here we show decreased plasma bile acid levels in both male and female participants with diabetic myocardial injury. Additionally, we observe increased myocardial lipid accumulation and cardiac dysfunction in cardiomyocyte-specific TGR5-deleted mice (both male and female) subjected to a high-fat diet and streptozotocin treatment or bred on the diabetic db/db genetic background. Further investigation reveals that TGR5 deletion enhances cardiac fatty acid uptake, resulting in lipid accumulation. Mechanistically, TGR5 deletion promotes localization of CD36 on the plasma membrane through the upregulation of CD36 palmitoylation mediated by the palmitoyl acyltransferase DHHC4. Our findings indicate that the TGR5-DHHC4 pathway regulates cardiac fatty acid uptake, which highlights the therapeutic potential of targeting TGR5 in the management of diabetic cardiomyopathy.

Advances in preclinical surgical therapy of cardiovascular diseases.

Cardiovascular disease is the most common cause of death worldwide, resulting in millions of deaths annually. Currently, there are still some deficiencies in the treatment of cardiovascular diseases. Innovative surgical treatments are currently being developed and tested in response to this situation. Large animal models, which are similar to humans in terms of anatomy, physiology, and genetics, play a crucial role in connecting basic research and clinical applications. This article reviews recent preclinical studies and the latest clinical advancements in cardiovascular disease based on large animal models, with a focus on targeted delivery, neural regulation, cardiac remodeling, and hemodynamic regulation. It provides new perspectives and ideas for clinical translation and offers new methods for clinical treatment.

The pig as an optimal animal model for cardiovascular research.

Cardiovascular disease is a worldwide health problem and a leading cause of morbidity and mortality. Preclinical cardiovascular research using animals is needed to explore potential targets and therapeutic options. Compared with rodents, pigs have many advantages, with their anatomy, physiology, metabolism and immune system being more similar to humans. Here we present an overview of the available pig models for cardiovascular diseases, discuss their advantages over other models and propose the concept of standardized models to improve translation to the clinical setting and control research costs.

Single-Cell Transcriptomic Analysis Reveals Myocardial Fibrosis Mechanism of Doxorubicin-Induced Cardiotoxicity.

Myocardial fibrosis is a pathological feature of doxorubicin-induced chronic cardiotoxicity that severely affects the prognosis of oncology patients. However, the specific cellular and molecular mediators driving doxorubicin-induced cardiac fibrosis, and the relative impact of different cell populations on cardiac fibrosis, remain unclear.This study aimed to explore the mechanism of doxorubicin-induced cardiotoxicity and myocardial fibrosis and to find potential therapeutic targets. Single-cell RNA sequencing was used to analyze the transcriptome of non-cardiomyocytes from normal and doxorubicin-induced chronic cardiotoxicity in mouse model heart tissue.We established a mouse model of doxorubicin-induced cardiotoxicity with a well-defined fibrotic phenotype. Analysis of single-cell sequencing results showed that fibroblasts were the major origin of extracellular matrix in doxorubicin-induced myocardial fibrosis. Further resolution of fibroblast subclusters showed that resting fibroblasts were converted to matrifibrocytes and then to myofibroblasts to participate in the myocardial remodeling process in response to doxorubicin treatment. Ctsb expression was significantly upregulated in fibroblasts after doxorubicin-induced.This study provides a comprehensive map of the non-cardiomyocyte landscape at high resolution, reveals multiple cell populations contributing to pathological remodeling of the cardiac extracellular matrix, and identifies major cellular sources of myofibroblasts and dynamic gene-expression changes in fibroblast activation. Finally, we used this strategy to detect potential therapeutic targets and identified Ctsb as a specific target for fibroblasts in doxorubicin-induced myocardial fibrosis.

Isolated Perfused Hearts for Cardiovascular Research: An Old Dog with New Tricks.

In modern cardiovascular research, isolated perfused hearts have become cost-effective and highly reproducible tools to investigate the mechanisms of cardiovascular diseases (CVDs). Since they were first introduced in the nineteenth century, isolated perfused hearts have been extensively used for testing novel therapies, elucidating cardiac metabolic and electrophysiological activities, and modeling CVDs, including ischemic heart disease, arrhythmias, and hyperacute rejection. In recent years, ex vivo heart perfusion (EVHP) has shown potential in cardiac transplantation by allowing prolonged preservation and reconditioning of donor hearts. In this review, we summarize the evolution of the isolated perfused heart technique and its applications in cardiovascular research to help researchers comprehensively understand the capabilities of isolated heart models and provide guidance to use them to investigate various CVDs.