Background: Myocardial ischemia/reperfusion injury (MIRI) remains a leading cause of morbidity and mortality in patients with cardiovascular disease. Ferroptosis, an iron-dependent form of regulated cell death, has been increasingly implicated in cardiomyocyte damage during MIRI. Heat shock factor 1 (HSF1) and heme oxygenase-1 (HMOX1) are stress-responsive proteins, but their interplay in regulating ferroptosis during myocardial injury has not been fully elucidated. This study aimed to investigate the role of the HSF1-HMOX1 axis in modulating ferroptosis and myocardial injury after ischemia/reperfusion (I/R). Methods: An I/R rat model was established by transient ligation of the left anterior descending coronary artery, with shamoperated rats serving as controls. H9c2 cardiomyocytes subjected to hypoxia/reoxygenation (H/R) and co-cultured with RAW 264.7 macrophages were used for in vitro experiments. HSF1 overexpression and knockdown, as well as HMOX1 knockdown via siRNA, were performed. Myocardial injury was assessed by measurement of serum creatine kinase-myocardial band (CK-MB) and cardiac troponin I (cTn-I), as well as histologic and immunohistochemical means. Ferroptosis was evaluated using cell viability assays, reactive oxygen species (ROS) detection, and protein detection of glutathione peroxidase 4 (GPX4), SLC7A11, and ACSL4 by means of Western blotting. Inflammatory responses and macrophage polarization were analyzed by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Results: HSF1 and HMOX1 expression were transiently upregulated in myocardial tissues during early I/R but decreased at 24 h. HSF1 overexpression further increased ROS accumulation and exacerbated ferroptosis, as reflected by GPX4 downregulation and ACSL4 upregulation. Conversely, HSF1 knockdown attenuated ferroptosis and injury. HMOX1 knockdown reversed the pro-ferroptotic effects of HSF1 overexpression, indicating that HMOX1 mediates HSF1-induced ferroptosis. Furthermore, the HSF1-HMOX1 axis promoted macrophage polarization toward the pro-inflammatory M1 phenotype, enhancing tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6 secretion. Conclusions: The HSF1-HMOX1 axis promotes ferroptosis and exacerbates myocardial damage in ischemia/reperfusion injury by integrating stress response pathways and inflammatory regulation. Inhibiting this axis may represent a promising therapeutic strategy for reducing MIRI and improving cardiac outcomes.

Background Increasing evidence shows sex-specific differences in the efficacy of cardiac resynchronization therapy (CRT). Without a clear cardiac rationale, relying solely on sex to evaluate resynchronization outcomes is insufficient. Objectives This study sought to assess whether QRS duration (QRSd) normalized to cardiac size (QRSd/left ventricular end-diastolic dimension [QRSd/LVEDD]) could underlie the observed sex-specific differences in resynchronization efficacy and guide CRT implantation. Methods This multicenter retrospective study screened 602 patients with heart failure who underwent biventricular or left bundle branch area pacing for resynchronization therapy. The primary composite outcome included all-cause mortality, heart failure hospitalizations, and ventricular tachyarrhythmic events. Interaction analysis and structural equation modeling were applied to evaluate whether QRSd/LVEDD could independently predict outcomes and elucidate sex-specific differences. Results Compared with male patients, female patients (n = 216) had a higher QRSd/LVEDD ratio (2.66 vs 2.48; P < 0.001). After QRSd/LVEDD adjustment, female patients no longer exhibited greater left ventricular ejection fraction improvement. Sex-specific differences initially observed in clinical outcomes (HR: 1.71; 95% CI: 1.17-2.48; P = 0.005) were eliminated by QRSd/LVEDD (HR: 1.14; 95% CI: 0.76-1.69; P = 0.527), with a significant dose-response relationship (P < 0.001). QRSd/LVEDD also stratified prognosis within each sex group (P < 0.001). No sex-specific differences were found among patients with the same QRSd/LVEDD (QRSd/LVEDD ≥2.55, P = 0.744; QRSd/LVEDD <2.55, P = 0.123). Structural equation modeling revealed that sex did not directly influence clinical outcomes (P = 0.693) but exerted an indirect effect through QRSd/LVEDD (P < 0.001). QRSd/LVEDD exhibited superior ability to predict clinical outcomes compared with QRSd and was integrated into machine learning modeling for individualized CRT risk prediction. Conclusions QRSd/LVEDD effectively eliminated sex-specific differences in CRT efficacy and outperformed QRSd in predicting clinical outcomes. Sex did not directly influence CRT outcomes but mediated its effect indirectly through QRSd/LVEDD.

BACKGROUND:Doxorubicin (Dox) is a widely-used anthracycline drug for various cancers, but its clinical application is limited due to cardiotoxicity. Targeting ferroptosis is a new and effective strategy for treating Dox-induced cardiomyopathy (DIC). The arachidonate lipoxygenase 5 (ALOX5) metabolism axis is closely linked to ferroptosis, but its role in DIC remains unknown. METHODS:In vivo and in vitro DIC models were established to investigate the role of the ALOX5 metabolism axis in DIC and to clarify the underlying mechanism using genetic and pharmacological approaches. RESULTS:Our findings revealed that ALOX5 and 5-hydroxyicosatetraenoic acid (5-HETE) levels were increased in DIC. Overexpression of Alox5 exacerbated Dox-induced cardiac dysfunction and myocardial injury, whereas pharmacological inhibition and genetic knockdown of ALOX5 alleviated these effects by modulating ferroptosis. Mechanistically, elevated ALOX5 catalyzed the metabolism of arachidonic acid to generate 5-HETE, which facilitated NRF2 ubiquitination-dependent degradation via PI3K/AKT/GSK-3β signaling, thereby contributing to cardiomyocyte ferroptosis. CONCLUSIONS:This study suggests that targeting cardiomyocyte ferroptosis mediated by the ALOX5 metabolism axis may represent a therapeutic strategy for DIC.

BACKGROUND:The circuit of scar-related upper loop macroreentry atrial flutter (AFL) surrounding the superior vena cava (SVC) has been described by prior case reports. However, the correlation between the circuit and arrhythmogenic substrates and the corresponding optimized ablation strategy need to be further investigated. OBJECTIVE:We aimed to identify the electrophysiologic substrate and corresponding ablation strategies of SVC-AFL using high-resolution mapping. METHODS:From June 1, 2017, to May 1, 2023, consecutive patients with macroreentrant atrial tachycardias (ATs) from 7 institutions were retrospectively evaluated. Patients with SVC-AFL were enrolled and analyzed. RESULTS:Of 1282 patients with macroreentrant ATs, 16 patients (1.2%; median age, 60.9 years; 8 male) had SVC-AFL (mean cycle length, 281.0 ± 55.1 ms), all identified during high-resolution activation mapping. All patients had prior cardiac surgery (14 [87.5%]) or catheter ablation (8 [50.0%]). A longitudinal surgical incision/scar extending from the SVC to the right atrium was observed in all patients, enabling macroreentry. SVC-AFLs with shorter circuits (<180 mm) had more slow conduction areas than those with longer circuits (>180 mm; 3.0 [2.0-4.0] vs 1.0 [1.0-1.5]; P = .023]. All ATs were terminated by ablating the channel between the surgical incision/scar and anatomic barriers. Cavotricuspid isthmus block was achieved in all patients. During a 21-month follow-up, all patients were free of atrial arrhythmias except for 4 patients experiencing short-lived paroxysmal ATs that did not require further ablation. CONCLUSION:A surgical incision/scar extending from the SVC to right atrium promotes the development of SVC-AFL. Substrate-based linear lesions along with prophylactic cavotricuspid isthmus ablation afford favorable clinical outcomes.

AIM:The aim of this study is to determine the possible role of N-methyl-D-aspartate receptor (NMDAR) dysregulation in the ischemic electrical remodeling observed in patients with myocardial infarction (MI) and elucidate the underlying mechanisms. METHODS:Human heart tissue was obtained from the border of the infarct and remote zones of patients with ischemic heart disease, and mouse heart tissue was obtained from the peri-infarct zone. NMDAR expression was detected using immunofluorescence (IF) and Western blotting (WB). Spontaneous ventricular arrhythmias (VAs) in mice were detected using electrocardiogram backpacks. Electrical remodeling post-MI was detected using patch clamp recordings, quantitative real-time polymerase chain reactions, IF, and WB. Mechanistic studies were performed using bioinformatic analysis, plasmid and small interfering RNA transfection, lentiviral packaging, and site-directed mutagenesis. RESULTS:NMDAR is highly expressed in patients with ischemic heart disease and mice with MI. NMDAR inhibition reduces the occurrence of VAs. Mechanistically, NMDAR activation promotes electrophysiological remodeling, as characterized by decreased Nav1.5, Kv11.1, Kv4.2, Kv7.1, Kir2.1, and Cav1.2 expression in patients with ischemic heart disease and mice with MI and rescues these ion channels dysregulation in mice with MI to varying degrees by NMDAR inhibition. Decreased Nav1.5 expression and inward sodium current density were attenuated by NMDAR inhibition in primary rat cardiomyocytes. Moreover, NMDAR activation upregulates T-Box Transcription Factor 3 (TBX3) post-translationally, further downregulating Nav1.5 transcriptionally. Furthermore, AKT1 is the predominant isoform in the ventricular myocardium upstream of TBX3 and mediates NMDAR-induced TBX3 upregulation in cardiomyocytes. CONCLUSION:NMDAR activation contributes to MI-induced VAs by regulating the AKT1-TBX3-Nav1.5 axis, providing novel therapeutic strategies for treating ischemic arrhythmias.

Background:Frequent premature ventricular contractions (PVCs) can induce cardiomyopathy; however, there is a lack of early indicators to assess the cardiac functional impact of PVCs originating from different sites. This study employed three-dimensional speckle-tracking imaging (3D-STI) to compare myocardial torsion and deformation characteristics of PVCs from varying origins during sinus beats, PVC beats, and compensatory beats, with the aim of examining the early indicators of cardiac function. Methods:Ninety-one patients (28 males, 63 females) with single-source PVCs who underwent successful radiofrequency ablation were enrolled. Preoperative echocardiographic parameters were collected, including mitral inflow velocity (E/A), tissue Doppler indices (EmS, EmL, and E/e'), and left ventricular ejection fraction (LVEF). We used 3D-STI to measure parameters such as peak left ventricular torsion angle, basal/apical rotation time-to-peak difference, and global longitudinal strain, radial strain, and circumferential strain to compare myocardial mechanical features of PVCs from different origins. Results:Left/right ventricular systolic function during PVC beats was significantly lower than during sinus beats (P<0.05), whereas compensatory beats exhibited superior function as compared to sinus rhythm. PVCs of different origins primarily affected apical rotation angle (RotA) (P=0.021) and global rotation angle (P=0.043) during sinus beats. During PVC beats, significant differences were observed in basal radial strain (P<0.001) and right ventricular longitudinal strain (P=0.013). Coupling interval showed a strong positive correlation with left ventricular global longitudinal strain (r=0.732; P<0.001). Conclusions:3D-STI enables the quantitative assessment of PVC-related myocardial motion. (I) PVC beats exhibited the worst systolic function, while compensatory beats demonstrated enhanced compensatory function. (II) Left ventricular global longitudinal peak strain, basal radial peak strain, and strain time-to-peak difference may serve as sensitive indicators for early cardiac dysfunction. (III) Shortening of the coupling interval is a critical risk factor for cardiac functional deterioration. This study provides novel imaging-based evidence for the early identification of and clinical intervention in PVC-induced myocardial damage.

Aims: Doxorubicin (Dox) is a potent chemotherapy agent, yet its clinical use is hampered by cardiotoxicity. Although extensive research has focused on Dox-induced cardiotoxicity (DIC), its mechanism remains elusive. Recent evidence implicates ferroptosis as a key contributor to DIC. The 15-lipoxygenase-1 (ALOX15), involved in lipid peroxidation, is known to play an essential role in ischemia-induced myocardial damage and heart failure; however, its function in DIC is undefined. This study seeks to elucidate the role of ALOX15 in DIC and unravel its underlying mechanism. Results: Both ALOX15 mRNA and protein levels were elevated in DIC models in vivo and in vitro. Inhibition or silencing of ALOX15 ameliorated lipid peroxidation, ferroptosis, and cardiac dysfunction in Dox-treated mice. Consistently, ALOX15 loss of function protected H9C2 cells against Dox and RSL3-induced toxicity. In addition, we found that linoleic acid increased the susceptibility of H9C2 cells toward Dox-induced damage, which was abolished by ALOX15 inhibition. Furthermore, Alox15 overexpression aggravated Dox-induced cell damage by aggravating reactive oxygen species (ROS)-mediated ferroptosis. Mechanistically, we discovered that the amelioration of Dox-induced ferroptosis by ALOX15 loss of function occurred through inhibiting the ROS-mediated mitogen-activated protein kinase (MAPK) signaling pathway activation. Innovation and Conclusion: These results reveal that ALOX15 regulates ferroptosis through ROS-mediated MAPK signaling pathway in DIC, suggesting a potential therapeutic target for DIC intervention. Antioxid. Redox Signal. 00, 000-000.

Cardiovascular aging is a progressive remodeling process constituting a variety of cellular and molecular alterations that are closely linked to mitochondrial dysfunction. Therefore, gaining a deeper understanding of the changes in mitochondrial function during cardiovascular aging is crucial for preventing cardiovascular diseases. Cardiac aging is accompanied by fibrosis, cardiomyocyte hypertrophy, metabolic changes, and infiltration of immune cells, collectively contributing to the overall remodeling of the heart. Similarly, during vascular aging, there is a profound remodeling of blood vessel structure. These remodeling present damage to endothelial cells, increased vascular stiffness, impaired formation of new blood vessels (angiogenesis), the development of arteriosclerosis, and chronic vascular inflammation. This review underscores the role of mitochondrial dysfunction in cardiac aging, exploring its impact on fibrosis and myocardial alterations, metabolic remodeling, immune response remodeling, as well as in vascular aging in the heart. Additionally, we emphasize the significance of mitochondria-targeted therapies in preventing cardiovascular diseases in the elderly.

Doxorubicin (Dox) is a widely used antitumor agent with dose-dependent and cumulative cardiotoxic effects. Resveratrol (Res) is a natural non-flavonoid polyphenol that can potentially provide cardiovascular benefits. We aimed to estimate the protective effect of Res on Dox-induced cardiotoxicity (DIC) and explore whether it was related to attenuating ferroptosis. We established DIC models in C57BL/6 J mice, H9C2 cardiomyoblasts, and neonatal rat cardiomyocytes (NRCMs). We further treated H9C2 cells with RSL3, a ferroptosis agonist, to investigate whether Res exerted protective effects through inhibiting ferroptosis. Ferrostatin-1 (Fer-1) was applied to suppress ferroptosis. Dox treatment caused cardiac dysfunction and resulted in apparent ferroptotic damage in cardiac tissue, involving increased iron accumulation, glutathione depletion, increased expression of ferroptosis-related proteins, and decreased expression of glutathione peroxidase 4, which were alleviated by Fer-1 and Res administration. These findings were also confirmed in Dox-treated H9C2 cells and NRCMs, with Fer-1 and Res effectively attenuating Dox-induced cytotoxicity and ferroptosis. Furthermore, Res protected H9C2 cells from RSL3-induced ferroptotic cell death, and the protective effect was similar to that of Fer-1. Both Dox and RSL3 treatment increased the phosphorylation levels of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinases; however, these changes were hindered by Res. This study demonstrates that Res effectively alleviates DIC by suppressing ferroptosis possibly through modulating the MAPK signaling pathway. Our results highlight that targeting ferroptosis can be a potential cardioprotective strategy for DIC.

OBJECTIVES:Serum matrix metalloproteinase (MMP) levels are associated with cardiovascular diseases. However, the causal associations between serum levels of specific MMPs and venous thromboembolism (VTE) remain unclear. The present study sought to explore the causal relationship between serum MMP levels and VTE by using the Mendelian randomization (MR) method.METHODS:In this study 2-sample MR study, the exposure data on serum MMP levels were derived from genome-wide association studies involving 21,758 individuals from 13 cohorts of European descent. The outcome data on VTE, including deep vein thrombosis and pulmonary embolism, were derived from the FinnGen research project. The primary method used was the inverse-variance weighting method. The MR-Egger intercept test and the Cochran Q test were used to evaluate pleiotropy and heterogeneity.RESULTS:Using the inverse-variance weighting method, higher serum MMP-12 levels were found to be associated with an increased risk of VTE (odds ratio, 1.04; 95% confidence interval, 1.01 to 1.07; p=0.001). Moreover, there was a weak association between the levels of certain MMPs and VTE. Sensitivity analyses revealed no significant heterogeneity and pleiotropy in our study, and the Steiger directionality test did not reveal a significant reverse causation association.CONCLUSIONS:There is a causal association between MMP-12 levels and VTE, which may have substantial implications for the diagnostic and therapeutic strategies used for VTE.

BACKGROUND:The latest information regarding the awareness of atrial fibrillation (AF) remains limited in China. OBJECTIVES:The present study aimed to understand the variation and disparity in awareness of AF in China. METHODS:The cross-sectional study used data from the 2020 nationwide epidemiology survey on AF among adults aged 18 years or older in mainland China to assess the prevalence of AF awareness. The awareness of AF diagnostic methods and outcomes was also assessed using an interviewer-administered questionnaire. RESULTS:Of the 114,039 adults responding to the survey, 1463 (age-standardized prevalence, 55.3% (95% confidence interval [CI], 47.7-62.9%) and 10,202 (8.2%, 95%CI 5.4-10.9%) were aware of AF in participants with and without AF, respectively. Of these, 36.4% (95%CI 30.0-42.9%) and 6.3% (95%CI 3.6-9.1%) considered electrocardiogram as a method of diagnosing AF, and 30.0% (95% CI 3.2-8.2%) and 5.2% (95%CI 2.7-7.6%) considered stroke as an outcome of AF. The proportion of participants who being aware of AF varied significantly across sociodemographic and cardiovascular disease subgroups, and was almost consistently lower in rural areas than those in urban areas. Overall, lack of AF awareness was associated with rural areas, geographical region, lower education levels, and without history and had no risk factors of cardiovascular disease. CONCLUSIONS:Nearly half of adults with AF, and >90% non-AF population are unaware of AF in China, with significant variation and disparity. Focused public health initiatives are needed to improve awareness and knowledge of AF among high-risk populations.

Background: Despite receiving pacemaker therapy, patients with heart failure with reduced ejection fraction (HFrEF) due to dilated cardiomyopathy (DCM) remain at an increased risk of adverse cardiovascular events. The high-sensitivity C-reactive protein (hs-CRP)-to-albumin ratio (CAR) is a novel indicator. This study aimed to assess the prognostic value of preoperative CAR in this population. Methods: Patients with DCM who underwent cardiac resynchronization therapy (CRT) or implantable cardiac defibrillator (ICD) implantation for HFrEF between 2018 and 2023 were involved. The primary endpoint was major adverse cardiac events (MACE). Cox regression models were used to investigate predictors for MACE. Receiver operating characteristic (ROC) curve analysis was utilized to evaluate the diagnostic efficacy and identify the optimal cutoff point. Results: We enrolled 250 patients, of whom 78 experienced MACE. Patients who experienced MACE had a significantly higher CAR than those without MACE (p < 0.001). Multivariate Cox regression analysis indicated CAR as an independent predictor for MACE (hazard ratio = 4.301, 95 % confidence interval [CI] 1.833–10.091, p < 0.001). ROC curve analysis demonstrated the discriminatory ability of CAR in predicting MACE (area under the curve [AUC] = 0.732, 95 % CI 0.666–0.792, p < 0.001), with an optimal threshold of 0.08. Furthermore, the incidence of MACE was significantly higher in the high-CAR (> 0.08) group compared to the low-CAR (≤ 0.08) group (48.8 % vs. 13.6 %, p < 0.001). Conclusion: Among patients with DCM and HFrEF treated with CRT or ICD, CAR can serve as an independent risk predictor, with higher levels associated with poorer outcomes.

Aim: To evaluate the costs and consequences of two front-line atrial fibrillation (AF) treatments from Chinese healthcare system perspective: radiofrequency catheter ablation (RFCA) using ThermoCool SmartTouch Catheter guided by Ablation Index (STAI), in comparison to antiarrhythmic drugs (AADs). Patients & methods: We simulated clinical and economic consequences for AF patients initially receiving STAI or AADs using a short-term decision tree model leading to a 10-year long-term Markov model. The model projected both clinical consequences and costs associated with, among others, AF, heart failure (HF), strokes, and deaths due to AF or AF related complications. Data informing the models included combination of a local real-world study and published clinical studies. Results: STAI was advantageous versus AADs on all 4 main clinical outcomes evaluated; AF: 25.83% lower (12.84% vs 38.67%), HF: 2.22% lower (1.33% vs 3.55%), stroke or post stroke: 1.82% lower (10.00% vs 11.82%) and deaths due to AF or AF related complications: 0.64% lower (4.11% vs 4.75%). The average total cost per patient in STAI group was yen 16,682 lower ( yen 123,124 vs yen 139,806). The one-way sensitivity analysis indicated that the difference in total cost was most sensitive to annual AF recurrence probability in AADs-treated patients. Probabilistic sensitivity analysis indicated a 98.5% probability that RFCA treatment would result in cost savings by the end of the 10th year. Conclusion: Radiofrequency catheter ablation using SmartTouch catheter guided by Ablation Index was superior to AADs as the first-line AF treatment in Chinese setting with better clinical outcomes and at lower costs over a 10-year time horizon.

Background Numerous studies have linked visceral adipose tissue (VAT) to gastrointestinal diseases. However, it remains unclear whether these associations reflect causal relationships. Methods We used a two-sample Mendelian randomization (MR) approach to elucidate the causal effect of VAT on nine non-tumour gastrointestinal diseases. The inverse-variance weighted method was used to perform the MR analyses. Complementary and multivariable MR analyses were performed to confirm the results. Results Genetically predicted higher VAT was associated with an increased risk of gastro-oesophageal reflux disease (GORD) (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.09–1.34; P = 3.06 × 10 −4 ), duodenal ulcer (DU) (OR, 1.40; 95% CI, 1.10–1.77; P = 0.005), cholelithiasis (OR, 1.75; 95% CI, 1.53–2.00; P = 1.14 × 10 −16 ), and non-alcoholic fatty liver disease (NAFLD) (OR, 2.68; 95% CI, 1.87–3.82; P = 6.26 × 10 −8 ). There were suggestive associations between VAT and gastric ulcer (GU) (OR, 1.22; 95% CI, 1.01–1.48; P = 0.035) and acute pancreatitis (AP) (OR, 1.26; 95% CI, 1.05–1.52; P = 0.013). However, there was little evidence to support the associations between VAT and inflammatory bowel disease, irritable bowel syndrome, or chronic pancreatitis. The associations with GORD, GU, and NAFLD remained in the multivariable MR analyses with adjustment for body mass index (BMI). Conclusions This study provided evidence in support of causal associations between VAT and GORD, GU, DU, cholelithiasis, AP, and NAFLD. Moreover, the associations between GORD, GU, and NAFLD were independent of the effect of BMI.

BackgroundLimited studies have explored the association between sexual factors [age at first sexual intercourse (AFS) and lifetime number of sexual partners (LNSP)] and cardiovascular diseases (CVDs), leaving the causality inconclusive.MethodsWe performed a bi-directional Mendelian randomization (MR) study to investigate the causality between sexual factors and CVDs, including coronary artery disease, myocardial infarction, atrial fibrillation (AF), heart failure (HF), and ischemic stroke (IS). Single-nucleotide polymorphisms (SNPs) for sexual factors were extracted from the UK Biobank. Statistics for each CVD were derived from two different databases. MR estimates were calculated per outcome database and were combined through meta-analysis. Several complementary sensitivity analyses were also performed.ResultsThe primary analysis suggested that AFS was causally associated with the risk of CVDs; the odds ratios (ORs) ranged from 0.686 [95% confidence interval (CI), 0.611-0.770] for HF to 0.798 (95% CI, 0.719-0.886) for AF. However, the association between AFS and IS (OR, 0.844; 95% CI, 0.632-1.126) was not consistent in the meta-analysis after excluding SNPs related to confounders. Moreover, non-significant associations were found between LNSP and CVDs. Reverse direction MR analysis showed that CVDs were not associated with sexual factors.ConclusionsGenetic evidence suggested that AFS was causally associated with the risk of CVDs except for IS, whereas non-significant association of LNSP with CVDs was detected. Further investigation into AFS could be warranted in preventing the progression of CVDs.

Circular RNAs (circRNAs) play a role in sepsis-related autophagy. However, the role of circRNAs in autophagy after sepsis-induced cardiomyopathy (SICM) is unknown, so we explored the circRNA expression profiles associated with autophagy in an acute sepsis mouse model. At a dose of 10 mg/kg, mice were intraperitoneally administered with lipopolysaccharides. The myocardial tissue was harvested after 6 h for microarray analysis, qRT-PCR, and western blotting. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis were evaluated, and a competing endogenous RNA network was constructed, to evaluate the role of circRNAs related to autophagy in SICM. In total, 1,735 differently expressed circRNAs were identified in the LPS-treated group, including 990 upregulated and 745 downregulated circRNAs. The expression level of the autophagy-specific protein p62 decreased, while the ratio of LC3 II to LC3 I increased. Additionally, 309 mRNAs and 187 circRNAs were correlated with autophagy in myocardial tissue after SICM. Of these, 179 circRNAs were predicted to function as "miRNA sponges". Some distinctive circRNAs and mRNAs found by ceRNA analysis might be involved in autophagy in SICM. These findings provide insights into circRNAs and identified new research targets that may be used to further explore the pathogenesis of SICM.

BACKGROUND:Atrial tachycardias (ATs) frequently develop after a surgical Maze procedure. We aimed to elucidate the electrophysiologic mechanisms and their arrhythmogenic substrates of these ATs.METHODS AND RESULTS:We retrospectively reviewed 20 patients (14 females, mean age of 55.5 ± 8.6 years) with post-Maze ATs who underwent high-resolution mapping at three institutions. The slow conduction areas, reentry circuits, voltage signals, complex electrograms, and their correlation with the surgical incisions and lesions placed in the surgical Maze procedures were analyzed. Thirty-six ATs with a mean cycle length of 260.0 ± 67.6 ms were mapped in these patients. Among them, 22 (61.1%) were anatomical macro-reentrant ATs (AMAT), 12 (33.3%) non-AMATs (localized ATs), and 2 (5.6%) focal ATs, respectively. Epicardial conduction bridges were observed in 6/20 (30.0%) patients and 7/36 (19.4%) ATs. Different arrhythmogenic substrates were identified in these ATs, including slow conduction regions within the previous lesion areas or between the incisions and anatomical structures, the prolonged activation pathways caused by the short lesions connecting the tricuspid annulus, and the circuits around the long incisions and/or lesions.CONCLUSIONS:Reentry is the main mechanism of the post-Maze ATs. The pro-arrhythmic substrates are most likely caused by surgical incisions and lesions. The slow conduction regions and the protected channels yielded from these areas are the major arrhythmogenic factors.

BackgroundCoronavirus Disease 2019 (COVID-19) has rapidly evolved as a global pandemic. Observational studies found that visceral adipose tissue (VAT) increased the likelihood of worse clinical outcomes in COVID-19 patients. Whereas, whether VAT is causally associated with the susceptibility, hospitalization, or severity of COVID-19 remains unconfirmed. We aimed to investigate the causal associations between VAT and susceptibility, hospitalization, and severity of COVID-19.MethodsWe applied a two-sample Mendelian randomization (MR) study to infer causal associations between VAT and COVID-19 outcomes. Single-nucleotide polymorphisms significantly associated with VAT were derived from a large-scale genome-wide association study. The random-effects inverse-variance weighted method was used as the main MR approach, complemented by three other MR methods. Additional sensitivity analyses were also performed.ResultsGenetically predicted higher VAT mass was causally associated with higher risks of COVID-19 susceptibility [odds ratios (ORs) = 1.13; 95% confidence interval (CI), 1.09–1.17; P = 4.37 × 10−12], hospitalization (OR = 1.51; 95% CI = 1.38–1.65; P = 4.14 × 10−20), and severity (OR = 1.58; 95% CI = 1.38–1.82; P = 7.34 × 10−11).ConclusionThis study provided genetic evidence that higher VAT mass was causally associated with higher risks of susceptibility, hospitalization, and severity of COVID-19. VAT can be a useful tool for risk assessment in the general population and COVID-19 patients, as well as an important prevention target.

Background:Numerous studies have been conducted to investigate the relationship between tea consumption and the risk of cardiovascular diseases (CVD); however, no conclusive results have been achieved. We conducted a Mendelian randomization (MR) study to elucidate the causal associations between tea consumption and several CVD outcomes, including coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), and heart failure (HF). Methods:Independent single-nucleotide polymorphisms (SNPs) genome-wide significantly associated with tea consumption were used as instrumental variables (IVs). Summary statistics for CVD outcomes were obtained from the corresponding genetic consortia and the FinnGen consortium. The inverse-variance weighted (IVW) method was the primary analytical method, and MR estimates from different data sources were combined using fixed-effects meta-analysis. Supplementary MR analyses, including the weighted median, MR-Egger, and the MR pleiotropy residual sum and outlier methods, were conducted to evaluate the robustness of the results. Further MR analyses were repeated by including more genetic variants at a higher P-value threshold. Results:We found that genetically predicted tea consumption was not causally associated with any CVD outcomes in the IVW method using data from large genetic consortia [CAD: odds ratio (OR) = 1.00, 95% confidence interval (CI), 0.91, 1.10, P = 0.997; MI: OR = 0.98, 95% CI, 0.90, 1.08, P = 0.751; AF: OR = 0.97, 95% CI, 0.92, 1.03, P = 0.350; HF: OR = 0.96, 95% CI, 0.88, 1.05, P = 0.401] or the FinnGen consortium (CAD: OR = 1.06, 95% CI, 0.96, 1.17, P = 0.225; MI: OR = 1.01, 95% CI, 0.89, 1.15, P = 0.882; AF: OR = 1.00, 95% CI, 0.88, 1.14, P = 0.994; HF: OR = 0.96, 95% CI, 0.88, 1.04, P = 0.362). The results were robust and consistent across meta-analysis, supplementary MR analyses, and analyses with more IVs included. Conclusion:This MR study revealed no causal association between tea consumption and four CVD outcomes, suggesting that tea consumption may not be beneficial for the primary prevention of CVD.