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Abstract Background Atrioventricular block (AVB) is a heterogeneous group of arrhythmias. AVB can lead to sudden arrest of the heart and subsequent syncope or sudden cardiac death. Few scholars have investigated the underlying molecular mechanisms of AVB. Finding molecular markers can facilitate understanding of AVB and exploration of therapeutic targets. Methods Two-sample Mendelian randomization (MR) analysis was undertaken with inverse variance weighted (IVW) model and Wald ratio as the primary approach. Reverse MR analysis was undertaken to identify the associated protein targets and gene targets. Expression quantitative trait loci (eQTL) data from the eQTLGen database and protein quantitative trait loci (pQTL) data from three previous large-scale proteomic studies on plasma were retrieved as exposure data. Genome-wide association study (GWAS) summary data (586 cases and 379,215 controls) for AVB were retrieved from the UK Biobank database. Colocalization analyses were undertaken to identify the effect of filtered markers on outcome data. Databases (DrugBank, Therapeutic Target, PubChem) were used to identify drugs that interacted with targets. Results We discovered that 692 genes and 42 proteins showed a significant correlation with the AVB phenotype. Proteins (cadherin-5, sTie-1, Notch 1) and genes (DNAJC30, ABO) were putative molecules to AVB. Drug–interaction analyses revealed anticancer drugs such as tyrosine-kinase inhibitors and TIMD3 inhibitors could cause AVB. Other substances (e.g. toxins, neurological drugs) could also cause AVB. Conclusions We identified the proteins (cadherin-5, sTie-1, Notch 1) and gene (DNAJC30, ABO) targets associated with AVB pathogenesis. Anticancer drugs (tyrosine-kinase inhibitors, TIMD3 inhibitors), toxins, or neurological drugs could also cause AVB.

Abstract Aims Recent years, several studies have suggested that abnormal baseline left ventricular (LV) function and structure are associated with left ventricular thrombus (LVT) formation. Despite this, most studies have given less attention to the potential role of left ventricular reverse remodelling (LVRR), that is, the improvement of LV function and structure, in resolving LVT. In this study, we aim to investigate the clinical characteristics, prognosis, and LVT resolution in patients with LVRR. Methods and results This is a retrospective study conducted at The First Affiliated Hospital of Dalian Medical University. Our cohort consists of patients diagnosed with LVT between 1 November 2015 and 31 May 2020. Enrolled patients were categorized into two groups: LVRR and Failure of LVRR. The primary endpoints included LVT resolution and embolic events. A total of 84 patients were included in the study, with 59 patients in the LVRR group and 25 patients in the Failure of LVRR group. In our study, patients in the LVRR group experienced higher incidence of LVT resolution and a lower risk of embolic events. Multivariate logistic analysis revealed that Failure of LVRR was the only independent negative predictor for LVT resolution and positive predictor for embolic events. Conclusions Patients with LVRR experience higher incidence of LVT resolution and have lower risk of embolic events, highlighting the significance of identifying and mitigating risk factors that contribute to abnormal LV function and structure in management of patients with LVT.

Abstract Background Percutaneous coronary intervention (PCI) with primary stenting, which stands for stent implantation regardless of obtaining satisfactory results with balloon angioplasty, has superseded conventional plain old balloon angioplasty with provisional stenting. With drug-coated balloon (DCB), primary DCB angioplasty with provisional stenting has shown non-inferiority to primary stenting for de novo coronary small vessel disease. However, the long-term efficacy and safety of such a strategy to the primary stenting on clinical endpoints in de novo lesions without vessel diameter restrictions remain uncertain. Study design The REC-CAGEFREE I is an investigator-initiated, multicenter, randomized, open-label trial aimed to enroll 2270 patients with acute or chronic coronary syndrome from 43 interventional cardiology centers in China to evaluate the non-inferiority of primary paclitaxel-coated balloons angioplasty to primary stenting for the treatment of de novo, non-complex lesions without vessel diameter restrictions. Patients who fulfill all the inclusion and exclusion criteria and have achieved a successful lesion pre-dilatation will be randomly assigned to the two arms in a 1:1 ratio. Protocol-guided DCB angioplasty and bailout stenting after unsatisfactory angioplasty are mandatory in the primary DCB angioplasty group. The second-generation sirolimus-eluting stent will be used as a bailout stent in the primary DCB angioplasty group and the treatment device in the primary stenting group. The primary endpoint is the incidence of Device-oriented Composite Endpoint (DoCE) within 24 months after randomization, including cardiac death, target vessel myocardial infarction, and clinically and physiologically indicated target lesion revascularization. Discussion The ongoing REC-CAGEFREE I trial is the first randomized trial with a clinical endpoint to assess the efficacy and safety of primary DCB angioplasty for the treatment of de novo, non-complex lesions without vessel diameter restrictions. If non-inferiority is shown, PCI with primary DCB angioplasty could be an alternative treatment option to primary stenting. Trial registration Registered on clinicaltrial.gov (NCT04561739).

Background: Oral health is of fundamental importance to maintain systemic health in humans. Stem cell-based oral tissue regeneration is a promising strategy to achieve the recovery of impaired oral tissue. As a highly conserved process of lysosomal degradation, autophagy induction regulates stem cell function physiologically and pathologically. Autophagy activation can serve as a cytoprotective mechanism in stressful environments, while insufficient or over-activation may also lead to cell function dysregulation and cell death. Aim of review: This review focuses on the effects of autophagy on stem cell function and oral tissue regeneration, with particular emphasis on diverse roles of autophagy in different oral tissues, including periodontal tissue, bone tissue, dentin pulp tissue, oral mucosa, salivary gland, maxillofacial muscle, temporomandibular joint, etc. Additionally, this review introduces the molecular mechanisms involved in autophagy during the regeneration of different parts of oral tissue, and how autophagy can be regulated by small molecule drugs, biomaterials, exosomes/RNAs or other specific treatments. Finally, this review discusses new perspectives for autophagy manipulation and oral tissue regeneration. Key scientific concepts of review: Overall, this review emphasizes the contribution of autophagy to oral tissue regeneration and highlights the possible approaches for regulating autophagy to promote the regeneration of human oral tissue.

BackgroundA previous investigation reported that an abnormal P-wave terminal force in lead V1 (PTFV1) is a marker for electrical remodeling of the left atrium (LA). We aimed to assess the relationship of PTFV1 with LA tachyarrhythmia (LATA) recurrence after radiofrequency catheter ablation (RFCA) in patients with paroxysmal atrial fibrillation (PAF) and normal LA size.MethodsPatients with PAF and normal LA size (LA volume index 4,000 μV*ms were 1.22 (1.13–1.32, p

IntroductionMultiple myeloma (MM) is a leading cause of hematopoietic cancer-related mortality, accounting for 20% of deaths. MM-targeted therapies have demonstrated efficacy, and since 2015, the United States Food and Drug Administration (FDA) has approved five targeted drugs. However, their cardiovascular safety has not been comprehensively evaluated.ObjectiveThis study aimed to investigate the association between MM-targeted therapy and cardiovascular adverse events (AEs).MethodsDisproportionality analysis was conducted on reports from the FDA AE Reporting System database from 2014 to the second quarter of 2023. Cardiovascular AEs were grouped into nine narrow categories using the Standardized Medical Dictionary for Regulatory Activities Queries (SMQs).ResultsA total of 3,228 cardiovascular AE cases involving MM-targeted therapy were extracted and analyzed. Significant disproportionality was identified for daratumumab, elotuzumab, and isatuximab. Among the nine narrow SMQ categories, the three most reported cardiovascular AEs were cardiomyopathy, cardiac arrhythmias, and embolic and thrombotic events. Noninfectious myocarditis/pericarditis, cardiac arrhythmias, and embolic and thrombotic events exhibited the strongest signal strengths. The cardiovascular AE risk was higher within the first month and gradually decreased thereafter; however, it increased rapidly again after 1 year. This trend was observed for all cardiovascular AEs. The Kaplan–Meier curve and the log-rank test revealed that isatuximab and elotuzumab exhibited a significantly lower probability of cardiovascular AEs than daratumumab (p < 0.001).ConclusionsMM-targeted therapy is significantly associated with an increased risk of previously unknown cardiovascular AE profiles, with the range and onset differing among various drugs, thereby warranting specific monitoring and appropriate management.

Abstract Aims Risk assessment for triple-vessel disease (TVD) remain challenging. Stress hyperglycemia represents the regulation of glucose metabolism in response to stress, and stress hyperglycemia ratio (SHR) is recently found to reflect true acute hyperglycemic status. This study aimed to evaluate the prognostic value of SHR and its role in risk stratification in TVD patients with acute coronary syndrome (ACS). Methods A total of 3812 TVD patients with ACS with available baseline SHR measurement were enrolled from two independent centers. The endpoint was cardiovascular mortality. Cox regression was used to evaluate the association between SHR and cardiovascular mortality. The SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) II (SSII) was used as the reference model in the model improvement analysis. Results During a median follow-up of 5.1 years, 219 (5.8%) TVD patients with ACS suffered cardiovascular mortality. TVD patients with ACS with high SHR had an increased risk of cardiovascular mortality after robust adjustment for confounding (high vs. median SHR: adjusted hazard ratio 1.809, 95% confidence interval 1.160–2.822, P = 0.009), which was fitted as a J-shaped pattern. The prognostic value of the SHR was found exclusively among patients with diabetes instead of those without diabetes. Moreover, addition of SHR improved the reclassification abilities of the SSII model for predicting cardiovascular mortality in TVD patients with ACS. Conclusions The high level of SHR is associated with the long-term risk of cardiovascular mortality in TVD patients with ACS, and is confirmed to have incremental prediction value beyond standard SSII. Assessment of SHR may help to improve the risk stratification strategy in TVD patients who are under acute stress.

Abstract Aims Rhythm control therapy has shown great benefits for patients with atrial fibrillation (AF) and heart failure (HF). However, few studies have evaluated the effects of rhythm control on left ventricular ejection fraction (LVEF) trajectory across the whole HF spectrum. Our study explored the prevalence and predictors of LVEF trajectory changes and their prognostic implications following rhythm control. Methods and results Depending on the treatment strategy, the cohort was classified into rhythm and rate control groups. Alterations in HF types and LVEF trajectory were recorded. The observational endpoints were all‐cause mortality and HF‐related admission. Predictors of LVEF trajectory improvement in the rhythm control group were evaluated. After matching, the two groups had similar age [mean age (years): rhythm/rate control: 63.96/65.13] and gender [male: rhythm/rate control: n = 228 (55.6%)/233 (56.8%)]. Based on baseline LVEF measurement, the post‐matched cohort had 490 HF with preserved ejection fraction (rhythm/rate control: n = 260/230; median LVEF: 58.00%/57.00%), 99 HF with mildly reduced ejection fraction (rhythm/rate control: n = 50/49; median LVEF: 45.00%/46.00%), and 231 HF with reduced ejection fraction (rhythm/rate control: n = 100/131; median LVEF: 32.50%/33.00%). Trajectory analysis found that the rhythm control group had a greater percentage of LVEF trajectory improvement than the rate control group [80 (53.3%) vs. 71 (39.4%), P = 0.012]. Cox regression analysis also showed that the rhythm control group was more likely to have improved LVEF trajectory compared with the rate control group {hazard ratio [HR] 1.671 [95% confidence interval (CI) 1.196–2.335], P = 0.003}. In the survival analysis, the rhythm control group experienced significant lower risks of all‐cause mortality [HR 0.600 (95% CI 0.366–0.983), P = 0.043] and HF‐related admission [HR 0.611 (95% CI 0.496–0.753), P

Abstract Background There is limited evidence on the association between arterial stenosis and the risk of all‐cause mortality in cancer patients (ACMC). This study investigated whether the status of arterial function and structure measured by brachial–ankle pulse wave velocity (baPWV) is associated with ACMC. Methods A total of 43,943 Chinese adults underwent a baPWV examination. Cox proportional hazards model was used to assess the association between the baPWV values and ACMC. Results During a total follow‐up duration of 3.81 ± 2.50 years, there were 157 deaths among 553 cancer cases diagnosed during the follow‐up. Patients with baPWV ≥18 m/s showed an increased risk of ACMC compared to patients with ideal vascular function. In the multivariate‐adjusted model, we observed a significant association between arterial stiffness severity and ACMC with a hazard ratio (HR) 2.72 (95% confidence interval [CI]: 1.55–4.80; p

Objectives The role of cardiac arrhythmia in ischaemic stroke is widely studied, but the size of the stroke risk in patients with sinus node dysfunction (SND) with and without atrial fibrillation (AF) is unclear. This systematic review and meta-analysis aimed to compare the risk of stroke and its associated factors in patients with SND with and without AF.Design A systematic review and meta-analysis was conducted based on the Grading of Recommendations, Assessment, Development and Evaluation approach.Data sources PubMed, EMBASE and Cochrane Database were searched until December 2022.Eligibility criteria for selecting studies Studies that investigate stroke in patients with SND diagnosed with or without AF/atrial flutter.Data extraction and synthesis Two independent authors screened studies for inclusion and extracted data. Literature quality assessment was performed using the Newcastle-Ottawa Scale and the Cochrane Collaboration Tool. The overall risk of stroke was estimated using the random-effects model. The generic inverse variance method was used to calculate the pooled estimates of stroke-associated factors. We performed a sensitivity analysis using a fixed-effects model.Results Of the 929 records retrieved, 6 papers (106 163 patients) met the inclusion criteria. The average yearly stroke incidence in patients with SND was 1.542% (95% CI: 1.334% to 1.749%). The stroke incidence was similar between the isolated SND (1.587%; 95% CI: 1.510% to 1.664%) and non-isolated (SND+AF) (1.660%; 95% CI: 0.705% to 2.615%) groups. AF (HR, 95% CI: 1.53 (1.01 to 2.33)), stroke/transient ischaemia attack/other thrombotic events (HR, 95% CI: 2.54 (1.14 to 5.69)), hypertension (HR, 95% CI: 1.51 (1.11 to 2.07)) and heart failure (HR, 95% CI: 1.41 (1.01 to 1.97)) were associated with stroke in the SND population.Conclusion Our findings suggest that patients with SND carry a similar risk of stroke to those with combined SND and AF. Future studies are needed to investigate whether interventions targeting stroke prevention, such as anticoagulation therapy, can help to prevent stroke in patients with SND.PROSPERO registration number CRD42023408436.

Abstract Background Diabetes mellitus (DM) and atherosclerosis are multifactorial conditions and share a common inflammatory basis. Three-vessel disease (TVD) represents a major challenge for coronary intervention. Nonetheless, the predictive value of high-sensitivity C-reactive protein (hs-CRP) for TVD patients with or without type 2 DM remains unknown. Herein, we aimed to ascertain the long-term predictive value of hs-CRP in TVD patients according to type 2 DM status from a large cohort. Methods A total of 2734 TVD patients with (n = 1040, 38%) and without (n = 1694, 62%) type 2 diabetes were stratified based on the hs-CRP (

BackgroundThe benefits of rhythm control for atrial fibrillation (AF) in heart failure with preserved ejection fraction (HFpEF) have not been conclusively determined. We assessed the effects of rhythm control on left atrial (LA) structure remodeling and prognosis in patients with AF and HFpEF.MethodsThis was a retrospective, real-world, observational study involving patients diagnosed with AF and HFpEF. The cohort was divided into rhythm-control and rate-control groups depending on their treatment strategies. The primary outcomes were all-cause mortality, rehospitalization for any cause, HF-related rehospitalization, and stroke. Differences in follow-up LA structure parameters were also analyzed.ResultsCompared to the rate-control group, patients in the rhythm-control group had a lower risk of HF-related rehospitalization even after adjusting for potential confounders (adjusted HR 0.605, 95% CI 0.413–0.887, p = 0.010). Moreover, rhythm-control therapy led to marked reductions in LA echocardiographic indicators and a higher proportion of LA reverse remodeling (LARR).ConclusionsRhythm-control therapy reverses LA structure remodeling and is associated with improved clinical outcomes; therefore, it is an optimal treatment approach for AF in HFpEF patients.

Background Doxorubicin‐induced myocardial injury is reflected by the presence of vacuolization in both clinical and animal models. The lack of scar tissue to replace the vacuolizated cardiomyocytes indicates that insufficient cardiac inflammation and healing occurred following doxorubicin injection. Whether improved macrophage activity by zymosan A (zymosan) ameliorates doxorubicin‐induced ventricular remodeling in mice is unknown. Methods and Results Mice were intravenously injected with vehicle or doxorubicin (5 mg/kg per week, 4 weeks), and cardiac structure and function were assessed by echocardiography. Two distinct macrophage subsets in hearts following doxorubicin injection were measured at different time points by flow cytometry. Moreover, cardiomyocyte vacuolization, capillary density, collagen content, and ventricular tensile strength were assessed. The therapeutic effect of zymosan (3 mg/kg, single injection) on doxorubicin‐induced changes in the aforementioned parameters was determined. At the cellular level, the polarization of monocytes to proinflammatory or reparative macrophages were measured, with or without doxorubicin (0.25 and 0.5 μmol/L). Doxorubicin led to less proinflammatory and reparative macrophage infiltration in the heart in the early phase, with decreased cardiac capillary density and collagen III in the chronic phase. In cell culture, doxorubicin (0.5 μmol/L) repressed macrophage transition toward both proinflammatory and reparative subset. Zymosan enhanced both proinflammatory and reparative macrophage infiltration in doxorubicin‐injected hearts, evoking a heightened acute inflammatory response. Zymosan alleviated doxorubicin‐induced cardiomyocyte vacuolization in the chronic phase, in parallel with enhanced collagen content, capillary density, and ventricular tensile strength. Conclusions Zymosan improved cardiac healing and ameliorated doxorubicin‐induced ventricular remodeling and dysfunction by activating macrophages at an optimal time.

ObjectiveThe purpose of this study was to evaluate the feasibility and outcomes of conduction system pacing (CSP) in patients with heart failure (HF) who had a severely reduced left ventricular ejection fraction (LVEF) of less than 30% (HFsrEF).MethodsBetween January 2018 and December 2020, all consecutive HF patients with LVEF

Abstract Mesenchymal stromal cell (MSC) implantation is a promising option for liver repair, but their poor retention in the injured liver milieu critically blunts therapeutic effects. The aim is to clarify the mechanisms underlying massive MSC loss post‐implantation and establish corresponding improvement strategies. MSC loss primarily occurs within the initial hours after implantation into the injured liver milieu or under reactive oxygen species (ROS) stress. Surprisingly, ferroptosis is identified as the culprit for rapid depletion. In ferroptosis‐ or ROS‐provoking MSCs, branched‐chain amino acid transaminase‐1 (BCAT1) is dramatically decreased, and its downregulation renders MSC susceptible to ferroptosis via suppressing the transcription of glutathione peroxidase‐4 (GPX4), a vital ferroptosis defensing enzyme. BCAT1 downregulation impedes GPX4 transcription via a rapid‐responsive metabolism‐epigenetics coordinating mechanism, involving α‐ketoglutarate accumulation, histone 3 lysine 9 trimethylation loss, and early growth response protein‐1 upregulation. Approaches to suppress ferroptosis (e.g., incorporating ferroptosis inhibitors in injection solvent and overexpressing BCAT1) significantly improve MSC retention and liver‐protective effects post‐implantation. This study provides the first evidence indicating that excessive MSC ferroptosis is the nonnegligible culprit for their rapid depletion and insufficient therapeutic efficacy after implantation into the injured liver milieu. Strategies suppressing MSC ferroptosis are conducive to optimizing MSC‐based therapy.

BackgroundThis study aims to assess the prevalence of atrial cardiomyopathy (ACM) in patients with new-onset metabolic syndrome (MetS) and investigate whether ACM could be a predictor of hospital admission for cardiovascular (CV) events.MethodsPatients with MetS who were free of clinically proven atrial fibrillation and other CV diseases (CVDs) at baseline were included in the present study. The prevalence of ACM was compared between MetS patients with and without left ventricular hypertrophy (LVH). The time to first hospital admission for a CV event between subgroups was assessed using the Cox proportional hazard model.ResultsA total of 15,528 MetS patients were included in the final analysis. Overall, LVH patients accounted for 25.6% of all newly diagnosed MetS patients. ACM occurred in 52.9% of the cohort and involved 74.8% of LVH patients. Interestingly, a significant percentage of ACM patients (45.4%) experienced MetS without LVH. After 33.2 ± 20.6 months of follow-up, 7,468 (48.1%) patients had a history of readmission due to CV events. Multivariable Cox regression analysis revealed that ACM was associated with an increased risk of admission for CVDs in the MetS patients with LVH [hazard ratio (HR), 1.29; 95% confidence interval (CI), 1.142–1.458; P

Abstract Mesenchymal stem cells (MSCs) delivered into the post-ischemic heart milieu have a low survival and retention rate, thus restricting the cardioreparative efficacy of MSC-based therapy. Chronic ischemia results in metabolic reprogramming in the heart, but little is known about how these metabolic changes influence implanted MSCs. Here, we found that excessive branched-chain amino acid (BCAA) accumulation, a metabolic signature seen in the post-ischemic heart, was disadvantageous to the retention and cardioprotection of intramyocardially injected MSCs. Discovery-driven experiments revealed that BCAA at pathological levels sensitized MSCs to stress-induced cell death and premature senescence via accelerating the loss of histone 3 lysine 9 trimethylation (H3K9me3). A novel mTORC1/DUX4/KDM4E axis was identified as the cause of BCAA-induced H3K9me3 loss and adverse phenotype acquisition. Enhancing BCAA catabolic capability in MSCs via genetic/pharmacological approaches greatly improved their adaptation to the high BCAA milieu and strengthened their cardioprotective efficacy. We conclude that aberrant BCAA accumulation is detrimental to implanted MSCs via a previously unknown metabolite-signaling-epigenetic mechanism, emphasizing that the metabolic changes of the post-ischemic heart crucially influence the fate of implanted MSCs and their therapeutic benefits.

Abstract Objective Ablation index (AI) is an effective ablation quality marker. Impedance is also an important factor for lesion formation. The present study evaluated the influence of the baseline impedance in the effect of ablation for atrial fibrillation (AF) guided by AI. Methods This was a retrospective study. 101 patients with paroxysmal AF (PAF) were enrolled. All patients underwent radiofrequency ablation guided by the same AI strategy. The ablation strategy was pulmonary vein (PV) isolation with non-PV triggers ablation. The baseline impedance of the ablation points was recorded. The patients were followed up every 3 months or so. Results During a median follow-up of 12 (4–14) months, freedom from AF/atrial tachycardia recurrence were 82.2%. No difference existed in baseline characteristics between the success group and the recurrence group. The average baseline impedance was 124.3 ± 9.7 Ω. The baseline impedance of the ablation points in success group was lower compared to the recurrence group (122.9 ± 9.4 vs. 130.5 ± 8.8 Ω, P

Abstract Background Programmed death-1 (PD-1) and programmed death- ligand 1 (PD-L1) inhibitors, such as pembrolizumab, nivolumab and atezolizumab, are major classes of immune checkpoint inhibitors that are increasingly used for cancer treatment. However, their use is associated with adverse cardiovascular events. We examined the incidence of new-onset cardiac complications in patients receiving PD-1 or PD-L1 inhibitors. Methods Patients receiving PD-1 or PD-L1 inhibitors since their launch up to 31st December 2019 at publicly funded hospitals of Hong Kong, China, without pre-existing cardiac complications were included. The primary outcome was a composite of incident heart failure, acute myocardial infarction, atrial fibrillation, or atrial flutter with the last follow-up date of 31st December 2020. Propensity score matching between PD-L1 inhibitor use and PD-1 inhibitor use with a 1:2 ratio for patient demographics, past comorbidities and non-PD-1/PD-L1 medications was performed with nearest neighbour search strategy (0.1 caliper). Univariable and multivariable Cox regression analysis models were conducted. Competing risks models and multiple propensity matching approaches were considered for sensitivity analysis. Results A total of 1959 patients were included. Over a median follow-up of 247 days (interquartile range [IQR]: 72-506), 320 (incidence rate [IR]: 16.31%) patients met the primary outcome after PD-1/PD-L1 treatment: 244 (IR: 12.57%) with heart failure, 38 (IR: 1.93%) with acute myocardial infarction, 54 (IR: 2.75%) with atrial fibrillation, 6 (IR: 0.31%) with atrial flutter. Compared with PD-1 inhibitor treatment, PD-L1 inhibitor treatment was significantly associated with lower risks of the composite outcome both before (hazard ratio [HR]: 0.32, 95% CI: [0.18-0.59], P value=0.0002) and after matching (HR: 0.34, 95% CI: [0.18-0.65], P value=0.001), and lower all-cause mortality risks before matching (HR: 0.77, 95% CI: [0.64-0.93], P value=0.0078) and after matching (HR: 0.80, 95% CI: [0.65-1.00], P value=0.0463). Patients who developed cardiac complications had shorter average readmission intervals and a higher number of hospitalizations after treatment with PD-1/PD-L1 inhibitors in both the unmatched and matched cohorts (P value

Abstract Aims The angiotensin receptor–neprilysin inhibitor (ARNI), sacubitril/valsartan, confers additional protective effects compared with angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers (ACEIs/ARBs) in terms of reversed left ventricular (LV) remodelling and improves the prognosis of patients with heart failure (HF). However, few studies have examined the effects of ARNI on the left atrium. Accordingly, this study compared the effects of ARNI and ACEI/ARB on left atrial (LA) remodelling in heart failure with reduced ejection fraction (HFrEF). Methods and results This was a single‐centre retrospective study of patients with HFrEF hospitalized at the First Affiliated Hospital of Dalian Medical University between 26 February 2016 and 8 July 2020. Patients were classified into ARNI and ACEI/ARB groups and further subgroups based on the left atrial volume index (LAVI): mildly abnormal (29 mL/m2 ≤ LAVI

A growing body of evidence on a wide spectrum of adverse cardiac events following oncologic therapies has led to the emergence of cardio-oncology as an increasingly relevant interdisciplinary specialty. This also calls for better risk-stratification for patients undergoing cancer treatment. Machine learning (ML), a popular branch discipline of artificial intelligence that tackles complex big data problems by identifying interaction patterns among variables, has seen increasing usage in cardio-oncology studies for risk stratification. The objective of this comprehensive review is to outline the application of ML approaches in cardio-oncology, including deep learning, artificial neural networks, random forest and summarize the cardiotoxicity identified by ML. The current literature shows that ML has been applied for the prediction, diagnosis and treatment of cardiotoxicity in cancer patients. In addition, role of ML in gender and racial disparities for cardiac outcomes and potential future directions of cardio-oncology are discussed. It is essential to establish dedicated multidisciplinary teams in the hospital and educate medical professionals to become familiar and proficient in ML in the future.

(1) Background: A plethora of studies have elucidated the safety and efficacy of catheter ablation (CA) for patients afflicted with atrial fibrillation (AF) and concomitant reduction in left ventricular ejection fraction (LVEF). Nevertheless, the literature on the benefits of CA in the specific etiological context of heart failure (HF) remains limited. This study delineates a comparative assessment of outcomes for patients with AF and reduced LVEF across the primary etiologies. (2) Methods: Our inquiry encompassed 216 patients diagnosed with congestive heart failure and an LVEF of less than 50 percent who were referred to our institution for circumferential pulmonary vein isolation (CPVI) between the years 2016 and 2020. The selection criteria included a detailed medical history while excluding those suffering from valvular disease, congenital heart disease, and hypertrophic cardiomyopathy. In an effort to scrutinize varying etiologies, patients were stratified into three categories: dilated cardiomyopathy (DCM, n = 56, 30.6%), ischemic cardiomyopathy (ICM, n = 68, 37.2%), and tachycardia-induced cardiomyopathy (TIC, n = 59, 32.2%). (3) Results: Following an average (±SD) duration of 36 ± 3 months, the prevalence of sinus rhythm was 52.1% in the DCM group, 50.0% in the ICM group, and 68.14% in the TIC group (p = 0.014). This study revealed a significant disparity between the DCM and TIC groups (p = 0.021) and the ICM and TIC groups (p = 0.007), yet no significant distinction was discerned between the TIC and ICM groups (p = 0.769). Importantly, there were no significant variations in the application of antiarrhythmic drugs or recurrence of procedures among the three groups. The mortality rates were 14.29% for the DCM group and 14.71% for the ICM group, which were higher than the 3.39% observed in the TIC group (DCM vs. TIC p = 0.035 (HR = 4.50 (95%CI 1.38–14.67)), ICM vs. TIC p = 0.021 (HR = 5.00 (95%CI 1.61–15.50))). A noteworthy enhancement in heart function was evidenced in the TIC group in comparison to the DCM and ICM groups, including a higher LVEF (p < 0.001), diminution of LV end-diastolic diameter (p < 0.001), and an enhanced New York Heart Association classification (p = 0.005). Hospitalization rates for heart failure were discernibly lower in TIC patients (0.98 (0,2) times) relative to those with DCM (1.74 (0,3) times, p < 0.01) and TIC (1.78 (0,4) times, p < 0.001). Patients with paroxysmal atrial fibrillation and brief episodes were found to achieve superior clinical outcomes through a catheter ablation strategy. (4) Conclusion: Patients diagnosed with TIC demonstrated a more pronounced benefit from catheter ablation compared to those with DCM and ICM. This encompassed an augmented improvement in cardiac function, an enhanced maintenance of sinus rhythm, and a reduced mortality rate.

Doxorubicin, a widely used chemotherapeutic drug in clinical oncology, causes a series of cardiac side effects referred to as doxorubicin-induced cardiotoxicity. Hyperhomocysteinaemia is an independent risk factor for multiple cardiovascular diseases. However, whether hyperhomocysteinaemia contributes to doxorubicin-induced cardiotoxicity is currently unknown. In this study, we explored the pathogenic effects of hyperhomocysteinaemia induced by dietary methionine supplementation (2% wt/wt in rodent chow) in a mouse model of doxorubicin-induced cardiotoxicity. Our data showed that methionine supplementation doubled serum homocysteine levels, inducing mild hyperhomocysteinaemia. Doxorubicin at a cumulative dosage of 25 mg/kg body weight led to significant weight loss and severe cardiac dysfunction, which were further exacerbated by methionine-induced mild hyperhomocysteinaemia. Doxorubicin-induced cardiac atrophy, cytoplasmic vacuolisation, myofibrillar disarray and loss, as well as cardiac fibrosis, were also exacerbated by methionine-induced mild hyperhomocysteinaemia. Additional folic acid supplementation (0.006% wt/wt) prevented methionine-induced hyperhomocysteinaemia and inhibited hyperhomocysteinaemia-aggravated cardiac dysfunction and cardiomyopathy. In particular, hyperhomocysteinaemia increased both serum and cardiac oxidative stress, which could all be inhibited by folic acid supplementation. Therefore, we demonstrated for the first time that hyperhomocysteinaemia could exacerbate doxorubicin-induced cardiotoxicity in mice, and the pathogenic effects of hyperhomocysteinaemia might at least partially correlate with increased oxidative stress and could be prevented by folic acid supplementation. Our study provides preliminary experimental evidence for the assessment of hyperhomocysteinaemia as a potential risk factor for chemotherapy-induced cardiotoxicity in cancer patients.

Background Heart failure with recovered ejection fraction (HFrecEF) has been a newly recognized entity since 2020. However, the concept has primarily focused on left ventricular ejection fraction improvement, with less focus on the recovery of the left atrium. In this study, we investigated changes in left atrial (LA) echocardiographic indices in HFrecEF. Methods and Results An inpatient cohort with heart failure with reduced ejection fraction (HFrEF) was identified retrospectively and followed up prospectively in a single tertiary hospital. The enrolled patients were classified into HFrecEF and persistent HFrEF groups. Alternations in LA parameters by echocardiography were calculated. The primary outcome was a composite of cardiovascular death or heart failure rehospitalization. A total of 699 patients were included (HFrecEF: n=228; persistent HFrEF: n=471). Compared with persistent HFrEF, the HFrecEF group had greater reductions in LA diameter, LA transverse diameter, LA superior–inferior diameter, LA volume, and LA volume index but not in LA sphericity index. Cox regression analysis showed that the HFrecEF group experienced lower risks of prespecified end points than the persistent HFrEF group after adjusting for confounders. Additionally, 136 (59.6%) and 62 (13.0%) patients showed LA reverse remodeling (LARR) for the HFrecEF and persistent HFrEF groups, respectively. Among the HFrecEF subgroup, patients with LARR had better prognosis compared with those without LARR. Multivariate logistic analysis demonstrated that age and coronary heart disease were 2 independent negative predictors for LARR. Conclusions In HFrecEF, both left ventricular systolic function and LA structure remodeling were improved. Patients with HFrecEF with LARR had improved clinical outcomes, indicating that the evaluation of LA size provides a useful biomarker for risk stratification of heart failure.

Abstract Aims There is an emerging interest in elucidating the natural history and prognosis for patients with heart failure with reduced ejection fraction (HFrEF) in whom left ventricular ejection fraction (LVEF) subsequently improves. The characteristics and outcomes were compared between heart failure with recovered ejection fraction (HFrecEF) and persistent HFrEF. Methods and results This is a retrospective study of adults who underwent at least two echocardiograms 3 months apart between 1 November 2015 and 31 October 2019 with an initial diagnosis of HFrEF. The subjects were divided into HFrecEF group (second LVEF > 40%, ≥10% absolute improvement in LVEF) and persistent HFrEF group (20% subgroups. The primary outcomes were all‐cause mortality and rehospitalization. A total of 1160 HFrEF patients were included [70.2% male, mean (standard deviation) age: 62 ± 13 years]. On the second echocardiogram, 284 patients (24.5%) showed HFrecEF and 876 patients (75.5%) showed persistent HFrEF. All‐cause mortality was identified in 23 (8.10%) HFrecEF and 165 (18.84%) persistent HFrEF, whilst 76 (26.76%) and 426 (48.63%) showed rehospitalizations, respectively. Survival analysis showed that the persistent HFrEF subgroup experienced a significantly higher mortality at 12 and 24 months and a higher hospitalization at 12, 24, 48, and more than 48 months following discharge. Multivariate Cox regression showed that persistent HFrEF had a higher risk of all‐cause mortality [hazard ratio (HR) 2.30, 95% confidence interval (CI) 1.49–3.56, P = 0.000] and rehospitalization (HR 1.85, 95% CI 1.45–2.36, P = 0.000) than the HFrecEF group. Subgroup analysis showed that the LVEF ≥ 20% improvement subgroup had lower rates of adverse outcomes compared with those with less improvement of 10–20%. Conclusions Heart failure with recovered ejection fraction is a distinct HF phenotype with better clinical outcomes compared with those with persistent HFrEF. HFrecEF patients have a relatively better short‐term mortality at 24 months but not thereafter.

BackgroundContemporary data on atrial cardiomyopathy (ACM) markers and ischemic cerebrovascular events (ICVE) in patients with acute myocardial infarction (AMI) is lacking. We aimed to examine whether ACM markers predict ICVE among AMI patients.Materials and methodsA total of 4,206 AMI cases diagnosed in clinical examinations between January 2016 and June 2021 were assessed for markers of ACM including B-type natriuretic peptide (BNP), P-wave terminal force in ECG lead V1 (PTFV1), and left atrium diameter (LAD). Left atrial enlargement (LAE) and abnormal PTFV1 were defined by previously published cut-off points. The primary outcome was incident ICVE composed of ischemic stroke (IS) and transient ischemic attack (TIA). Receiver operating curve analyses were used to compare the predictive performance of the CHA2DS2-VASc score combined with ACM markers to the CHA2DS2-VASc score alone.ResultsDuring a median follow-up of 44.0 months, 229 (5.44%) ICVE occurred. Of these, 156 individuals developed IS and the remaining 73 cases were diagnosed with TIAs. The ICVE group showed larger PTFV1 and increased LAD as well as elevated BNP levels at baseline. In the multivariate analysis, we found significant associations with ICVE for PTFV1 (HR per 1,000 μV*ms, 1.143; 95% CI, 1.093–1.196), LAD (HR per millimeter, 1.148; 95% CI, 1.107–1.190), but not BNP after adjusting for known ICVE risk factors and interim atrial fibrillation (AF). The addition of abnormal PTFV1 and LAE improved the predictive accuracy of the CHA2DS2-VASc score with C-statistic increasing from 0.708 to 0.761 (p < 0.001).ConclusionAtrial cardiomyopathy markers including PTFV1 and LAD were associated with incident ICVE independent of well-established risk factors and AF occurrence. The addition of ACM markers with CHA2DS2-VASc score may well discriminate individuals at high risk of ICVE in AMI patients.

BackgroundThe occurrence of new-onset atrial fibrillation (NOAF) post-acute myocardial infarction (AMI) is associated with worse outcomes. In this study, we sought to assess the predictive effect of stress hyperglycemia ratio (SHR) and neutrophil to lymphocyte ratio (NLR) to predict NOAF in patients with AMI.Materials and methodsWe recruited 3,194 individuals with AMI but free of atrial fibrillation (AF). AMI cases were stratified into groups according to SHR and NLR quartiles and were further categorized based on diabetes status. High SHR and high NLR were defined as the highest quartile of SHR and NLR. A nomogram incorporating risk factors for NOAF was constructed using multivariate logistic regression analyses. The performance of the novel nomogram was tested for predictive performance, agreement between the actual and predicted probability, and clinical utility using area under the curve (AUC), bootstrapped calibration curves, and decision curve analysis, respectively.ResultA total of 245 (7.67%) patients developed NOAF post-AMI. The NOAF cases had higher values of SHR and NLR than non-NOAF patients after AMI regardless of diabetes status. After adjusting for potential confounders, high SHR and NLR were independently associated with NOAF post-AMI. Moreover, the novel nomogram incorporating high NLR and high SHR for NOAF risk estimation in patients with AMI showed satisfactory performance assessed by the AUC, calibration curves, decision curve analysis.ConclusionSHR and NLR were independently associated with NOAF in AMI patients. The constructed novel nomogram that incorporates SHR and NLR might assist in NOAF risk stratification post-AMI.

Abstract Background Catheter ablation is an established therapy for atrial fibrillation (AF), but recurrence after ablation remains a great challenge. Additionally, little is known about the effect of renal function on the efficiency of AF ablation. This study aimed to evaluate the predictors of the prognosis of catheter ablation for AF, especially the effect of renal function. Methods A total of 306 drug-refractory symptomatic patients with AF who underwent first-time catheter ablation were enrolled in the present study. Individuals underwent circumferential pulmonary vein isolation for paroxysmal AF and stepwise ablation for persistent AF. Results The follow-up time was 27.2 ± 19.5 months, 202 patients (66.01%) were free of atrial tachyarrhythmia (non-recurrence group), and the other 104 patients experienced recurrence (recurrence group). The recurrence group had a larger left atrial diameter (LAD) and left atrial volume (LAV), a higher LAV index (LAVI) (both, p

Some studies have shown that sodium-glucose cotransporter (SGLT) 2 inhibitors can definitively attenuate the occurrence of cardiovascular diseases such as heart failure (HF), dilated cardiomyopathy (DCM), and myocardial infarction. With the development of research, SGLT2 inhibitors can also reduce the risk of arrhythmias. So in this review, how SGLT2 inhibitors play a role in reducing the risk of arrhythmia from the perspective of electrical remodeling and structural remodeling are explored and then the possible mechanisms are discussed. Specifically, we focus on the role of SGLT2 inhibitors in Na+ and Ca2 + homeostasis and the transients of Na+ and Ca2 +, which could affect electrical remodeling and then lead to arrythmia. We also discuss the protective role of SGLT2 inhibitors in structural remodeling from the perspective of fibrosis, inflammation, oxidative stress, and apoptosis. Ultimately, it is clear that SGLT2 inhibitors have significant benefits on cardiovascular diseases such as HF, myocardial hypertrophy and myocardial infarction. It can be expected that SGLT2 inhibitors can reduce the risk of arrhythmia.

Background: Recent clinical trials indicate that sodium–glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in myocardial infarction (MI) patients, but the underlying mechanisms remain unknown. As arrhythmia often occurs during myocardial infarction, it is the main cause of death.Objective: The purpose of this study was to investigate the influence of empagliflozin (EMPA), an SGLT2 inhibitor, on cardiac electrophysiological remodeling and arrhythmia susceptibility of myocardial infarction mice.Methods: ECG was obtained from mice 1 week after MI to determine the QT interval. In an electrophysiological study and optical mapping was performed to evaluate the function of EMPA and underlying mechanisms of post-myocardial-infarction in mice.Results: EMPA treatment significantly reduced the QT interval of MI mice (MI + EMPA 50.24 ms vs. MI 64.68 ms). The membrane potential and intracellular Ca [Cai] were mapped from 13 MI hearts and five normal hearts using an optical mapping technique. A dynamic pacing protocol was used to determine action potential duration and [Cai] at baseline and after EMPA (10 umol/L) infusion. EMPA perfusion did not change the APD80 and CaT80 in normal ventricles while shortening them in an infarct zone, bordering zone, and remote zone of MI hearts at 200 ms, 150 ms, 120 ms, and 100 ms pacing cycle length. The conduction velocity of infarcted ventricles was 0.278 m/s and 0.533 m/s in normal ventricles at baseline (p < 0.05). After EMPA administration, the conduction velocity of infarcted ventricles increased to 0.363 m/s, whereas no significant changes were observed in normal ventricles. The action potential rise time, CaT rise time, and CaT tau time were improved after EMPA perfusion in infarcted ventricles, whereas no significant changes were observed in normal ventricles. EMPA decreases early afterdepolarizations premature ventricular beats, and ventricular fibrillation (VF) in infarcted ventricles. The number of phase singularities (baseline versus EMPA, 6.26 versus 3.25), dominant frequency (20.52 versus 10.675 Hz), and ventricular fibrillation duration (1.072 versus 0.361 s) during ventricular fibrillation in infarcted ventricles were all significantly decreased by EMPA.Conclusion: Treatment with EMPA improved post-MI electrophysiological remodeling and decreased substrate for VF of MI mice. The inhibitors of SGLT2 may be a new class of agents for the prevention of ventricle arrhythmia after chronic MI.

ObjectivesEpidemiological data on intraventricular conduction disturbances (IVCDs) are limited in the Chinese population. We aimed to investigate the prevalence and incidence of different types of IVCDs among Chinese adults.MethodsFrom June 2006 to October 2007, a total of 100,250 individuals from the Kailuan Study underwent electrocardiogram examinations. Follow-up visits were performed biennially. The prevalence and incidence of right bundle branch block (RBBB), incomplete RBBB (IRBBB), left bundle branch block (LBBB), incomplete LBBB, left anterior fascicular block (LAFB), left posterior fascicular block (LPFB) and non-specific IVCD (NIVCD) were calculated. Their association with risk factors and cardiovascular diseases was also investigated.ResultsThe prevalence and incidence of all IVCDs were 3.19 and 1.70%, respectively. RBBB, IRBBB, and LAFB were the IVCD types that had the highest prevalence and incidence. The prevalence (3.67% vs. 1.29%; P < 0.001) and incidence (1.93% vs. 0.84%; P < 0.001) of IVCDs were higher among males than among females. The prevalence and incidence of most IVCD types increased with age. IRBBB, LBBB, and LAFB were significantly associated with hypertension. LBBB and NIVCD were associated with diabetes mellitus. In addition, LBBB and LAFB were related to prior myocardial infarction.ConclusionIVCDs differ in prevalence and incidence according to sex and age group. They also show disparate associations with other cardiovascular comorbidities. These differences need to be considered in daily clinical practice.

IntroductionAnthracycline chemotherapy drugs can produce cardiotoxicity in patients with breast cancer, leading to myocardial cell death and fibrosis, further developing into cardiac failure. However, the condition of myocardial microcirculation was unknown in breast cancer after anthracycline chemotherapy. As a result, intravoxel incoherent motion (IVIM) imaging was used to non-invasively observe the condition of myocardial microcirculation in a patient with breast cancer after anthracycline chemotherapy.Case reportA 43-year-old female patient with a right breast lump was reported. Preoperative ultrasound-guided needle biopsy showed invasive carcinoma of the right breast with fibroadenoma. Sentinel lymph node biopsy combined with simplified radical surgery for right breast cancer was performed. Postoperative pathological findings reported breast cancer (pT2N2M0 IIIA). The patient underwent eight sessions of the EC-TH chemotherapy scheme, and the EC and the TH schemes were adopted for the first four sessions and the last four sessions, respectively. During chemotherapy, during which there was the occurrence of Grade II myelosuppression, chest CT and abdomen CT showed no metastasis, and ECG and cardiac ultrasound reports returned to normal. Cardiac cine magnetic resonance and IVIM imaging were performed at the beginning of the first chemotherapy session (baseline) and after the third, fifth, and eighth chemotherapy sessions, respectively. We found that the fast apparent diffusion coefficient (ADCfast) and f parameters appeared to show a downward trend from the baseline to the fifth chemotherapy session, where the IVIMfast values declined from 163 × 10−3 mm2/s to 148 × 10−3 mm2/s and finally to 134 × 10−3 mm2/s and f values declined from 45% to 36% and then to 30%, respectively. ADCfast and f values showed an inclination from the fifth and eighth chemotherapy sessions.ConclusionOur case report showed that IVIM technology can likely detect non-invasive myocardial microcirculation early and quantitatively after anthracycline chemotherapy in patients with breast cancer. That is, IVIM technology seems to be helpful for cardiovascular risk monitoring and prognosis assessment of myocardial microcirculation in patients with breast cancer after anthracycline chemotherapy.

Abstract Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate cardiovascular functions, but their role in mesenchymal stromal cells (MSC)‐based therapy has never been investigated. It is found that overexpression of farnesoid X receptor (FXR), a main receptor for bile acids, improves the retention and cardioprotection of adipose tissue‐derived MSC (ADSC) administered by intramyocardial injection in mice with myocardial infarction (MI), which shows enhanced antiapoptotic, proangiogenic, and antifibrotic effects. RNA sequencing, LC‐MS/MS, and loss‐of‐function studies reveal that FXR overexpression promotes ADSC paracrine angiogenesis via Angptl4. FXR overexpression improves ADSC survival in vivo but fails in vitro. By performing bile acid‐targeted metabolomics using ischemic heart tissue, 19 bile acids are identified. Among them, cholic acid and deoxycholic acid significantly increase Angptl4 secretion from ADSC overexpressing FXR and further improve their proangiogenic capability. Moreover, ADSC overexpressing FXR shows significantly lower apoptosis by upregulating Nqo‐1 expression only in the presence of FXR ligands. Retinoid X receptor α is identified as a coactivator of FXR. It is first demonstrated that there is a bile acid pool in the myocardial microenvironment. Targeting the bile acid‐FXR axis may be a novel strategy for improving the curative effect of MSC‐based therapy for MI.

4-hydroxyl coumarin (HC), an important intermediate during the synthesis procedure of rodenticide and anti-cardiovascular drug, shows highly medicinal value and economic value. To achieve the efficient adsorption of HC from natural biological samples, a novel magnetic surface molecularly imprinted polymer (HC/SMIPs) was constructed by employing methacrylic acid (MAA) as functional monomer, organic silane modified magnetic particles as matrix carrier and HC as template molecule. Due to the numerous specific imprinted cavities on the HC/SMIPs, the maximum adsorption capacity of HC/SMIPs for 4-hydroxycoumarin could reach to 22.78 mg g−1 within 20 min. In addition, HC/SMIPs exhibited highly selective adsorption for 4-hydroxycoumarin compared with other active drug molecules (osthole and rutin) and showed excellent regeneration performance. After 8 cycles of adsorption-desorption tests, the adsorption capacity of HC/SMIPs just slightly decreased by 6.64%. The efficient selective removal and easy recycle of 4-hydroxycoumarin from biological samples by HC/SMIPs made a highly promising to advance the application of imprinting polymers in complex practical environments.

Abstract Few intravenously administered mesenchymal stromal cells (MSCs) engraft to the injured myocardium, thereby limiting their therapeutic efficacy for the treatment of ischemic heart injury. Here, it is found that irisin pretreatment increases the cardiac homing of adipose tissue‐derived MSCs (ADSCs) administered by single and multiple intravenous injections to mice with MI/R by more than fivefold, which subsequently increases their antiapoptotic, proangiogenic, and antifibrotic effects in rats and mice that underwent MI/R. RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis, and loss‐of‐function studies identified CSF2RB as a cytokine receptor that facilitates the chemotaxis of irisin‐treated ADSCs in the presence of CSF2, a chemokine that is significantly upregulated in the ischemic heart. Cardiac‐specific CSF2 knockdown blocked the cardiac homing and cardioprotection abilities of intravenously injected irisin‐treated ADSCs in mice subjected to MI/R. Moreover, irisin pretreatment reduced the apoptosis of hydrogen peroxide‐induced ADSCs and increased the paracrine proangiogenic effect of ADSCs. ERK1/2‐SOD2, and ERK1/2‐ANGPTL4 are responsible for the antiapoptotic and paracrine angiogenic effects of irisin‐treated ADSCs, respectively. Integrin αV/β5 is identified as the irisin receptor in ADSCs. These results provide compelling evidence that irisin pretreatment can be an effective means to optimize intravenously delivered MSCs as therapy for ischemic heart injury.

Cardio-oncology, a nascent specialty, has evolved as a concerted strategy to address the cardiovascular complications of cancer therapies. On the other hand, emerging evidence has shown that some anti-tumor drugs, such as CD20-targeted rotuximab, also have markedly cardioprotective effects in addition to treating cancers. Rituximab is a CD20-targeted monoclonal antibody and kill tumor B-cells through antibody-mediated and antibody-independent pathways, indicating that B cells participate and promote the progression of cardiovascular diseases. In this review, we mainly present the evidence that B cells contribute to the development of hypertrophy, inflammation, and maladaptive tissue remodeling, with the aim of proposing novel immunomodulatory therapeutic strategies targeting B cells and their products for the treatment of heart failure.

BackgroundRecurrence after atrial fibrillation (AF) ablation is still common.ObjectiveThis study aimed to evaluate the predictive abilities of AF duration and early recurrence (ER) to discriminate high-risk patients for recurrence.MethodsWe enrolled 1,763 consecutive patients with AF who were scheduled to receive the index radiofrequency catheter ablation (RFCA) from January 2016 to August 2021 in Dalian, China. Long AF duration (LAFD) was considered if the course of AF lasted for ≥ 12 months. ER was defined as any atrial tachycardia (AT) or AF event longer than 30 s occurring within a 3-month post-RFCA.ResultsLate recurrence occurred in 643 (36.5%) of the 1,763 patients at a median of 35 months after RFCA. Multivariate analysis identified LAFD (hazard ratio (HR): 1.80, 95% confidence interval (CI): 1.38–2.35, p < 0.001) and ER (HR: 2.34, 95% CI: 1.82–3.01, p < 0.001) as strong independent predictors of late recurrence in non-paroxysmal AF. Similarly, LAFD (HR: 1.48, 95% CI: 1.20–1.84, p < 0.001) and ER (HR: 3.40, 95% CI: 2.68–4.30, p < 0.001) were significantly associated with late recurrence in paroxysmal AF. Receiver operating curve analyses revealed that the CAAP-AF (CAD, Atrial diameter, Age, Persistent or longstanding AF, Antiarrhythmic drugs failed, Female) had the highest predict power [area under ROC curve (AUC) 0.586]. The addition of ER and LAFD to the CAAP-AF score significantly improved risk discrimination for late recurrence after AF ablation from 0.586 to 0.686.ConclusionLong AF duration and ER were independently associated with late recurrence. The prediction performance of the CAAP-AF model for recurrence was improved by the addition of LAFD and ER.

ObjectivesInsulin resistance (IR) has been shown to play important role in the pathogenesis of type 2 diabetes mellitus (T2DM). There is an intricate interplay between IR, dyslipidemia, and serum uric acid (SUA) in people with and without diabetes. Physical activity has a positive impact on insulin sensitivity in insulin-resistant populations. However, the effect of different intensities of physical activity on insulin levels under different lipid indices and SUA levels is unclear.MethodsTo explore the association between physical activity and insulin, we enrolled 12,982 participants aged above 18 years from the National Health and Nutrition Examination Survey (NHANES) conducted between 2009 and 2018. Next, we conducted multivariate logistic regression analyses, generated fitted smoothing curves, and visualized the data using generalized additive models.ResultsIncreased intensities of physical activity can significantly reduce insulin levels. The association between physical activity and insulin persisted even after adjusting for confounding factors, with β value (95% CI) = −17.10 (−21.64, −12.56) in moderate group, β value (95% CI) = −28.60 (−33.08, −24.11) in high group, respectively. High-intensity physical activity significantly lowered insulin levels in the lower and higher SUA tertiles, and three tertiles of LDL-c, HDL-c, and TG. Moreover, the link between physical activity and insulin was stronger in male individuals.ConclusionThis study shows that physical activity can significantly lower insulin levels, and high-intensity physical activity still has additional potential benefits for insulin levels, even in the condition of dyslipidemia and hyperuricemia.

Abstract Background Our recent study has revealed that many hospitalized patients with acquired long QT syndrome (ALQTS) are cancer patients. This study aims to determine the risk factors and outcomes of hospitalized cancer patients with ALQTS. Methods We performed a matched case-control study within a cohort of 10,180 cancer patients hospitalized between September 2013 and April 2016. Among them, 150 patients defined as having severe ALQTS with a markedly prolonged QT interval (QTc ≥ 500 ms) were compared with 293 age-, sex- and cancer-type-matched controls (non-ALQTS). Death as the endpoint was followed for up to 2 years. Cox regression and Kaplan-Meier survival analyses were performed to assess the effects of particular clinical variables on all-cause mortality. Multivariate logistic regression was performed to calculate odds ratios (OR) for various predictors of QT prolongation. Results The mortality was significantly higher in ALQTS group (63.3% vs. 33.4%). Hypertension, hypokalemia, hypocalcemia, QT-prolonging drugs, infection, anemia, anti-microtubule agents were contributing factors to ALQTS. Renal insufficiency, male gender and hypokalemia were found to be independent risk factors for all-cause mortality in ALQTS group. Conclusion Markedly prolonged QT interval was seen in 1.5% of hospitalized cancer patients. The all-cause mortality was high in cancer patients with severe ALQTS.

Abstract Background Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have shed great light on cardiac regenerative medicine and specifically myocardial repair in heart failure patients. However, the treatment efficacy and the survival of iPSC-CMs in vivo after transplantation have yielded inconsistent results. Objectives The objective of this study was to evaluate the ability of human iPSC-CMs to improve myocardial function in a rat postinfarction heart failure model. Methods Eight-week-old male Sprague-Dawley rats were randomly selected to receive an intramyocardial injection of 5% albumin solution with or without 1 × 107 human iPSC-CMs 10 days after undergoing left anterior descending (LAD) coronary artery ligation. Cyclosporine A and methylprednisolone were administered before iPSC-CM injection and until the rats were killed to prevent graft rejection. Cardiac function was evaluated by echocardiography. The survival of grafted cardiomyocytes was confirmed by observing the fluorescent cell tracer Vybrant™ CM-DiI or expression of the enhanced green fluorescent protein (eGFP) in transplanted cells, or survival was demonstrated by polymerase chain reaction (PCR)-based detection of human mitochondrial DNA. Sirius red stain was used to evaluate the fibrosis ratio. Hematoxylin-eosin staining was used to observe the formation of teratomas. Results Four weeks after intramyocardial injection of iPSC-CMs, animals undergoing iPSC-CM transplantation had lower mortality than the control group. Animals injected with cell-free solution (control group) demonstrated significant left ventricular (LV) functional deterioration, whereas grafting of iPSC-CMs attenuated this remodeling process. In the control group, the ejection fraction deteriorated by 10.11% (from 46.36 to 41.67%), and fractional shortening deteriorated by 9.23% (from 24.37 to 22.12%) by 4 weeks. In the iPSC-CM injection group, the ejection fraction improved by 18.86% (from 44.09 to 52.41%), and fractional shortening improved by 23.69% (from 23.08 to 28.54%). Cell labeling, tracking, and molecular biology techniques indicated that the grafted cardiomyocytes survived in the rat heart 1 month after iPSC-CM transplantation. Myocardial fibrosis was also attenuated in the iPSC-CM treatment group. Conclusions Human iPSC-CM grafts survived in infarcted rat hearts and restored myocardial function 4 weeks after transplantation. Cell replacement therapy also reversed ventricular remodeling, indicating the potential of iPSC-CMs for cardiac repair strategies.

Background: The Brugada Electrocardiographic Indices Registry is a comprehensive data registry composed of patients with Brugada patterns on the electrocardiogram (ECG). The aim is to test the hypotheses that (i) ECG indices combining both depolarization and repolarization abnormalities can better predict spontaneous ventricular arrhythmias than existing ECG markers in Brugada syndrome and (ii) that serial ECG measurements will provide additional information for risk stratification, especially in asymptomatic patients. Methods: Patients with both Brugada pattern ECGs and Brugada syndrome are eligible for inclusion in this registry. Baseline characteristics and ECG variables reflecting depolarization and repolarization will be determined. The primary outcome is spontaneous ventricular tachycardia/ventricular fibrillation or sudden cardiac death. Secondary outcomes are inducible ventricular tachycardia/ventricular fibrillation and syncope. Results: As of November 15, 2019, 39 investigators from 32 cities in 18 countries had joined this registry. As of December 15, 2019, 1383 cases had been enrolled. Conclusions: The Brugada Electrocardiographic Indices Registry will evaluate the disease life course, risk factors, and prognosis in a large series of Brugada patients. It will therefore provide insights for improving risk stratification.

Aims: Catheter ablation should be considered in patients with atrial fibrillation (AF) and with heart failure (HF) with reduced ejection fraction (EF; HFrEF) to improve survival and reduce heart failure hospitalization. Careful patient selection for AF ablation is key to achieving similar outcome benefits. However, limited data exist regarding predictors of recovered ejection fraction. We aimed to evaluate the predictors of recovered ejection fraction in consecutive patients with HF undergoing AF ablation.Methods and Results: A total of 156 patients [67.3% men, median age 63 (11)] with AF and HF underwent initial catheter ablation between September 2017 and October 2019 in the First Affiliated Hospital of Dalian Medical University. Overall, the percentage of recovered ejection fractions was 72.3%. Recovered EFs were associated with a 39% reduction in all-cause hospitalization compared to non-recovered EFs at the 1-year follow-up [23.8 vs. 62.8 (odds ratio) OR 2.09 (1.40–3.12), P < 0.001]. Univariate analysis for recovered EFs showed that diabetes (P = 0.083), prevalent HF (P = 0.014), prevalent AF (P = 0.051), LVEF (P = 0.022), and E/E′ (P = 0.001) were associated with EF improvement. Multivariate analysis showed that the only independent predictor of EF recovery was E/E′ [OR 1.13 (1.03–1.24); P = 0.011]. A receiver operating characteristic analysis determined that the suitable cut-off value for E/E′ was 15 (sensitivity 38.7%, specificity 89.2%, the area under curve 0.704).Conclusions: Ejection fraction (EF) recovery occurred in 72.3% of patients, associated with a 39% reduction in all-cause hospitalization compared to the non-recovered EFs in our cohort. The only independent predictor of recovered EF was E/E′ < 15 in our series.

Background Subclinical atrial fibrillation (SCAF) is often asymptomatic nonetheless harmful. In patients with cardiac implantable electronic devices, we evaluated the combined performance of homocysteine and uric acid (UA) biomarkers to discriminate high‐risk patients for SCAF. Methods and Results We enrolled 1224 consecutive patients for evaluation of SCAF in patients with cardiac implantable electronic devices in Dalian, China, between January 2013 and December 2019. Clinical data and blood samples were obtained from patients selected according to the absence or presence of atrial high‐rate episodes >6 minutes. Blood samples were obtained, and homocysteine and UA biomarkers were tested in all patients to distinguish their prognostic performance for SCAF. Homocysteine and UA biomarkers were significantly different in SCAF versus no SCAF. On multivariable Cox regression analysis with potential confounders, elevated homocysteine and UA biomarkers were significantly associated with an increased risk of SCAF. A rise of 1 SD in homocysteine (5.7 μmol/L) was associated with an increased risk of SCAF in men and women regardless of their UA levels. Similarly, a 1‐SD increase in UA (91 μmol/L) was associated with an increased risk of SCAF among the patients with high levels of homocysteine in men (hazard ratio, 1.81; 95% CI, 1.43–2.30) and women (hazard ratio, 2.11; 95% CI, 1.69–2.62). The addition of homocysteine and UA to the atrial fibrillation risk factors recommended by the 2020 European Society of Cardiology Guidelines significantly improved risk discrimination for SCAF. Conclusions Homocysteine and UA biomarkers were strongly associated with SCAF. The prediction performance of the European Society of Cardiology model for SCAF was increased by the addition of the selected biomarkers. Registration URL: https://www.chictr.org.cn; Unique identifier: Chi‐CTR200003837.

High-density lipoprotein (HDL) homeostasis is important in maintaining both cardiovascular and renal health. Scavenger receptor class B type 1 (SR-B1), the major HDL receptor in mammals, plays a crucial role in reverse cholesterol transport and HDL metabolism. Evidence from mouse study has well demonstrated that HDL disorders caused by Srb1 inactivation accelerate atherosclerosis and even induce lethal cardiovascular diseases. However, the renal consequences of Srb1 dysfunction are still unknown. Here we explored this issue in both Srb1 knockout (Srb1-/-) mice and atherosclerotic low-density lipoprotein receptor knockout (Ldlr-/-) mice with Srb1 deletion. Our data showed that no apparent renal damage was observed in 5-month-old Srb1-/- mice fed on standard rodent chow diet as well as Srb1-/- mice fed on a high-fat diet (HFD) for 12 weeks. However, 5-month-old Srb1/Ldlr-/- mice fed on rodent chow had increased urinary albumin excretion and developed spontaneous intraglomerular Oil-red O (ORO)-positive lipoprotein deposition that is similar to lesions observed in human lipoprotein glomerulopathy (LPG). HFD feeding accelerated LPG-like lesions in Srb1/Ldlr-/- mice, inducing severe proteinuria and significantly promoting intraglomerular ORO-positive lipoprotein deposition. Interestingly, probucol reversed HFD-induced HDL disorders and almost fully abrogated LPG-like lesions in Srb1/Ldlr-/- mice. In conclusion, the present study demonstrates that SR-B1 dysfunction leads to LPG-like lesions in atherosclerotic mice, which could be rescued by probucol. SR-B1 loss-of-function mutant carriers therefore might be susceptible to developing metabolic nephropathy in addition to cardiovascular diseases, and probucol might be a potential therapeutics.

Background: The predictive power of the CHADS2 and CHA2DS2-VASc scores for the presence of Left atrial thrombus (LAT)/ spontaneous echo contrast (SEC) in non-valvular atrial fibrillation (NVAF) is modest. The aim of this analysis is to define clinical and ultrasonic variables associated with LAT/SEC and to propose nomograms for individual risk prediction.Methods: Data on 1,813 consecutive NVAF patients who underwent transesophageal echocardiography (TEE) from January 2016 to January 2021 were collected. The univariate and multivariate logistic regression analyses were used to construct a nomogram. We examined the predictive ability of the risk scores by calculating the area under the curve (AUC). Moreover, the performance of the nomogram was assessed with respect to calibration, discrimination, and clinical usefulness.Results: LAT/SEC was found in 260 (21.0%) and 124 (21.6%) patients in the training and validation cohorts, respectively. On multivariate analysis, independent factors for LAT/SEC were Age, left atrial diameter (LAD), left ventricular ejection fraction (LVEF), hypertension (HTN), previous stroke or transient ischemic attack, Non-paroxysmal AF and a nomogram was built based on these variables. The calibration curve for the probability of LAT/SEC showed good prediction agreement with actual observation. The nomogram achieved good concordance indexes of 0.836 and 0.794 in predicting LAT/SEC in the training and validation cohorts, respectively. Decision curve analysis demonstrated that the nomogram would be clinically useful.Conclusions: In this study, a nomogram was constructed that incorporated six characteristics of NVAF patients. The nomogram may be of great value for the prediction of LAT/SEC in NVAF patients.

Aims: HFA-PEFF score has been proposed for diagnosing heart failure with preserved ejection fraction (HFpEF). Currently, there are only a limited number of tools for predicting the prognosis. In this study, we evaluated whether the HFA-PEFF score can predict mortality in patients with HFpEF.Methods: This single-center, retrospective observational study enrolled patients diagnosed with HFpEF at the First Affiliated Hospital of Dalian Medical University between January 1, 2015, and April 30, 2018. The subjects were divided according to their HFA-PEFF score into low (0–2 points), intermediate (3–4 points), and high (5–6 points) score groups. The primary outcome was all-cause mortality.Results: A total of 358 patients (mean age: 70.21 ± 8.64 years, 58.1% female) were included. Of these, 63 (17.6%), 156 (43.6%), and 139 (38.8%) were classified into the low, intermediate, and high score groups, respectively. Over a mean follow-up of 26.9 months, 46 patients (12.8%) died. The percentage of patients who died in the low, intermediate, and high score groups were 1 (1.6%), 18 (11.5%), and 27 (19.4%), respectively. A multivariate Cox regression identified HFA-PEFF score as an independent predictor of all-cause mortality [hazard ratio (HR):1.314, 95% CI: 1.013–1.705, P = 0.039]. A Cox analysis demonstrated a significantly higher rate of mortality in the intermediate (HR: 4.912, 95% CI 1.154–20.907, P = 0.031) and high score groups (HR: 5.291, 95% CI: 1.239–22.593, P = 0.024) than the low score group. A receiver operating characteristic (ROC) analysis indicated that the HFA-PEFF score can effectively predict all-cause mortality after adjusting for age and New York Heart Association (NYHA) class [area under the curve (AUC) 0.726, 95% CI 0.651–0.800, P = 0.000]. With an HFA-PEFF score cut-off value of 3.5, the sensitivity and specificity were 78.3 and 54.8%, respectively. The AUC on ROC analysis for the biomarker component of the score was similar to that of the total score.Conclusions: The HFA-PEFF score can be used both to diagnose HFpEF and predict the prognosis. The higher scores are associated with higher all-cause mortality.

Introduction: Understanding the epidemiology of cardiovascular disease (CVD) related comorbidity is a key strategy for improving the outcomes of patients with cancer. Therefore, this study aimed to assess the distribution of cardiovascular comorbidities and cardiovascular risk factors (CVRF) among five cancer sites.Methods: This is a single-centered, cross-sectional study performed in Dalian, China. Between 2008 and 2018, all newly diagnosed cancer in the First Affiliated Hospital of Dalian Medical University, China were screened. Clinical data were extracted from a comprehensive electronic health record system.Results: 35861 patients with lung, colorectal, gastric, breast, and thyroid cancer were collected retrospectively. The most prevalent CVDs in descending order were hypertension (21.9%), followed by coronary heart disease (6.5%), atrial fibrillation (2.9%), and heart failure (1%). The prevalence of hypertension significantly varies between lung (21.3%), colorectal (27.3%), gastric (22.5%), breast (16.7%), and thyroid cancer (22.4%) (P < 0.001). CVRF varies with cancer sites. Age, sex, total cholesterol, triglyceride, low-density lipoprotein cholesterol, systolic blood pressure, smoking, alcohol use, and diabetes mellitus (DM) are common risk factors associated with CVD at different cancer sites. The association between DM and presence of CVD was strong in breast (odds ratio [OR] = 4.472, 95% confidence interval [CI]: 3.075–6.504, P < 0.001), lung (OR = 3.943; 95% CI: 3.270–4.754, P < 0.001), colorectal (OR = 3.049; 95% CI: 2.326–3.996, P < 0.001), and gastric (OR = 2.508; 95% CI: 1.927–3.264, P < 0.001) cancer.Conclusion: Cancer patients had a significant burden of CVD and increased CVRF. The prevalence of CVRF and CVD comorbidity differ for cancer types. DM remains significantly associated with CVD at different cancer sites except for thyroid cancer.

Background: Corin is a transmembrane serine protease that activates pro-forms of atrial and brain natriuretic peptides. Numerous studies have indicated that corin played an important role in cardiovascular diseases (CVDs). However, there have been few studies about the correlation between single-nucleotide polymorphisms (SNPs) in the 3' untranslated region (3'UTR) of CORIN and CVDs. The aims of this study were to investigate the associations of three SNPs (rs3749585, rs4695253, and rs12641823) in the 3'UTR of CORIN with CVDs and to find the seed regions of microRNAs (miRNAs) that bind to SNPs of CORIN.Methods and Results: A case–control study (n = 3,537) was performed in a Han population of northeastern China. CVDs included essential hypertension (EH), atrial fibrillation (AF), heart failure (HF), and coronary artery disease (CAD). Genotyping was performed using high-resolution melt analysis. In the EH-control study, rs3749585T was significantly associated with the risk of EH after adjusting for sex and age in allelic (padj = 0.049; OR: 1.113) and dominant (padj = 0.015, OR: 1.233) models. Rs4695253T was significantly associated with the risk of EH in the recessive model after adjusting for sex and age (padj = 0.005, OR: 2.084). Rs3749585T was significantly and negatively associated with AF in the dominant and additive models after adjusting for sex, age, EH, HF, T2DM, and CAD (dominant: padj = 0.009, OR: 0.762; additive: padj = 0.048, OR: 0.873). In the HF-control study and CAD-control study, none of the three SNPs was associated with HF and CAD after adjusting for covariates in any models (padj > 0.05). The levels of high-density lipoprotein (HDL) in rs4695253CC+CT were lower than the levels of HDL in rs4695253TT (42.47 ± 10.30 vs. 48.0 ± 10.24 mg/dl, padj = 0.008). The levels of total cholesterol (TC) in rs4695253CC+CT were lower than the levels of TC in rs4695253TT (164.01 ± 49.15 vs. 180.81 ± 43.92 mg/dl, padj = 0.036). Luciferase assay revealed that the relative luciferase activity of rs3749585CC-transfected cells was significantly decreased by miR-494-3p, in comparison to cells transfected with rs3749585TT (p < 0.001). A significant decrease in the relative luciferase activity of rs3749585TT reporter was observed as compared with rs3749585CC reporter in the presence of miR-1323 or miR-548o-3p (p = 0.017 and 0.012, respectively).Conclusions: We found significant associations between rs3749585T and rs4695253T and EH, between rs4695253T and the levels of TC and HDL, and between rs3749585T and AF. Hsa-miR-494-3p may serve as a potential therapeutic target for EH and AF patients in the future.

Objective: Both serum uric acid (SUA) levels and lipid components, such as LDL, HDL, and Lp(a), have been reported to associate with CAD. However, the influence of SUA status at different concentrations of lipid indices for the risk of myocardial revascularization (MRT) in ACS patients is currently unknown.Methods: We retrospectively analyzed a hospital-based sample of 14,234 ACS patients with no previous history of percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery. All patients went for coronary angiography. Binary logistic regression models were performed, and the odds ratios (OR) at 95% confidence interval (CIs) were used to approximate the associated risk of UA and lipid profile for myocardial revascularization, with the lowest quartile/tertile serving as the reference category.Results: Overall, 8,818 (61.9%) patients undergone MRT out of 14,234 patients. Elevated SUA and HDL were negatively associated with an increased likelihood of MRT during admission (P < 0.001). However, LDL and Lp(a) levels were positively associated with MRT among ACS patients. Furthermore, interaction analyses between SUA and lipid profiles, particularly LDL and Lp(a), compared with those in the lowest quartile of SUA levels, show that patients in higher SUA quartiles grouped by lipid components had a significantly lower chance of undergoing MRT, with the lowest OR (95%CI) for subjects being 0.222 (0.170-0.290), 0.478 (0.374-0.612), and 0.604 (0.468-0.780) in LDL tertiles, being 0.671(0.523-0.862), 0.316(0.242-0.413), and 0.410 (0.310-0.542) in Lp(a) tertiles, respectively. In the three tertiles of HDL levels, the incidence of MRT dropped steadily as SUA levels increased. Also, we further analyzed ACS patients without diabetes. Compared with the first quartile of SUA levels, the risks of MRT were significantly lower in different tertiles of lipids components [LDL, Lp(a), HDL].Conclusion: An increase in SUA levels may decrease the chance of undergoing MRT in ACS patients, even in those with increased Lp(a) and LDL-c. Elevated serum uric acid may play a protective role during an acute stage of ACS.