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Abstract Sialic acids are predominantly found at the terminal ends of glycoproteins and glycolipids and play key roles in cellular communication and function. The process of sialylation, a form of post-translational modification, involves the covalent attachment of sialic acid to the terminal residues of oligosaccharides and glycoproteins. This modification not only provides a layer of electrostatic repulsion to cells but also serves as a receptor for various biological signaling pathways. Sialylation is involved in several pathophysiological processes. Given its multifaceted involvement in cellular functions, sialylation presents a promising avenue for therapeutic intervention. Current studies are exploring agents that target sialic acid residues on sialoglycans or the sialylation process. These efforts are particularly focused on the fields of cancer therapy, stroke treatment, antiviral strategies, and therapies for central nervous system disorders. In this review, we aimed to summarize the biological functions of sialic acid and the process of sialylation, explore their roles in various pathophysiological contexts, and discuss their potential applications in the development of novel therapeutics.

Abstract Aims This study investigated the S2I2N0–3 score, a simple tool comprising stroke history, insulin‐treated diabetes, and N‐terminal pro‐brain natriuretic peptide, for forecasting mortality and morbidity in heart failure (HF) with reduced ejection fraction (HFrEF). Methods and results Analysing 890 GUIDE‐IT HFrEF trial participants, we stratified them by baseline S2I2N0–3 risk score into three risk groups. We examined the score's association with five adverse outcomes over short (90 days) and extended periods (median follow‐up of 15 months) using Cox and competing risk models. Our analysis revealed significant positive associations between the S2I2N0–3 strata and adverse outcomes. When analysed as a continuous variable, each point increment of the S2I2N0–3 score was associated with a higher risk of short‐ and long‐term cardiovascular death [short term: hazard ratio (HR) 1.43, 95% confidence interval (CI) 1.03–1.98; long term: HR 1.18, 95% CI 1.02–1.38], all‐cause death (HR 1.52, 95% CI 1.12–2.07; HR 1.18, 95% CI 1.03–1.36), HF hospitalization (HR 1.39, 95% CI 1.20–1.62; HR 1.18, 95% CI 1.06–1.31), any hospitalization (HR 1.19, 95% CI 1.06–1.34; HR 1.09, 95% CI 1.00–1.19), and the composite outcome of cardiovascular death and HF hospitalization (HR 1.39, 95% CI 1.21–1.60; HR 1.17, 95% CI 1.06–1.30). The S2I2N0–3 demonstrated reliable prognostic value, with C‐indices ranging from 0.619 to 0.753 across outcomes and time points. When compared with the Meta‐Analysis Global Group in Chronic Heart Failure (MAGGIC) score using Z‐statistics, net reclassification index, and integrated discrimination improvement, the S2I2N0–3 showed comparable predictive power for all outcomes during both short‐ and long‐term follow‐ups. Conclusions The S2I2N0–3 risk score had modest predictive values for both short‐ and long‐term clinical outcomes in HFrEF patients, offering equivalent performance to the established MAGGIC score.

Background: Several observational cohort studies have been conducted to investigate the effectiveness and safety of direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs) in patients who have both atrial fibrillation (AF) and cancer. Herein, we conducted a meta-analysis to present a comprehensive overview of the real-world evidence on DOACs in patients with AF and cancer. Methods: A comprehensive search strategy was performed in PubMed and Embase until February 2024 for studies that enrolled AF patients with cancer who received DOACs or VKAs. The adjusted risk ratios (RRs) and 95% confidence intervals (CIs) of each outcome were extracted and pooled by a random-effects model. Results: Seven observational cohort studies were eligible for data extraction. The random-effects model analysis indicated that compared with VKA use, the use of DOACs was significantly associated with reduced risks of stroke or systemic embolism (RR=0.79, 95 % CI 0.64–––0.97), major bleeding (RR=0.84, 95 % CI 0.71–––0.99), intracranial bleeding (RR=0.61, 95 % CI 0.54–––0.69), and gastrointestinal bleeding (RR=0.87, 95 % CI 0.80–––0.95) in AF patients with concurrent cancer. Conclusions: Compared with VKAs, the use of DOACs was associated with decreased risks of thrombotic and bleeding events in AF patients with cancer. Data from real-world scenarios support the use of DOACs as a favorable treatment option for this specific patient population.

Background Acute venous thromboembolism (VTE) in children presents unique challenges due to the limitations of standard anticoagulation therapies. Herein, we aimed to systematically review randomized controlled trials (RCTs) evaluating the efficacy and safety of direct oral anticoagulants (DOACs) in pediatric patients with acute VTE. Methods PubMed and Embase databases were searched for RCTs comparing DOACs to standard anticoagulation in pediatric VTE patients. Efficacy outcomes included VTE recurrence and all-cause mortality, while safety outcomes comprised major bleeding and other adverse events. Results Three RCTs with 790 participants were included. When compared with standard anticoagulation, DOACs demonstrated a reduced risk of VTE recurrence (risk difference[RD] = −3%, 95% confidence interval[CI]: −6% to 0%, P = 0.04) and an increased risk of any adverse event (RD = 8%, 95% CI: 1% to 14%, P = 0.02). No significant differences were found in all-cause mortality, major bleeding, clinically relevant non-major bleeding, or total bleeding between the DOAC and control groups. Conclusion DOACs, primarily dabigatran and rivaroxaban, are non-inferior to standard anticoagulants in reducing VTE recurrence in pediatric patients, with comparable safety profiles. Further research is essential to confirm these findings.

Introduction: Whether the hypertension burden is associated with stroke incidence is inconclusive. In this study, we aimed to investigate the relationship between hypertension burden and stroke risk in patients with heart failure with preserved ejection fraction (HFpEF). Methods: HFpEF patients from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial were divided into three groups (low, medium, and high risk) according to their hypertension burden values. Higher hypertension burden risk represented the longer duration of hypertension. We evaluated the association of hypertension burden with stroke risk using Fine and Gray's competing risk models. Results: A total of 3431 HFpEF patients (mean age: 68.5 ± 9.58 years, 51.6% females) were enrolled. During a median follow-up of 3.3 years, per 10-point increase in hypertension burden was associated with any stroke (hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.08–1.21), new-onset stroke (HR 1.14, 95% CI 1.07–1.21), and ischemic stroke (HR 1.10, 95% CI 1.02–1.17). When hypertension burden was analyzed as a categorical variable, any stroke risk was increased in the medium- (HR 1.59, 95% CI 1.01–2.40) and high-risk (HR 3.19, 95% CI 2.05–4.97) groups when compared with the low-risk group. For the outcomes of new-onset (HR 2.92, 95% CI 1.80–4.74) and ischemic stroke (HR 2.46, 95% CI 1.41–4.29), similar results were observed in patients with high-versus low-risk hypertension burden. Conclusions: Increasing hypertension burden was associated with an increased risk of stroke, suggesting that shortening hypertension duration might appropriately minimize the stroke incidence in HFpEF patients.

BackgroundChatGPT, an artificial intelligence (AI) based on large-scale language models, has sparked interest in the field of health care. Nonetheless, the capabilities of AI in text comprehension and generation are constrained by the quality and volume of available training data for a specific language, and the performance of AI across different languages requires further investigation. While AI harbors substantial potential in medicine, it is imperative to tackle challenges such as the formulation of clinical care standards; facilitating cultural transitions in medical education and practice; and managing ethical issues including data privacy, consent, and bias. ObjectiveThe study aimed to evaluate ChatGPT’s performance in processing Chinese Postgraduate Examination for Clinical Medicine questions, assess its clinical reasoning ability, investigate potential limitations with the Chinese language, and explore its potential as a valuable tool for medical professionals in the Chinese context. MethodsA data set of Chinese Postgraduate Examination for Clinical Medicine questions was used to assess the effectiveness of ChatGPT’s (version 3.5) medical knowledge in the Chinese language, which has a data set of 165 medical questions that were divided into three categories: (1) common questions (n=90) assessing basic medical knowledge, (2) case analysis questions (n=45) focusing on clinical decision-making through patient case evaluations, and (3) multichoice questions (n=30) requiring the selection of multiple correct answers. First of all, we assessed whether ChatGPT could meet the stringent cutoff score defined by the government agency, which requires a performance within the top 20% of candidates. Additionally, in our evaluation of ChatGPT’s performance on both original and encoded medical questions, 3 primary indicators were used: accuracy, concordance (which validates the answer), and the frequency of insights. ResultsOur evaluation revealed that ChatGPT scored 153.5 out of 300 for original questions in Chinese, which signifies the minimum score set to ensure that at least 20% more candidates pass than the enrollment quota. However, ChatGPT had low accuracy in answering open-ended medical questions, with only 31.5% total accuracy. The accuracy for common questions, multichoice questions, and case analysis questions was 42%, 37%, and 17%, respectively. ChatGPT achieved a 90% concordance across all questions. Among correct responses, the concordance was 100%, significantly exceeding that of incorrect responses (n=57, 50%; P

Abstract Aims Liver fibrosis scores (LFSs) are non‐invasive and effective tools for estimating cardiovascular risks. To better understand the advantages and limitations of currently available LFSs, we determined to compare the predictive values of LFSs in heart failure with preserved ejection fraction (HFpEF) for primary composite outcome, atrial fibrillation (AF), and other clinical outcomes. Methods and results This was a secondary analysis of the TOPCAT trial, and 3212 HFpEF patients were enrolled. Five LFSs, namely, non‐alcoholic fatty liver disease fibrosis score (NFS), fibrosis‐4 score (FIB‐4), BARD, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, and Health Utilities Index (HUI) scores were adopted. Cox proportional hazard model and competing risk regression model were performed to assess the associations between LFSs and outcomes. The discriminatory power of each LFS was evaluated by calculating the area under the curves (AUCs). During a median follow‐up of 3.3 years, a 1‐point increase in the NFS [hazard ratio (HR) 1.10; 95% confidence interval (CI) 1.04–1.17], BARD (HR 1.19; 95% CI 1.10–1.30), and HUI (HR 1.44; 95% CI 1.09–1.89) scores was associated with an increased risk of primary outcome. Patients with high levels of NFS (HR 1.63; 95% CI 1.26–2.13), BARD (HR 1.64; 95% CI 1.25–2.15), AST/ALT ratio (HR 1.30; 95% CI 1.05–1.60), and HUI (HR 1.25; 95% CI 1.02–1.53) were at an increased risk of primary outcome. Subjects who developed AF were more likely to have high NFS (HR 2.21; 95% CI 1.13–4.32). High levels of NFS and HUI scores were a significant predictor of any hospitalization and hospitalization for heart failure. The AUCs for the NFS in predicting primary outcome (0.672; 95% CI 0.642–0.702) and incident of AF (0.678; 95% CI 0.622–0.734) were higher than other LFSs. Conclusions In light of these findings, NFS appears to have superior predictive and prognostic utility compared with AST/ALT ratio, FIB‐4, BARD, and HUI scores. Clinical trial registration: (https://clinicaltrials.gov). Unique identifier: NCT00094302.

Abstract Objective The triglyceride–glucose (TyG) index has been shown to be a new alternative measure for insulin resistance. However, no study has attempted to investigate the association of the TyG index with incident atrial fibrillation (AF) in the general population without known cardiovascular diseases. Methods Individuals without known cardiovascular diseases (heart failure, coronary heart disease, or stroke) from the Atherosclerosis Risk in Communities (ARIC) cohort were recruited. The baseline TyG index was calculated as the Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. The association between the baseline TyG index and incident AF was examined using Cox regression. Results Of 11,851 participants, the mean age was 54.0 years; 6586 (55.6%) were female. During a median follow-up of 24.26 years, 1925 incidents of AF cases (0.78/per 100 person-years) occurred. An increased AF incidence with a graded TyG index was found by Kaplan‒Meier curves (P 9.20 levels (aHR 1.18, 95% CI 1.03, 1.37) of the TyG index were associated with an increased risk of AF compared with the middle TyG index category (8.80–9.20). The exposure-effect analysis confirmed the U-shaped association between the TyG index and AF incidence (P = 0.041). Further sex-specific analysis showed that a U-shaped association between the TyG index and incident AF still existed in females but not in males. Conclusions A U-shaped association between the TyG index and AF incidence is observed in Americans without known cardiovascular diseases. Female sex may be a modifier in the association between the TyG index and AF incidence. Graphical Abstract

Abstract Background The triglyceride and glucose (TyG) index has been linked to various cardiovascular diseases. However, it's still unclear whether the TyG index is associated with arterial stiffness and coronary artery calcification (CAC). Methods We conducted a systematic review and meta-analysis of relevant studies until September 2022 in the PubMed, Cochrane Library, and Embase databases. We used a random-effects model to calculate the pooled effect estimate and the robust error meta-regression method to summarize the exposure-effect relationship. Results Twenty-six observational studies involving 87,307 participants were included. In the category analysis, the TyG index was associated with the risk of arterial stiffness (odds ratio [OR]: 1.83; 95% CI 1.55–2.17, I2 = 68%) and CAC (OR: 1.66; 95% CI 1.51–1.82, I2 = 0). The per 1-unit increment in the TyG index was also associated with an increased risk of arterial stiffness (OR: 1.51, 95% CI 1.35–1.69, I2 = 82%) and CAC (OR: 1.73, 95% CI 1.36–2.20, I2 = 51%). Moreover, a higher TyG index was shown to be a risk factor for the progression of CAC (OR = 1.66, 95% CI 1.21–2.27, I2 = 0, in category analysis, OR = 1.47, 95% CI 1.29–1.68, I2 = 41% in continuity analysis). There was a positive nonlinear association between the TyG index and the risk of arterial stiffness (Pnonlinearity

Background and aim: Current observational studies have compared the effectiveness and safety of edoxaban with other oral anticoagulants in patients with AF, but the results are still disputed. This meta-analysis was conducted to compare the effect of edoxaban in patients with AF. Methods: We performed systematic research from the PubMed, EMBASE, and Cochrane Library databases until November 2022 to obtain relevant observational studies. Adjusted risk ratios (RRs) and 95 % confidence intervals (CIs) of the outcomes were collected and pooled by a random-effects model. This study was prospectively registered in PROSPERO (CRD42022314222). Results: A total of 17 observational studies were included in this meta-analysis. Compared with vitamin K antagonists, edoxaban was associated with lower risks of stroke or systemic embolism (RR = 0.67, 95 % CI:0.61–0.74), major bleeding (RR = 0.54, 95 % CI:0.44–0.67), and intracranial hemorrhage (RR = 0.51, 95 % CI:0.29–0.90). Compared with dabigatran or rivaroxaban, edoxaban was associated with reduced risks of stroke or systemic embolism (dabigatran [RR = 0.76, 95 % CI:0.66–0.87]; rivaroxaban [RR = 0.81, 95 % CI:0.70–0.94]) and major bleeding (dabigatran [RR = 0.82, 95 % CI:0.69–0.98]; rivaroxaban [RR = 0.81, 95 % CI:0.70–0.94]). Compared with apixaban, edoxaban was associated with a reduced risk of stroke or systemic embolism (RR = 0.87, 95 % CI:0.79–0.97), but had similar risks of bleeding events. Conclusions: Our current evidence suggested that edoxaban might have superior effectiveness and/or safety outcomes than vitamin K antagonists, dabigatran, rivaroxaban, and apixaban for stroke prevention in patients with AF.

Abstract Background Epicardial adipose tissue (EAT) has been suggested to exert deleterious effects on myocardium and cardiovascular disease (CVD) consequence. We evaluated the associations of EAT thickness with adverse outcomes and its potential mediators in the community. Methods Participants without heart failure (HF) who had undergone cardiac magnetic resonance (CMR) to measure EAT thickness over the right ventricular free wall from the Framingham Heart Study were included. The correlation of EAT thickness with 85 circulating biomarkers and cardiometric parameters was assessed in linear regression models. The occurrence of HF, atrial fibrillation, coronary heart disease (CHD), and other adverse events was tracked since CMR was implemented. Their associations with EAT thickness and the mediators were evaluated using Cox regression and causal mediation analysis. Results Of 1554 participants, 53.0% were females. Mean age, body mass index, and EAT thickness were 63.3 years, 28.1 kg/m2, and 9.8 mm, respectively. After fully adjusting, EAT thickness positively correlated with CRP, LEP, GDF15, MMP8, MMP9, ORM1, ANGPTL3, and SERPINE1 and negatively correlated with N-terminal pro-B-type natriuretic peptide (NT-proBNP), IGFBP1, IGFBP2, AGER, CNTN1, and MCAM. Increasing EAT thickness was associated with smaller left ventricular end-diastolic dimension, thicker left ventricular wall thickness, and worse global longitudinal strain (GLS). During a median follow-up of 12.7 years, 101 incident HF occurred. Per 1-standard deviation increment of EAT thickness was associated with a higher risk of HF (adjusted hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.19–1.72, P

Abstract Background Obesity is an strong risk factor for atrial fibrillation (AF), and obesity can affect the prognosis of AF. However, the role of weight loss on outcomes after ablation remains unclear. Objectives This study aims to determine the relationship between weight loss and outcomes in patients with AF ablation, as well as the potential dose–response relationship. Methods The Cochrane Library, PubMed, and Embase databases were searched to identify studies that reported a relationship between weight loss and ablation up to August 17, 2021. Relative risks (RRs) were pooled using random-effects models. Results One randomized, open-labeled clinical trial and seven cohort studies involving 1283 patients were included. The mean body mass index of all included studies was over 30 kg/m2. The clinical trial showed a non-significant benefit of weight loss intervention on AF recurrence (Odd risk [OR] = 1.02, 95% confidence interval [CI] 0.70–1.47). Meta-analysis based on observational studies showed that the recurrence rate of AF after ablation was significantly reduced (RR = 0.43, 95% CI 0.22–0.81, I2 = 97%) in relatively obese patients with weight loss compared with the control group. Each 10% reduction in weight was associated with a decreased risk of AF recurrence after ablation (RR = 0.54, 95% CI 0.33–0.88) with high statistical heterogeneity (I2 = 76%). An inverse linear association (Pnon-linearity = 0.27) between AF relapse and increasing weight loss was found. Conclusions Our results first suggest an inverse dose–response association between weight loss and risk of recurrent AF after ablation, with moderate certainty. Graphical Abstract

Abstract Background Current guidelines recommend rhythm control for improving symptoms and quality of life in symptomatic patients with atrial fibrillation (AF). However, the long-term prognostic outcomes of rhythm control compared with rate control are still inconclusive. In this meta-analysis, we aimed to assess the effects of early rhythm control compared with rate control on clinical outcomes in newly diagnosed AF patients. Methods We systematically searched the PubMed and Embase databases up to August 2022 for randomized and observational studies reporting the associations of early rhythm control (defined as within 12 months of AF diagnosis) with effectiveness outcomes. The primary outcome was a composite of death, stroke, admission to hospital for heart failure (HF), or acute coronary syndrome (ACS). Hazard ratios (HRs) and 95% confidence intervals (CIs) from each study were pooled using a random-effects model, complemented with an inverse variance heterogeneity or quality effects model. Results A total of 8 studies involving 447,202 AF patients were included, and 23.5% of participants underwent an early rhythm-control therapy. In the pooled analysis using the random-effects model, compared with rate control, the early rhythm-control strategy was significantly associated with reductions in the primary composite outcome (HR = 0.88, 95% CI: 0.86–0.89) and secondary outcomes, including stroke or systemic embolism (HR = 0.78, 95% CI: 0.71–0.85), ischemic stroke (HR = 0.81, 95% CI: 0.69–0.94), cardiovascular death (HR = 0.83, 95% CI: 0.70–0.99), HF hospitalization (HR = 0.90, 95% CI: 0.88–0.92), and ACS (HR = 0.86, 95% CI: 0.76–0.98). Reanalyses using the inverse variance heterogeneity or quality effects model yielded similar results. Conclusions Our current meta-analysis suggested that early initiation of rhythm control treatment was associated with improved adverse effectiveness outcomes in patients who had been diagnosed with AF within 1 year. Registration The study protocol was registered to PROSPERO (CRD42021295405).

Background It is still unclear whether there is a sex difference in the prognosis of patients with hypertrophic cardiomyopathy (HCM). Therefore, we performed a meta‐analysis to elucidate the association between sex and adverse outcomes in patients with HCM. Methods and Results The PubMed, Cochrane Library, and Embase databases were used to search for studies on sex differences in prognosis in patients with HCM up to August 17, 2021. Summary effect sizes were calculated using a random effects model. The protocol was registered in PROSPERO (International prospective register of systematic reviews) (registration number‐ CRD42021262053). A total of 27 cohorts involving 42 365 patients with HCM were included. Compared with male subjects, female subjects had a higher age at onset (mean difference=5.61 [95% CI, 4.03–7.19]), a higher left ventricular ejection fraction (standard mean difference=0.09 [95% CI, 0.02–0.15]) and a higher left ventricular outflow tract gradient (standard mean difference=0.23 [95% CI, 0.18–0.29]). The results showed that compared with male subjects with HCM, female subjects had higher risks of HCM‐related events (risk ratio [RR]=1.61 [95% CI, 1.33–1.94], I2=49%), major cardiovascular events (RR=3.59 [95% CI, 2.26–5.71], I2=0%), HCM‐related death (RR=1.57 [95% CI, 1.34–1.82], I2=0%), cardiovascular death (RR=1.55 [95% CI, 1.05–2.28], I2=58%), noncardiovascular death (RR=1.77 [95% CI, 1.46–2.13], I2=0%) and all‐cause mortality (RR=1.43 [95% CI, 1.09–1.87], I2=95%), but not atrial fibrillation (RR=1.13 [95% CI, 0.95–1.35], I2=5%), ventricular arrhythmia (RR=0.88 [95% CI, 0.71–1.10], I2=0%), sudden cardiac death (RR=1.04 [95% CI, 0.75–1.42], I2=38%) or composite end point (RR=1.24 [95% CI, 0.96–1.60], I2=85%). Conclusions Based on current evidence, our results show significant sex‐specific differences in the prognosis of HCM. Future guidelines may emphasize the use of a sex‐specific risk assessment for the diagnosis and management of HCM.

Abstract Background The triglyceride-glucose (TyG) index is a new alternative measure for insulin resistance. This meta-analysis was conducted to assess the associations of the TyG index with the risks of cardiovascular diseases and mortality in the general population. Methods The PubMed, Cochrane Library and Embase databases were searched for randomized controlled trials or observational cohort studies reporting associations of the TyG index with cardiovascular diseases and mortality from inception to April 16, 2022. Effect sizes were pooled using random-effects models. Robust error meta-regression methods were applied to fit nonlinear dose–response associations. Evidence quality levels and recommendations were assessed using the Grading of Recommendations Assessment, Development and Evaluation system (GRADE). Results Twelve cohort studies (6 prospective and 6 retrospective cohorts) involving 6,354,990 participants were included in this meta-analysis. Compared with the lowest TyG index category, the highest TyG index was related to a higher incidence of coronary artery disease (CAD) (3 studies; hazard ratio [HR] = 2.01; 95% confidence interval [CI] 1.68–2.40; I2 = 0%), myocardial infarction (MI) (2 studies; HR = 1.36; 95% CI 1.18–1.56; I2 = 35%), and composite cardiovascular disease (CVD) (5 studies; HR = 1.46; 95% CI 1.23–1.74; I2 = 82%). However, there was no association between the TyG index and mortality (cardiovascular mortality [3 studies; HR = 1.10; 95% CI 0.82–1.47; I2 = 76%] or all-cause mortality [4 studies; HR = 1.08; 95% CI 0.92–1.27; I2 = 87%]). In the dose–response analysis, there was a linear association of the TyG index with the risk of CAD (Pnonlinear = 0.3807) or CVD (Pnonlinear = 0.0612). GRADE assessment indicated very low certainty for CVD, MI, cardiovascular mortality and all-cause mortality, and moderate certainty for CAD. Conclusions Based on our current evidence, a higher TyG index may be associated with an increased incidence of CAD (moderate certainty), MI (very low certainty) and CVD (very low certainty) in the general population. There is a potential linear association of the TyG index with CAD and the composite CVD incidence. Further prospective studies (especially in non-Asians) are needed to confirm our findings.

Background: There has been an increasing use of transcatheter tricuspid valve repair (TTVR) recently. However, the periprocedural, short-term, and long-term outcomes of TTVR remain unclear. Objectives: To determine the clinical outcomes in patients with significant tricuspid regurgitation undergoing TTVR. Design: Systematic review and meta-analysis. Data Source and Methods: The systematic review and meta-analysis is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and EMBASE were searched for clinical trials and observational studies until March 2022. Studies reporting the incidence of clinical outcomes after TTVR were included. The clinical outcomes included periprocedural, short-term (in-hospital or within 30 days), and long-term (>6-month follow-up) outcomes. The primary outcome was all-cause mortality whereas the secondary outcomes included technical success, procedural success, cardiovascular mortality, rehospitalization for heart failure (HHF), major bleeding, and single leaflet device attachment. The incidence of these outcomes across studies was pooled by a random-effects model. Results: A total of 21 studies with 896 patients were included. A total of 729 (81.4%) patients underwent isolated TTVR while only 167 (18.6%) patients underwent combined mitral and tricuspid valve repair. Over 80% of the patients used coaptation devices while approximately 20% used annuloplasty devices. The median follow-up duration was 365 days. Technical and procedural success was high at 93.9% and 82.1%, respectively. The pooled perioperative, short-term, and long-term all-cause mortality for patients undergoing TTVR was 1.0%, 3.3%, and 14.1%, respectively. The long-term cardiovascular mortality rate was 5.3% while the HHF rate was 21.5%. Major bleeding and single leaflet device attachment were two major complications, accounting for 14.3% and 6.4%, respectively, during long-term follow-up. Conclusion: TTVR is associated with high procedural success and low procedural and short-term mortality. However, all-cause mortality, cardiovascular mortality, and HHF rates remain high during long-term follow-up. Registration: PROSPERO (CRD42022310020).

Abstract Background The associations between vitamin D and coronavirus disease 2019 (COVID-19) infection and clinical outcomes are controversial. The efficacy of vitamin D supplementation in COVID-19 is also not clear. Methods We identified relevant cohort studies that assessed the relationship between vitamin D, COVID-19 infection and associated death and randomized controlled trials (RCTs) that reported vitamin D supplementation on the outcomes in patients with COVID-19 by searching the PubMed, EMBASE, and medRxiv databases up to June 5th, 2021. Evidence quality levels and recommendations were assessed using the GRADE system. Results Eleven cohort studies with 536,105 patients and two RCTs were identified. Vitamin D deficiency (

BackgroundCardiac power-to-left ventricular mass (power/mass) is an index reflecting the muscular hydraulic pump capability of the heart, and the E/e’ ratio is a specific indicator for identifying increased left ventricular filling pressure. Limited data exist regarding the prognostic value of incorporating power/mass and E/e’ ratio in heart failure with preserved ejection fraction (HFpEF).Materials and methodsIn total, 475 patients with HFpEF from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial with complete baseline echocardiography data were included in our analysis. Patients were categorized into four groups according to power/mass and E/e’ ratio. The risk of outcomes was examined using Cox proportional hazards models and competing risk models.ResultsPatients with low power/mass and high E/e’ were more likely to be males (60.5%), with higher waist circumference, and had a higher prevalence of diabetes (52.1%), atrial fibrillation (50.4%), and lower estimated glomerular filtration rate (eGFR). Combined resting power/mass and E/e’ have graded correlations with left ventricular (LV) dysfunction and clinical outcomes in patients with HFpEF. After multivariable adjustments, an integrative approach combining power/mass and E/e’ remained to be a powerful prognostic predictor, with the highest HRs of clinical outcomes observed in patients with low power/mass and high E/e’ (all-cause mortality: HR 3.45; 95% CI: 1.69–7.05; P = 0.001; hospitalization for heart failure: HR 3.27; 95% CI: 1.60–6.67; P = 0.001; and primary endpoint: HR 3.07; 95% CI: 1.73–5.42; P < 0.001).ConclusionIn patients with HFpEF, an echo-derived integrated approach incorporating resting power/mass and E/e’ ratio remained to be a powerful prognosis predictor and may be useful to risk-stratify patients with this heterogeneous syndrome.Clinical Trial Registration[https://clinicaltrials.gov], identifier [NCT00094302].

Background B‐type natriuretic peptide (BNP) is a well‐known biomarker for prognosis in heart failure with patients with preserved ejection fraction. However, the clinical predictive ability of BNP for the risk of stroke in HFpEF is not clear. Methods and Results A total of 799 patients with HFpEF from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial were included. Association of baseline BNP with risk of stroke was assessed using the Cox proportional hazard model. The discriminatory ability of BNP was expressed using the C index. The improvement in 5‐year stroke prediction was assessed by C statistic, categorical net reclassification improvement index, and relative integrated discrimination improvement. A total of 34 (4.3%) patients among the 799 patients with HFpEF experienced stroke events over a median of 2.85 years of follow‐up. The stroke group showed a higher BNP level than the nonstroke group (375 pg/mL versus 241 pg/mL, respectively; P=0.006). Higher BNP levels were associated with increased risk of stroke after multivariable adjustment (hazard ratio, 3.29 [95% CI, 1.51–7.16]) and had a moderate performance for stroke prediction (C index, 0.67). Adding BNP to CHADS2/CHA2DS2‐VASc/R2CHADS2 scores improved their predictive value for stroke (CHADS2: C index, 0.67; BNP+CHADS2: C index, 0.77; net reclassification improvement, 40.9%; integrated discrimination improvement, 3.0%; CHA2DS2‐VASc: C index, 0.64; BNP+CHA2DS2‐VASc: C index, 0.74; net reclassification improvement, 41.4%; integrated discrimination improvement, 2.2%; R2CHADS2: C index, 0.70; BNP+R2CHADS2: C index, 0.78; net reclassification improvement, 40.9%; integrated discrimination improvement, 3.2%). Conclusions BNP is associated with an increased risk of stroke in patients with HFpEF and may be a valuable biomarker for stroke prediction in HFpEF.

BackgroundSeveral published studies have examined the association of coffee consumption with atrial fibrillation (AF) risk, but their findings are still controversial. Therefore, we performed a systematic review and dose–response meta-analysis of prospective studies to determine the relationship between coffee consumption and the risk of incident AF.MethodsWe systematically retrieved the PubMed and Embase databases until October 2021 for pertinent studies that reported the association of coffee consumption (caffeinated or decaffeinated coffee) with AF risk. A cubic spline random-effects model was used to fit the potential dose–response curve. The effect estimates were expressed as adjusted risk ratios (RRs) and 95% CIs.ResultsA total of 10 prospective studies (11 cohorts) involving 30,169 AF events and 723,825 participants were included. In the dose–response analysis, there was a linear inverse association between coffee intake and risk of AF although not statistically significant (Pnon–linearity = 0.25). Compared with participants with no coffee consumption, the RRs (95% CI) of AF risk estimated directly from the dose–response curve were 1.01 (0.98–1.03), 1.00 (0.97–1.04), 0.99 (0.92–1.02), 0.95 (0.89–1.01), 0.94 (0.87–1.01), 0.89 (0.79–1.02), and 0.87 (0.76–1.02) for 1–7 cups of coffee per day, respectively. One cup per day increased in coffee consumption was associated with a 2% reduced risk of AF (RR = 0.98, 95% CI: 0.97–1.00, P = 0.02).ConclusionsOur evidence from this meta-analysis suggested that coffee consumption had a trend toward reducing the risk of AF in a dose–response manner. Further studies could be conducted to reinforce our findings.

BackgroundPatients with atrial fibrillation (AF) and frailty are a considerable group in clinical practice. However, existing studies provide insufficient evidence of anticoagulation strategies for these patients. Therefore, we conducted a meta-analysis to determine the effectiveness and safety outcomes of direct oral anticoagulants (DOACs) for these patients.MethodsRandomized controlled trials or observational studies reporting the data about the DOACs and warfarin therapy among frail AF patients were included. The search was performed in the PubMed and Embase databases up to March 2022. Frailty was defined using the most widely used claims-based frailty index or the cumulative deficit model-based frailty index.ResultsA total of 4 studies involving 835,520 patients were included. Compared with warfarin, DOACs therapy reduced the risks of stroke or systemic embolism (HR = 0.79, 95%CI: 0.69–0.90), ischemic stroke (HR = 0.79, 95%CI: 0.71–0.87), hemorrhagic stroke (HR = 0.52, 95%CI: 0.35–0.76), and all-cause death (HR = 0.90, 95%CI: 0.84–0.96). In safety outcomes, DOACs was significantly associated with reduced risks of major bleeding (HR = 0.79, 95%CI: 0.64–0.97) and intracranial hemorrhage (HR = 0.58, 95%CI: 0.52–0.65) compared to warfarin, but there were no statistically differences in gastrointestinal bleeding (HR = 0.97, 95%CI: 0.73–1.29).ConclusionsDOACs exerted superior effectiveness and safety outcome than warfarin in AF patients with frailty.

BackgroundDepression is a possible influence factor for the increased risk of incident atrial fibrillation (AF). Although several investigations have assessed their association, the results are still controversial. Therefore, we conducted a meta-analysis to evaluate the association between depression or using antidepressants and AF.MethodsWe systemically performed the literature retrieval from two electronic databases PubMed and EMBASE until March 2022 to extract relevant data. The hazard ratios (HRs) and odds ratios (OR) from included studies with 95% confidence intervals (CIs) were adjusted into the risk ratio (RR) and pooled by using the random-effects model.ResultsTotally 9 studies about the associations between depression or antidepressants and incident AF risk were included in this meta-analysis. Among them, 5 studies specifically analyzed the impact of antidepressants on the risk of AF. The outcomes of our analysis indicated that depression or depressive symptoms could increase AF risk (RR = 1.15, 95% CI, 1.03–1.27, P < 0.01). In addition, the use of antidepressants can also increase AF risk (RR = 1.16, 95% CI, 1.07–1.25, P < 0.001). These results remained unchanged when we remove the source of heterogeneity or adjust the analysis model into the fixed-effects model.ConclusionsBased on existing investigations, both depression and the use of antidepressants are closely related to the increase of incident AF risk.

BackgroundThe use of anticoagulants is an established strategy to prevent stroke, embolism, and cardiovascular mortality in patients with atrial fibrillation (AF), but its role in the prevention of incident diabetes is unclear. We aimed to investigate this question by using participant data from cohort studies.MethodsWe conducted a meta-analysis of participants to investigate the impact of direct oral anticoagulants (DOACs) on the risk of new-onset diabetes in AF patients. The collection of related data was performed in the PubMed and EMBASE databases until December 2021, including studies associated with evaluating the correlation between DOACs and incident diabetes. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted by the random-effects model with an inverse variance method.ResultsTwo cohort studies with a total of 24,434 patients were included in this study (warfarin: n = 6,906; DOACs: n = 17,528). Compared with warfarin, the use of DOACs could reduce the incident diabetic risk in AF patients (HR = 0.75, 95%CI: 0.68–0.82). Investigations about the effects of three major classes of DOACs showed that the individual use of dabigatran (HR = 0.76, 95%CI: 0.64–0.90), rivaroxaban (HR = 0.74, 95%CI: 0.64–0.87), apixaban (HR = 0.74, 95%CI: 0.60–0.92) and the combined use of rivaroxaban and apixaban (HR = 0.74, 95%CI: 0.66–0.84) could reduce the risk of new-onset diabetes compared with warfarin. This risk reduction effect could be observed in both male and female groups (HR = 0.73, 95%CI: 0.64–0.84, P < 0.00001; HR = 0.82, 95%CI: 0.82–0.99, P = 0.04).ConclusionsTreatment with DOACs compared with warfarin reduced the risk of new-onset diabetes in both male and female patients with AF.

Abstract Aims Coexisting of atrial fibrillation (AF) in patients with heart failure with preserved ejection fraction (HFpEF) could increase the risk of mortality. In this study, we aimed to assess the values of the CHADS2, R2CHADS2, and CHA2DS2‐VASc scores for AF prediction in HFpEF patients. Methods and results We performed a retrospective analysis on symptomatic HFpEF patients in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. Associations of the CHADS2, R2CHADS2, and CHA2DS2‐VASc scores with the risk of incident AF in HFpEF patients without baseline AF (n = 2202) were assessed using the multivariable competing risk regression models. The discriminatory performances of these scores were calculated using the C‐index. During a median follow‐up of 3.3 years, the average incidence of AF was 1.80 per 100 patient‐years in HFpEF patients. When score was analysed as a continuous variable, per 1‐point increase in the CHADS2 (hazard ratio [HR] = 1.42, 95% confidence interval [CI]: 1.20–1.68, C‐index: 0.71), R2CHADS2 (HR = 1.25, 95% CI: 1.10–1.42, C‐index: 0.69), or CHA2DS2‐VASc (HR = 1.30, 95% CI: 1.16–1.46, C‐index: 0.70) scores was associated with an increased risk of incident AF. When score was analysed as a categorical variable, patients with CHADS2 ≥ 3 (HR = 2.62, 95% CI: 1.70–4.04), R2CHADS2 ≥ 3 (HR = 2.55, 95% CI: 1.56–4.17), or CHA2DS2‐VASc ≥ 4 (HR = 2.54, 95% CI: 1.59–4.07) had a higher risk of incident AF compared with the corresponding controls. Conclusions Our data first suggest that the CHADS2, R2CHADS2, and CHA2DS2‐VASc scores could predict the risk of incident AF in HFpEF patients with modest predictive abilities.

Abstract Background The C2HEST score has been validated for predicting AF in the general population or post-stroke patients. We aimed to assess whether this risk score could predict incident AF and other clinical outcomes in heart failure with preserved ejection fraction (HFpEF) patients. Methods A total of 2202 HFpEF patients without baseline AF in the TOPCAT trial were stratified by baseline C2HEST score. Cox proportional hazard model and competing risk regression model was used to explore the relationship between C2HEST score and outcomes, including incident AF, stroke, all-cause death, cardiovascular death, any hospitalization, and HF hospitalization. The discriminative ability of the C2HEST score for various outcomes was assessed by calculating the area under the curve (AUC). Results The incidence rates of incident AF, stroke, all-cause death, cardiovascular death, any hospitalization, and HF hospitalization were 1.79, 0.70, 3.81, 2.42, 15.50, and 3.32 per 100 person-years, respectively. When the C2HEST score was analyzed as a continuous variable, increased C2HEST score was associated with increased risk of incident AF (HR 1.50, 95% CI 1.29–1.75), as well as increased risks of all-cause death, cardiovascular death, any hospitalization, and HF hospitalization. The AUC for the C2HEST score in predicting incident AF (0.694, 95% CI 0.640–0.748) was higher than all-cause death, cardiovascular death, any hospitalization, or HF hospitalization. Conclusions The C2HEST score could predict the risk of incident AF as well as death and hospitalization with moderately good predictive abilities in patients with HFpEF. Its simplicity may allow the possibility of quick risk assessments in busy clinical settings.

Abstract Clarifying mechanisms underlying the ecological succession of gut microbiota is a central theme of gut ecology. Under experimental manipulations of zebrafish hatching and rearing environments, we test our core hypothesis that the host development will overwhelm environmental dispersal in governing fish gut microbial community succession due to host genetics, immunology, and gut nutrient niches. We find that zebrafish developmental stage substantially explains the gut microbial community succession, whereas the environmental effects do not significantly affect the gut microbiota succession from larvae to adult fish. The gut microbiotas of zebrafish are clearly separated according to fish developmental stages, and the degree of homogeneous selection governing gut microbiota succession is increasing with host development. This study advances our mechanistic understanding of the gut microbiota assembly and succession by integrating the host and environmental effects, which also provides new insights into the gut ecology of other aquatic animals.

Abstract Aims The aim of the study was to explore the risk factors and evaluate the prognostic implication of pulmonary hospitalization on heart failure (HF) with preserved ejection fraction (HFpEF). Methods and results We performed a secondary analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT). A total of 1714 patients with HFpEF were analysed in our study. In the multivariate Cox proportional hazards regression analysis, history of chronic obstructive pulmonary disease (COPD), smoking, bone fracture after the age of 45, and previous HF hospitalization were identified as independent risk factors for pulmonary hospitalization. To evaluate the prognostic significance of pulmonary hospitalization, patients were categorized into five groups according to the causes of their first hospitalization. The all‐cause and cardiovascular (CV) mortality risks in these five groups were compared using time‐varying Cox proportional hazards model. Compared with patients without hospitalization during follow‐up, those with pulmonary hospitalization were associated with a 204% increase [hazard ratio (HR) 3.04, 95% confidence interval (CI) 2.07–4.47, P

ABSTRACT Understanding interactions within the gut microbiome and its stability are of critical importance for deciphering ecological issues within the gut ecosystem. Recent studies indicate that long-term instability of gut microbiota is associated with human diseases, and recovery of stability is helpful in the return to health. However, much less is known about such topics in fish, which encompass nearly half of all vertebrate diversity. Here, we examined the assembly and succession of gut microbiota in more than 550 zebrafish, and evaluated the variations of microbial interactions and stability across fish development from larva to adult using molecular ecological network analysis. We found that microbial interactions and stability in the fish gut ecosystem generally increased with host development. This could be attributed to the development of the zebrafish immune system, the increasing amount of space available for microbial colonization within the gut, and the greater stability of nutrients available for the colonized microbiota in adult zebrafish. Moreover, the potential keystone taxa, even those with relatively low abundances, played important roles in affecting the microbial interactions and stability. These findings indicate that regulating rare keystone taxa in adult fish may have great potential in gut microbial management to maintain gut ecosystem stability, which could also provide references for managing gut microbiota in humans and other animals. IMPORTANCE Understanding gut microbial stability and the underlying mechanisms is an important but largely ignored ecological issue in vertebrate fish. Here, using a zebrafish model and network analysis of the gut microbiota we found that microbial interactions and stability in the gut ecosystem increase with fish development. This finding has important implications for microbial management to maintain gut homeostasis and provide better gut ecosystem services for the host. First, future studies should always consider using fish of different age groups to gain a full understanding of gut microbial networks. Second, management of the keystone taxa, even those that are only present at a low abundance, during the adult stage may be a viable pathway to maintain gut ecosystem stability. This study greatly expands our current knowledge regarding gut ecosystem stability in terms of ecological networks affected by fish development, and also highlights potential directions for gut microbial management in humans and other animals.

Background:Respiratory diseases related to chronic pulmonary ventilation dysfunction are mainly composed of chronic obstructive pulmonary disease (COPD) and asthma. Our meta-analysis aimed to illustrate the association of COPD or asthma with risk of atrial fibrillation (AF).MethodsWe systematically searched the databases of the PubMed, Embase, and Cochrane library until December 2021 for studies focusing on the relationship between COPD or asthma and AF risk. Due to the potential heterogeneity across studies, the random-effects model was used to pool the studies.ResultsOur meta-analysis included 14 studies. Based on the random-effects model, the pooled analysis showed that COPD (risk ratio[RR] = 1.74, 95% confidence interval [CI]: 1.70–1.79) and asthma (RR = 1.08, 95% CI: 1.04–1.12) were significantly associated with an increased risk of AF. The results did not change after each study was excluded.ConclusionOur current data suggested that COPD or asthma with associated with an increased risk of AF.

BackgroundSeveral studies have investigated the effect of direct oral anticoagulants (DOACs) in Latin American patients with atrial fibrillation (AF), but the results remain controversial. Therefore, we aimed to compare the efficacy and safety of DOACs vs. warfarin in Latin American patients with AF.MethodsWe systematically searched the PubMed and Embase databases until November 2021 for studies that compared the effect of DOACs vs. warfarin in Latin patients with AF. Adjusted hazard ratios (HRs) and 95% CIs were pooled by a random-effects model using an inverse variance method.ResultsFour post-hoc analyses of randomized clinical trials (RCTs) involving 42,411 DOACs and 29,270 warfarin users were included. In Latin American patients with AF, for the effectiveness outcomes, the use of DOACs compared with warfarin was significantly associated with decreased risks of stroke or systemic embolism (SSE) (HR = 0.78; 95%CI.64–0.96), stroke (HR = 0.75; 95%CI.57–0.99), hemorrhagic stroke (HR = 0.14; 95%CI.05–0.36), all-cause death (HR = 0.89; 95% CI.80–1.00), but not ischemic stroke and cardiovascular death. For the safety outcomes, compared with warfarin, the use of DOACs was associated with reduced risks of major or non-major clinically relevant (NMCR) bleeding (HR = 0.70; 95% CI.57–0.86), major bleeding (HR = 0.70; 95%CI.53–0.92), intracranial hemorrhage (ICH) (HR = 0.42; 95%CI.24–0.74), or any bleeding (HR = 0.70;95% CI.62–0.78), but not gastrointestinal bleeding. In non-Latin American patients with AF, for the effectiveness outcomes, the use of DOACs compared with warfarin was significantly associated with decreased risks of SSE (HR = 0.87; 95%CI.75–1.00), hemorrhagic stroke (HR = 0.41; 95%CI.28–0.60), cardiovascular death (HR = 0.87; 95% CI.81–0.94), all-cause death (HR = 0.90; 95% CI.85–0.94). Conversely, the risk of myocardial infarction increased (HR = 1.34; 95% CI 1.13–1.60), but not ischemic stroke. For the safety outcomes, compared with warfarin, the use of DOACs was associated with reduced risks of major or NMCR bleeding (HR = 0.75; 95%CI.61–0.92), major bleeding (HR = 0.76; 95%CI.63–0.92), ICH (HR = 0.42; 95%CI.36–0.52), and any bleeding (HR = 0.81; 95% CI.71–0.92), but not gastrointestinal bleeding.ConclusionCurrent pooled data from the four post-hoc analyses of RCTs suggested that compared with warfarin, DOACs appeared to have significant reductions in SSE, stroke, hemorrhagic stroke, all-cause death, major or NMCR bleeding, major bleeding, ICH, and any bleeding, but comparable risks of ischemic stroke, cardiovascular death, and gastrointestinal bleeding in Latin American patients with AF. DOACs appeared to have significant reductions in SSE, hemorrhagic stroke, all-cause death, cardiovascular death, major or NMCR bleeding, major bleeding, ICH, and any bleeding, and increased the risk of myocardial infarction, but comparable risks of stroke, ischemic stroke, and gastrointestinal bleeding in non-Latin American patients with AF.

BackgroundSeveral published studies have disagreements on whether the use of antidepressants is associated with increased risk of arrhythmias. In this study, we performed this meta-analysis to assess the association of antidepressants with cardiac arrhythmias in patients who require antidepressants.MethodsThe PubMed and Embase databases were systematically searched until December 2021 to find studies that investigated the association between antidepressant use and cardiac arrhythmias. Studies that assessed the effects of any antidepressant on arrhythmias in patients who require antidepressants compared with those who require no antidepressants were included. We used a random-effects model to pool the adjusted risk ratios (RRs) and 95% confidence intervals (CIs). The stability of the results was examined by omitting an individual study at a time.ResultsA total of 3,396 studies were screened and 6 studies with 2,626,746 participants were finally included in this meta-analysis. When compared with no antidepressants, the use of antidepressants was significantly associated with an increased risk of atrial fibrillation (RR = 1.37, 95% CI: 1.16–1.61). However, there was no difference in the risk of ventricular arrhythmias or sudden cardiac death (RR = 1.33, 95% CI: 0.88–2.01) between the two studied groups. In the subgroup analysis, tricyclic antidepressants (RR = 1.12, 95% CI: 0.89–1.41), selective serotonin reuptake inhibitors (RR = 1.46, 95% CI: 0.63–3.38), and selective serotonin reuptake inhibitors (RR = 0.99, 95% CI: 0.97–1.01) did not increase the risk of ventricular arrhythmias and/or sudden cardiac death.ConclusionRecently published data suggested that the use of antidepressants did not increase the risk of ventricular arrhythmias or sudden cardiac death. Antidepressants were associated with an increased risk of atrial fibrillation but that still needs further confirmation.

Background: Overweight and mildly obese individuals have a lower risk of death than their normal-weight counterparts; this phenomenon is termed “obesity paradox.” Whether this “obesity paradox” exists in patients with heart failure (HF) or can be modified by comorbidities is still controversial. Our current study aimed to determine the association of body mass index (BMI) with outcomes with patients with HF with preserved ejection fraction (HFpEF) with or without coexisting atrial fibrillation (AF).Methods: Patients with HFpEF from the Americas in the TOPCAT trial were categorized into the 3 groups: normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2), and obesity (≥30 kg/m2). The Cox proportional-hazards models were used to calculate the adjusted hazard ratios (HRs) and CIs.Results: We identified 1,749 patients with HFpEF, 42.1% of which had baseline AF. In the total population of HFpEF, both overweight (HR = 0.59, 95% CI: 0.42–0.83) and obesity (HR = 0.49, 95% CI: 0.35–0.69) were associated with a reduced risk of all-cause death. Among patients with HFpEF without AF, overweight (HR = 0.51, 95% CI: 0.27–0.95) and obesity (HR = 0.64, 95% CI: 0.43–0.98) were associated with a lower risk of all-cause death. In those with AF, obesity (HR = 0.62, 95% CI: 0.40–0.95) but not overweight (HR = 0.81, 95% CI: 0.54–1.21) was associated with a decreased risk of all-cause death.Conclusions: The “obesity paradox” assessed by BMI exists in patients with HFpEF regardless of comorbid AF.Clinical Trial Registration:https://clinicaltrials.gov, identifier: NCT00094302.

BackgroundArrhythmia is a very common complication of coronavirus disease 2019 (COVID-19); however, the prevalence of ventricular arrhythmia and associated outcomes are not well-explored. Here, we conducted a systematic review and meta-analysis to determine the prevalence and associated death of ventricular arrhythmia and sudden cardiac death (SCD) in patients with COVID-19.MethodsDatabases of PubMed, Cochrane Library, Embase, and MdeRxiv were searched. Studies that could calculate the prevalence of ventricular arrhythmia/SCD during hospital admission or associated death in patients with COVID-19 were included. The study was registered with the PROSPERO (CRD42021271328).ResultsA total of 21 studies with 13,790 patients were included. The pooled prevalence of ventricular arrhythmia was 5% (95% CI: 4–6%), with a relatively high-SCD prevalence (1.8% in hospitalized COVID-19 and 10% in deceased cases of COVID-19). Subgroup analysis showed that ventricular arrhythmia was more common in patients with elevated cardiac troponin T [ES (effect size): 10%, 95% CI: −0.2 to 22%] and in European (ES: 20%, 95% CI: 11–29%) populations. Besides, ventricular arrhythmia was independently associated with an increased risk of death in patients with COVID-19 [odds ratio (OR) = 2.83; 95% CI: 1.78–4.51].ConclusionVentricular arrhythmia and SCD resulted as a common occurrence with a high prevalence in patients with COVID-19 admitted to the hospital. Furthermore, ventricular arrhythmia significantly contributed to an increased risk of death in hospitalized patients with COVID-19. Clinicians might be vigilant of ventricular arrhythmias for patients with COVID-19, especially for severe cases.Systematic Review Registrationwww.york.ac.uk/inst/crd, identifier: CRD42021271328.

Background: The use of direct oral anticoagulants (DOACs) is recommended as the preferred treatment drug in patients with nonvalvular atrial fibrillation (AF). However, the effectiveness and safety of DOACs compared with vitamin K antagonists (VKAs) in patients with cancer and AF are still controversial. Therefore, we performed a meta-analysis regarding the effectiveness and safety of DOACs vs. VKAs in AF patients with cancer.Methods: A search of the Pubmed and EMBASE databases until August 2021 was performed. Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model with an inverse variance method.Results: Thirteen studies were deemed to meet the criteria. For the effectiveness outcomes, the use of DOACs compared with VKAs use was significantly associated with decreased risks of stroke or systemic embolism (RR = 0.66, 95% CI: 0.54–0.80) and venous thromboembolism (RR = 0.40, 95% CI: 0.26–0.61), but not ischemic stroke (RR = 0.79, 95% CI: 0.56–1.11), myocardial infarction (RR = 0.78, 95% CI: 0.56–1.11), cardiovascular death (RR = 0.76, 95% CI: 0.53–1.09), and all-cause death (RR = 0.82, 95% CI: 0.43–1.56). For the safety outcomes, compared with VKAs use, the use of DOACs was associated with reduced risks of intracranial bleeding (RR = 0.60, 95% CI: 0.50–0.71) and gastrointestinal bleeding (RR = 0.87, 95% CI: 0.80–0.95). There were no significant differences in major bleeding (RR = 0.87, 95% CI: 0.74–1.04), major or nonmajor clinically relevant bleeding (RR = 0.87, 95% CI: 0.74–1.01), and any bleeding (RR = 0.88, 95% CI: 0.76–1.03).Conclusion: Compared with VKAs, DOACs appeared to have significant reductions in stroke or systemic embolism, venous thromboembolism, intracranial bleeding, and gastrointestinal bleeding, but comparable risks of ischemic stroke, myocardial infarction, cardiovascular death, all-cause death, major bleeding, major or nonmajor clinically relevant bleeding, and any bleeding in patients with AF and cancer.

Background: Several bleeding risk assessment models have been developed in atrial fibrillation (AF) patients with oral anticoagulants, but the most appropriate tool for predicting bleeding remains uncertain. Therefore, we aimed to assess the diagnostic accuracy of the Hypertension, Abnormal liver/renal function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs/alcohol concomitantly (HAS-BLED) score compared with other risk scores in anticoagulated patients with AF.Methods: We comprehensively searched the PubMed and Embase databases until July 2021 to identify relevant pieces of literature. The predictive abilities of risk scores were fully assessed by the C-statistic, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) values, calibration data, and decision curve analyses.Results: A total of 39 studies met the inclusion criteria. The C-statistic of the HAS-BLED score for predicting major bleeding was 0.63 (0.61–0.65) in anticoagulated patients regardless of vitamin k antagonists [0.63 (0.61–0.65)] and direct oral anticoagulants [0.63 (0.59–0.67)]. The HAS-BLED had the similar C-statistic to the Hepatic or renal disease, Ethanol abuse, Malignancy, Older, Reduced platelet count or function, Re-bleeding risk, Hypertension (uncontrolled), Anemia, Genetic factors, Excessive fall risk, Stroke (HEMORR2HAGES), the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA), the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT), the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF), or the Age, Biomarkers, Clinical History (ABC) scores, but significantly higher C-statistic than the Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke/transient ischemic attack history (CHADS2) or the Congestive heart failure/left ventricular ejection fraction ≤ 40%, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke/transient ischemic attack/thromboembolism history, Vascular disease, Age 65–74 years, Sex (female) (CHA2DS2-VASc) scores. NRI and IDI values suggested that the HAS-BLED score performed better than the CHADS2 or the CHA2DS2-VASc scores and had similar or superior predictive ability compared with the HEMORR2HAGES, the ATRIA, the ORBIT, or the GARFIELD-AF scores. Calibration and decision curve analyses of the HAS-BLED score compared with other scores required further assessment due to the limited evidence.Conclusion: The HAS-BLED score has moderate predictive abilities for bleeding risks in patients with AF regardless of type of oral anticoagulants. Current evidence support that the HAS-BLED score is at least non-inferior to the HEMORR2HAGES, the ATRIA, the ORBIT, the GARFIELD-AF, the CHADS2, the CHA2DS2-VASc, or the ABC scores.

ABSTRACT Understanding mechanisms governing the resistance and resilience of microbial communities is essential for predicting their ecological responses to environmental disturbances. Although we have a good understanding of such issues for soil and lake ecosystems, how ecological resistance and resilience regulate the microbiota in the fish gut ecosystem remains unclear. Using the zebrafish model, we clarified the potential mechanisms governing the gut microbiota after exposure to silver nanoparticles (AgNPs). Here, we explored the ecological resistance and resilience of gut microbiota in zebrafish exposed to different concentrations of AgNPs (i.e., 10, 33 and 100 μg/liter) for 15, 45, 75 days. The high-throughput sequencing analysis of the 16S rRNA gene showed that AgNP exposure significantly reduced the α-diversity of gut microbiota and resulted in obvious dynamics of community composition and structure. However, the rebound of zebrafish gut microbiota was pushed toward an alternative state after 15 days of AgNP exposure. We found that homogeneous selection was a more prevalent contributor in driving gut community recovery after AgNP exposure. The resilience and resistance of gut microbiota responses to AgNP disturbance might be mainly determined by the predominant keystone taxa such as Acinetobacter and Gemmata. This study not only expanded our understanding of fish gut microbiota’s responses to pollutants but also provided new insights into maintaining host-microbiome stability during environmental perturbations. IMPORTANCE Understanding the ecological mechanisms governing the resistance and resilience of microbial communities is a key issue to predict their responses to environmental disturbances. Using the zebrafish model, we wanted to clarify the potential mechanisms governing the resistance and resilience of gut microbiota after exposure to silver nanoparticles (AgNPs). We found that AgNP contamination significantly reduced the α-diversity of gut microbiota and resulted in obvious changes in community composition. The resilience and resistance of gut microbiota to AgNPs might be associated with the predominant keystone taxa (e.g., Acinetobacter and Gemmata). This study greatly expanded our understanding of how fish gut microbiota responds to environmental perturbations and maintains stability.

Background: Epidemiological studies have shown that atrial fibrillation (AF) is a potential cardiovascular complication of coronavirus disease 2019 (COVID-19). We aimed to perform a systematic review and meta-analysis to clarify the prevalence and clinical impact of AF and new-onset AF in patients with COVID-19.Methods: PubMed, Embase, the Cochrane Library, and MedRxiv up to February 27, 2021, were searched to identify studies that reported the prevalence and clinical impact of AF and new-onset AF in patients with COVID-19. The study was registered with PROSPERO (CRD42021238423).Results: Nineteen eligible studies were included with a total of 21,653 hospitalized patients. The pooled prevalence of AF was 11% in patients with COVID-19. Older (≥60 years of age) patients with COVID-19 had a nearly 2.5-fold higher prevalence of AF than younger (

Background: Recent observational studies have compared effectiveness and safety profiles between non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in patients with atrial fibrillation (AF). Nevertheless, the confounders may exist due to the nature of clinical practice-based data, thus potentially influencing the reliability of results. This systematic review and meta-analysis were conducted to compare the effect of NOACs with warfarin based on the propensity score-based observational studies vs. randomized clinical trials (RCTs).Methods: Articles included were systematically searched from the PubMed and EMBASE databases until March 2021 to obtain relevant studies. The primary outcomes were stroke or systemic embolism (SSE) and major bleeding. Hazard ratios (HRs) and 95% confidence intervals (CIs) of the outcomes were extracted and then pooled by the random-effects model.Results: A total of 20 propensity score-based observational studies and 4 RCTs were included. Compared with warfarin, dabigatran (HR, 0.82 [95% CI, 0.71–0.96]), rivaroxaban (HR, 0.80 [95% CI, 0.75–0.85]), apixaban (HR, 0.75 [95% CI, 0.65–0.86]), and edoxaban (HR, 0.71 [95% CI, 0.60–0.83]) were associated with a reduced risk of stroke or systemic embolism, whereas dabigatran (HR, 0.76 [95% CI, 0.65–0.87]), apixaban (HR, 0.61 [95% CI, 0.56–0.67]), and edoxaban (HR, 0.58 [95% CI, 0.45–0.74]) but not rivaroxaban (HR, 0.92 [95% CI, 0.84–1.00]) were significantly associated with a decreased risk of major bleeding based on the observational studies. Furthermore, the risk of major bleeding with dabigatran 150 mg was significantly lower in observational studies than that in the RE-LY trial, whereas the pooled results of observational studies were similar to the data from the corresponding RCTs in other comparisons.Conclusion: Data from propensity score-based observational studies and NOAC trials consistently suggest that the use of four individual NOACs is non-inferior to warfarin for stroke prevention in AF patients.

Background: Since evidence regarding the relationship between physical activity (PA) and atrial fibrillation (AF) incidence is inconsistent among studies, we performed a dose–response meta-analysis to comprehensively evaluate the exposure–effect association between PA and incident AF and the potential sex difference in the general population.Methods: The PubMed and Embase databases were searched for eligible studies published up to July 2020 (PROSPERO: CRD42018091692). The non-linear or linear exposure–effect relationship between PA and AF was examined using the robust error meta-regression method.Results: A total of 16 prospective studies involving 1,449,017 individuals and 39,884 AF cases were included. We observed an inverse non-linear association between PA level and incident AF (I2 = 0%, pnon−linearity < 0.001). In the linear model, a 5 metabolic equivalent of task (MET)-h/week increase in PA was associated with a decreased risk of AF [risk ratio (RR) = 0.992, 95% confidence interval (CI): 0.988–0.996, I2 = 0%]. In the sex-stratified analysis, we observed an inverse non-linear relationship between PA level and AF risk in females (I2 = 90%, pnon−linearity < 0.0001) but not in males (I2 = 0%, pnon−linearity = 0.40). In the linear model, a 5 MET-h/week increase in PA was associated with a reduced risk of AF in females (RR = 0.982, 95% CI: 0.975–0.989, I2 = 71%) but not in males (RR = 0.998, 95% CI: 0.994–1.002, I2 = 0%), with a significant interaction observed between the two groups (pinteraction < 0.0001).Conclusion: There was an inverse non-linear relationship between PA level and incident AF in the general population. The beneficial effect of PA in reducing AF risk might be predominantly observed in females.

Aims: The aim of the study was to determine the associations of weight loss or gain with all-cause mortality risk in heart failure with preserved ejection fraction (HFpEF).Methods and Results: Non-lean patients from the Americas from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist study were analyzed (n = 1,515). Weight loss and weight gain were defined as a decrease or increase in weight ≥5% between baseline and 1 year. To determine the associations of weight change and mortality risk, we used adjusted Cox proportional hazards models and restricted cubic spline models. The mean age was 71.5 (9.6) years. Weight loss and gain were witnessed in 19.3 and 15.9% patients, respectively. After multivariable adjustment, weight loss was associated with higher risk of mortality (HR 1.42, 95% CI 1.06–1.89, P = 0.002); weight gain had similar risk of mortality (HR 0.98, 95% CI 0.68–1.42, P = 0.932) compared with weight stability. There was linear relationship between weight change and mortality risk. The association of weight loss and mortality was different for patients with and without diabetes mellitus (interaction p = 0.009).Conclusion: Among patients with HFpEF, weight loss was independently associated with higher risk of all-cause mortality, and weight gain was not associated with better survival.Clinical Trial Registration:https://clinicaltrials.gov, Identifier: NCT00094302.

Aims: To investigate the relationship between body-weight fluctuation and risks of clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF).Methods and Results:We measured intra-individual variations in body weight from baseline and follow-up visits in 1,691 participants with HFpEF from the Americas from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. The primary endpoint was any cardiovascular events (a composite of death from cardiovascular disease, non-fatal myocardial infarction, aborted cardiac arrest, or hospitalization for HF). The body-weight fluctuation was measured according to average successive variability and high variability was defined as greater than or equal to the median. After adjustment for risk factors, mean body weight and weight change, each increase of 1 standard deviation in body-weight variability was significantly associated with increased risks of any cardiovascular events (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.15–1.33, P < 0.001). Patients with high variability had a 47% increased risk of any cardiovascular events and 27% increased risk of all-cause death compared with those with low variability. Such association was similar among patients with New York Heart Association functional class I/II vs. III/IV, obesity vs. non-obesity, and weight loss, gain vs. stability (the P-values for interaction were all insignificant).Conclusion: Among patients with HFpEF, body-weight fluctuation was associated with increased risks of cardiovascular events independent of traditional cardiovascular risk factors, and regardless of HF severity, baseline weight or weight change direction.Clinical Trial Registration: Aldosterone antagonist therapy for adults with heart failure and preserved systolic function (TOPCAT), https://clinicaltrials.gov, identifier [NCT00094302].

Background: Heart failure with preserved ejection fraction (HFpEF) affects women more frequently than men. However, data on sex-specific associations of adverse health outcomes and left ventricular structure and function and with microalbuminuria in patients with HFpEF are scarce.Methods: In 1,334 participants enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) Trial, we estimated the sex-specific multivariable-adjusted risk and LV traits with urine microalbumin/creatine ratio (ACR), using Cox or linear regression.Results: In total, 604 (45.3%) were women. In multivariable-adjusted analyses, a doubling of ACR in both men and women was associated with higher posterior (+0.014 cm, p = 0.012/+0.012 cm, p = 0.033) wall thickness and left ventricular mass index (+2.55 mg/m2, p = 0.004/+2.45 mg/m2, p = 0.009), whereas was also associated with higher septal (+0.018 cm, p = 0.002) and left atrial volume index (+1.44 mL/m2, p = 0.001) in men. ACR was a key predictor of all-cause (HR, 1.11; p = 0.006) and cardiovascular (HR, 1.17; p = 0.002) death in women, whereas in men ACR was associated with HF hospitalization (HR, 1.23; p < 0.001), any hospitalization (HR, 1.06; p = 0.006), and myocardial infarction (HR, 1.19; p = 0.017). The interactions of sex with ACR were significant for hospitalization for heart failure and any hospitalization (p ≤ 0.034).Conclusions: Outcomes and cardiac structure and function in patients with HFpEF appear to be influenced by ACR that vary according to sex. In men, ACR was significant associated with LV diastolic function, hospitalization, and myocardial infarction, whereas in women was associated with mortality.

Early repolarization syndrome (ERS) may be a near-Mendelian or an oligogenic disease; however, no direct evidence has been provided to support this theory.We described a large Chinese family with nocturnal sudden cardiac death induced by ERS in most of the young male adults. One missense mutation (p.Q1916R) was found in the major subunit of the L-type calcium channel gene CACNA1C by the direct sequencing of candidate genes. A concomitant gain-of-function variant in the sodium channel gene SCN5A (p.R1193Q) was found to rescue the phenotype of the female CACNA1C-Q1916R mutation carriers, which led to the incomplete penetrance. The functional studies, via the exogenous expression approach, revealed that the CACNA1C-Q1916R mutation led to a decreasing L-type calcium current and the protein expression defect. The decreased calcium current produced by the mutant channel was improved by isoproterenol but exacerbated by testosterone. The effects of CACNA1C-Q1916R mutation and testosterone on cellular electrophysiology were further confirmed by the human ventricular action potential simulation.Our results demonstrated that the loss-of-function CACNA1C-Q1916R mutation contributed to ERS-related sudden cardiac death, and the phenotypic incomplete penetrance was modified by the SCN5A-R1193Q variant and sex. These findings suggest that phenotypes of ERS are modified by multiple genetic factors, which supports the theory that ERS may be an oligogenic disease.

Background Several studies have investigated the impact of body mass index (BMI) on the prognosis of atrial fibrillation, but the results remain controversial. We sought to estimate the association of BMI with atrial fibrillation–related outcomes. Methods and Results We systematically searched the Cochrane Library, PubMed, and Elsevier databases for all studies reporting associations between BMI and atrial fibrillation–related outcomes. Relative risks (RRs) and 95% CIs were extracted and pooled. Nine studies with 49 364 participants were included. Underweight BMI was associated with an increased risk of stroke or systemic embolism (RR 1.67, 95% CI 1.12–2.49), all‐cause mortaliity (RR 2.61, 95% CI 2.21–3.09), and cardiovascular death (RR 2.49, 95% CI 1.38–4.50). Nevertheless, the pooled RRs of overweight and obese patients were lower than those of normal‐weight patients for stroke or systemic embolism (overweight: RR 0.91, 95% CI 0.80–1.04; obese: RR 0.84, 95% CI 0.72–0.98; grade 1 obesity: RR 0.89, 95% CI 0.71–1.11; grade 2 obesity: RR 0.64, 95% CI 0.45–0.91; grade 3 obesity: RR 0.82, 95% CI 0.54–1.25), all‐cause death (overweight: RR 0.78, 95% CI 0.62–0.96; obese: RR 0.84, 95% CI 0.64–1.10; grade 1 obesity: RR 0.64, 95% CI 0.57–0.73; grade 2 obesity: RR 0.70, 95% CI 0.47–1.03; grade 3 obesity: RR 0.72, 95% CI 0.59–0.88), and cardiovascular death (overweight: RR 0.79, 95% CI 0.58–1.08; obese: RR 0.99, 95% CI 0.79–1.24). Conclusions Underweight BMI is associated with an increased risk of stroke or systemic embolism, cardiovascular death, and all‐cause death in Asian patients with atrial fibrillation, whereas in all atrial fibrillation patients, overweight and obese BMI was not associated with increased risks of these outcomes.

Background: The safety and efficacy of coronary artery bypass grafting (CABG) and second-generation drug-eluting stents (DESs) in patients with coronary artery disease (CAD) remain controversial. Therefore we aimed to compare the outcomes of CAD patients treated with CABG and second-generation DESs. Methods: We systematically searched the PubMed, Cochrane Library, Ovid, and Elsevier databases. Studies comparing second-generation DESs with CABG in CAD patients were included. RevMan 5.3 was used to extract and pool the data from the applicable studies. Results: Six trials (N=6604 participants) were included in this meta-analysis. Among all of the CAD patients, second-generation DESs were associated with no differences in the risks of all-cause death [risk ratio (RR) 1.18, 95% confidence interval (CI) 0.98–1.43, P=0.09], cardiovascular death (RR 1.14, 95% CI 0.81–1.59, P=0.45), myocardial infarction (RR 1.22, 95% CI 0.98–1.54, P=0.08), and stroke (RR 0.83, 95% CI 0.59–1.17, P=0.29), but increased the risks of revascularization (RR 1.95, 95% CI 1.66–2.30, P