A signature based on circadian rhythm-associated genes for the evaluation of prognosis and the tumour microenvironment in HNSCC.

The morbidity and mortality rates of head and neck squamous cell carcinoma (HNSCC) remain high worldwide. Therefore, there is an urgent need to identify a new prognostic biomarker to guide the personalized treatment of HNSCC patients. Increasing evidence suggests that circadian rhythm genes play an important role in the development and progression of cancer. We aimed to explore the value of circadian rhythm genes in predicting prognosis and guiding the treatment of HNSCC. We first obtained a list of circadian rhythm genes from previous research. The sequencing data were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Finally, univariate Cox proportional hazard analysis, least absolute shrinkage and selection operator (LASSO) regression, and multivariate Cox proportional hazard analysis were performed to develop a prognostic signature (Circadian Rhythm-Related Gene Prognostic Index, CRRGPI) consisting of nine circadian rhythm genes. The signature exhibited good performance in predicting overall survival. Patients with low CRRGPI scores had lower metabolic activities and an active antitumour immunity ability. Additionally, a clinical cohort was used to further evaluate the ability of the CRRGPI to predict the efficacy of immune checkpoint inhibitors. In conclusion, the novel circadian rhythm-related gene signature can provide a precise prognostic evaluation with the potential capacity to guide individualized treatment regimens for HNSCC patients.

The Impacts of Nirmatrelvir-Ritonavir on Myocardial Injury and Long-Term Cardiovascular Outcomes in Hospitalized Patients with COVID-19 amid the Omicron Wave of the Pandemic.

PURPOSE: Even though nirmatrelvir-ritonavir can improve the short-term morbidity and mortality in COVID-19 patients, the effects of this treatment on long-term major adverse cardiovascular events (MACEs), especially myocardial injury, remains undetermined. METHODS: This prospective cohort study identified hospitalized adult patients with COVID-19 between April 19, 2022, and June 9, 2022, amid the omicron wave of the pandemic. Matched nirmatrelvir-ritonavir-treated and non-treated cohorts were formed using the propensity score matching method. The primary outcome of this study was the incidence of MACEs (cardiovascular death, myocardial infarction, stroke, new-onset heart failure or heart failure hospitalization or ventricular arrhythmia) from 30 days to 16 months after the diagnosis of COVID-19. RESULTS: Two 949-patient cohorts with balanced baseline characteristics were formed by propensity score matching. Patients with nirmatrelvir-ritonavir, compared to those untreated, had a lower level of troponin I peak as well as the incidence of troponin I elevation. During the follow-up period, 59 patients in the nirmatrelvir-ritonavir group and 86 patients in the control group developed MACEs (P = 0.020). Regarding specific constituents of MACEs, the differences are mainly reflected in new-onset heart failure or heart failure hospitalization. COVID-19 clinical severity and troponin I peak were the independent predictors, while nirmatrelvir-ritonavir was the independent protective factor for the occurrence of MACEs in this population. CONCLUSION: Nirmatrelvir-ritonavir was effective in reducing myocardial injury as well as long-term adverse cardiovascular outcomes among hospitalized patients with COVID-19 amid the omicron wave of the pandemic.

The impacts of prophylactic anticoagulation therapy during hospitalization on long-term cardiovascular outcomes in high-risk COVID-19 patients amid the omicron wave of the pandemic.

Background: Although prophylactic anticoagulation therapy is suggested to be adopted in severe COVID-19 patients, its effects on the long-term cardiovascular (CV) outcomes, namely the risk of major adverse CV events(MACEs) in high-risk CV patients amid the omicron wave of the pandemic, remain unknown. Methods: We conducted this prospective cohort study of consecutive adults hospitalized COVID-19 between 19 April and 12 June 2022, COVID-19 patients with at least two CV risk factors or pre-existing CV diseases were enrolled. A propensity score matching(PSM) method was used to evaluated the effects of prophylactic anticoagulation therapy in hospital on long-term MACEs, including CV death, non-fatal myocardial infarction, non-fatal stroke, hospitalization due to unstable angina pectoris, coronary revascularization and arterial or venous thrombosis. Results: Two cohorts (with or without anticoagulants during hospitalization) of each 230 patients with balanced baseline characteristics were formed using PSM. During the 15-month follow-up period, 13 patients with anticoagulants and 29 patients without anticoagulants developed MACEs. Overall, the anticoagulation group had a significantly lower risk of MACEs than the control group (hazard ratio [HR] 0.431; 95 % confidence interval [CI]: 0.224-0.830, P = 0.010). Regarding specific constituents of MACEs, the differences were mainly reflected in arterial or venous thrombosis. The significantly lower HRs of overall MACEs were significantly observed in subgroup of age > 75 years, women, higher D dimer level, unvaccinated and non-nirmatrelvir-ritonavir prescribed patients. Conclusions: Prophylactic anticoagulation therapy during hospitalization was effective in reducing long-term MACEs among COVID-19 patients with CV risk factors or pre-existing CV diseases amid the omicron wave of the pandemic.

Hydrogen sulfide protects cardiomyocytes from doxorubicin-induced ferroptosis through the SLC7A11/GSH/GPx4 pathway by Keap1 S-sulfhydration and Nrf2 activation.

Recent studies have demonstrated that ferroptosis, a novel form of nonapoptotic regulated cell death plays an important role in doxorubicin (DOX)-induced cardiotoxicity (DoIC). Hydrogen sulfide (H2S) is emerging as the third important gaseous mediator in cardiovascular system. However, whether H2S has an effect on DOX-induced ferroptosis remains unknown. Here, we found that DOX not only triggered cardiomyocyte ferroptosis but also significantly inhibited the synthesis of endogenous H2S in the murine model of chronic DoIC. Application of NaHS, an H2S donor obviously activated the SLC7A11/GSH/GPx4 antioxidant pathway and thus alleviated DOX-induced ferroptosis and cardiac injury in mice. In contrast, cardiac-specific knockout of cystathionine γ-lyase gene (Cse) in mice (Csef/f/Cre+) to abolish the cardiac synthesis of endogenous H2S evidently exacerbated DOX-induced ferroptosis and cardiac dysfunction. A further suppression of SLC7A11/GSH/GPx4 pathway was obtained in Csef/f/Cre+ mice with DoIC, as compared to Csef/f/Cre- mice with DoIC. The aggravation caused by cardiac-specific Cse deficiency was remarkably rescued by exogenous supplementation of NaHS. Moreover, in DOX-stimulated H9c2 cardiomyocytes, pretreatment with NaHS dose-dependently enhanced the activity of SLC7A11/GSH/GPx4 pathway and subsequently mitigated ferroptosis and mitochondrial impairment. On the contrary, transfection with Cse siRNA in DOX-stimulated H9c2 cardiomyocytes markedly inhibited SLC7A11/GSH/GPx4 pathway, thus leading to aggravated ferroptosis and more damage to mitochondrial structure and function. In addition, the protective effect of NaHS on DOX-induced ferroptosis was closely related to the S-sulfhydrated Keap1, which in turn promoted nuclear translocation of Nrf2 and the transcription of SLC7A11 and GPx4. In conclusion, our findings suggest that H2S may exert protective effect on DoIC by inhibiting DOX-induced ferroptosis via Keap1/Nrf2-dependent SLC7A11/GSH/GPx4 antioxidant pathway.

Comparative analysis of immune checkpoint inhibitors in first-line treatment of esophageal squamous cell carcinoma: a network meta-analysis.

Aim: To evaluate the efficacy and safety of first-line immunochemotherapy in the treatment of advanced esophageal squamous cell carcinoma (CRD42021287033). Methods: PubMed, Embase, Cochrane Library and Web of Science were systematically searched to obtain randomized controlled trials, and the outcome indicators of the reports were compared and analyzed. Results: A total of 3163 patients from five reported randomized controlled trials were included in the meta-analysis. The results showed the comprehensive benefits of toripalimab combined with chemotherapy, in terms of overall survival (hazard ratio: 0.59; 95% CI: 0.43-0.81) and progression-free survival (hazard ratio: 0.58; 95% CI: 0.46-0.73). Conclusion: Toripalimab combined with chemotherapy may be a better choice for first-line immunochemotherapy, although this needs to be verified by clinical studies.

The treatment of cancer is an issue of importance to the general public. A number of drugs are available to treat cancer, including those that enhance the body's natural defense. Such drugs are also the first choice for cancer of the esophagus, which cannot be removed surgically. In this study, we analyzed five different first-choice drugs in different ways, including how long the patient survives and how long the patient lives without their disease getting worse. We found that toripalimab, which strengthens the body's natural defense, may be the best combination choice for use in combination with chemotherapy. Although further studies are needed to increase the reliability of the conclusions, we preliminarily consider that this drug is particularly promising.

The initial timing and dosage pattern of sacubitril/valsartan in patients with acute myocardial infarction undergoing percutaneous coronary intervention.

BACKGROUND: In real-world clinical practice, the initiation and up-titration of sacubitril/valsartan remain challenging due to symptomatic hypotension in patients with acute myocardial infarction(AMI). The purpose of this study was to investigate the efficacy of different initial timing and dosage of sacubitril/valsartan in AMI patients. METHODS: This prospective and observational cohort study enrolled AMI patients treated with percutaneous coronary intervention(PCI), and were categorized according to the initial timing and average daily doses of sacubitril/valsartan prescription. The primary endpoint was defined as a composite of cardiovascular death, recurrent AMI, coronary revascularization, heart failure(HF) hospitalization and ischaemic stroke. Secondary outcomes included the new-onset HF, and the composite endpoints in AMI patients complicated with HF at baseline. RESULTS: The study population consisted of 915 AMI patients. After a median follow-up of 38 months, early use or high dosage of sacubitril/valsartan was associated with an improvement in primary endpoint as well as the incidence of new-onset HF. Early use of sacubitril/valsartan also ameliorated the primary endpoint in AMI patients with left ventricular ejection fraction(LVEF) ≤50% as well as LVEF>50%. Besides, early use of sacubitril/valsartan improved the clinical outcomes in AMI patients complicated with HF at baseline. The low dose was well tolerated and may be associated with similar outcomes compared with high dose under some circumstances(LVEF>50% or HF at baseline). CONCLUSIONS: Early use or high dosage of sacubitril/valsartan medication is associated with an improvement in clinical outcome. The low dose of sacubitril/valsartan is well tolerated and may be an acceptable alternative strategy.

The Imbalance of p53-Park7 Signaling Axis Induces Iron Homeostasis Dysfunction in Doxorubicin-Challenged Cardiomyocytes.

Doxorubicin (DOX)-induced cardiotoxicity (DoIC) is a major side effect for cancer patients. Recently, ferroptosis, triggered by iron overload, is demonstrated to play a role in DoIC. How iron homeostasis is dysregulated in DoIC remains to be elucidated. Here, the authors demonstrate that DOX challenge exhibits reduced contractile function and induction of ferroptosis-related phenotype in cardiomyocytes, evidenced by iron overload, lipid peroxide accumulation, and mitochondrial dysfunction. Compared to Ferric ammonium citrate (FAC) induced secondary iron overload, DOX-challenged cardiomyocytes show a dysfunction of iron homeostasis, with decreased cytoplasmic and mitochondrial iron-sulfur (FeS) cluster-mediated aconitase activity and abnormal expression of iron homeostasis-related proteins. Mechanistically, mass spectrometry analysis identified DOX-treatment induces p53-dependent degradation of Parkinsonism associated deglycase (Park7) which results in iron homeostasis dysregulation. Park7 counteracts iron overload by regulating iron regulatory protein family transcription while blocking mitochondrial iron uptake. Knockout of p53 or overexpression of Park7 in cardiomyocytes remarkably restores the activity of FeS cluster and iron homeostasis, inhibits ferroptosis, and rescues cardiac function in DOX treated animals. These results demonstrate that the iron homeostasis plays a key role in DoIC ferroptosis. Targeting of the newly identified p53-Park7 signaling axis may provide a new approach to prevent DoIC.

Delivery of mitochondria confers cardioprotection through mitochondria replenishment and metabolic compliance.

Mitochondrial dysfunction is a hallmark of heart failure. Mitochondrial transplantation has been demonstrated to be able to restore heart function, but its mechanism of action remains unresolved. Using an in-house optimized mitochondrial isolation method, we tested efficacy of mitochondria transplantation in two different heart failure models. First, using a doxorubicin-induced heart failure model, we demonstrate that mitochondrial transplantation before doxorubicin challenge protects cardiac function in vivo and prevents myocardial apoptosis, but contraction improvement relies on the metabolic compatibility between transplanted mitochondria and treated cardiomyocytes. Second, using a mutation-driven dilated cardiomyopathic human induced pluripotent stem cell-derived cardiomyocyte model, we demonstrate that mitochondrial transplantation preferentially boosts contraction in the ventricular myocytes. Last, using single-cell RNA-seq, we show that mitochondria transplantation boosts contractility in dystrophic cardiomyocytes with few transcriptomic alterations. Together, we provide evidence that mitochondria transplantation confers myocardial protection and may serve as a potential therapeutic option for heart failure.

A Meta-analysis of Total Neoadjuvant Therapies Combining Chemoradiotherapy with Induction or Consolidated Chemotherapy for Locally Advanced Rectal Cancer.

OBJECTIVE: Total neoadjuvant therapy (TNT) combining chemoradiotherapy (CRT) with chemotherapy (CT) was a novel pre-surgical approach to cancer treatment. This meta-analysis aimed to compare the clinical outcomes between neoadjuvant CRT (nCRT) with induction CT and nCRT with consolidated CT in locally advanced rectal cancer (LARC) patients. METHOD: In July 2022, a literature search was conducted using the following public databases: PubMed, MEDLINE, Embase, the Cochrane Library, and Web of Science, retrieved all relevant articles comparing nCRT-combining induction CT with nCRT-combining-consolidated CT treatments for LARC patients. RESULTS: Four eligible studies were identified, including a total of 995 LARC patients: 473 in the nCRT with consolidated CT group and 522 in the nCRT with induction CT group. The organ preservation (OP) rate of the nCRT with consolidated CT group was higher than that of the nCRT with induction CT group (RR [relative risk]: 1.53; 95% CI (confidence interval): 1.09-2.14). The pathological complete response (PCR, RR: 1.22; 95% CI 0.37-2.17), the 3-year disease-free survival (DFS, RR 1.02; 95% CI 0.71-1.46), the local recurrence (LR, RR 0.98; 95% CI 0.52-1.85), rates of R0 resection (RR 0.74; 95% CI 0.55-1.10), compliance (RR 0.52; 95% CI 0.12-2.26), and grade 3--4 toxicities (RR 0.78; 95% CI 0.57-1.06) were all similar between the two groups. CONCLUSION: In this meta-analysis of TNT regimens for rectal cancer, consolidative CT following nCRT was associated with similar PCR, 3-year DFS, LR, R0 resection, compliance, and grade 3-4 toxicities compared to induction CT prior to nCRT but a higher rate of organ preservation.

Roles of oral microbiota and oral-gut microbial transmission in hypertension.

INTRODUCTION: Considerable evidence has linked periodontitis (PD) to hypertension (HTN), but the nature behind this connection is unclear. Dysbiosis of oral microbiota leading to PD is known to aggravate different systematic diseases, but the alteration of oral microbiota in HTN and their impacts on blood pressure (BP) remains to be discovered. OBJECTIVES: To characterize the alterations of oral and gut microbiota and their roles in HTN. METHODS: We performed a cross-sectional (95 HTN participants and 39 controls) and a 6-month follow-up study (52 HTN participants and 26 controls) to analyze the roles of oral and gut microbiota in HTN. Saliva, subgingival plaques, and feces were collected for 16S rRNA gene sequencing or metagenomic analysis. C57BL/6J mice were pretreated with antibiotics to deplete gut microbiota, and then transplanted with human saliva by gavage to test the impacts of abnormal oral-gut microbial transmission on HTN. RESULTS: BP in participants with PD was higher than no PD in both cross-sectional and follow-up cohort. Relative abundances of 14 salivary genera, 15 subgingival genera and 10 gut genera significantly altered in HTN and those of 7 salivary genera, 12 subgingival genera and 6 gut genera significantly correlated with BP. Sixteen species under 5 genera were identified as oral-gut transmitters, illustrating the presence of oral-gut microbial transmission in HTN. Veillonella was a frequent oral-gut transmitter stably enriched in HTN participants of both cross-sectional and follow-up cohorts. Saliva from HTN participants increased BP in hypertensive mice. Human saliva-derived Veillonella successfully colonized in mouse gut, more abundantly under HTN condition. CONCLUSIONS: PD and oral microbiota are strongly associated with HTN, likely through oral-gut transmission of microbes. Ectopic colonization of saliva-derived Veillonella in the gut may aggravate HTN. Therefore, precise manipulations of oral microbiota and/or oral-gut microbial transmission may be useful strategies for better prevention and treatment of HTN.

The relationships between cholesterol crystals, NLRP3 inflammasome, and coronary atherosclerotic plaque vulnerability in acute coronary syndrome: An optical coherence tomography study.

Background: Cholesterol crystals (CCs) in lesions are the hallmark of advanced atherosclerotic plaque. Previous studies have demonstrated that CCs could activate NLRP3 inflammasome, which played an important role in atherosclerotic lesion progression. However, the relationship between CCs, NLRP3 inflammasome pathway, and plaque vulnerability in patients with ACS is still not elucidated. Methods: Two hundred sixty-nine consecutive acute coronary syndrome (ACS) patients with 269 culprit lesions were included in this study. CCs and other plaque characteristics within the culprit lesion segment were evaluated by optical coherence tomography (OCT) before percutaneous coronary intervention (PCI). The NLRP3 mRNA expression in peripheral blood mononuclear cells (PBMCs) and the serum levels of interleukin (IL)-1ß, IL-18, and other biological indices were measured. Results: Cholesterol crystals were observed in 105 (39%) patients with 105 culprit lesions. There were no significant differences in baseline clinical characteristics between the patients with CCs (CCs group, n = 105) and the patients without CCs (non-CCs group, n = 164) within the culprit lesion segment except for lipoprotein(a) [Lp(a)]. The CCs group had a higher level of NLRP3 mRNA expression in PBMCs and higher levels of serum cytokine IL-1ß and IL-18. OCT showed that the CCs group had longer lesion length, more severe diameter stenosis, and less minimum luminal area (MLA) than the non-CCs group (all p < 0.05). The frequency of thin-cap fibroatheroma (TCFA), thrombus, accumulation of macrophages, plaque rupture, micro-channel, calcification, spotty calcification, and layered plaque was higher in the CCs group than in the non-CCs groups (all p < 0.05). Multivariate logistic analysis revealed that the level of NLRP3 expression (OR = 10.204), IL-1ß levels (OR = 3.523), IL-18 levels (OR = 1.006), TCFA (OR = 3.593), layered plaque (OR = 5.287), MLA (OR = 1.475), macrophage accumulation (OR = 2.881), and micro-channel (OR = 3.185) were independently associated with CCs. Conclusion: Acute coronary syndrome patients with CCs in culprit lesions had a higher expression of NLRP3, IL-1ß, and IL-18, and had more vulnerable plaque characteristics than patients without CCs. CCs might have interacted with NLRP3 inflammasome activation in patients with ACS, which could contribute to plaque vulnerability in culprit lesions.

A newly designed disk-lobe occluder with isogenous barbs for left atrial appendage closure: Initial multicenter experience.

Background: Although the implant success rate of left atrial appendage closure (LAAC) has increased and complications have decreased over time, there are still anatomically and technically complicated cases where novel LAA occluders may simplify the procedure and thus might potentially improve the clinical outcome. Objectives: This study aimed to assess the safety and efficacy of the newly designed device with isogenous barbs in LAAC. Methods: Eight centers in China participated in this prospective study from July 2016 to April 2018. Peri- and post-procedural safety and efficacy were evaluated through scheduled follow-ups and transesophageal echocardiography (TEE). Results: A total of 175 patients with a mean age of 68.4 ± 9.2 years old, a mean CHA2DS2-VASc score of 4.7 ± 1.8, and a mean HAS-BLED score of 3.2 ± 1.3, were included. The device was successfully implanted in 173 patients (98.9%). The device size ranged from 18 to 34 mm. Clinically relevant pericardial effusion (PEF) in the perioperative period, occurred in 3 patients (1.7%). TEE follow-up was available in 167 (96.5%) patients at 12-month. During follow-up, 9 patients suffered serious adverse event: 4 death (2.3%), 1 ischemic stroke (0.6%), and 2 gastro-intestinal bleeding (1.2%) and 2 device-related thrombus (DRT) (1.2%). Estimated annual thromboembolism rate reduced by 90% and estimated annual major bleeding rate reduced by 81% after LAAC with the newly designed device. Conclusion: The newly designed device with isogenous barbs for LAAC could be performed effectively with a low incidence of adverse events and a high incidence of anatomic closure.

Characteristics, prognosis, and treatment response in HFpEF patients with high vs. normal ejection fraction.

Background: Heart failure with preserved ejection fraction (HFpEF) patients varied by left ventricular ejection fraction (LVEF) have different clinical characteristics, prognosis, and treatment response. With data from our prospective HFpEF cohort, we assessed the possible relationship between clinical characteristics, outcome as well as treatment response and LVEF. Methods: We compared differences in baseline characteristics and clinical outcomes across LVEF categories (50%≤LVEF <60% vs. LVEF≥60%) in 1,502 HFpEF patients, and determined whether LVEF modified the treatment response. During 5-year follow-up, all-cause mortality was used as the primary endpoints, and composite endpoints (all-cause mortality or HF hospitalization) were set as the secondary endpoint. Results: Patients with higher LVEF were statistically older, more likely to be women and have a history of atrial fibrillation. Patients with lower LVEF category were more likely to have a history of coronary artery disease. The incidences of all-cause mortality and composite endpoints were higher in patients with higher LVEF. Also, LVEF modified the spironolactone treatment effect for the primary outcome and secondary endpoint with stronger estimated benefits at the lower LVEF category with respect to all-cause mortality (HR 0.734, 95% CI 0.541-0.997, P = 0.048) and all-cause mortality or HF hospitalization (HR 0.767, 95% CI 0.604-0.972, P = 0.029). Conclusion: The characteristics and outcomes of HFpEF patients varied substantially by LVEF. Patients with higher LVEF encountered more adverse events than those with lower LVEF. The potential efficacy of spironolactone was greatest at the lower category of LVEF spectrum in HFpEF.

Integrative Pan-Cancer Analysis Confirmed that FCGR3A is a Candidate Biomarker Associated With Tumor Immunity.

Background: Fc gamma receptor 3A (FCGR3A) encodes a receptor for the Fc portion of immunoglobulin G, which plays a significant role in the immune response. However, the role of FCGR3A in cancers remains unclear. This study aimed to visualize the prognostic landscape of FCGR3A in pan-cancer and investigate the relationship between FCGR3A expression and tumor microenvironment. Method: Based on the TCGA database, GTEx database, and GDSC database, we analyzed the expression of FCGR3A in pan-cancers and adjacent normal tissues and its relationship with prognosis, immune cells infiltration, immune-related genes, DNA mismatch repair (MMR) genes, DNA methylation, and drugs sensitivity. The gene alteration frequency of FCGR3A was acquired on the cBioportal website. Moreover, we constructed PPI networks, performed GO and KEGG analysis to illustrate the function, and signaling pathways of FCGR3A-related genes, and conducted gene set enrichment analysis (GSEA) of FCGR3A to further explore its potential biological functions. Result: The differential analysis results of the publicly available databases showed that FCGR3A was generally highly expressed in pan-cancer. Survival analysis revealed that FCGR3A predominated as a risk prognostic factor in most cancers. Additionally, the expression of FCGR3A was confirmed to be associated with several immune cells infiltration, multiple immune checkpoint genes, and DNA mismatch repair genes expression in generalized carcinoma. We also identified a negative correlation between FCGR3A and DNA methylation levels. Through GO/KEGG and GESA, we found that FCGR3A was involved in many pathologic and physiological processes, and was most closely related to tumor immune-related pathways. Drug sensitivity analysis showed that higher FCGR3A expression predicts a low IC50 value for the vast majority of drugs. Conclusions: FCGR3A may be an immune-oncogenic molecule that correlates with tumor immune infiltration levels and affects drug sensitivity, thus it can be served as a promising biomarker for cancer detection, prognosis, therapeutic design, and follow-up.

Secretion of miRNA-326-3p by senescent adipose exacerbates myocardial metabolism in diabetic mice.

BACKGROUND: Adipose tissue homeostasis is at the heart of many metabolic syndromes such as diabetes. Previously it has been demonstrated that adipose tissues from diabetic patients are senescent but whether this contributes to diabetic cardiomyopathy (DCM) remains to be elucidated. METHODS: The streptozotocin (STZ) type 1 diabetic mice were established as animal model, and adult mouse ventricular myocytes (AMVMs) isolated by langendorff perfusion as well as neonatal mouse ventricular myocytes (NMVMs) were used as cell models. Senescent associated ß galactosidase (SA-ß-gal) staining and RT-qPCR were used to identify the presence of adipose senescence in diabetic adipose tissue. Senescent adipose were removed either by surgery or by senolytic treatment. Large extracellular vesicles (LEVs) derived from adipose tissue and circulation were separated by ultracentrifugation. Cardiac systolic and diastolic function was evaluated through cardiac ultrasound. Cardiomyocytes contraction function was evaluated by the Ionoptix HTS system and live cell imaging, mitochondrial morphology and functions were evaluated by transmission electron microscope, live cell fluorescent probe and seahorse analysis. RNA-seq for AMVMs and miRNA-seq for LEVs were performed, and bioinformatic analysis combined with RT-qPCR and Western blot were used to elucidate underlying mechanism that senescent adipose derives LEVs exacerbates myocardial metabolism. RESULTS: SA-ß-gal staining and RT-qPCR identified the presence of adipose tissue senescence in STZ mice. Through surgical as well as pharmacological means we show that senescent adipose tissue participates in the pathogenesis of DCM in STZ mice by exacerbates myocardial metabolism through secretion of LEVs. Specifically, expression of miRNA-326-3p was up-regulated in LEVs isolated from senescent adipose tissue, circulation, and cardiomyocytes of STZ mice. Up-regulation of miRNA-326-3p coincided with myocardial transcriptomic changes in metabolism. Functionally, we demonstrate that miRNA-326-3p inhibited the expression of Rictor and resulted in impaired mitochondrial and contractile function in cardiomyocytes. CONCLUSION: We demonstrate for the first time that senescent adipose derived LEVs exacerbates myocardial metabolism through up-regulated miRNA-326-3p which inhibits Rictor in cardiomyocytes. Furthermore, reducing senescence burden in adipose tissue is capable of relieving myocardial metabolism disorder in diabetes mellitus.

Extracellular vesicles from hypoxia-preconditioned mesenchymal stem cells alleviates myocardial injury by targeting thioredoxin-interacting protein-mediated hypoxia-inducible factor-1α pathway.

BACKGROUND: Extracellular vesicles (EVs) derived from hypoxia-preconditioned (HP) mesenchymal stem cells (MSCs) have better cardioprotective effects against myocardial infarction (MI) in the early stage than EVs isolated from normoxic (NC)-MSCs. However, the cardioprotective mechanisms of HP-EVs are not fully understood. AIM: To explore the cardioprotective mechanism of EVs derived from HP MSCs. METHODS: We evaluated the cardioprotective effects of HP-EVs or NC-EVs from mouse adipose-derived MSCs (ADSCs) following hypoxia in vitro or MI in vivo, in order to improve the survival of cardiomyocytes (CMs) and restore cardiac function. The degree of CM apoptosis in each group was assessed by the terminal deoxynucleotidyl transferase dUTP nick end-labeling and Annexin V/PI assays. MicroRNA (miRNA) sequencing was used to investigate the functional RNA diversity between HP-EVs and NC-EVs from mouse ADSCs. The molecular mechanism of EVs in mediating thioredoxin-interacting protein (TXNIP) was verified by the dual-luciferase reporter assay. Co-immunoprecipitation, western blotting, and immunofluorescence were performed to determine if TXNIP is involved in hypoxia-inducible factor-1 alpha (HIF-1α) ubiquitination and degradation via the chromosomal region maintenance-1 (CRM-1)-dependent nuclear transport pathway. RESULTS: HP-EVs derived from MSCs reduced both infarct size (necrosis area) and apoptotic degree to a greater extent than NC-EVs from CMs subjected to hypoxia in vitro and mice with MI in vivo. Sequencing of EV-associated miRNAs showed the upregulation of 10 miRNAs predicted to bind TXNIP, an oxidative stress-associated protein. We showed miRNA224-5p, the most upregulated miRNA in HP-EVs, directly combined the 3' untranslated region of TXNIP and demonstrated its critical protective role against hypoxia-mediated CM injury. Our results demonstrated that MI triggered TXNIP-mediated HIF-1α ubiquitination and degradation in the CRM-1-mediated nuclear transport pathway in CMs, which led to aggravated injury and hypoxia tolerance in CMs in the early stage of MI. CONCLUSION: The anti-apoptotic effects of HP-EVs in alleviating MI and the hypoxic conditions of CMs until reperfusion therapy may partly result from EV miR-224-5p targeting TXNIP.

Initial Invasive or Conservative Strategy in Heart Failure With Preserved Ejection Fraction and Coronary Artery Disease.

Background: In patients with both heart failure with preserved ejection fraction (HFpEF) and coronary artery disease (CAD), whether adopting an initial invasive strategy benefits better in clinical outcomes compared with those who received an initial conservative strategy remains inconclusive. Methods: With data from the heart failure (HF) cohort study, we analyzed patients who had HFpEF and CAD amenable to the invasive intervention using propensity score matching of 1:1 ratio to compare the initial invasive strategy and the initial conservative strategy of medical therapy alone. The primary outcome was the composite endpoints of all-cause mortality or cardiovascular hospitalization, and the secondary outcome was all-cause mortality or cardiovascular hospitalization. Results: Of 1,718 patients, 706 were treated with the invasive strategy and 1,012 with the conservative strategy initially. Propensity score matching was used to assemble a matched cohort of 1,320 patients receiving the invasive intervention (660 patients) or the medical therapy alone (660 patients). With a follow-up of 5 years, 378 (57.3%) in the invasive-strategy group and 403 (61.1%) in the conservative-strategy group reached the primary endpoint, and there was no significant difference in the rate of the primary endpoint (P = 0.162). The initial invasive strategy only improved the secondary outcome of cardiovascular hospitalization (P = 0.035). Also, the multivariable Cox regression model revealed that antiplatelet therapy, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB), or statin prescription was associated with a decreased risk of the primary outcome. Conclusion: In this well-profiled, propensity-matched cohort of patients with HFpEF and CAD, the addition of invasive intervention to medical therapy did not improve the long-term composite of all-cause mortality or cardiovascular hospitalization.

Circular RNA Fbxl5 Regulates Cardiomyocyte Apoptosis During Ischemia Reperfusion Injury via Sponging microRNA-146a.

Objective: Cardiomyocyte apoptosis critically contributes to ischemia reperfusion injury (IRI), which lacks effective therapeutic strategies. Circular RNAs (circRNAs) serve as novel diagnostic and therapeutic targets in various cardiovascular diseases. CircRNA Fbxl5 is one of the abundantly expressed circRNAs in the heart and its role in myocardial IRI remains elusive. Materials and Methods: Wild-type (WT) mice and neonatal mice ventricular myocytes (NMVMs) were used and subjected to myocardial IRI and anoxia reoxygenation (AR), respectively. Molecular and histological analyses and echocardiography were used to determine the extent of apoptosis, infarct size, and cardiac function. Results: We found that circRNA Fbxl5 was significantly upregulated in the myocardium, as well as in NMVMs subjected to AR. Knockdown of circRNA Fbxl5 ameliorated cardiomyocyte apoptosis, thereby decreasing infarct size and preserving cardiac function. Additionally, in vitro knockdown of circRNA Fbxl5 in NMVMs subjected to AR recapitulated the in vivo findings. Mechanistically, we identified that circRNA Fbxl5 directly sponged and suppressed the endogenous microRNA-146a (miR-146a), thereby weakening its inhibitory effect on MED1, which could further promote the apoptosis of cardiomyocytes. Conclusion: Our findings revealed a novel and critical role for circRNA Fbxl5 in regulating cardiomyocyte apoptosis, and added additional insight into circRNAs mediated during myocardial IRI. The underlying miR-146a-MED1 signaling serves as an important cascade in regulating the apoptosis of cardiomyocytes.

Association of Neutrophil to Lymphocyte Ratio With Plaque Rupture in Acute Coronary Syndrome Patients With Only Intermediate Coronary Artery Lesions Assessed by Optical Coherence Tomography.

Objectives: Plaque vulnerability and rupture rather than plaque size are the major cause of clinical events in patients with intermediate coronary lesions. Therefore, the present study was aimed to explore potential markers associated with plaque rupture in acute coronary syndrome (ACS) patients with intermediate coronary lesions. Methods: A total of 82 ACS patients presenting with only intermediate coronary lesions (40-70% stenosis demonstrated by quantitative coronary angiography) and no severe stenosis in other main coronary arteries [median age 63 years, 53 male and 29 female] were enrolled. Plaque morphology were assessed by optical coherence tomography (OCT). Hematological indices were assayed by automated hematological analyzer. Results: Plaque rupture was identified in 14 patients by OCT. Neutrophil to lymphocyte ratio (NLR) in patients with plaque rupture (n = 14) was significantly higher than that in patients with non-plaque rupture (n = 68) [3.85 (3.28, 4.77) vs. 2.13 (1.40, 2.81), p < 0.001]. Multivariate logistic regression analysis revealed that NLR was one of the independent risk factors for plaque rupture in intermediate coronary artery lesions (odds ratio 1.64, 95% confidence intervals 1.18-2.29, p = 0.003). ROC curve analysis found a cutoff point of NLR > 2.94 for plaque rupture with 93.8% sensitivity and 77.9% specificity. Conclusion: NLR, an inflammatory biomarker, is closely associated with plaque rupture in intermediate coronary artery lesions. Monitoring NLR may be useful in risk stratification and management for intermediate coronary artery lesions.