Current treatment modalities can only reap a limited efficacy in reversing myocardial damage and promoting functional recovery in patients with myocardial infarction. Therefore, there is an urgent need to explore new therapeutic approaches to enhance cardiac repair. MSCs were pretreated with empagliflozin to obtain EMPA-EVs, with non-pretreated MSC-EVs serving as controls. In vitro experiments were conducted to evaluate the effects of the two types of EVs on macrophage phenotypic transformation, cardiomyocyte apoptosis, and vascular endothelial cell lumen formation. In vivo experiments, a rat model of myocardial infarction was constructed, and EMPA-EVs, non-pretreated MSC-EVs, or phosphate-buffered saline were administered via myocardial injection. Post-treatment assessments included left ventricular ejection fraction, myocardial infarction area, and levels of pro-inflammatory cytokines in myocardial tissue. In addition, AGGF1 was depleted in EMPA-EVs to observe their anti-apoptotic, anti-inflammatory, and pro-angiogenic effects. Compared with non-pretreated MSC-EVs, EMPA-EVs increased the proportion of macrophages transforming into anti-inflammatory phenotypes, decreased the rate of apoptotic cardiomyocytes, and promoted the formation of vascular endothelial cell lumen. Animal experiments showed that the left ventricular ejection fraction of rats in the EMPA-EVs group was higher than that in the control group, the myocardial infarction area was reduced, and the level of pro-inflammatory factors in myocardial tissue decreased. Moreover, AGGF1 expression was significantly upregulated in EMPA-EVs, and the anti-apoptotic, anti-inflammatory, and pro-angiogenic effects of EMPA-EVs were inhibited upon AGGF1 knockdown. EMPA-EVs can promote cardiac repair in myocardial infarction, and this therapeutic effect involves the upregulation of AGGF1 and may promise a cell-free therapeutic strategy. MSC-EVs pretreated with empagliflozin exerted myocardial protective functions after myocardial infarction at least partially by activating the AGGF1/AKT signaling pathway to synergistically inhibit myocardial cell apoptosis, regulate the transformation of macrophages to pro-repair phenotypes, and promote angiogenesis

BACKGROUND:Spermidine (SPD) exhibits potential protective effects against diabetic-induced BK channel dysfunction, though the molecular mechanisms remain unclear. This study investigated SPD-mediated regulation of large-conductance calcium- and voltage-activated potassium channel (BK channel) function in coronary smooth muscle cells (SMCs) and the underlying molecular pathways. METHODS:Rats were randomly divided into: control (Ctrl), diabetes mellitus (DM), and DM with SPD treatment (DM + SPD) groups. Vascular function was assessed using coronary artery tension measurements, while BK channel activity was evaluated via whole-cell patch clamp. Primary vascular SMCs were isolated for in vitro studies. SPD-binding proteins were identified through pull-down assays coupled with LC-MS/MS analysis. RESULTS:SPD treatment improved coronary BK channel-dependent vasorelaxation by up-regulating BK-β1 subunit expression. Mechanistically, SPD directly bound to pyruvate kinase M2 (PKM2), inhibiting PKM2 nuclear translocation and subsequent signal transducer and activator of transcription 3 (STAT3) activation. Furthermore, STAT3 transcriptionally regulated F-box protein 32 (FBXO32), which modulated BK-β1 expression. CONCLUSIONS:SPD protects BK channel function in diabetic conditions through inhibition of the PKM2/STAT3 signaling axis, revealing a novel therapeutic pathway for diabetic vascular complications. However, given the exploratory experimental nature of this study, these findings should be considered hypothesis-generating and require further validation in independent studies.

Background:The relationship between plasma free triiodothyronine (FT3) levels and the risk of ventricular arrhythmias (VA) in patients with acute myocardial infarction (AMI) remains unclear. Objective:This study aimed to investigate whether the level of FT3 influences VA in patients with AMI. Methods:A multicenter prospective study was conducted to collect patients diagnosed with AMI from three centers between January 2018 and December 2021. Patients were categorized into VA and Non-VA groups. FT3 levels were compared between groups, and multivariate logistic regression analyses were performed to evaluate the relationship. Results:A total of 3277 consecutive patients (mean age: 64.6 years) were included, with 123 (3.9%) developing VA during hospitalization. The VA group had significantly lower FT3 levels compared to the Non-VA group ([3.74 ± 0.77 pmol/L] vs [4.13 ± 0.81 pmol/L], P < 0.001). Multivariate analysis identified FT3 level as an independent predictor of VA risk (adjusted odds ratio [OR]: 0.761; 95% confidence interval [CI]: 0.591-0.980; P = 0.035). A dose-dependent association was observed, with progressively lower VA risks across increasing FT3 quartiles (P trend = 0.007). Each 1 standard deviation decrease in FT3 levels was associated with a 19.9% increased VA risk (OR = 0.801; 95% CI: 0.651-0.984; P = 0.035). Conclusion:This study confirmed a significant association between plasma FT3 levels and the risk of ventricular arrhythmias during hospitalization in patients with myocardial infarction. Low FT3 levels are associated with an increased risk of VA in patients with AMI.

Background:Concealed accessory pathways (CAP) and atrioventricular nodal reentry tachycardia (AVNRT) represent diagnostically challenging forms of paroxysmal supraventricular tachycardia, with conventional sinus rhythm ECGs often failing to reveal characteristic abnormalities. Methods:We developed CSPANet, a novel deep learning architecture that integrates a Channel and Spatial Parallel Attention (CSPA) module for enhanced ECG feature extraction. The architecture features parallel processing through two specialized attention mechanisms: a channel attention submodule that adaptively weights clinically significant ECG leads using complementary feature pathways, working in concert with a spatial attention submodule that captures essential morphological patterns through synergistic multi-scale pooling and convolutional feature extraction. Results:In a comparative study of nine classical CNNs, ResNet50 demonstrated superior performance, achieving the highest sensitivity and specificity and validating the efficacy of residual learning for this task. The proposed CSPANet, integrating our novel channel and spatial parallel attention (CSPA) mechanism, achieved a test set accuracy of 92.6%, sensitivity of 79.0%, specificity of 95.0%, and precision of 79.7%, surpassing all other representative attention mechanisms. Ablation studies confirmed the individual and synergistic contributions of the CSPA and Stem modules, with their combined integration yielding the most significant performance gains, including an 11.7% increase in sensitivity and an 8.8% increase in precision over the baseline ResNet20 model. Conclusion:CSPANet's ability to differentiate CAP and AVNRT from sinus rhythm ECGs offers a transformative clinical tool, facilitating optimized ablation planning and enhancing procedural safety. By addressing a key diagnostic gap, this approach underscores the potential of deep learning to refine arrhythmia management.

Background: Calcific aortic valve disease (CAVD) is a progressive condition characterized by inflammation and fibrous calcification remodeling, with aortic valve fibrosis (AVF) representing the associated subclinical phase. Early intervention with oral medication during the AVF stage may prevent and slow the development and progression of CAVD. Previous studies have demonstrated that individuals with diabetes are at an elevated risk of CAVD and also experience a significantly higher incidence of aortic valve stenosis, which rapidly advances from mild to severe stages. Significantly, the adverse effects of glucose fluctuations (GFs) on cardiovascular diseases exceed those associated with persistent hyperglycemia. Nonetheless, the mechanisms through which GFs contribute to AVF, the early stage of CAVD, remain inadequately understood. Consequently, this study aimed to investigate the inflammatory mechanisms underlying AVF induction in response to fluctuations in glucose levels. Methods: Diabetic rat models were established through intraperitoneal injection of streptozotocin (STZ). GFs in these diabetic rats were managed by alternating between a Western diet and periods of fasting. Infliximab was administered to inhibit inflammation mediated by tumor necrosis factor-alpha (TNF-α). For the in vivo study, echocardiographic assessments of the aortic valve and left ventricular function were conducted on the diabetic rats after eight weeks. Aortic valves from various groups of rats were dissected to test fibrosis, extracellular matrix remodeling, and variations in inflammatory factors, which were examined using hematoxylin and eosin (HE) staining, modified Movat–Russell pentachrome staining, and immunohistochemical staining, respectively. For the in vitro study, porcine valvular interstitial cell (VIC) cultures were used to establish GF-induced fibrosis, thereby elucidating the underlying inflammatory mechanisms. Results: Our study demonstrated that GFs exacerbate AVF and dysfunction in diabetic patients. This is characterized by increased peak blood flow velocity and peak cross-valve gradient of the aortic valve. Furthermore, we observed intensified TNF-α-mediated inflammatory responses, characterized by the upregulation of T lymphocytes and macrophages, as well as activation of the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3) pathway. Notably, these pathological processes were ameliorated by the administration of infliximab, resulting in the downregulation of fibrotic and inflammatory markers, as well as improved echocardiographic indices. Our research findings indicate that TNF-α-mediated inflammation exacerbates fibrotic aortic valve processes through GFs, which are mediated by the JAK1/STAT3 signaling pathway. Conclusions: Targeting TNF-α may serve as a potential therapeutic target to mitigate the progression of inflammation-induced aortic valve damage and fibrosis.

BACKGROUND:TRPC6 (transient receptor potential canonical 6) channels, encoded by the TRPC6 gene, are widely expressed in cardiomyocytes and play a critical role in maintaining intracellular Ca2+ homeostasis. Variants in TRPC6 are associated with chemotherapy-related cardiomyopathy. Specifically, the TRPC6 A404V polymorphism, with a minor (404 V) allele frequency of 12% in the general population, has been identified in patients undergoing anthracycline therapy. However, the underlying mechanisms remain largely unexplored. METHODS:Using patch-clamp recordings, Ca2+ imaging, computational analysis, and molecular biology techniques, we assessed the effects of doxorubicin and its metabolite, doxorubicinol, on regulating TRPC6 alanine (A) at position 404 replaced by valine (V; A404V) channel expression and function in a heterologous expression system and native cardiac cells. RESULTS:Both additive and recessive models demonstrated a significant association between the TRPC6 A404V variant and doxorubicin-related cardiomyopathy. The TRPC6 A404V channel exhibited higher membrane expression levels compared with the wild type (WT) control. Patch-clamp recordings showed that both TRPC6 WT and A404V channels remained mostly inactive at baseline. Application of 50 μmol/L 1-oleoyl acetyl-sn-glycerol (OAG), a TRPC6 activator, significantly increased the inward- and outward-current densities of WT and A404V channels. Furthermore, a 24-hour treatment with 0.5 μmol/L doxorubicin enhanced TRPC6 mRNA expression and potentiated the OAG effects on both WT and A404V channels, with a more pronounced response in A404V channels. Treatment with 0.5 μmol/L doxorubicinol had no effect on OAG-induced current densities in either WT or A404V channels. Doxorubicin effects on intracellular Ca2+ levels were confirmed by Ca2+ imaging in native cardiac cells. Computational modeling revealed that the A404V mutation induces a conformational change in the OAG-binding pocket, enhancing its interaction with OAG in the A404V protein compared with the WT control. CONCLUSIONS:The TRPC6 A404V is a gain-of-function variant that exhibits enhanced activity in the presence of doxorubicin. Therefore, the TRPC6 A404V variant represents a risk factor for anthracycline-induced cardiotoxicity in patients with cancer.

Background: Ferroptosis has been increasingly implicated in the pathophysiology of atrial fibrillation (AF). Pentoxifylline (PTX), a methylxanthine derivative, has shown potential therapeutic benefits in cardiovascular diseases; however, its unique role in ferroptosis-associated AF remains unclear. This study aimed to elucidate the molecular mechanisms through which PTX may exert therapeutic effects on ferroptosis-related AF, using a multifaceted approach integrating network pharmacology, bioinformatics, and experimental validation.Methods:Two transcriptomic datasets, GSE41177 and GSE79768, were retrieved from the Gene Expression Omnibus (GEO) to identify differentially expressed genes (DEGs) in AF. Ferroptosis-related genes (FRGs) were collected from the FerrDb database. PTX-associated targets were predicted using Super-PRED and SwissTargetPrediction. Overlapping DEGs and predicted PTX targets were intersected with FRGs to identify potential pharmacological targets. Candidate genes were further refined through protein-protein interaction (PPI) network construction and five topological algorithms (Degree, Maximum Neighborhood Component [MNC], Maximal Clique Centrality [MCC], Edge Percolated Component [EPC], and Closeness). Genes exhibiting consistent expression patterns in both GEO datasets were defined as key genes. Diagnostic value was assessed using receiver operating characteristic (ROC) curves. The immune infiltration landscape and correlations with key genes were analyzed via the CIBERSORT algorithm and Spearman correlation. Molecular docking was performed, and PyMOL was used to assess binding affinities between PTX and key gene-encoded proteins. In addition, regulatory networks involving non-coding RNAs and key genes were predicted. Single-cell RNA sequencing (scRNA-seq) was applied to determine cell-type–specific gene expression. Finally, the therapeutic effects of PTX and the underlying ferroptosis-related molecular pathways were evaluated both in an acetylcholine (ACh)-CaCl2-induced AF rat model and in angiotensin II (AngII)-stimulated HL-1 cardiomyocytes.Results:From a total of 10,511 DEGs and 315 predicted PTX targets, 87 overlapping pharmacological targets were identified. Thirteen of these overlapped with known FRGs. Among them, PIK3CA and TLR4 emerged as key genes of interest based on PPI network centrality and consistent expression across datasets. Immune profiling revealed significant differences in six immune cell types between AF and control samples, with activated dendritic cells and follicular helper T cells negatively correlated with key gene expression. Molecular docking indicated favorable binding affinities between PTX and both PIK3CA (−4.33 kcal/mol) and TLR4 (−3.72 kcal/mol). Further analysis identified 23 microRNAs (miRNAs) predicted to target PIK3CA and TLR4, of which 21 miRNAs interacted with 22 long non-coding RNAs (lncRNAs), suggesting a complex regulatory network. scRNA-seq analysis revealed enriched PIK3CA expression in mast cells and elevated TLR4 expression in neutrophils and monocytes/macrophages, suggesting involvement of immune-related mechanisms. In vivo, PTX significantly reduced AF susceptibility, shortened AF duration, and attenuated atrial structural remodeling. In AngII-stimulated HL-1 cardiomyocytes, PTX markedly suppressed intracellular Fe2+ accumulation. In both models, these protective effects coincided with downregulation of TLR4 and upregulation of PIK3CA, implicating modulation of ferroptosis-related pathways as the underlying mechanism.Conclusions:This study identifies PIK3CA and TLR4 as pivotal genes in the ferroptosis-associated molecular network of AF and as potential therapeutic targets of PTX. These findings support the potential of PTX to mitigate AF by regulating ferroptosis through these targets, providing a preclinical mechanistic basis for the potential value of PTX in AF management.

OBJECTIVE:To investigate the characteristics of blood pressure (BP) circadian rhythm disruption and its relationship with prognosis in patients with acute anterior ST-elevation myocardial infarction (STEMI) after emergency percutaneous coronary intervention (PCI). METHODS:A total of 330 patients with anterior STEMI who underwent emergency PCI were enrolled in this study (MI group). Additionally, 131 physical examination patients were selected as the control group. Based on 24-h ambulatory blood pressure monitoring (ABPM) results, BP rhythm in both groups was classified into Extreme dipper, Dipper, Non-dipper, and Reverse dipper. The characteristics of BP rhythm were compared between the two groups. Patients with anterior MI were followed up for 1 year postoperatively. The occurrence of major adverse cardiovascular events (MACE) was compared among subgroups with different BP rhythms. RESULTS:The proportion of dipper BP in the study group (11.21%) was significantly lower than that of the control group (63.36%) (p = 0.001). The proportions of non-dipper (43.03%) and reverse dipper (40%) BP in the MI group were higher than the control group (22.90% and 7.63%, respectively; all p < 0.001). Multivariate Cox regression analysis, using dipper BP as the reference, showed that reverse dipper BP was independently associated with MACE (HR = 6.417, p = 0.002). The cumulative risk of the primary endpoint event (Log Rank p = 0.021) was significantly higher in the reverse dipper group compared to the dipper group. CONCLUSION:Patients with anterior STEMI are still under the burden of disrupted BP circadian rhythm and reduced dipper BP rhythm. The reverse dipper BP rhythm may serve as an independent factor of MACE.

[This corrects the article DOI: 10.3389/fcvm.2023.1194771.].

Atrial Fibrillation (AF) following Myocardial Infarction (MI) is a common clinical complication that significantly impairs patient prognosis and quality of life. This review examines the clinical risks and underlying pathophysiological mechanisms of post-MI AF. The pathophysiology of AF after MI involves multiple maladaptive processes, particularly atrial structural and electrical remodeling, which collectively establish the arrhythmogenic substrate. This review summarizes the molecular mechanisms contributing to AF in the post-infarction setting. Furthermore, it was synthesized current evidence on pharmacological interventions targeting this substrate, highlighting four primary mechanisms of action: anti-fibrotic effects, modulation of calcium homeostasis, endogenous hormone regulation, and anti-inflammatory actions. Consequently, elucidating the complex and dynamic pathophysiological changes that drive atrial fibrillation after myocardial infarction may inform the development of targeted therapeutic strategies for post-infarction AF.

Background:The study aimed to compare the efficacy and safety of simplified single-freezing protocol with achieving -40 °C within 60 s of freezing as the observation index and the conventional time-to-isolation (TTI)-guided double-freezing protocol using second-generation cryoballoon in the treatment of atrial fibrillation (AF). Methods:A retrospective analysis was performed. After propensity score matching, 146 patients who underwent conventional TTI-guided protocol freezing (conventional group) and 146 patients who underwent single-freezing temperature-guided protocol freezing (simplified group) using second-generation cryoballoon were included. Procedure time, X-ray time and dose, complications, success rate, and recurrence rate during follow-up were analyzed. Results:Compared with the conventional group, the simplified group showed a significant reduction in procedure time (98.8 ± 16.3 vs. 79.4 ± 12.7 min, P < 0.001), and X-ray time (24.3 ± 6.8 vs. 17.8 ± 4.9 min, P < 0.001) and dose (681.1 ± 337.8 vs. 540.1 ± 343.7 mGy, P < 0.001). There was no significant difference in the success rate of acute pulmonary vein isolation between the two groups of patients (145/146 vs. 146/146, P = 0.975) and the proportion of maintaining sinus rhythm during follow-up (114/146 vs. 109/146, P = 0.842). Cox regression analysis showed that simplified protocol is not a predictive factor for recurrence in AF cryoablation. Conclusions:In summary, the single-freezing temperature-guided protocol demonstrates comparable efficacy and safety to conventional TTI-guided protocol of second-generation cryoballoon in the AF ablation with the advantages of reducing procedure time and radiation exposure.

Aim: Pulsed field ablation (PFA) has emerged as a promising strategy for catheter ablation of atrial fibrillation (AF). This study compared perioperative outcomes of pulmonary vein isolation (PVI) performed using robotic magnetic navigation (RMN), cryoballoon (CRYO) ablation, and PFA. Methods: This retrospective study included patients with AF who underwent PVI using RMN ablation (RMN group, n = 112), CRYO ablation (CRYO group, n = 189), or PFA (PFA group, n = 50). Procedural characteristics, perioperative complications, and postoperative recovery were analyzed. Results: Total procedure time was longer in the PFA group than in the CRYO group but shorter than in the RMN group (123.9 ± 14.0 vs. 98.3 ± 14.3 vs. 147.9 ± 19.3 min, P < 0.001). However, left atrial procedure time was shortest in the PFA group (26.6 ± 6.4 vs. 44.7 ± 12.1 vs. 95.1 ± 20.5 min, P < 0.001). Fluoroscopy time was comparable between the PFA and CRYO groups, and significantly shorter in the RMN group (15.2 ± 3.0 vs. 15.0 ± 3.1 vs. 7.4 ± 2.5 min, P < 0.001). Although acute procedural success was comparable across groups, first-pass PVI was achieved more frequently with PFA than with CRYO or RMN {50/50 [100%] vs. 170/189 [89.9%] vs. 100/112 [89.3%], P = 0.030}. The overall incidence of perioperative complications did not differ significantly among the three groups. Conclusion: PFA demonstrated acute safety and efficacy comparable to those of RMN and CRYO ablation for AF, while offering shorter left atrial procedure time and a higher rate of first-pass isolation.

Objective: The outcomes of ablation for atrial fibrillation (AF) in patients with pulmonary vein (PV) variants remain controversial. The aim of this study was to compare procedure data and outcomes in paroxysmal AF patients with PV variant for cryoballoon (CRYO) ablation and robotic magnetic navigation (RMN) ablation. Methods: A retrospective analysis assigned 256 patients underwent CRYO ablation and 254 patients underwent RMN ablation. They were divided into PV variant patients who underwent CRYO ablation (CRYO variant group, 58 cases); PV normal patients who underwent CRYO ablation (CRYO normal group, 198 cases); PV variant patients who underwent RMN ablation (RMN variant group, 49 cases); and the PV normal patients who underwent RMN ablation (RMN normal group, 205 cases). Results: Compared with the RMN variant group, the procedure time (91.7 +/- 14.8 min vs. 150.0 +/- 16.4 min, p < 0.001) was significantly decreased in the CRYO variant group, while the X-ray time (20.9 +/- 6.3 min vs. 7.4 +/- 3.1 min, p < 0.001) and dose (574.0 +/- 302.5 mGy vs. 206.5 +/- 102.2 mGy, p < 0.001) were significantly increased. The rates of maintaining sinus rhythm during 1 year of follow-up were similar in both groups (47/58 vs. 42/49, p = 0.497). Compared with the CRYO variant group, the procedure time, X-ray time, and dose were decreased in the CRYO normal group. However, there was no significant difference in procedure time, X-ray time, and dose between the RMN normal group and the RMN variant group. No matter which method was used, there was no significant difference in the 1-year follow-up recurrence rate between PV variant and PV normal patients. COX regression analysis showed that the ablation method is not a predictive factor for recurrence in PV variant ablation. Conclusions: CRYO and RMN have similar outcomes during a 1-year follow-up for patients with PV variants. Unlike RMN ablation, PV variants increase the procedure difficulty of CRYO ablation, manifested by increased procedure time, X-ray time, and dose.

Gain-of-function mutations in the transient receptor potential 6 (TRPC6) channel have recently been recognized as risk factors for both doxorubicin (DOX)-induced cardiomyopathy. Functional evaluation of TRPC6 missense variants is therefore important for cancer patients undergoing anthracycline treatment. However, traditional electrophysiological methods are labor-intensive and time-consuming. In this study, we compared the functional responses of TRPC6 missense variants to 1-oleoyl-2-acetyl-sn-glycerol (OAG), a TRPC6 agonist, using molecular docking and patch clamp recording techniques. For the wild-type (WT) TRPC6 structure (PDB ID: 6UZ8), OAG exhibited a binding energy of -4.49 kcal/mol and a dissociation constant (Kd) of 0.511 mM. Twenty TRPC6 missense variants were identified from cancer patients in the Mayo Clinic database. Of these, fifteen variants had resolvable structures, nine of which displayed increased Kd values and six decreased Kd values compared to WT in molecular docking analysis. Patch clamp recordings revealed that TRPC6 WT and mutant channels were inactive at baseline but were activated upon 50 μM OAG stimulation, except two loss-of-function variants. Moreover, a 24-h treatment with 0.5 μM DOX significantly enhanced OAG-induced channel activation. All three variants identified in patients with heart failure demonstrated gain-of-function properties in both electrophysiological measurements and in-silico predictions. Importantly, the results obtained from molecular docking and patch clamp recordings were strongly correlated, showing an 82% concordance, higher than the predictions from AlphaMissense. These findings indicate that our computational analysis provides a rapid and reliable method for predicting the functional impact of TRPC6 missense variants, which may aid clinical decision-making in cancer patients receiving chemotherapy.

ABSTRACT Myocardial infarction (MI) often results in significant loss of cardiomyocytes (CMs), contributing to adverse ventricular remodelling and heart failure. Therefore, promoting CM survival during the acute stage of MI is crucial. This study aimed to investigate the potential role of GPX3 in cardiac repair following MI. First, plasma GPX3 levels were measured in patients with acute MI (AMI), and myocardial GPX3 expression was assessed in a mouse MI model. Furthermore, the effects of GPX3 on MI were investigated through CM‐specific overexpression or knockdown in vitro and in vivo models. RNA sequencing and subsequent experiments were performed to uncover the molecular mechanisms underlying GPX3‐related effects. Multi‐omics database analysis and experimental verification revealed a significant upregulation of GPX3 expression in ischemic myocardium following MI and in CMs exposed to oxygen–glucose deprivation (OGD). Immunofluorescence results further confirmed elevated cytoplasmic GPX3 expression in CMs under hypoxic conditions. In vitro, GPX3 overexpression mitigated reactive oxygen species (ROS) production and enhanced CM survival during hypoxia, while GPX3 knockdown inhibited these processes. In vivo, CM‐specific GPX3 overexpression in the infarct border zone significantly attenuated CM apoptosis and alleviated myocardial injury, promoting cardiac repair and long‐term functional recovery. Mechanistically, GPX3 overexpression upregulated LSD1 and Hif1α protein expression, and rescue experiments confirmed the involvement of the LSD1/Hif1α pathway in mediating the protective effects of GPX3. Overall, our findings suggest that GPX3 exerts a protective role in ischemic myocardium post‐MI, at least partially through the LSD1/Hif1α axis, highlighting its potential as a therapeutic target for MI treatment.

BACKGROUND:Atrial fibrillation (AF) recurrence after catheter ablation remains a clinical challenge despite guideline-recommended efficacy. Emerging evidence implicates inflammatory biomarkers in predicting arrhythmia recurrence. This study investigated the novel CALLY index, a composite inflammatory marker, as a prognostic indicator for postablation AF recurrence. METHODS:In this prospective cohort study, 556 consecutive AF patients undergoing catheter ablation (June 2018-June 2023) were stratified into recurrence and sinus rhythm (SR) maintenance groups. Cox regression and Kaplan-Meier analyses evaluated associations between the CALLY index and recurrence risk. Predictive accuracy was assessed via receiver operating characteristic (ROC) curves and area under the curve (AUC). RESULTS:Over a median 12-month follow-up, 102 patients (18.3%) experienced recurrence. The SR group exhibited significantly higher CALLY indices than the recurrence group (3.24 ± 1.68 vs. 1.89 ± 0.57; p < 0.001). Univariate Cox regression identified the CALLY index as inversely associated with recurrence (HR: 0.439, 95% CI: 0.292-0.659; p < 0.001), with persistence after multivariable adjustment (HR: 0.887, 95% CI: 0.789-0.956; p = 0.031). Tertile-based stratification revealed a 29% lower recurrence risk in the high-CALLY group versus the low-CALLY group (HR: 0.71, 95% CI: 0.68-0.76; p = 0.017). ROC analysis demonstrated optimal discrimination at a CALLY threshold ≥ 1.433 (AUC: 0.7899; sensitivity: 76.4%; specificity: 74.8%; p < 0.001). CONCLUSION:The CALLY index independently predicts AF recurrence postablation, offering potential utility in risk stratification. These findings support its integration into clinical decision-making to optimize post-procedural management.

The steady increase in life expectancy throughout the world is contributing to an increased incidence of atrial fibrillation (AF), which imposes a significant socioeconomic toll on affected patients and societies. The mechanisms underlying atrial fibrillation are multifaceted and vary among individuals. Hypoxia is a process that is closely linked to AF onset and progression. Hypoxia-inducible factor 1-alpha (HIF-1α) is a transcription factor that serves as a key regulator of oxygen homeostasis within cells through its activation under hypoxic conditions and subsequently coordinates various pathophysiological responses. High levels of HIF-1α expression are evident in AF patients, and facilitate the progression from persistent AF to permanent AF. Thus, HIF-1α may serve as a promising target for novel therapeutic strategies aimed at the prevention and treatment of AF. This review provides an overview and synthesis of recent studies probing the relationship between HIF-1α and AF, providing a foundation for future studies and the development targeted drug therapies.

Diabetic cardiomyopathy (DCM) begins with a subclinical stage featuring cardiac hypertrophy, fibrosis, and disrupted signaling. These changes, especially fibrosis and stiffness, often lead to clinical heart failure. The mechanism involves metabolic dysregulation, oxidative stress, and inflammation, leading to cardiac damage and dysfunction. During the progression of the disease, the myocardium senses surrounding mechanical cues, including extracellular matrix properties, tensile tension, shear stress, and pressure load, which significantly influence the pathological remodeling of the heart through mechanotransduction. At the molecular level, the mechanisms by which mechanical cues are sensed and transduced to mediate myocardial mechanical remodeling in DCM remain unclear. The mechanosensitive transcription factors YAP and TAZ fill this gap. This article reviews the latest findings of how YAP and TAZ perceive a wide range of mechanical cues, from shear stress to extracellular matrix stiffness. We focus on how these cues are relayed through the cytoskeleton to the nucleus, where they trigger downstream gene expression. Here, we review recent progress on the crucial role of YAP and TAZ mechanotransduction in the pathological changes observed in DCM, including myocardial fibrosis, hypertrophy, inflammation, mitochondrial dysfunction, and cell death.

BACKGROUND:Malignant ventricular arrhythmia (MVA) is a severe complication that can occur after acute myocardial infarction, often leading to sudden cardiac death. METHODS:A total of 4471 patients from 2 medical centers were included in this study. The primary endpoint was a composite of MVA and in-hospital death. Seven state-of-the-art artificial intelligence (AI) models were developed and optimized by nested 5-fold cross-validation. Predictive performance was evaluated using the area under the receiver-operating characteristic (AUROC) curve, the calibration curve, and the decision analysis curve. RESULTS:Among the enrolled patients, 3456 were assessed for model development and validation and 1015 patients from another medical center were asssessed for external validation. In the validation group, the eXtreme Gradient Boosting (XGBoost) model achieved the highest AUROC of 0.792 (95% confidence interval [CI] 0.740-0.845) for the composite endpoint. The Light Gradient Boosting Machine (LightGBM) model demonstrated superior performance for MVA prediction (AUROC = 0.827, 95% CI 0.768-0.885), whereas the Random Forest (RF) model outperformed the others for mortality prediction (AUROC = 0.784, 95% CI 0.720-0.848). In the external validation group, the AUROC of the XGBoost model with 15 variables for predicting the primary endpoint event was 0.726. The AUROCs were 0.704 for the LightGBM model with 15 variables for predicting MVA and 0.823 for the RF model with 20 variables for predicting in-hospital death. The Web-based prediction system showed real-time risk assessment capabilities. CONCLUSIONS:Our study presents an interpretable AI framework integrating multimodel analysis for acute myocardial infarction risk management. The system offers clinicians a validated tool for personalized risk assessment that can potentially improve patient outcomes through early intervention strategies.

BACKGROUND:Coronary atherosclerosis (CA) is a leading cause of cardiovascular diseases with the high morbidity and mortality; however, the current diagnostic methods, primarily based on symptoms, signs, lab examination and imaging, are often inadequate for detecting subclinical or early-stage CA, costly, and inaccessible in many cases. The objective of this study was to discover sensitive and specific biomarkers for the diagnosis of CA severity. METHODS:We enrolled 443 participants, including CA patients and healthy controls, from three independent cohorts: discovery, testing, and blinded validation. Multi-omics data integration during the discovery phase identified key features of atherosclerotic progression and potential biomarkers. Biomarker panels were refined using random forest models in the testing cohort, and their performance was evaluated in a blinded validation cohort to assess their ability to monitor the occurrence and development of CA. RESULTS:Multi-omics analysis revealed that plasma metabolites exhibited the strongest correlation with CA severity, effectively distinguished different CA stages from healthy controls. Post hoc analysis confirmed the diagnostic model's robustness, with an AUC value higher than .933 (95% CI: .828-.984, sensitivity 93.75%, and specificity 80%). In the blinded validation cohort, the biomarker panel achieved AUC values of .821-.898 for CA occurrence and .649-.849 for CA severity. Notably, 90% of these biomarkers remained significant after adjusting for comorbidities (p < .05). CONCLUSIONS:This study identified significant metabolic changes during CA progression and established biomarker panels with potential diagnostic value for assessing CA severity. Key metabolites including cholesteryl sulphate, azelaic acid, tryptophan, arabinofuranosyluracil, TMAO, ADMA, LPC18:2, tartaric acid, L-citrulline, and L-proline, purine, sorbitol, and 2-aminoadipic acid. These findings highlight the potential of these biomarkers to improve early diagnosis and personalised management of CA.