The involvement of soluble epoxide hydrolase in the development of cardiovascular diseases through epoxyeicosatrienoic acids.

Arachidonic acid (AA) has three main metabolic pathways: the cycloxygenases (COXs) pathway, the lipoxygenases (LOXs) pathway, and the cytochrome P450s (CYPs) pathway. AA produces epoxyeicosatrienoic acids (EETs) through the CYPs pathway. EETs are very unstable in vivo and can be degraded in seconds to minutes. EETs have multiple degradation pathways, but are mainly degraded in the presence of soluble epoxide hydrolase (sEH). sEH is an enzyme of bifunctional nature, and current research focuses on the activity of its C-terminal epoxide hydrolase (sEH-H), which hydrolyzes the EETs to the corresponding inactive or low activity diol. Previous studies have reported that EETs have cardiovascular protective effects, and the activity of sEH-H plays a role by degrading EETs and inhibiting their protective effects. The activity of sEH-H plays a different role in different cells, such as inhibiting endothelial cell proliferation and migration, but promoting vascular smooth muscle cell proliferation and migration. Therefore, it is of interest whether the activity of sEH-H is involved in the initiation and progression of cardiovascular diseases by affecting the function of different cells through EETs.

Application of a circular-shaped pulsed field ablation catheter with magnetic sensors for pulmonary vein isolation: a multi-centre clinical study report.

AIMS: A few studies have reported the effect and safety of pulsed field ablation (PFA) catheters for ablating atrial fibrillation (AF), which were mainly based on basket-shaped or flower-shaped designs. However, the clinical application of a circular-shaped multi-electrode catheter with magnetic sensors is very limited. To study the efficacy and safety of a PFA system in patients with paroxysmal AF using a circular-shaped multi-electrode catheter equipped with magnetic sensors for pulmonary vein isolation (PVI). METHODS AND RESULTS: A novel proprietary bipolar PFA system was used for PVI, which utilized a circular-shaped multi-electrode catheter with magnetic sensors and allowed for three-dimensional model reconstruction, mapping, and ablation in one map. To evaluate the efficacy, efficiency, and safety of this PFA system, a prospective, multi-centre, single-armed, pre-market clinical study was performed. From July 2021 to December 2022, 151 patients with paroxysmal AF were included and underwent PVI. The study examined procedure time, immediate success rate, procedural success rate at 12 months, and relevant complications. In all 151 patients, all the pulmonary veins were acutely isolated using the studied system. Pulsed field ablation delivery was 78.4 ± 41.8 times and 31.3 ± 16.7 ms per patient. Skin-to-skin procedure time was 74.2 ± 29.8 min, and fluoroscopy time was 13.1 ± 7.6 min. The initial 11 (7.2%) cases underwent procedures with deep sedation anaesthesia, and the following cases underwent local anaesthesia. In the initial 11 cases, 4 cases (36.4%) presented transient vagal responses, and the rest were all successfully preventatively treated with atropine injection and rapid fluid infusion. No severe complications were found during or after the procedure. During follow-up, 3 cases experienced atrial flutter, and 11 cases had AF recurrence. The estimated 12-month Kaplan-Meier of freedom from arrhythmia was 88.4%. CONCLUSION: The PFA system, comprised of a circular PFA catheter with magnetic sensors, could rapidly achieve PVI under three-dimensional guidance and demonstrated excellent safety with comparable effects.

CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation.

BACKGROUND: Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown. METHODS: In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events. RESULTS: Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation. Mechanistically, CD151 restrains endothelial release of proinflammatory molecules for less leukocyte infiltration. At the subcellular level, CD151 determines the integrity of multivesicular bodies/lysosomes and confines the production of exosomes that carry cytokines such as ANGPT2 (angiopoietin-2) and proteases such as cathepsin-D. At the molecular level, CD151 docks VCP (valosin-containing protein)/p97, which controls protein quality via mediating deubiquitination for proteolytic degradation, onto endolysosomes to facilitate VCP/p97 function. At the endolysosome membrane, CD151 links VCP/p97 to (1) IFITM3 (interferon-induced transmembrane protein 3), which regulates multivesicular body functions, to restrain IFITM3-mediated exosomal sorting, and (2) V-ATPase, which dictates endolysosome pH, to support functional assembly of V-ATPase. CONCLUSIONS: Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells determines vascular information. Thus, the IFITM3/V-ATPase-tetraspanin-VCP/p97 complexes on endolysosome, as a protein quality control and inflammation-inhibitory machinery, could be beneficial for therapeutic intervention against vascular inflammation.

NT-proBNP ratio is a potential predictor for COVID-19 outcomes in adult Chinese patients: a retrospective study.

Despite the progressive decline in the virulence of the novel coronavirus, there has been no corresponding reduction in its associated hospital mortality. Our aim was to redefine an accurate predictor of mortality risk in COVID-19 patients, enabling effective management and resource allocation. We conducted a retrospective analysis of 2917 adult Chinese patients diagnosed with COVID-19 who were admitted to our hospital during two waves of epidemics, involving the Beta and Omicron variants. Upon admission, NT-proBNP levels were measured, and we collected demographic, clinical, and laboratory data. We introduced a new concept called the NT-proBNP ratio, which measures the NT-proBNP level relative to age-specific maximum normal values. The primary outcome was all-cause in-hospital mortality. Our analysis revealed a higher in-hospital mortality rate in 2022, as shown by the Kaplan-Meier Survival Curve. To assess the predictive value of the NT-proBNP ratio, we employed the time-dependent receiver operating characteristic (ROC) curve. Notably, the NT-proBNP ratio emerged as the strongest predictor of mortality in adult Chinese hospitalized COVID-19 patients (area under the curve, AUC = 0.826; adjusted hazard ratio [HR], 3.959; 95% confidence interval [CI] 3.001-5.221; P < 0.001). This finding consistently held true for both the 2020 and 2022 subgroups. The NT-proBNP ratio demonstrates potential predictive capability compared to several established risk factors, including NT-proBNP, hsCRP, and neutrophil-to-lymphocyte ratio, when it comes to forecasting in-hospital mortality among adult Chinese patients with COVID-19.Trial registration Clinical Trial Registration: www.clinicaltrials.gov NCT05615792.

Nuclear AGO2 promotes myocardial remodeling by activating ANKRD1 transcription in failing hearts.

Heart failure (HF) is manifested by transcriptional and posttranscriptional reprogramming of critical genes. Multiple studies have revealed that microRNAs could translocate into subcellular organelles such as the nucleus to modify gene expression. However, the functional property of subcellular Argonaute2 (AGO2), the core member of the microRNA machinery, has remained elusive in HF. AGO2 was found to be localized in both the cytoplasm and nucleus of cardiomyocytes, and robustly increased in the failing hearts of patients and animal models. We demonstrated that nuclear AGO2 rather than cytosolic AGO2 overexpression by recombinant adeno-associated virus (serotype 9) with cardiomyocyte-specific troponin T promoter exacerbated the cardiac dysfunction in transverse aortic constriction (TAC)-operated mice. Mechanistically, nuclear AGO2 activates the transcription of ANKRD1, encoding ankyrin repeat domain-containing protein 1 (ANKRD1), which also has a dual function in the cytoplasm as part of the I-band of the sarcomere and in the nucleus as a transcriptional cofactor. Overexpression of nuclear ANKRD1 recaptured some key features of cardiac remodeling by inducing pathological MYH7 activation, whereas cytosolic ANKRD1 seemed cardioprotective. For clinical practice, we found ivermectin, an antiparasite drug, and ANPep, an ANKRD1 nuclear location signal mimetic peptide, were able to prevent ANKRD1 nuclear import, resulting in the improvement of cardiac performance in TAC-induced HF.

Artificial-intelligence-based risk prediction and mechanism discovery for atrial fibrillation using heart beat-to-beat intervals.

BACKGROUND: Early diagnosis of atrial fibrillation (AF) is important for preventing stroke and other complications. Predicting AF risk in advance can improve early diagnostic efficiency. Deep learning has been used for disease risk prediction; however, it lacks adherence to evidence-based medicine standards. Identifying the underlying mechanisms behind disease risk prediction is important and required. METHODS: We developed an explainable deep learning model called HBBI-AI to predict AF risk using only heart beat-to-beat intervals (HBBIs) during sinus rhythm. We proposed a possible AF mechanism based on the model's explainability and verified this conjecture using confirmed AF risk factors while also examining new AF risk factors. Finally, we investigated the changes in clinicians' ability to predict AF risk using only HBBIs before and after learning the model's explainability. FINDINGS: HBBI-AI consistently performed well across large in-house and external public datasets. HBBIs with large changes or extreme stability were critical predictors for increased AF risk, and the underlying cause was autonomic imbalance. We verified various AF risk factors and discovered that autonomic imbalance was associated with all these factors. Finally, cardiologists effectively understood and learned from these findings to improve their abilities in AF risk prediction. CONCLUSIONS: HBBI-AI effectively predicted AF risk using only HBBI information through evaluating autonomic imbalance. Autonomic imbalance may play an important role in many risk factors of AF rather than in a limited number of risk factors. FUNDING: This study was supported in part by the National Key R&D Program and the National Natural Science Foundation of China.

LncRNA CHKB-DT Downregulation Enhances Dilated Cardiomyopathy Through ALDH2.

BACKGROUND: Human cardiac long noncoding RNA (lncRNA) profiles in patients with dilated cardiomyopathy (DCM) were previously analyzed, and the long noncoding RNA CHKB (choline kinase beta) divergent transcript (CHKB-DT) levels were found to be mostly downregulated in the heart. In this study, the function of CHKB-DT in DCM was determined. METHODS: Long noncoding RNA expression levels in the human heart tissues were measured via quantitative reverse transcription-polymerase chain reaction and in situ hybridization assays. A CHKB-DT heterozygous or homozygous knockout mouse model was generated using the clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9 system, and the adeno-associated virus with a cardiac-specific promoter was used to deliver the RNA in vivo. Sarcomere shortening was performed to assess the primary cardiomyocyte contractility. The Seahorse XF cell mitochondrial stress test was performed to determine the energy metabolism and ATP production. Furthermore, the underlying mechanisms were explored using quantitative proteomics, ribosome profiling, RNA antisense purification assays, mass spectrometry, RNA pull-down, luciferase assay, RNA-fluorescence in situ hybridization, and Western blotting. RESULTS: CHKB-DT levels were remarkably decreased in patients with DCM and mice with transverse aortic constriction-induced heart failure. Heterozygous knockout of CHKB-DT in cardiomyocytes caused cardiac dilation and dysfunction and reduced the contractility of primary cardiomyocytes. Moreover, CHKB-DT heterozygous knockout impaired mitochondrial function and decreased ATP production as well as cardiac energy metabolism. Mechanistically, ALDH2 (aldehyde dehydrogenase 2) was a direct target of CHKB-DT. CHKB-DT physically interacted with the mRNA of ALDH2 and fused in sarcoma (FUS) through the GGUG motif. CHKB-DT knockdown aggravated ALDH2 mRNA degradation and 4-HNE (4-hydroxy-2-nonenal) production, whereas overexpression of CHKB-DT reversed these molecular changes. Furthermore, restoring ALDH2 expression in CHKB-DT+/- mice alleviated cardiac dilation and dysfunction. CONCLUSIONS: CHKB-DT is significantly downregulated in DCM. CHKB-DT acts as an energy metabolism-associated long noncoding RNA and represents a promising therapeutic target against DCM.

Gut microbiota-dependent phenylacetylglutamine in cardiovascular disease: current knowledge and new insights.

Phenylacetylglutamine (PAGln) is an amino acid derivate that comes from the amino acid phenylalanine. There are increasing studies showing that the level of PAGln is associated with the risk of different cardiovascular diseases. In this review, we discussed the metabolic pathway of PAGln production and the quantitative measurement methods of PAGln. We summarized the epidemiological evidence to show the role of PAGln in diagnostic and prognostic value in several cardiovascular diseases, such as heart failure, coronary heart disease/atherosclerosis, and cardiac arrhythmia. The underlying mechanism of PAGln is now considered to be related to the thrombotic potential of platelets via adrenergic receptors. Besides, other possible mechanisms such as inflammatory response and oxidative stress could also be induced by PAGln. Moreover, since PAGln is produced across different organs including the intestine, liver, and kidney, the cross-talk among multiple organs focused on the function of this uremic toxic metabolite. Finally, the prognostic value of PAGln compared to the classical biomarker was discussed and we also highlighted important gaps in knowledge and areas requiring future investigation of PAGln in cardiovascular diseases.

Chinese Society of Cardiology guidelines on the diagnosis and treatment of adult fulminant myocarditis.

Fulminant myocarditis is an acute diffuse inflammatory disease of myocardium. It is characterized by acute onset, rapid progress and high risk of death. Its pathogenesis involves excessive immune activation of the innate immune system and formation of inflammatory storm. According to China's practical experience, the adoption of the "life support-based comprehensive treatment regimen" (with mechanical circulation support and immunomodulation therapy as the core) can significantly improve the survival rate and long-term prognosis. Special emphasis is placed on very early identification,very early diagnosis,very early prediction and very early treatment.

Molecular recognition and activation of the prostacyclin receptor by anti-pulmonary arterial hypertension drugs.

The prostacyclin (PGI2) receptor (IP) is a Gs-coupled receptor associated with blood pressure regulation, allergy, and inflammatory response. It is a main therapeutic target for pulmonary arterial hypertension (PAH) and several other diseases. Here we report cryo-electron microscopy (cryo-EM) structures of the human IP-Gs complex bound with two anti-PAH drugs, treprostinil and MRE-269 (active form of selexipag), at global resolutions of 2.56 and 2.41 angstrom, respectively. These structures revealed distinct features governing IP ligand binding, receptor activation, and G protein coupling. Moreover, comparison of the activated IP structures uncovered the mechanism and key residues that determine the superior selectivity of MRE-269 over treprostinil. Combined with molecular docking and functional studies, our structures provide insight into agonist selectivity, ligand recognition, receptor activation, and G protein coupling. Our results provide a structural template for further improving IP-targeting drugs to reduce off-target activation of prostanoid receptors and adverse effects.

The Translation, Culture-Adaptation and Psychometric Evaluation of the Cardiac Rehabilitation Barriers Scale Among Chinese Older Population.

Purpose: This study aimed to translate and cross-culturally adapt the cardiac rehabilitation barriers scale to the Chinese, and examine its reliability and validity among the older population. Methods: An approach comprising translation, cultural adaptation, reliability, and validity examination in the Chinese version was conducted in two hospitals in Jilin, China. The t-tests were used to compare the sex differences between each item. Participants included Chinese individuals >60 who were eligible for the cardiac rehabilitation program. Results: In total, 325 participants completed the questionnaire with an average age of 61.23 ± 9.68 years. The item-total correlations were 0.432 to 0.678. Factor analysis of CRBS-C (Kaiser Meyer Olkin = 0.867, Bartlett's test p = 0.000) revealed four factors: logistical factors, comorbidities/functional status, perceived need/healthcare factors, and work/time conflict. The confirmatory factor analysis (CFA) indicated a good model fit (χ2/df = 1.84, RMSEA = 0.051, CFI = 0.953, TLI = 0.945, SRMR=0.046). Cronbach's alpha was 0.88 for the scale, ranging from 0.801 to 0.88 for each item, which indicates the internal reliability was acceptable. Conclusion: The Chinese version of the CRRS has acceptable reliability and validity in the Chinese elderly population.

Ganglioside GM3 Protects Against Abdominal Aortic Aneurysm by Suppressing Ferroptosis.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a potentially life-threatening vascular condition, but approved medical therapies to prevent AAA progression and rupture are currently lacking. Sphingolipid metabolism disorders are associated with the occurrence and development of AAA. It has been discovered that ganglioside GM3, a sialic acid-containing type of glycosphingolipid, plays a protective role in atherosclerosis, which is an important risk factor for AAA; however, the potential contribution of GM3 to AAA development has not been investigated. METHODS: We performed a metabolomics study to evaluated GM3 level in plasma of human patients with AAA. We profiled GM3 synthase (ST3GAL5) expression in the mouse model of aneurysm and human AAA tissues through Western blotting and immunofluorescence staining. RNA sequencing, affinity purification and mass spectrometry, proteomic analysis, surface plasmon resonance analysis, and functional studies were used to dissect the molecular mechanism of GM3-regulating ferroptosis. We conditionally deleted and overexpressed St3gal5 in smooth muscle cells (SMCs) in vivo to investigate its role in AAA. RESULTS: We found significantly reduced plasma levels of GM3 in human patients with AAA. GM3 content and ST3GAL5 expression were decreased in abdominal aortic vascular SMCs in patients with AAA and an AAA mouse model. RNA sequencing analysis showed that ST3GAL5 silencing in human aortic SMCs induced ferroptosis. We showed that GM3 interacted directly with the extracellular domain of TFR1 (transferrin receptor 1), a cell membrane protein critical for cellular iron uptake, and disrupted its interaction with holo-transferrin. SMC-specific St3gal5 knockout exacerbated iron accumulation at lesion sites and significantly promoted AAA development in mice, whereas GM3 supplementation suppressed lipid peroxidation, reduced iron deposition in aortic vascular SMCs, and markedly decreased AAA incidence. CONCLUSIONS: Together, these results suggest that GM3 dysregulation promotes ferroptosis of vascular SMCs in AAA. Furthermore, GM3 may constitute a new therapeutic target for AAA.

LncRNA MIR217HG aggravates pressure-overload induced cardiac remodeling by activating miR-138/THBS1 pathway.

AIM: Cardiac hypertrophy and fibrosis are associated with cardiac remodeling and heart failure. We have previously shown that miRNA-217, embedded within the third intron of MIR217HG, aggravates pressure overload-induced cardiac hypertrophy by targeting phosphatase and tensin homolog. However, whether the MIR217HG transcript itself plays a role in cardiac remodeling remains unknown. METHODS: Real-time PCR assays and RNA in situ hybridization were performed to detect MIR217HG expression. Lentiviruses and adeno-associated viruses with a cardiac-specific promoter (cTnT) were used to control MIR217HG expression in vitro and in vivo. Transverse aortic constriction (TAC) surgery was performed to develop cardiac remodeling models. Cardiac structure and function were analyzed using echocardiography and invasive pressure-volume analysis. KEY FINDINGS: MIR217HG expression was increased in patients with heart failure. MIR217HG overexpression aggravated pressure-overload-induced myocyte hypertrophy and fibrosis both in vivo and in vitro, whereas MIR217HG knockdown reversed these phenotypes. Mechanistically, MIR217HG increased THBS1 expression by sponging miR-138. MiR-138 recognized the 3'UTR of THBS1 and repressed THBS1 expression in the absence of MIR217HG. Silencing THBS1 expression reversed MIR217HG-induced cardiac hypertrophy and remodeling. CONCLUSION: MIR217HG acts as a potent inducer of cardiac remodeling that may contribute to heart failure by activating the miR-138/THBS1 pathway.

AGO2 Protects Against Diabetic Cardiomyopathy by Activating Mitochondrial Gene Translation.

BACKGROUND: Diabetes is associated with cardiovascular complications. microRNAs translocate into subcellular organelles to modify genes involved in diabetic cardiomyopathy. However, functional properties of subcellular AGO2 (Argonaute2), a core member of miRNA machinery, remain elusive. METHODS: We elucidated the function and mechanism of subcellular localized AGO2 on mouse models for diabetes and diabetic cardiomyopathy. Recombinant adeno-associated virus type 9 was used to deliver AGO2 to mice through the tail vein. Cardiac structure and functions were assessed by echocardiography and catheter manometer system. RESULTS: AGO2 was decreased in mitochondria of diabetic cardiomyocytes. Overexpression of mitochondrial AGO2 attenuated diabetes-induced cardiac dysfunction. AGO2 recruited TUFM, a mitochondria translation elongation factor, to activate translation of electron transport chain subunits and decrease reactive oxygen species. Malonylation, a posttranslational modification of AGO2, reduced the importing of AGO2 into mitochondria in diabetic cardiomyopathy. AGO2 malonylation was regulated by a cytoplasmic-localized short isoform of SIRT3 through a previously unknown demalonylase function. CONCLUSIONS: Our findings reveal that the SIRT3-AGO2-CYTB axis links glucotoxicity to cardiac electron transport chain imbalance, providing new mechanistic insights and the basis to develop mitochondria targeting therapies for diabetic cardiomyopathy.

Genetic insights into associations of multisite chronic pain with common diseases and biomarkers using data from the UK Biobank.

BACKGROUND: Chronic pain is a common, complex, and challenging condition, for which specialised healthcare is required. We investigated the relationship between multisite chronic pain (MCP) and different disease traits identify safe biomarker interventions that can prevent MCP. METHODS: Univariable and multivariable Mendelian randomisation (MR) analysis were conducted to investigate associations between MCP and 36 common diseases in the UK Biobank. Subsequently, we estimated the potential effect of expression of 4774 proteins on MCP utilising existing plasma protein quantitative trait locus data. For the significant biomarkers, we performed phenome-wide MR (Phe-MR) with 1658 outcomes to predict potential safety profiles linked to biomarker intervention. RESULTS: Multisite chronic pain had a substantial impact on psychiatric and neurodevelopmental traits (major depression and attention deficit hyperactivity disorder), cardiovascular diseases (myocardial infarction, coronary artery disease, and heart failure), respiratory outcomes (asthma, chronic obstructive pulmonary disease, and sleep apnoea), arthropathies, type 2 diabetes mellitus, and cholelithiasis. Higher genetically predicted levels of S100A6, DOCK9, ferritin, and ferritin light chain were associated with a risk of MCP, whereas PTN9 and NEUG were linked to decreased MCP risk. Phe-MR results suggested that genetic inhibition of DOCK9 increased the risk of 21 types of disease, whereas the other biomarker interventions were relatively safe. CONCLUSIONS: We established that MCP has an effect on health conditions covering various physiological systems and identified six novel biomarkers for intervention. In particular, S100A6, PTN9, NEUG, and ferritin light chain represent promising targets for MCP prevention, as no significant side-effects were predicted in our study.

High intake of cruciferous vegetables reduces the risk of gastrointestinal cancers: results from observational studies.

The relationship between cruciferous vegetables (CV) and the risk of gastrointestinal (GI) cancers has been extensively investigated. However, epidemiologic investigations have produced inconsistent results. This meta-analysis investigated the association between CV intake and the risk of GI cancers. Due to the heterogeneity, fixed- or random-effects models were used for the analyses. The final analysis included 81 articles covering 89 studies. In comparison to the lowest consumption categories, the highest consumption categories of CV were associated with a lower risk for all GI cancers [rate ratio (RR): 0.81, 95% confidence interval (95% CI) 0.76-0.87]. Compared to a CV intake of 75 g/day, subjects with CV intake <75 g/day experienced a 7% reduction in risk (RR: 0.93; 95% CI: 0.84-0.96) for each 50 g increase in consumption. A negative correlation was identified between CV intake and the risk of esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, and colorectal cancer (CRC), but not gallbladder cancer (RR: 0.70; 95% CI: 0.38-1.27). High intake of broccoli and cabbage was associated with a decreased risk of gastric cancer (RR: 0.64; 95% CI: 0.47-0.87) and gallbladder cancer (RR: 0.46; 95% CI: 0.29-0.75). These results confirm the association between high intake of CV with a reduced risk of GI cancers.

Myocardial injury and related mortality in hospitalized patients with COVID-19 during the Omicron pandemic: new perspectives and insights.

Myocardial injury is one of the most common comorbidity in SARS-CoV-2 infected patients, and has poor prognosis. However, the incidence of myocardial injury in patients with SARS-CoV-2 infection has not been sufficiently investigated during the Omicron wave. We conducted a retrospective study of 2690 patients with confirmed SARS-CoV-2 Omicron infection from Tongji Hospital. The results indicated that the myocardial injury accounted for 30.8% of the total patients with SARS-CoV-2 infection and was associated with higher in-hospital mortality than those without injury before and after propensity score matching (PSM) [adjusted hazard ratio (HR), 10.61; 95% confidence interval (CI), 7.76-14.51; P â€‹< â€‹0.001; adjusted HR, 2.70; 95% CI, 1.86-3.93; P â€‹< â€‹0.001; respectively]. Further, the levels of cytokines (IL-1ß, IL-6, IL-10, and TNF-α) in patients with myocardial injury were higher than those without injury, and the higher levels of cytokines in the myocardial injury group were associated with increased mortality. Administration of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB) could significantly reduce the mortality in patients with myocardial injury (adjusted HR, 0.52; 95% CI, 0.38-0.71; P â€‹< â€‹0.001). Additionally, the level of angiotensin II increased in patients with SARS-CoV-2 infection was even higher in myocardial injury group compared to those without injury. Collectively, the study summarized the clinical characteristic and outcome of SARS-CoV-2 infected patients with myocardial injury during the Omicron wave in China, and validated the protective role of ACEI/ARB in improving the survival of those with myocardial injury.

Self-recruited neutrophils trigger over-activated innate immune response and phenotypic change of cardiomyocytes in fulminant viral myocarditis.

Fulminant myocarditis (FM) is a life-threatening inflammatory disease. However, the mechanisms underlying its acute onset are unknown. By dynamic cardiac function measurement, we discovered that the initiation of sudden hemodynamic collapse was on day 4 in the mouse model of FM. Single-cell RNA-sequencing study revealed that healthy cardiomyocytes (CMs) lost their contractile and metabolic function and differentiated into pro-angiogenic and pro-inflammatory CMs. Meanwhile, neutrophils, the most expanded immune cells, exhibited a unique developmental trajectory only after migrating to the heart, where they continuously attracted peripheral neutrophils via Cxcl2/Cxcl3, resulting in the acute accumulation of neutrophils in the heart. Well-differentiated cardiac-infiltrating neutrophils, rather than viruses, induced phenotypic changes in CMs. Moreover, neutrophils could amplify cytokine storm by recruiting and activating pro-inflammatory monocytes. Blockade of the self-recruiting loop of neutrophils by targeting the Cxcl2/Cxcl3-Cxcr2 axis substantially alleviated FM in mice. Collectively, we provide a comprehensive single-cell atlas of immune cells and CMs in FM, elucidate the disease pathogenesis, and suggest potential therapeutic strategies.

Glimepiride, a novel soluble epoxide hydrolase inhibitor, protects against heart failure via increasing epoxyeicosatrienoic acids.

BACKGROUND: Epoxyeicosatrienoic acids (EETs), which exert multiple endogenous protective effects, are hydrolyzed into less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). However, commercial drugs related to EETs or sEH are not yet in clinical use. METHODS: Firstly, the plasma concentration of EETs and DHETs of 316 patients with heart failure (HF) were detected and quantitated by liquid chromatography-tandem mass spectrometry. Then, transverse aortic constriction (TAC)-induced HF was introduced in cardiomyocyte-specific Ephx2-/- mice. Moreover, Western blot, real-time PCR, luciferase reporter, ChIP assays were employed to explore the underlying mechanism. Finally, multiple sEH inhibitors were designed, synthesized, and validated in vitro and in vivo. RESULTS: The ratios of DHETs/EETs were increased in the plasma from patients with HF. Meanwhile, the expression of sEH was upregulated in the heart of patients and mice with HF, especially in cardiomyocytes. Cardiomyocyte-specific Ephx2-/- mice ameliorated cardiac dysfunction induced by TAC. Consistently, Ephx2 knockdown protected Angiotensin II (AngII)-treated cardiomyocytes via increasing EETs in vitro. Mechanistically, AngII could enhance the expression of transcript factor Krüppel-like factor 15 (KLF15), which in turn upregulated sEH. Importantly, glimepiride was identified as a novel sEH inhibitor, which benefited from the elevated EETs during HF. CONCLUSIONS: Glimepiride attenuates HF in mice in part by increasing EETs. CLINICAL TRIAL IDENTIFIER: NCT03461107 (https://clinicaltrials.gov).

Epoxyeicosatrienoic Acids Prevent Cardiac Dysfunction in Viral Myocarditis via Interferon Type I Signaling.

Myocarditis is a challenging inflammatory disease of the heart, and better understanding of its pathogenesis is needed to develop specific drug therapies. Epoxyeicosatrienoic acids (EETs), active molecules synthesized by CYP (cytochrome P450) enzymes from arachidonic acids and hydrolyzed to less active dihydroxyeicosatrienoic acids by sEH (soluble epoxide hydrolase), have been attributed anti-inflammatory activity. Here, we investigated whether EETs have immunomodulatory activity and exert protective effects on coxsackie B3 virus-induced myocarditis. Viral infection altered eicosanoid epoxide and diol levels in both patients with myocarditis and in the murine heart and correlated with the increased expression and activity of sEH after coxsackie B3 virus infection. Administration of a sEH inhibitor prevented coxsackie B3 virus-induced cardiac dysfunction and inflammatory infiltration. Importantly, EET/sEH inhibitor treatment attenuated viral infection or improved viral resistance by activating type I IFN (interferon) signaling. At the molecular level, EETs enhanced the interaction between GSK3ß (glycogen synthase kinase-3 beta) and TBK1 (TANK-binding kinase 1) to promote IFN-ß production. Our findings revealed that EETs and sEH inhibitors prevent the progress of coxsackie B3 virus-induced myocarditis, particularly by promoting viral resistance by increasing IFN production.