His bundle pacing combined with atrioventricular node ablation for atrial fibrillation: a systematic review and meta-analysis.

INTRODUCTION AND OBJECTIVE: His bundle pacing (HBP) could replace failed biventricular pacing (BVP) in guidelines (IIa Indication), but the high capture thresholds and backup lead pacing requirements limit its development. We assessed the efficacy and safety of HBP combined with atrioventricular node ablation (AVNA) for atrial fibrillation (AF) and compared with BVP and left bundle branch pacing (LBBP). METHODS: We reviewed PubMed, Embase, Web of Science, and Cochrane Library databases on left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) score, QRS duration (QRSd), and pacing threshold. RESULTS: Thirteen studies included 1115 patients (639 with HBP, 338 with BVP, and 221 with LBBP). Compared with baseline, HBP improved LVEF (mean difference [MD]: 9.24 [6.10, 12.37]; p < 0.01), reduced NYHA score (MD: -1.12 [-1.34, -0.91]; p < 0.01), increased QRSd (MD: 10.08 [4.45, 15.70]; p < 0.01), and rose pacing threshold (MD: 0.16 [0.05, 0.26]; p < 0.01). HBP had comparable efficacy to BVP and LBBP and lower QRSd (p < 0.05). HBP had a lower success rate (85.97%) and more complications (16.1%). CONCLUSION: HBP combined with AVNA is effective for AF, despite having a lower success rate and more complications. Further trials are required to determine whether HBP is superior to BVP and LBBP.

Exploring the impact of metabolites function on heart failure and coronary heart disease: insights from a Mendelian randomization (MR) study.

BACKGROUND: Heart failure (HF) and coronary heart disease (CHD) are major causes of morbidity and mortality worldwide. While traditional risk factors such as hypertension, diabetes, and smoking have been extensively studied, the role of metabolite functions in the development of these cardiovascular conditions has been less explored. This study employed a Mendelian randomization (MR) approach to investigate the impact of metabolite functions on HF and CHD. METHODS: To assess the causal impacts of specific metabolite risk factors on HF and CHD, this study utilized genetic variants associated with these factors as instrumental variables. Comprehensive genetic and phenotypic data from diverse cohorts, including genome-wide association studies (GWAS) and cardiovascular disease registries, were incorporated into the research. RESULTS: Our results encompass 61 metabolic cell phenotypes, with ten providing strong evidence of the influence of metabolite functions on the occurrence of HF and CHD. We found that elevated levels of erucate (22:1n9), lower levels of α-tocopherol, an imbalanced citrulline-to-ornithine ratio, elevated γ-glutamyl glycine levels, and elevated 7-methylguanine levels independently increased the risk of these cardiovascular conditions. These findings were consistent across different populations and robust to sensitivity analyses. CONCLUSION: This MR study provides valuable insights into the influence of metabolite functions on HF and CHD. However, further investigation is needed to fully understand the precise mechanisms by which these metabolite factors contribute to the onset of these conditions. Such research could pave the way for the development of targeted therapeutic strategies.

The mechanism and therapeutic strategies in doxorubicin-induced cardiotoxicity: Role of programmed cell death.

Doxorubicin (DOX) is the most commonly used anthracycline anticancer agent, while its clinical utility is limited by harmful side effects like cardiotoxicity. Numerous studies have elucidated that programmed cell death plays a significant role in DOX-induced cardiotoxicity (DIC). This review summarizes several kinds of programmed cell death, including apoptosis, pyroptosis, necroptosis, autophagy, and ferroptosis. Furthermore, oxidative stress, inflammation, and mitochondrial dysfunction are also important factors in the molecular mechanisms of DIC. Besides, a comprehensive understanding of specific signal pathways of DIC can be helpful to its treatment. Therefore, the related signal pathways are elucidated in this review, including sirtuin deacetylase (silent information regulator 2 [Sir2]) 1 (SIRT1)/nuclear factor erythroid 2-related factor 2, SIRT1/Klotho, SIRT1/Recombinant Sestrin 2, adenosine monophosphate-activated protein kinase, AKT, and peroxisome proliferator-activated receptor. Heat shock proteins function as chaperones, which play an important role in various stressful situations, especially in the heart. Thus, some of heat shock proteins involved in DIC are also included. Hence, the last part of this review focuses on the therapeutic research based on the mechanisms above.

Causal roles of immune cells in cardiovascular diseases: A Mendelian randomization (MR) study.

Background: Despite being a major global cause of mortality, the exact underlying mechanisms of cardiovascular diseases (CVDs) remain uncertain. This study aimed to elucidate the possible pathological connection between circulating activated immune cell types and the advancement of CVD. Methods: A two-sample Mendelian randomization analysis was performed on publicly available genetic databases to examine the potential causal relationships among 731 immune phenotypes and CVD risks. The study focused on four distinct immune signatures: relative cell counts (RC), absolute cell counts (AC), morphological parameters (MP), and median fluorescence intensities (MFI). A sensitivity analysis was performed to assess the findings' consistency, robustness, and potential pleiotropic effects. Results: Significant associations between CVD and various immunophenotypes were observed in this study. Specifically, two phenotypes exhibited protective effects against CVD. The odds ratio (OR) for activated and secretory CD4+ regulatory T-cells (Tregs) was 0.757 [95% confidence interval (CI): 0.628-0.913; p = 0.004], whereas that for B-cell activating factor receptor on IgD-CD38+ memory B-cells was 0.654 (95% CI: 0.468-0.915; p = 0.013). Conversely, three major immunophenotypes were linked to heightened risks of CVD: CD80 on myeloid dendritic cells (OR: 1.181; 95% CI: 1.015-1.376; p = 0.032), the proportion of CD28+ CD45RA+ CD8+ T-cells in total T-cell population (OR: 1.064; 95% CI: 1.002-1.128; p = 0.041), and the proportion of CD28-CD45RA+ CD8+ T-cells in total T-cell population (OR: 1.005; 95% CI: 1.000-1.011; p = 0.045). Conclusion: This study underscores significant correlations between specific immune phenotypes and the risks associated with CVD onset, thus providing valuable perspectives for forthcoming clinical inquiries.

Observational and genetic association of non-alcoholic fatty liver disease and calcific aortic valve disease.

Background: Non-alcoholic fatty liver disease (NAFLD) has emerged as a predominant driver of chronic liver disease globally and is associated with increased cardiovascular disease morbidity and mortality. However, the association between NAFLD and calcific aortic valve disease remains unclear. We aimed to prospectively investigate the association between NAFLD and incident aortic valve calcification (AVC), as well as its genetic relationship with incident calcific aortic valve stenosis (CAVS). Methods: A post hoc analysis was conducted on 4226 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) database. We employed the adjusted Cox models to assess the observational association between NAFLD and incident AVC. Additionally, we conducted two-sample Mendelian randomization (MR) analyses to investigate the genetic association between genetically predicted NAFLD and calcific aortic valve stenosis (CAVS), a severe form of CAVD. We repeated the MR analyses by excluding NAFLD susceptibility genes linked to impaired very low-density lipoprotein (VLDL) secretion. Results: After adjustment for potential risk factors, participants with NAFLD had a hazard ratio of 1.58 (95% CI: 1.03-2.43) for incident AVC compared to those without NAFLD. After excluding genes associated with impaired VLDL secretion, the MR analyses consistently showed the significant associations between genetically predicted NAFLD and CAVS for 3 traits: chronic elevation of alanine aminotransferase (odds ratio = 1.13 [95% CI: 1.01-1.25]), imaging-based NAFLD (odds ratio = 2.81 [95% CI: 1.66-4.76]), and biopsy-confirmed NAFLD (odds ratio = 1.12 [95% CI: 1.01-1.24]). However, the association became non-significant when considering all NAFLD susceptibility genes. Conclusions: NAFLD was independently associated with an elevated risk of incident AVC. Genetically predicted NAFLD was also associated with CAVS after excluding genetic variants related to impaired VLDL secretion.

Prevotella copri promotes vascular calcification via lipopolysaccharide through activation of NF-κB signaling pathway.

Emerging evidence indicates that alteration of gut microbiota plays an important role in chronic kidney disease (CKD)-related vascular calcification (VC). We aimed to investigate the specific gut microbiota and the underlying mechanism involved in CKD-VC. We identified an increased abundance of Prevotella copri (P. copri) in the feces of CKD rats (induced by using 5/6 nephrectomy followed by a high calcium and phosphate diet) with aortic calcification via amplicon sequencing of 16S rRNA genes. In patients with CKD, we further confirmed a positive correlation between abundance of P. copri and aortic calcification scores. Moreover, oral administration of live P. copri aggravated CKD-related VC and osteogenic differentiation of vascular smooth muscle cells in vivo, accompanied by intestinal destruction, enhanced expression of Toll-like receptor-4 (TLR4), and elevated lipopolysaccharide (LPS) levels. In vitro and ex vivo experiments consistently demonstrated that P. copri-derived LPS (Pc-LPS) accelerated high phosphate-induced VC and VSMC osteogenic differentiation. Mechanistically, Pc-LPS bound to TLR4, then activated the nuclear factor κB (NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome signals during VC. Inhibition of NF-κB reduced NLRP3 inflammasome and attenuated Pc-LPS-induced VSMC calcification. Our study clarifies a novel role of P. copri in CKD-related VC, by the mechanisms involving increased inflammation-regulating metabolites including Pc-LPS, and activation of the NF-κB/NLRP3 signaling pathway. These findings highlight P. copri and its-derived LPS as potential therapeutic targets for VC in CKD.

The activation of LBH-CRYAB signaling promotes cardiac protection against I/R injury by inhibiting apoptosis and ferroptosis.

Myocardial ischemia-reperfusion (I/R) injury stands out among cardiovascular diseases, and current treatments are considered unsatisfactory. For cardiomyocytes (CMs) in ischemic tissues, the upregulation of Limb-bud and Heart (LBH) and αB-crystallin (CRYAB) and their subsequent downregulation in the context of cardiac fibrosis have been verified in our previous research. Here, we focused on the effects and mechanisms of activated LBH-CRYAB signaling on damaged CMs during I/R injury, and confirmed the occurrence of mitochondrial apoptosis and ferroptosis during I/R injury. The application of inhibitors, ectopic expression vectors, and knockout mouse models uniformly verified the role of LBH in alleviating both apoptosis and ferroptosis of CMs. p53 was identified as a mutual downstream effector for both LBH-CRYAB-modulated apoptosis and ferroptosis inhibition. In mouse models, LBH overexpression was confirmed to exert enhanced cardiac protection against I/R-induced apoptosis and ferroptosis, suggesting that LBH could serve as a promising target for the development of I/R therapy.

Remnant cholesterol and the risk of aortic valve calcium progression: insights from the MESA study.

BACKGROUND: Remnant cholesterol (RC) is implicated in the risk of cardiovascular disease. However, comprehensive population-based studies elucidating its association with aortic valve calcium (AVC) progression are limited, rendering its precise role in AVC ambiguous. METHODS: From the Multi-Ethnic Study of Atherosclerosis database, we included 5597 individuals (61.8 ± 10.1 years and 47.5% men) without atherosclerotic cardiovascular disease at baseline for analysis. RC was calculated as total cholesterol minus high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), as estimated by the Martin/Hopkins equation. Using the adjusted Cox regression analyses, we examined the relationships between RC levels and AVC progression. Furthermore, we conducted discordance analyses to evaluate the relative AVC risk in RC versus LDL-C discordant/concordant groups. RESULTS: During a median follow-up of 2.4 ± 0.9 years, 568 (10.1%) participants exhibited AVC progression. After adjusting for traditional cardiovascular risk factors, the HRs (95% CIs) for AVC progression comparing the second, third, and fourth quartiles of RC levels with the first quartile were 1.195 (0.925-1.545), 1.322 (1.028-1.701) and 1.546 (1.188-2.012), respectively. Notably, the discordant high RC/low LDL-C group demonstrated a significantly elevated risk of AVC progression compared to the concordant low RC/LDL-C group based on their medians (HR, 1.528 [95% CI 1.201-1.943]). This pattern persisted when clinical LDL-C threshold was set at 100 and 130 mg/dL. The association was consistently observed across various sensitivity analyses. CONCLUSIONS: In atherosclerotic cardiovascular disease-free individuals, elevated RC is identified as a residual risk for AVC progression, independent of traditional cardiovascular risk factors. The causal relationship of RC to AVC and the potential for targeted RC reduction in primary prevention require deeper exploration.

Fucoxanthin alleviated myocardial ischemia and reperfusion injury through inhibition of ferroptosis via the NRF2 signaling pathway.

Background: Myocardial ischemia and reperfusion injury (MIRI) is a severe complication of revascularization therapy in patients with myocardial infarction. Therefore, there is an urgent requirement to find more therapeutic solutions for MIRI. Recently, ferroptosis, which is characterized by lipid peroxidation, was considered a critical contributor to MIRI. Fucoxanthin (FX), a natural antioxidant carotenoid, which is abundant in brown seaweed, exerts protective effects under various pathological conditions. However, whether FX alleviates MIRI is unclear. This study aims to clarify the effects of FX on MIRI. Methods: Mice with left anterior descending artery ligation and reperfusion were used as in vivo models. Neonatal rat cardiomyocytes (NRCs) induced with hypoxia and reperfusion were used as in vitro models. TTC-Evans blue staining was performed to validate the infarction size. Transmission electron microscopy was employed to detect mitochondrial injury in cardiomyocytes. In addition, 4 weeks after MIRI, echocardiography was performed to measure cardiac function; fluorescent probes and western blots were used to detect ferroptosis. Results: TTC-Evans blue staining showed that FX reduced the infarction size induced by MIRI. Transmission electron microscopy showed that FX ameliorated the MIRI-induced myofibril loss and mitochondrion shrinkage. Furthermore, FX improved LVEF and LVFS and inhibited myocardial hypertrophy and fibrosis after 4 weeks in mice with MIRI. In the in vitro study, calcein AM/PI staining and TUNEL staining showed that FX reduced cell death caused by hypoxia and reperfusion treatment. DCFH-DA and MitoSOX probes indicated that FX inhibited cellular and mitochondrial reactive oxygen species (ROS). Moreover, C11-BODIPY 581/591 staining, ferro-orange staining, MDA assay, Fe2+ assay, 4-hydroxynonenal enzyme-linked immunosorbent assay, and western blot were performed and the results revealed that FX ameliorated ferroptosis in vitro and in vivo, as indicated by inhibiting lipid ROS and Fe2+ release, as well as by modulating ferroptosis hallmark FTH, TFRC, and GPX4 expression. Additionally, the protective effects of FX were eliminated by the NRF2 inhibitor brusatol, as observed from western blotting, C11-BODIPY 581/591 staining, and calcein AM/PI staining, indicating that FX exerted cardio-protective effects on MIRI through the NRF2 pathway. Conclusion: Our study showed that FX alleviated MIRI through the inhibition of ferroptosis via the NRF2 signaling pathway.

Angiotensin IV ameliorates doxorubicin-induced cardiotoxicity by increasing glutathione peroxidase 4 and alleviating ferroptosis.

BACKGROUND: Doxorubicin (DOX)-induced cardiotoxicity is an important cause of poor prognosis in cancer patients treated with DOX. Angiotensin IV (Ang IV) has multiple protective effects against cardiovascular diseases, including diabetic cardiomyopathy and myocardial infarction, but its role in DOX-induced cardiotoxicity is currently unclear. In this study, we investigated the effects of Ang IV on DOX-induced cardiotoxicity. METHODS: The viability of primary cardiomyocytes was measured by Cell Counting Kit-8 assays and Hoechst 33342/propidium iodide staining in vitro. ELISAs (serum cTnT and CK-MB) and echocardiography were performed to assess myocardial injury and cardiac function in vivo. Phalloidin staining, haematoxylin and eosin staining and wheat germ agglutinin staining were conducted to detect cardiomyocyte atrophy. We also performed C11 BODIPY staining, measured the levels of Ptgs2 and malondialdehyde and detected the concentrations of ferrous ions, glutathione and oxidized glutathione to indicate ferroptosis. RESULTS: Ang IV not only attenuated DOX-induced atrophy and cardiomyocyte injury in vitro but also alleviated myocardial injury and improved cardiac function in DOX-treated mice in vivo. Moreover, Ang IV reversed DOX-induced downregulation of glutathione peroxidase 4 (GPX4) and inhibited ferroptosis both in vitro and in vivo. Knockdown of GPX4 by siRNA abolished the cardioprotective effects of Ang IV. Furthermore, Ang IV increased GPX4 levels and ameliorated ferroptosis in RAS-selective lethal 3-treated primary cardiomyocytes. CONCLUSIONS: Ang IV ameliorates DOX-induced cardiotoxicity by upregulating GPX4 and inhibiting ferroptosis. Ang IV may be a promising candidate to protect against DOX-induced cardiotoxicity in the future.

Guiding ablation strategies for ventricular tachycardia in patients with structural heart disease by analyzing links and conversion patterns of traceable abnormal late potential zone.

BACKGROUND: Substrate-based ablation can treat uninducible or hemodynamically instability scar-related ventricular tachycardia (VT). However, whether a correlation exists between the critical VT isthmus and late activation zone (LAZ) during sinus rhythm (SR) is unknown. OBJECTIVE: To demonstrate the structural and functional properties of abnormal substrates and analyze the link between the VT circuit and abnormal activity during SR. METHODS: Thirty-six patients with scar-related VT (age, 50.0 ± 13.7 years and 86.1% men) who underwent VT ablation were reviewed. The automatic rhythmia ultrahigh resolution mapping system was used for electroanatomic substrate mapping. The clinical characteristics and mapping findings, particularly the LAZ characteristics during SR and VT, were analyzed. To determine the association between the LAZ during the SR and VT circuits, the LAZ was defined as five activation patterns: entrance, exit, core, blind alley, and conduction barrier. RESULTS: Forty-five VTs were induced in 36 patients, 91.1% of which were monomorphic. The LAZ of all patients was mapped during the SR and VT circuits, and the consistency of the anatomical locations of the LAZ and VT circuits was analyzed. Using the ultrahigh resolution mapping system, interconversion patterns, including the bridge, T, puzzle, maze, and multilayer types, were identified. VT ablation enabled precise ablation of abnormal late potential conduction channels. CONCLUSION: Five interconversion patterns of the LAZ during the SR and VT circuits were summarized. These findings may help formulate more precise substrate-based ablation strategies for scar-related VT and shorter procedure times.

Chinese expert consensus on the construction of the fluoroless cardiac electrophysiology laboratory and related techniques.

Transcatheter radiofrequency ablation has been widely introduced for the treatment of tachyarrhythmias. The demand for catheter ablation continues to grow rapidly as the level of recommendation for catheter ablation. Traditional catheter ablation is performed under the guidance of X-rays. X-rays can help display the heart contour and catheter position, but the radiobiological effects caused by ionizing radiation and the occupational injuries worn caused by medical staff wearing heavy protective equipment cannot be ignored. Three-dimensional mapping system and intracardiac echocardiography can provide detailed anatomical and electrical information during cardiac electrophysiological study and ablation procedure, and can also greatly reduce or avoid the use of X-rays. In recent years, fluoroless catheter ablation technique has been well demonstrated for most arrhythmic diseases. Several centers have reported performing procedures in a purposefully designed fluoroless electrophysiology catheterization laboratory (EP Lab) without fixed digital subtraction angiography equipment. In view of the lack of relevant standardized configurations and operating procedures, this expert task force has written this consensus statement in combination with relevant research and experience from China and abroad, with the aim of providing guidance for hospitals (institutions) and physicians intending to build a fluoroless cardiac EP Lab, implement relevant technologies, promote the standardized construction of the fluoroless cardiac EP Lab.

Supramolecular Assemblies of Glycopeptides Enhance Gap Junction Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes via Inducing Spheroids Formation to Optimize Cardiac Repair.

Stem cell-based therapies have demonstrated significant potential for use in heart regeneration. An effective paradigm for heart repair in rodent and large animal models is the transplantation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Despite this, the functional and phenotypical immaturity of 2D-cultured hiPSC-CMs, particularly their low electrical integration, poses a caveat for clinical translation. In this study, a supramolecular assembly of a glycopeptide containing a cell adhesion motif-RGD, and saccharide-glucose (Bio-Gluc-RGD) is designed to enable the 3D spheroid formation of hiPSC-CMs, promoting cell-cell and cell-matrix interactions that occur during spontaneous morphogenesis. HiPSC-CMs in spheroids are prone to be phenotypically mature and developed robust gap junctions via activation of the integrin/ILK/p-AKT/Gata4 pathway. Monodispersed hiPSC-CMs encapsulated in the Bio-Gluc-RGD hydrogel are more likely to form aggregates and, therefore, survive in the infarcted myocardium of mice, accompanied by more robust gap junction formation in the transplanted cells, and hiPSC-CMs delivered with the hydrogels also displayed angiogenic effect and anti-apoptosis capacity in the peri-infarct area, enhancing their overall therapeutic efficacy in myocardial infarction. Collectively, the findings illustrate a novel concept for modulating hiPSC-CM maturation by spheroid induction, which has the potential for post-MI heart regeneration.

Reappraisal and New Observations on Idiopathic Ventricular Arrhythmias Ablated From the Noncoronary Aortic Sinus.

BACKGROUND: The electrophysiological characteristics of idiopathic ventricular arrhythmias (VAs) from the noncoronary sinus (NCS) have not been fully described. OBJECTIVES: This study sought to investigate electrophysiological characteristics and catheter ablation in patients with idiopathic NCS-VA. METHODS: This study comprised 11 patients undergoing radiofrequency (RF) catheter ablation for idiopathic NCS-VA. Angiography was performed to confirm the origin in the aortic sinus before RF ablation. RESULTS: Clinical arrhythmias presented left bundle block/inferior axis morphology in all patients. QRS morphology of R' and R/s' pattern was dominantly found in lead III. Mapping in the right ventricle demonstrated the earliest ventricular activation (EVA) site at the His Bundle region, whereas mapping in the NCS demonstrated that the EVA preceded the activation at the His Bundle region by 12.1 ± 7.9 milliseconds. All VAs were successfully ablated in <2.5 seconds within the NCS with 1 RF application. The successful ablation site was at the nadir of NCS in 10 patients, and near the junction of NCS and the right coronary sinus in the remaining one. A discrete potential can be observed at the EVA site within the NCS in 10 patients (91%); however, an excellent pace mapping at the EVA site was obtained in only 2 patients. Junctional beats did not occur during RF application in all 11 patients. There were no complications or clinical recurrence during a mean follow-up of 26.0 ± 9.8 months. CONCLUSIONS: NCS-VA presents a peculiar electrocardiogram. A discrete potential can be mapped within the NCS during VA and sinus rhythm, and can be used in guiding ablation.

Amine oxidase copper-containing 3 aggravates cardiac remodelling by generating hydrogen peroxide after myocardial infarction.

Amine oxidase copper-containing 3 (AOC3) is a member of the semicarbazide-sensitive amine oxidase enzyme family. It acts as an ectoenzyme catalysing the oxidative deamination of primary amines and generating hydrogen peroxide (H2 O2 ). While AOC3 is implicated in cardiovascular diseases such as atherosclerosis, its role in cardiac remodelling after myocardial infarction (MI) is unclear. In this study, we first confirmed a long-term upregulation of AOC3 in both cardiac myofibroblasts after MI in vivo and angiotensin II (ANGII)-treated cardiac fibroblasts in vitro. AOC3 knockdown not only inhibited the activation of cardiac fibroblasts induced by ANGII but also alleviated cardiac fibrosis in mice after MI. Using sh-AOC3 lentiviruses, exogenous recombinant AOC3 (r-AOC3), semicarbazide (an AOC3 inhibitor), and catalase (a hydrogen peroxide scavenger) treatments, we also demonstrated that AOC3 promoted H2 O2 generation, increased oxidative stress, and enhanced ERK1/2 activation, which were responsible for the activation of cardiac fibroblasts. In particular, AOC3 knockdown also improved cardiac function and hypertrophy after MI. Through a coculture system, we confirmed that AOC3 expressed on cardiac myofibroblasts was able to enhance oxidative stress and induce hypertrophy of cardiomyocytes by promoting H2 O2 generation. Similarly, r-AOC3 promoted H2 O2 generation and resulted in oxidative stress and hypertrophy of cardiomyocytes, which were almost inhibited by both semicarbazide and catalase. In conclusion, AOC3 plays a critical role in cardiac fibrosis and hypertrophy after MI by promoting the generation of H2 O2 . AOC3 is a promising therapeutic target against cardiac remodelling. © 2023 The Pathological Society of Great Britain and Ireland.

Maturation of induced pluripotent stem cell-derived cardiomyocytes and its therapeutic effect on myocardial infarction in mouse.

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have an irreplaceable role in the treatment of myocardial infarction (MI), which can be injected into the transplanted area with new cardiomyocytes (Cardiomyocytes, CMs), and improve myocardial function. However, the immaturity of the structure and function of iPSC-CMs is the main bottleneck at present. Since collagen participates in the formation of extracellular matrix (ECM), we synthesized nano colloidal gelatin (Gel) with collagen as the main component, and confirmed that the biomaterial has good biocompatibility and is suitable for cellular in vitro growth. Subsequently, we combined the PI3K/AKT/mTOR pathway inhibitor BEZ-235 with Gel and found that the two combined increased the sarcomere length and action potential amplitude (APA) of iPSC-CMs, and improved the Ca2+ processing ability, the maturation of mitochondrial morphological structure and metabolic function. Not only that, Gel can also prolong the retention rate of iPSC-CMs in the myocardium and increase the expression of Cx43 and angiogenesis in the transplanted area of mature iPSC-CMs, which also provides a reliable basis for the subsequent treatment of mature iPSC-CMs.

Trimethylamine-N-oxide (TMAO) promotes balloon injury-induced neointimal hyperplasia via upregulating Beclin1 and impairing autophagic flux.

BACKGROUND AND AIMS: TMAO is a microbiota-dependent metabolite associated with increased risk of various cardiovascular diseases. However, the relationship between TMAO and vascular injury-related neointimal hyperplasia is unclear. This study aimed to explore whether TMAO promotes neointimal hyperplasia after balloon injury and elucidate the underlying mechanism. METHODS AND RESULTS: Through hematoxylin and eosin staining and immunohistochemistry staining, we found that supplementary TMAO promoted balloon injury-induced neointimal hyperplasia, while reducing TMAO by antibiotic administration produced the opposite result. TMAO showed limited effect on rat aortic vascular smooth muscle cells (RAOSMCs) proliferation and migration. However, TMAO notably induced dysfunction of rat aortic vascular endothelial cells (RAOECs) in vitro and attenuated reendothelialization of carotid arteries after balloon injury in vivo. Autophagic flux was measured by fluorescent mRFP-GFP-LC3, transmission electron microscopy, and western blot. TMAO impaired autophagic flux, as evidenced by the accumulation of p62 and LC3II and high autophagosome to autolysosome ratios. Furthermore, we confirmed that Beclin1 level increased in TMAO-treated RAOECs and carotid arteries. Knocking down Beclin1 alleviated TMAO-induced autophagic flux impairment and neointimal hyperplasia. CONCLUSIONS: TMAO promoted neointimal hyperplasia through Beclin1-induced autophagic flux blockage, suggesting that TMAO is a potential target for improvement of vascular remodeling after injury.

An injectable co-assembled hydrogel blocks reactive oxygen species and inflammation cycle resisting myocardial ischemia-reperfusion injury.

The overproduction of reactive oxygen species (ROS) and burst of inflammation following cardiac ischemia-reperfusion (I/R) are the leading causes of cardiomyocyte injury. Monotherapeutic strategies designed to enhance anti-inflammatory or anti-ROS activity explicitly for treating I/R injury have demonstrated limited success because of the complex mechanisms of ROS production and induction of inflammation. Intense oxidative stress leads to sustained injury, necrosis, and apoptosis of cardiomyocytes. The damaged and necrotic cells can release danger-associated molecular patterns (DAMPs) that can cause the aggregation of immune cells by activating Toll-like receptor 4 (TLR4). These immune cells also promote ROS production by expressing NADPH oxidase. Finally, ROS production and inflammation form a vicious cycle, and ROS and TLR4 are critical nodes of this cycle. In the present study, we designed and prepared an injectable hydrogel system of EGCG@Rh-gel by co-assembling epigallocatechin-3-gallate (EGCG) and the rhein-peptide hydrogel (Rh-gel). The co-assembled hydrogel efficiently blocked the ROS-inflammation cycle by ROS scavenging and TLR4 inhibition. Benefited by the abundant noncovalent interactions of π-π stacking and hydrogen bonding between EGCG and Rh-gel, the co-assembled hydrogel had good mechanical strength and injectable property. Following the injection EGCG@Rh-gel into the damaged region of the mice's heart after I/R, the hydrogel enabled to achieve long-term sustained release and treatment, improve cardiac function, and significantly reduce the formation of scarring. Further studies demonstrated that these beneficial outcomes arise from the reduction of ROS production, inhibition of inflammation, and induction of anti-apoptosis in cardiomyocytes. Therefore, EGCG@Rh-gel is a promising drug delivery system to block the ROS-inflammation cycle for resisting myocardial I/R injury. STATEMENT OF SIGNIFICANCE: 1. Monotherapeutic strategies designed to enhance anti-inflammatory or anti-ROS effects for treating I/R injury have demonstrated limited success because of the complex mechanisms of ROS and inflammation. 2. ROS production and inflammation form a vicious cycle, and ROS and TLR4 are critical nodes of this cycle. 3. Here, we designed an injectable hydrogel system of EGCG@Rh-gel by co-assembling epigallocatechin-3-gallate (EGCG) and a rhein-peptide hydrogel (Rh-gel). EGCG@Rh-gel efficiently blocked the ROS-inflammation cycle by ROS scavenging and TLR4 inhibition. 4. EGCG@Rh-gel achieved long-term sustained release and treatment, improved cardiac function, and significantly reduced the formation of scarring after I/R. 5. The beneficial outcomes arise from reducing ROS production, inhibiting inflammation, and inducing anti-apoptosis in cardiomyocytes.

Identification of core genes associated with the anti-atherosclerotic effects of Salvianolic acid B and immune cell infiltration characteristics using bioinformatics analysis.

BACKGROUND: Atherosclerosis (AS) is the greatest contributor to pathogenesis of atherosclerotic cardiovascular disease (ASCVD), which is associated with increased mortality and reduced quality of life. Early intervention to mitigate AS is key to prevention of ASCVD. Salvianolic acid B (Sal B) is mainly extracted from root and rhizome of Salvia Miltiorrhiza Bunge, and exerts anti-atherosclerotic effect. The purpose of this study was to screen for anti-AS targets of Sal B and to characterize immune cell infiltration in AS. METHODS: We identified targets of Sal B using SEA ( http://sea.bkslab.org/ ) and SIB ( https://www.sib.swiss/ ) databases. GSE28829 and GSE43292 datasets were obtained from Gene Expression Omnibus database. We identified differentially expressed genes (DEGs) and performed enrichment analysis. Weighted gene co-expression network analysis (WGCNA) was used to determine the most relevant module associated with atherosclerotic plaque stability. Intersecting candidate genes were evaluated by generating receiver operating characteristic (ROC) curves and molecular docking. Then, immune cell types were identified using CIBERSOFT and single-sample gene set enrichment analysis (ssGSEA), the relationship between candidate genes and immune cell infiltration was evaluated. Finally, a network-based approach to explore the candidate genes relationship with microRNAs (miRNAs) and Transcription factors (TFs). RESULTS: MMP9 and MMP12 were been selected as candidate genes from 64 Sal B-related genes, 81 DEGs and turquoise module with 220 genes. ROC curve results showed that MMP9 (AUC = 0.815, P<0.001) and MMP12 (AUC = 0.763, P<0.001) were positively associated with advanced atherosclerotic plaques. The results of immune infiltration showed that B cells naive, B cells memory, Plasma cells, T cells CD8, T cells CD4 memory resting, T cells CD4 memory activated, T cells regulatory (Tregs), T cells gamma delta, NK cells activated, Monocytes, and Macrophages M0 may be involved in development of AS, and the candidate genes MMP9 and MMP12 were associated with these immune cells to different degrees. What' s more, miR-34a-5p and FOXC1, JUN maybe the most important miRNA and TFs. CONCLUSION: The anti-AS effects of Sal B may be related to MMP9 and MMP12 and associated with immune cell infiltration, which is expected to be used in the early intervention of AS.

Cardiomyocyte Atrophy, an Underestimated Contributor in Doxorubicin-Induced Cardiotoxicity.

Left ventricular (LV) mass loss is prevalent in doxorubicin (DOX)-induced cardiotoxicity and is responsible for the progressive decline of cardiac function. Comparing with the well-studied role of cell death, the part of cardiomyocyte atrophy (CMA) playing in the LV mass loss is underestimated and the knowledge of the underlying mechanism is still limited. In this review, we summarized the recent advances in the DOX-induced CMA. We found that the CMA caused by DOX is associated with the upregulation of FOXOs and "atrogenes," the activation of transient receptor potential canonical 3-NADPH oxidase 2 (TRPC3-Nox2) axis, and the suppression of IGF-1-PI3K signaling pathway. The imbalance of anabolic and catabolic process may be the common final pathway of these mechanisms. At last, we provided some strategies that have been demonstrated to alleviate the DOX-induced CMA in animal models.