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Background: Catecholamine vasopressors are commonly used for intra- or post-operative hypotension for cardiac surgery, which have a side effect of new-onset atrial fibrillation (AF) and myocardial ischemia. However, it is not entirely clear whether catecholamine vasopressors increase the risk of new-onset AF after noncardiac surgery., Aim: The aim of this study was to analyze the association between the use of catecholamine vasopressors and the risk of developing new-onset AF after noncardiac surgery., Methods: In this prospective trial, available data from eligible elderly individuals receiving noncardiac surgery at a single center from November 2022 to January 2024 were gathered. Propensity score matching (PSM) was used to balance patient baseline characteristics and to control for confounders. To determine the association between catecholamine vasopressors and the risk of new-onset AF, univariate and multivariate logistic regression analyses were performed., Results: A total of 6000 subjects were included in this study (mean [SD] age, 70.73 [6.37] years; 910 [50.9%] males). After PSM, the patients were stratified into catecholamine vasopressor (n = 357) and comparator groups (n = 1432). A total of 18/357 patients in the catecholamine vasopressor group developed AF, and 25/1432 patients in the comparator group developed AF (incidence rate, 5.0% vs 1.7%). Compared with the comparator group, the catecholamine vasopressor group had an increased risk of new-onset AF (aOR, 2.77; 95% CI, 1.28-5.89). Some sensitivity analyses also revealed consistent findings of increased new-onset AF risk associated with catecholamine vasopressor treatment., Conclusion: The findings from this study suggest that catecholamine vasopressor treatment is associated with an increased risk of new-onset AF and may help physicians select a modest medication for patients while also assessing the risk of new-onset AF., Competing Interests: All authors declare no competing interests in this work., (© 2024 Li et al.)

Context: Chlordecone (CLD) is a carcinogenic organochlorine pesticide. CLD was shown to disturb the activity of cardiac Na + -K + -ATPase and Ca 2+ -Mg 2+ -ATPase. Conditions affecting these transmembrane pumps are often associated with cardiac arrhythmias (CA). However, little is known about the role of CLD on atrial fibrillation (AF) incidence, the most common type of CA., Hypotheses: 1) Daily ingestion of CLD induces arrhythmogenic cardiac remodeling. 2) A phase of CLD withdrawal can reduce CLD-induced AF susceptibility., Methods: Adult male Wistar rats (250 g-275 g) ingested daily-doses of CLD (0 μg/L, 0.1 μg/L, or 1 μg/L) diluted in their quotidian water for 4 weeks. From day (D)29 to D56, all rats received CLD-free water. Vulnerability to AF and cardiac function were evaluated at D28 and D56 by electrophysiological study, echocardiography, and optical-mapping. Levels of genes and proteins related to inflammation, fibrosis, and senescence were quantified by qPCR and immunoassays., Results: Twenty-eight days of CLD exposure were associated with significantly increased AF vulnerability compared to CLD-free rats. Contamination with 1 μg/L CLD significantly reduced atrial conduction velocity (ERP, APD). CLD-weaning normalized food consumption and weight intake. However, after the CLD-withdrawal period of 28 days, AF inducibility, atrial inflammation (IL6, IL1β), and atrial fibrosis (Masson's trichrome staining) remained significantly higher in rats exposed to 1 μg/L CLD compared to 0 μg/L., Conclusions: Prolonged CLD ingestion provokes atrial conduction slowing and increased risk of AF. Although CLD-weaning, some persistent damages occurred in the atrium like atrial fibrosis and atrial senescence signals, which are accompanied by atrial inflammation and arrhythmogenicity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Roddy Hiram reports financial support was provided by Montreal Heart Institute Foundation. Roddy Hiram reports was provided by Fondation canadienne pour l innovation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Sepsis is considered a high risk factor for new-onset atrial fibrillation (NOAF), with neutrophil extracellular traps (NETs) being implicated in the pathogenesis of numerous diseases. However, the precise role of NETs and NETs-related genes (NRGs) in the occurrence of NOAF in sepsis remains inadequately elucidated. The objective of this study was to identify hub NRGs connecting sepsis and AF, and to investigate the potential association between NETs and NOAF in sepsis., Methods: The AF and sepsis microarray datasets were retrieved from the Gene Expression Omnibus (GEO) database for analysis of shared pathophysiological mechanisms and NRGs implicated in both sepsis and AF using bioinformatics techniques. The CIBERSORT algorithm was employed to assess immune cell infiltration and identify common immune characteristics in these diseases. Additionally, a rat model of lipopolysaccharide (LPS)-induced sepsis was utilized to investigate the association between NETs, NRGs, and sepsis-induced AF. Western blotting, enzyme-linked immunosorbent assay, hematoxylin-eosin staining, immunohistochemistry, and immunofluorescence were employed to assess the expression of NRGs, the formation of NETs, and the infiltration of neutrophils. Electrophysiological analysis and multi-electrode array techniques were utilized to examine the vulnerability and conduction heterogeneity of AF in septic rats. Furthermore, intervention was conducted in LPS-induced sepsis rats using DNase I, a pharmacological agent that specifically targets NETs, in order to assess its impact on neutrophil infiltration, NETs formation, hub NRGs protein expression, and AF vulnerability., Results: A total of 61 commonly differentially expressed genes (DEGs) and four hub DE-NRGs were identified in the context of sepsis and AF. Functional enrichment analysis revealed that these DEGs were predominantly associated with processes related to inflammation and immunity. Immune infiltration analysis further demonstrated the presence of immune infiltrating cells, specifically neutrophil infiltration, in both sepsis and AF. Additionally, a positive correlation was observed between the relative expression of the four hub DE-NRGs and neutrophil infiltration. In rats with LPS-induced sepsis, we observed a notable upregulation in the expression of four DE-NRGs, the formation of NETs, and infiltration of neutrophils in atrial tissue. Through electrophysiological assessments, we identified heightened vulnerability to AF, reduced atrial surface conduction velocity, and increased conduction heterogeneity in LPS-induced sepsis rats. Notably, these detrimental effects can be partially ameliorated by treatment with DNase I., Conclusions: Through bioinformatics analysis and experimental validation, we identified four hub NRGs in sepsis and AF. Subsequent experiments indicated that the formation of NETs in the atria may contribute to the pathogenesis of NOAF in sepsis. These discoveries offer potential novel targets and insights for the prevention and treatment of NOAF in sepsis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: Atrial fibrillation (AF), the most common arrhythmia, is characterized by atrial electrical and structural remodeling. Previous studies have found that sodium-glucose cotransporter 2 inhibitor (SGLT2i) can protect myocardium in a glucose independent mechanism. But the role of SGLT2i in regulating AF remains largely unknown. This study, we aimed to investigate the effect of Dapagliflozin (DAPA) in reducing AF susceptibility via inhibiting electrical and structural remodeling., Method: The mouse model was established by Angiotensin II (2000 ng/kg/min) infusion for 3 weeks, and an in vitro model was generated by stimulating HL-1 and primary mouse fibroblast with Ang II (1 μM) for 24 h. Programmed electrical stimulation, ECG and whole-cell patch clamp were used to detect DAPA effect on atrial electrical remodeling induced by Ang II. To observe DAPA effect on atrial structural remodeling induced by Ang II, we used echocardiographic, H&E and Masson staining to evaluate atrial dilation. To further explore the protective mechanism of DAPA, we adopt in silico molecular docking approaches to investigate the binding affinity of Ang II and CaMKII at Met-281 site. Western blot was to detect expression level of CaMKII, ox-CaMKII, Nav1.5, Kv4.3, Kv4.2, Kchip2, Kir2.1 and Cx40., Results: Ang II induced AF, atrial dilatation and fibrosis, led to atrial electrical and structural remodeling. However, these effects were markedly abrogated by DAPA treatment, a specific SGLT2i. Our observation of atrial electrical activity in mice revealed that DAPA could rescue the prolonged action potential duration (APD) and the abnormal currents of I K1 , I to and I NaL triggered by Ang II infusion. DAPA could reduce the binding affinity of Ang II and CaMKII at Met-281 site, which indicated that DAPA may directly alleviate the activation of CaMKII caused by Ang II. DAPA could reduce the upregulation of ox-CaMKII caused by Ang II infusion in atrial tissues. Moreover, DAPA also ameliorated the aberrant expression levels of electrical activity related proteins (Nav1.5, Kv4.3, Kv4.2, Kchip2, Kir2.1 and Cx40) and fibrosis related signal pathways (TGF-β1, p-smad/smad) caused by Ang II. Furthermore, we confirmed that DAPA, as well as other SGLT2i (EMPA, CANA), could reverse these abnormalities caused by Ang II incubation in HL-1 cells and primary mouse fibroblasts, respectively., Conclusion: Overall, our study identifies DAPA, a widely used SGLT2i, contributes to inhibiting Ang II-induced ox-CaMKII upregulation and electrical and structural remodeling to reduce AF susceptibility, suggesting that DAPA may be a potential therapy of treating AF., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Competing Interests: None.

Inflammation and infiltration of immune cells are intricately linked to the pathogenesis of atrial fibrillation (AF). Triggering receptor expressed on myeloid cells-1 (TREM-1), an enhancer of inflammation, is implicated in various cardiovascular disorders. However, the precise role and potential mechanisms of TREM-1 in the development of AF remain ambiguous. Atrial samples from patients with AF were used to assess the expression levels of TREM-1. An angiotensin II (Ang II)-induced AF mouse model was established to assess the functionality of TREM-1. Cardiac function and AF inducibility were assessed through echocardiography, programmed transvenous cardiac pacing, and atrial electrophysiological mapping. Peripheral blood and atrial inflammatory cells were assessed using flow cytometry. Using histology, bulk RNA sequencing, biochemical analyses, and cell cultures, the mechanistic role of TREM-1 in AF was elucidated. TREM-1 expression was upregulated and co-localized with macrophages in the atria of patients with AF. Pharmacological inhibition of TREM-1 decreased Ang II-induced atrial enlargement and electrical remodeling. TREM-1 inhibition also ameliorated Ang II-induced NLRP3 inflammasome activation, inflammatory factor release, atrial fibrosis, and macrophage infiltration. Transcriptomic analysis revealed that TREM-1 modulates Ang II-induced inflammation through the PI3K/AKT/FoxO3a signaling pathway. In vitro studies further supported these findings, demonstrating that TREM-1 activation exacerbates Ang II-induced inflammation, while overexpression of FoxO3a counteracts this effect. This study discovered the critical role of TREM-1 in the pathogenesis of AF and its underlying molecular mechanisms. Inhibition of TREM-1 provides a new therapeutic strategy for the treatment of AF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Histone deacetylase (HDAC) inhibitors are emerging as promising treatments for hematological malignancies, with potential applications extending to solid tumors in the future. Given their wide-ranging biological effects, there is a pressing need for a thorough understanding of the toxicities linked to HDAC inhibition. In this study, a pharmacovigilance analysis was conducted using the FDA Adverse Event Reporting System database. Suspected adverse events linked to HDAC inhibitors were detected through various statistical methodologies, including reporting odds ratio, proportional reporting ratio, information component, and Empirical Bayes Geometric Mean. Our study findings have illuminated that, among the total reported cases examined, gastrointestinal disorders accounted for 13% patients of the cohort, while lymphatic system disorders comprised 8% cases of the cohort, all of which manifested as adverse events induced by HDAC inhibitors. Importantly, the usage of HDAC inhibitors was found to be associated with incidents of atrial fibrillation, heart failure, respiratory failure, hepatic dysfunction, and acute kidney injury. Romidepsin and belinostat demonstrated more pronounced signals of adverse events compared to panobinostat and vorinostat, emphasizing the need for vigilant monitoring of adverse events in this particular population. Furthermore, atrial fibrillation (clinical priority score of 7 points) emerged as the paramount medical event warranting utmost clinical attention. Eventually, multiple adverse events were observe to emerge within the initial and second months following the initiation of treatment. Vigilant monitoring and supportive care strategies are critical in addressing the toxicities associated with HDAC inhibitors, particularly those concerning cardiotoxicity, respiratory toxicity, renal toxicity, and hepatotoxicity., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Zolpidem is a non-benzodiazepine hypnotic widely used to manage insomnia. Zolpidem-triggered atrial fibrillation (AF) in patients with cardiomyopathy has never been reported before., Case Presentation: A 40-year-old man with Duchenne muscular dystrophy-related cardiomyopathy attempted suicide and developed new-onset AF after zolpidem overdose. One year before admission, the patient visited our clinic due to chest discomfort and fatigue after daily walks for 1 month; both electrocardiography (ECG) and 24-hour Holter ECG results did not detect AF. After administration of cardiac medication (digoxin 0.125 mg/day, spironolactone 40 mg/day, furosemide 20 mg/day, bisoprolol 5 mg/day, sacubitril/valsartan 12/13 mg/day), he felt better. AF had never been observed before this admission via continuous monitoring during follow-up. Sixteen days before admission, the patient saw a sleep specialist and started zolpidem tartrate tablets (10 mg/day) due to insomnia for 6 months; ECG results revealed no significant change. The night before admission, the patient attempted suicide by overdosing on 40 mg of zolpidem after an argument, which resulted in severe lethargy. Upon admission, his ECG revealed new-onset AF, necessitating immediate cessation of zolpidem. Nine hours into admission, AF spontaneously terminated into normal sinus rhythm. Results from the ECG on the following days and the 24-hour Holter ECG at 1-month follow-up showed that AF was not detected., Conclusions: This study provides valuable clinical evidence indicating that zolpidem overdose may induce AF in patients with cardiomyopathy. It serves as a critical warning for clinicians when prescribing zolpidem, particularly for patients with existing heart conditions. Further large-scale studies are needed to validate this finding and to explore the mechanisms between zolpidem and AF., (© 2024. The Author(s).)

Atrial fibrillation (AF) is the most common arrhythmia, and atrial fibrosis is a pathological hallmark of structural remodeling in AF. Prostaglandin I 2 (PGI 2 ) can prevent the process of fibrosis in various tissues via cell surface Prostaglandin I 2 receptor (IP). However, the role of PGI 2 in AF and atrial fibrosis remains unclear. The present study aimed to clarify the role of PGI 2 in angiotensin II (Ang II)-induced AF and the underlying molecular mechanism. PGI 2 content was decreased in both plasma and atrial tissue from patients with AF and mice treated with Ang II. Treatment with the PGI 2 analog, iloprost, reduced Ang II-induced AF and atrial fibrosis. Iloprost prevented Ang II-induced atrial fibroblast collagen synthesis and differentiation. RNA-sequencing analysis revealed that iloprost significantly attenuated transcriptome changes in Ang II-treated atrial fibroblasts, especially mitogen-activated protein kinase (MAPK)-regulated genes. We demonstrated that iloprost elevated cAMP levels and then activated protein kinase A, resulting in a suppression of extracellular signal-regulated kinase1/2 and P38 activation, and ultimately inhibiting MAPK-dependent interleukin-6 transcription. In contrast, cardiac fibroblast-specific IP-knockdown mice had increased Ang II-induced AF inducibility and aggravated atrial fibrosis. Together, our study suggests that PGI 2 /IP system protects against atrial fibrosis and that PGI 2 is a therapeutic target for treating AF.The prospectively registered trial was approved by the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2200056733. Data of registration was 2022/02/12., (© 2024. The Author(s).)

Background: Second-generation antipsychotics increase the risk of atrial fibrillation. This study explores whether the atypical antipsychotic ziprasidone triggers inflammasome signaling, leading to atrial arrhythmia., Methods: Electromechanical and pharmacological assessments were conducted on the rabbit left atria (LA). The patch-clamp technique was used to measure ionic channel currents in single cardiomyocytes. Detection of cytosolic reactive oxygen species production was performed in atrial cardiomyocytes., Results: The duration of action potentials at 50 % and 90 % repolarization was dose-dependently shortened in ziprasidone-treated LA. Diastolic tension in LA increased after ziprasidone treatment. Ziprasidone-treated LA showed rapid atrial pacing (RAP) triggered activity. PI3K inhibitor, Akt inhibitor and mTOR inhibitor abolished the triggered activity elicited by ziprasidone in LA. The NLRP3 inhibitor MCC950 suppressed the ziprasidone-induced post-RAP-triggered activity. MCC950 treatment reduced the reverse-mode Na + /Ca 2+ exchanger current in ziprasidone-treated myocytes. Cytosolic reactive oxygen species production decreased in ziprasidone-treated atrial myocytes after MCC950 treatment. Protein levels of inflammasomes and proinflammatory cytokines, including NLRP3, caspase-1, IL-1β, IL-18, and IL-6 were observed to be upregulated in myocytes treated with ziprasidone., Conclusions: Our findings suggest ziprasidone induces atrial arrhythmia, potentially through upregulation of the NLRP3 inflammasome and enhancement of reactive oxygen species production via the PI3K/Akt/mTOR pathway., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Ibrutinib could increase the risk of atrial fibrillation (AF) in chronic lymphocytic leukemia (CLL) patients. However, the precise mechanism underlying ibrutinib-induced AF remains incompletely elucidated., Methods: We investigated the proportion of ibrutinib-treated CLL patients with new-onset AF. Optical mapping was conducted to reveal the proarrhythmic effect of ibrutinib on HL-1 cells. Fluorescence staining and western blot were used to compare connexins 43 and 40 expression in ibrutinib-treated and control groups. To identify autophagy phenotypes, we used western blot to detect autophagy-related proteins, transmission electron microscopy to picture autophagosomes, and transfected mCherry-GFP-LC3 virus to label autophagosomes and lysosomes. Hydroxychloroquine as an autophagy inhibitor was administered to rescue ibrutinib-induced Cx43 and Cx40 degradation., Results: About 2.67% of patients developed atrial arrhythmias after ibrutinib administration. HL-1 cells treated with ibrutinib exhibited diminished conduction velocity and a higher incidence of reentry-like arrhythmias compared to controls. Cx43 and Cx40 expression reduced along with autophagy markers increased in HL-1 cells treated with ibrutinib. Inhibiting autophagy upregulated Cx43 and Cx40., Conclusions: The off-target effect of ibrutinib on the PI3K-AKT-mTOR signaling pathway caused connexin degradation and atrial arrhythmia via promoting autophagy., Clinical Trial Registration: ChiCTR2100046062, https://clin.larvol.com/trial-detail/ChiCTR2100046062., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Background: Atrial fibrillation (AF) is often associated with atrial fibrosis and oxidative stress. Neferine, a bisbenzylisoquinoline alkaloid, has been reported to exert an antiarrhythmic effect. However, its impact on Angiotensin II (Ang II) infusion-induced AF and the underlying mechanism remains unclear. This study aimed to investigate whether neferine alleviates Ang II-induced AF and explore the underlying mechanisms., Methods: Mice subjected to Ang II infusion to induce AF were concurrently treated with neferine or saline. AF incidence, myocardial cell size, fibrosis, and oxidative stress were then examined., Results: Neferine treatment inhibited Ang II-induced AF, atrial size augmentation, and atrial fibrosis. Additionally, we observed that Ang II increased reactive oxygen species (ROS) generation, induced mitochondrial membrane potential depolarization, and reduced glutathione (GSH) and superoxide dismutase (SOD) levels, which were reversed to some extent by neferine. Mechanistically, neferine activated the Nrf2/HO-1 signaling pathway and inhibited TGF-β/p-Smad2/3 in Ang II-infused atria. Zinc Protoporphyrin (ZnPP), an HO-1 inhibitor, reduced the anti-oxidative effect of neferine to some extent and subsequently abolished the beneficial effect of neferine on Ang II-induced AF., Conclusions: These findings provide hitherto undocumented evidence that the protective role of neferine in Ang II-induced AF is dependent on HO-1.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is an important contributor to mortality and morbidity. Ubquitin-specific protease 7 (USP7), one of the most abundant ubiquitin-specific proteases (USP), participated in many cellular events, such as cell proliferation, apoptosis, and tumourigenesis. However, its role in AF remains unknown. Here, the mice were treated with Ang II infusion to induce the AF model. Echocardiography was used to measure the atrial diameter. Electrical stimulation was programmed to measure the induction and duration of AF. The changes in atrial remodeling were measured using routine histologic analysis. Here, a significant increase in USP7 expression was observed in Ang II-stimulated atrial cardiomyocytes and atrial tissues, as well as in atrial tissues from patients with AF. The administration of p22077, the inhibitor of USP7, attenuated Ang II-induced inducibility and duration of AF, atrial dilatation, connexin dysfunction, atrial fibrosis, atrial inflammation, and atrial oxidase stress, and then inhibited the progression of AF. Mechanistically, the administration of p22077 alleviated Ang II-induced activation of TGF-β/Smad2, NF-κB/NLRP3, NADPH oxidases (NOX2 and NOX4) signals, the up-regulation of CX43, ox-CaMKII, CaMKII, Kir2.1, and down-regulation of SERCA2a. Together, this study, for the first time, suggests that USP7 is a critical driver of AF and revealing USP7 may present a new target for atrial fibrillation therapeutic strategies., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background: Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a risk factor for stroke. Randomized trials have demonstrated that anticoagulation can reduce strokes in AF patients. Yet, widespread underutilization of this therapy continues. To address this practice gap, we designed a study to implement and evaluate the effectiveness of a best practice advisory (BPA) for an Atrial Fibrillation Decision Support Tool (AFDST) embedded within our electronic health record., Methods: Our intervention is provider-facing, focused on decision support. Clinical setting is ambulatory patients being seen by primary care physicians. We prospectively enrolled 608 patients in our health system who are currently receiving less than optimal anticoagulation therapy as determined by the AFDST and randomized them to one of two arms - 1) usual care, in which the AFDST is available for use; or 2) addition of a BPA to the AFDST notifying clinicians that their patient stands to gain significant benefit from a change in current therapy. Primary outcome was effectiveness of the BPA measured by change to "appropriate thromboprophylaxis" based on the AFDST recommendation at 3 months post-enrollment. Secondary endpoints included Reach and Adoption from the RE-AIM (Reach, Effectiveness, Adoption, Implementation, & Maintenance) framework for implementation studies., Results: Among 562 patients with a minimum follow-up of 3 months, addition of a BPA to the AFDST resulted in significant improvement in anticoagulation therapy, 5 % (12/248) versus 11 % (33/314) p = 0.02, odds ratio 2.31 (95 % CI, 1.17-4.87)., Conclusions: A BPA added to an AF decision support tool improved anticoagulation therapy among AF patients in a primary care academic health system setting., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Methamphetamine use has emerged as a major risk factor for cardiovascular and cerebrovascular disease in young adults. The aim of this study was to investigate a possible association of methamphetamine use with cardioembolic stroke., Methods and Results: We performed a retrospective study of patients with acute ischemic stroke admitted at our medical center between 2019 and 2022. All patients were screened for methamphetamine use and cardiomyopathy, defined as left ventricular ejection fraction ≤45%. Among 938 consecutive patients, 46 (4.9%) were identified as using methamphetamine. Compared with the nonmethamphetamine group (n=892), the methamphetamine group was significantly younger (52.8±9.6 versus 69.7±15.2 years; P <0.001), included more men (78.3% versus 52.8%; P <0.001), and had a significantly higher rate of cardiomyopathy (30.4% versus 14.0%; P <0.01). They were also less likely to have a history of atrial fibrillation (8.7% versus 33.4%; P <0.01) or hyperlipidemia (28.3% versus 51.7%; P <0.01). Compared with patients with cardiomyopathy without methamphetamine use, the patients with cardiomyopathy with methamphetamine use had significantly lower left ventricular ejection fraction (26.0±9.59% versus 32.47±9.52%; P <0.01) but better functional outcome at 3 months, likely attributable to significantly younger age and fewer comorbidities. In the logistic regression model of clinical variables, methamphetamine-associated cardiomyopathy was found to be significantly associated with cardioembolic stroke (odds ratio, 1.79 [95% CI, 1.04-3.06]; P <0.05)., Conclusions: We demonstrate that methamphetamine use is significantly associated with cardiomyopathy and cardioembolic stroke in young adults.

A number of pharmacological drugs have side effects that contribute to the occurrence of atrial fibrillation, the most common type of cardiac rhythm disorders. The clinical use of antihistamines is widespread; however, information regarding their anti- and/or proarrhythmic effects is contradictory. In this work, we studied the effects and mechanisms of the potential proarrhythmic action of the first-generation antihistamine chloropyramine (Suprastin) in the atrial myocardium and pulmonary vein (PV) myocardial tissue. In PV, chloropyramine caused depolarization of the resting potential and led to reduction of excitation wave conduction. These effects are likely due to suppression of the inward rectifier potassium current (IK1). In presence of epinephrine, chloropyramine induced spontaneous automaticity in the PV and could not be suppressed by atrial pacing. Chloropyramine change functional characteristics of PV and contribute to occurrence of atrial fibrillation. It should be noted that chloropyramine does not provoke atrial tachyarrhythmias, but create conditions for their occurrence during physical exercise and sympathetic stimulation., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Age is a significant risk factor for ischemic stroke. However, the influence of aging on coagulation parameters in non-valvular atrial fibrillation (NVAF) patients treated with direct oral anticoagulants (DOACs) remains unclear. A total of 775 samples were collected from 224 NVAF patients receiving apixaban, edoxaban or rivaroxaban. The samples were categorized into three age groups: (i) ≤ 64 years, (ii) 65-74 years, and (iii) ≥ 75 years (apixaban: N = 48, 108, 119; edoxaban: N = 63, 68, 126; rivaroxaban: N = 115, 90, 38, respectively). Coagulation parameters including fibrinogen (Fbg), factor II, factor V, factor VII, factor X, and D-dimer, were compared between the three age groups for each drug. The slopes in the correlation between drug concentrations and modified diluted prothrombin time (mdPT) were also assessed. Fbg and factor V increased with age, while factor II and factor X decreased. Factor VII and D-dimer showed no significant differences across age categories. The slope in response to drug concentrations was similar between the age groups. In NVAF patients treated with apixaban, edoxaban and rivaroxaban, some coagulation parameters exhibited age-related variation. However, the response of mdPT to drug concentration was consistent across age categories., (© 2024. Japanese Society of Hematology.)

Apixaban has been associated with prolongation of the international normalized ratio (INR), but data surrounding the extent of elevation and its clinical significance are limited. Due to interaction between apixaban and the prothrombin assay, elevations in INR in patients receiving apixaban are common and not always grounds for concern. However, in high risk patients, elevations can represent a need for closer monitoring. This case summarizes an 82-year-old woman with a history of atrial fibrillation and left middle cerebral artery strokes with no residual deficits. She presented with right-sided hemiparesis and aphasia and underwent a mechanical thrombectomy with TICI 2b recanalization of a left M1 occlusion. Post-thrombectomy, she was found to have a left atrial thrombus and 10 days later was started on apixaban 5 mg twice daily. On the fourth day of apixaban therapy, she experienced an INR increase to 2.3, prompting initiation of a vitamin K challenge for nutritional deficiency. Despite initial improvement, her INR increased to 2.7 a week after apixaban was initiated, coinciding with a decline in mental status and an apixaban peak level of 435.6 ng/mL (reference range 91-321 ng/mL). A computed tomography (CT) scan of her head showed new intracranial hemorrhage in the area of her previous infarction, prompting apixaban reversal with andexanet alfa. Unfortunately, the patient expired. This case report highlights the importance and difficulty in performing therapeutic drug monitoring in patients receiving oral anti-factor Xa inhibitors, revealing a downside to administration of high-risk medications that do not have readily available monitoring., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Among patients with atrial fibrillation (AF), a nonpharmacologic option (e.g., percutaneous left atrial appendage occlusion [LAAO]) is needed for patients with oral anticoagulant (OAC) contraindications. Among beneficiaries in the Medicare fee-for-service coverage 20% sample databases (2015-18) who had AF and an elevated CHA 2 DS 2 -VASc score, we assessed the association between percutaneous LAAO versus OAC use and risk of stroke, hospitalized bleeding, and death., Methods: Patients undergoing percutaneous LAAO were matched to up to five OAC users by sex, age, date of enrollment, index date, CHA 2 DS 2 -VASc score, and HAS-BLED score. Overall, 17 156 patients with AF (2905 with percutaneous LAAO) were matched (average ± SD 78 ± 6 years, 44% female). Cox proportional hazards model were used., Results: Median follow-up was 10.3 months. After multivariable adjustments, no significant difference for risk of stroke or death was noted when patients with percutaneous LAAO were compared with OAC users (HRs [95% CIs]: 1.14 [0.86-1.52], 0.98 [0.86-1.10]). There was a 2.94-fold (95% CI: 2.50-3.45) increased risk for hospitalized bleeding for percutaneous LAAO compared with OAC use. Among patients 65 to <78 years old, those undergoing percutaneous LAAO had higher risk of stroke compared with OAC users. No association was present in those ≥78 years., Conclusion: In this analysis of real-world AF patients, percutaneous LAAO versus OAC use was associated with similar risk of death, nonsignificantly elevated risk of stroke, and an elevated risk of bleeding in the post-procedural period. Overall, these results support results of randomized trials that percutaneous LAAO may be an alternative to OAC use for patients with contraindications., (© 2024 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Aims: AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca 2+ activated K + (K Ca 2) channel. The aim of this extension phase 1 study was to test AP30663 at higher single doses compared to the first-in-human trial., Methods: Sixteen healthy male volunteers were randomized into 2 cohorts: 6- and 8-mg/kg intravenous single-dose administration of AP30663 vs. placebo. Safety, pharmacokinetic and pharmacodynamic data were collected., Results: AP30663 was associated with mild and transient infusion site reactions with no clustering of other adverse events but with an estimated maximum mean QTcF interval prolongation of 45.2 ms (95% confidence interval 31.5-58.9) in the 6 mg/kg dose level and 50.4 ms (95% confidence interval 36.7-64.0) with 8 mg/kg. Pharmacokinetics was dose proportional with terminal half-life of around 3 h., Conclusion: AP30663 in doses up to 8 mg/kg was associated with mild and transient infusion site reactions and an increase of the QTcF interval. Supporting Information support that the QTc effect may be explained by an off-target inhibition of the I Kr channel., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

There are clinical situations where information about the anticoagulant effects of Apixaban could be useful. Specialised methods for measuring Apixaban concentrations are not available at all medical laboratories while methods for measuring the functional effects of Apixaban, using clot time ratio (CTR), can be performed in most medical laboratories around the clock using well-established measurement procedures. The aim of this study was to investigate CTR in trough and peak samples during Apixaban treatment of atrial fibrillation and to correlate the findings to bleeds and thrombotic events. Three trough- and three peak samples from 61 patients (31 on Apixaban 5 mg twice daily and 30 on Apixaban 2.5 mg twice daily) were analysed with MRX PT DOAC. Patients were followed for 30 + /-15 months, and bleeds and thrombotic events were documented. The effect of Apixaban could be measured with MRX PT DOAC and there was a statistically significant difference between CTR in trough samples compared to peak samples (p < 0.001). A total of 21 patients suffered bleeds during follow-up; two patients suffered major bleeds, and 19 suffered minor bleeds. Patients with major bleeds had both mean peak- and mean trough CTR above the respective first to third quartile (Q1-Q3) range. Four patients suffered thromboembolic events. Generally, the peak CTRs were below or in the lower end of the peak Q1-Q3 for these patients. The new test MRX PT DOAC can be used to measure the effect of Apixaban during the treatment of atrial fibrillation. High mean peak- and mean trough CTR were seen in 2 patients with major bleeds, and low peak CTR was seen in 4 patients with thromboembolic events., (© 2024. The Author(s).)

Background: The efficacy and safety of non-vitamin-K antagonist oral anticoagulants (NOACs) across the spectrum of body mass index (BMI) and body weight (BW) remain uncertain., Methods: We analyzed data from COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation), which pooled patient-level data from the 4 pivotal randomized trials of NOAC versus warfarin in patients with atrial fibrillation. The primary efficacy and safety outcomes were stroke or systemic embolic events (stroke/SEE) and major bleeding, respectively; secondary outcomes were ischemic stroke/SEE, intracranial hemorrhage, death, and the net clinical outcome (stroke/SEE, major bleeding, or death). Each outcome was examined across BMI and BW. Because few patients had a BMI <18.5 kg/m 2 (n=598), the primary analyses were restricted to those with a BMI ≥18.5 kg/m 2 ., Results: Among 58 464 patients, the median BMI was 28.3 (interquartile range, 25.2-32.2) kg/m 2 , and the median BW was 81.0 (interquartile range, 70.0-94.3) kg. The event probability of stroke/SEE was lower at a higher BMI irrespective of treatment, whereas the probability of major bleeding was lower at a higher BMI with warfarin but relatively unchanged across BMI with NOACs. NOACs reduced stroke/SEE overall (adjusted hazard ratio [HR adj ], 0.80 [95% CI, 0.73-0.88]; P <0.001), with a generally consistent effect across BMI ( P trend across HRs, 0.48). NOACs also reduced major bleeding overall (HR adj , 0.88 [95% CI, 0.82-0.94]; P <0.001), but with attenuation of the benefit at a higher BMI (trend test across BMI [ P trend ], 0.003). The overall treatment effects of NOACs versus warfarin for secondary outcomes were consistent across BMI, with the exception of the net clinical outcome and death. While these outcomes were overall reduced with NOACs (net clinical outcome, HR adj , 0.91 [95% CI, 0.87-0.95]; P <0.001; death, HR adj , 0.91 [95% CI, 0.86-0.97]; P =0.003), these benefits were attenuated at higher BMI ( P trend , 0.001 and 0.08, respectively). All findings were qualitatively similar when analyzed across BW., Conclusions: The treatment effect of NOACs versus warfarin in atrial fibrillation is generally consistent for stroke/SEE across the spectrum of BMI and BW, whereas the reduction in major bleeding is attenuated in those with higher BMI or BW. Death and the net clinical outcome are overall reduced with NOACs over warfarin, although there remain uncertainties for these outcomes at a very high BMI and BW., Competing Interests: S.M.P. reports consulting fees from Janssen. E.B. has received consulting fees from Amgen, Boehringer Ingelheim/Lilly, Cardurion, MyoKardia, NovoNordisk, and Verve. J.S. has received consultant or speaker fees from Abbott, Alexion, Amgen, AstraZeneca, Bayer, Berlin-Chemie, Biosense Webster, Biotronik, Boehringer Ingelheim, Boston Scientific, BMS, Daiichi Sankyo, Medscape, Medtronic, Menarini, Merck/MSD, Organon, Pfizer, SAJA, Servier, and WebMD. He reports ownership of Swiss EP and CorXL. G.B. reports speaker fees of small amounts from Bayer, Boehringer Ingelheim, Boston Scientific, Daiichi Sankyo, and Janssen, outside the submitted work. E.A.B. reports consulting fees from Novo Nordisk, Esperion, PriMed, Medscape, Amgen and Servier, and participation on clinical end point committees for studies sponsored by Kowa Pharmaceuticals. S.J.C. reports personal fees from BMS, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Portola during the conduct of the study. J.E. reports honoraria and grant support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Sanofi Aventis, and Eli Lilly as well as a personnel award from the Heart and Stroke Foundation. C.B.G. reports personal fees from Bayer and Boston Scientific; grants and personal fees from Boehringer Ingelheim, Bristol Myers Squibb, Janssen, and Pfizer; and grants from Daiichi-Sankyo during the conduct of the study; personal fees from AbbVie, Espero, Medscape, Medtronic Inc, Merck, the National Institutes of Health, Novo Nordisk, Roche, Rho Pharmaceuticals, CeleCor, Correvio, Philips, Abiomed, and Anthos Therapeutics; grants from Akros, AstraZeneca, the US Food and Drug Administration, Glaxo Smith Kline, Medtronic Foundation, and Apple; and grants and personal fees from Novartis and The Medicines Company outside the submitted work. D.A.M. reports consulting fees from Abbott Laboratories, ARCA Biopharma, InCarda, Inflammatix, Merck & Co, Novartis, and Roche Diagnostics. M.R.P. reports grants from Astra Zeneca, Bayer, Janssen, Procyrion, and Heartflow; and personal fees from Bayer, Janssen, Mytonomy, and Procyrion outside the submitted work. L.W. reports grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, GlaxoSmithKline, Merck & Co, and Roche Diagnostics and personal fees from Abbott outside the submitted work. R.P.G. reports grant support to his institution from Anthos and Daiichi-Sankyo, and personal fees from Artivion, Bayer, Daiichi-Sankyo, Medical Education Resources, Medscape, Menarini, Pfizer, SAJA Pharmaceuticals, Sanofi, and Servier. S.M.P., E.B., M.G.P., E.M.A., E.A.B., D.A.M., C.T.R., and R.P.G. report being members of the TIMI (Thrombolysis in Myocardial Infarction) Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc, Roche, Siemens Healthcare Diagnostics, Inc, The Medicines Company, and Zora Biosciences. The other authors report no conflicts.

Background: Phase III trials should be integrated by post authorisation safety studies (PASS) to confirm their conclusions in real life. In this setting, comorbidities are commonly more prevalent, decisions about drugs and regimens are left to the attending physicians and therapy monitoring is not usually as strict as in pivotal trials., Aims and Methods: To evaluate real life safety and effectiveness of edoxaban and rivaroxaban, ETNA-AF Europe (ETNA-AF-Eu) and XANTUS studies were reviewed and compared. A further comparison between data collected in these studies and in the pivotal studies ENGAGE AF-TIMI 48 and ROCKET-AF was also performed., Results: ETNA-AF-Eu and XANTUS showed lower bleeding, stroke, cardiovascular- and all-cause mortality rates as compared to those observed in Phase 3 trials, even when including subgroups with lower comorbidities. Patients in ETNA-AF-Eu were older, with a larger proportion of octogenarians (≥85 years in 10.5%) and patients with impaired renal function as compared to patients in XANTUS (CrCl <50 ml/min in 18.2% vs 12.2%) and in ENGAGE AF-TIMI 48 and ROCKET-AF, without paying any excess tribute in terms of safety. Therapy persistence was very high in the two real life studies (91.9% in ETNA-AF-Eu and 79.9% in XANTUS), thus showing that edoxaban and rivaroxaban are well tolerated in real life., Conclusion: The ETNA-AF-Eu and XANTUS confirmed the safety and effectiveness of edoxaban and rivaroxaban in real life., Competing Interests: Declaration of Competing Interest Roberto Cemin: small grant for participation to investigators' meeting for Daiichi-Sankyo. Riccardo Cappato: consultant to Boston Scientific, Medtronic, St. Jude, Biosense Webster, ELA Sorin, Boehringer Ingelheim, Bayer HealthCare, Abbott, Pfizer. speaker's Bureau: Boston Scientific, Medtronic, St. Jude, Biosense Webster, BARD, Sanofi, Boehringer Ingelheim, Bayer HealthCare, Abbott. investigator: Medtronic, Biosense Webster, Sanofi, Cameron Health, BARD, Bayer HealthCare, Abbott, Pfizer. grants: Boston Scientific, Medtronic, St. Jude, Biosense Webster, BARD, ELA Sorin. Equity and Intellectual Property Rights: Cameron Health, Atacor Inc., (Copyright © 2023 Elsevier B.V. All rights reserved.)

While novel oral anticoagulants are increasingly used to reduce risk of stroke in patients with atrial fibrillation, vitamin K antagonists such as warfarin continue to be used extensively for stroke prevention across the world. While effective in reducing the risk of strokes, the complex pharmacodynamics of warfarin make it difficult to use clinically, with many patients experiencing under- and/or over- anticoagulation. In this study we employed a novel implementation of deep reinforcement learning to provide clinical decision support to optimize time in therapeutic International Normalized Ratio (INR) range. We used a novel semi-Markov decision process formulation of the Batch-Constrained deep Q-learning algorithm to develop a reinforcement learning model to dynamically recommend optimal warfarin dosing to achieve INR of 2.0-3.0 for patients with atrial fibrillation. The model was developed using data from 22,502 patients in the warfarin treated groups of the pivotal randomized clinical trials of edoxaban (ENGAGE AF-TIMI 48), apixaban (ARISTOTLE) and rivaroxaban (ROCKET AF). The model was externally validated on data from 5730 warfarin-treated patients in a fourth trial of dabigatran (RE-LY) using multilevel regression models to estimate the relationship between center-level algorithm consistent dosing, time in therapeutic INR range (TTR), and a composite clinical outcome of stroke, systemic embolism or major hemorrhage. External validation showed a positive association between center-level algorithm-consistent dosing and TTR (R 2  = 0.56). Each 10% increase in algorithm-consistent dosing at the center level independently predicted a 6.78% improvement in TTR (95% CI 6.29, 7.28; p < 0.001) and a 11% decrease in the composite clinical outcome (HR 0.89; 95% CI 0.81, 1.00; p = 0.015). These results were comparable to those of a rules-based clinical algorithm used for benchmarking, for which each 10% increase in algorithm-consistent dosing independently predicted a 6.10% increase in TTR (95% CI 5.67, 6.54, p < 0.001) and a 10% decrease in the composite outcome (HR 0.90; 95% CI 0.83, 0.98, p = 0.018). Our findings suggest that a deep reinforcement learning algorithm can optimize time in therapeutic range for patients taking warfarin. A digital clinical decision support system to promote algorithm-consistent warfarin dosing could optimize time in therapeutic range and improve clinical outcomes in atrial fibrillation globally., (© 2024. The Author(s).)

Background: There is uncertainty regarding the clinical benefit of anticoagulant (AC) treatment in patients with cancer with atrial fibrillation (AF). We aimed to evaluate the distribution and patterns of AC use and its impact on all-cause mortality in cancer patients with AF., Methods: A total of 1,653 patients with cancer diagnosed with AF were included in this retrospective cohort analysis. Multivariable logistic regression was applied to identify the clinical predictors of anticoagulant prescription. Kaplan-Meier curve with a log-rank test was used to compare the probability of survival between the AC and non-AC groups. Multivariate Cox proportional hazard regression models were implemented to evaluate the influences of various variables on all-cause death., Results: Of 1,653 patients with cancer with AF, 971 (58.7%) did not receive a prescription for AC. Among patients with CHA2DS2-VASC ≥2 in men or ≥3 in women and HAS-BLED <3, 56.5% were not prescribed AC. Rivaroxaban and warfarin are more frequently used than dabigatran, mainly in patients with lung and breast cancer. Over a median follow-up of 36 months, 776 deaths were identified. The Kaplan-Meier curve suggested that patients with AC prescriptions had better clinical outcomes. On multivariate Cox proportional risk regression analysis, AC prescription was significantly associated with a lower risk of all-cause mortality (hazard ratio, 0.78; 95% confidence interval, 0.66-0.91; P = 0.002)., Conclusions: The prescription of anticoagulants in patients with cancer with AF was suboptimal. AC prescription at discharge was associated with a decreased risk of all-cause mortality., Impact: This study highlights the importance of AC prescriptions in patients with cancer with AF., (©2023 American Association for Cancer Research.)

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an increased morbidity and mortality. There is clinical evidence that an increasing number of cardiovascular and non-cardiovascular drugs, mainly anticancer drugs, can induce AF either in patients with or without pre-existing cardiac disorders, but drug-induced AF (DIAF) has not received the attention that it might deserve. In many cases DIAF is asymptomatic and paroxysmal and patients recover sinus rhythm spontaneously, but sometimes, DIAF persists, and it is necessary to perform a cardioversion. Furthermore, DIAF is not mentioned in clinical guidelines on the treatment of AF. The risk of DIAF increases in elderly and in patients treated with polypharmacy and with risk factors and comorbidities that commonly coexist with AF. This is the case of cancer patients. Under these circumstances ascribing causality of DIAF to a given drug often represents a clinical challenge. We review the incidence, the pathophysiological mechanisms, risk factors, clinical relevance, and treatment of DIAF. Because of the limited information presently available, further research is needed to obtain a deeper insight into DIAF. Meanwhile, it is important that clinicians are aware of the problem that DIAF represents, recognize which drugs may cause DIAF, and consider the possibility that a drug may be responsible for a new-onset AF episode., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Oral anticoagulants (OAC) are underutilized in older patients with atrial fibrillation, despite proven clinical benefits. Our objective was to investigate baseline characteristics, treatment patterns, and impact of anticoagulation upon clinical outcomes with respect to age., Methods: Adults with newly diagnosed atrial fibrillation were recruited into the prospective observational registry, GARFIELD-AF, and followed up for 24 months. Adjusted hazard ratios (HR) were obtained via Cox proportional-hazards models with applied weights, to quantify the association of age with clinical outcomes. Comparative effectiveness of OAC vs No OAC and non-vitamin K oral anticoagulants (NOAC) vs vitamin K antagonists (VKA) were assessed using a propensity score with an overlap weighting scheme., Results: Of 52,018 patients, 32.6% were 65-74 years of age, 29.3% were 75-84 years, and 7.9% were ≥85 years. OAC treatment was associated with a numerical reduction in all-cause mortality among those aged 65-74 years (HR; 95% confidence interval) (0.86; 0.69-1.06) and aged 75-84 years (0.89; 0.75-1.05) and a significant reduction in patients ≥85 years (0.77; 0.63-0.95) vs no OAC. Similarly, OACs were associated with a decrease in stroke: 65-74 (0.51; 0.35-0.76) and ≥85 years (0.58; 0.34-0.99) and a numerical decrease in 75-84 years (0.84; 0.59-1.18). No increase in major bleeding was observed in patients aged ≥85 treated with OACs. Compared with VKA, NOACs were associated with a significant reduction in all-cause mortality in patients aged <65 and 65-74, with numerical reductions in those aged 75-84 and ≥85 years., Conclusions: Older patients using OACs saw lower all-cause mortality and stroke risk; NOACs had less mortality and major bleeding compared with VKAs., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists, mostly warfarin, for the main indications for oral anticoagulation, prevention and treatment of venous thromboembolism, and prevention of embolic stroke in atrial fibrillation. While DOACs offer practical, fixed-dose anticoagulation in many patients, specific restrictions or contraindications may apply. DOACs are not sufficiently effective in high-thrombotic risk conditions such as antiphospholipid syndrome and mechanical heart valves. Patients with cancer-associated thrombosis may benefit from DOACs, but the bleeding risk, particularly in those with gastrointestinal or urogenital tumors, must be carefully weighed. In patients with frailty, excess body weight, and/or moderate-to-severe chronic kidney disease, DOACs must be cautiously administered and may require laboratory monitoring. Reversal agents have been developed and approved for life-threatening bleeding. In addition, the clinical testing of potentially safer anticoagulants such as factor XI(a) inhibitors is important to further optimize anticoagulant therapy in an increasingly elderly and frail population worldwide.

A direct oral anticoagulant rivaroxaban fails to prevent stroke and systemic embolism in one-to-several percent of patients with nonvalvular atrial fibrillation (NVAF), but the reasons are unknown. The study used semi-mechanistic in vitro-in vivo prediction (IVIVP) modeling to explore the reasons for ineffective thrombosis prevention in NVAF patients. Steady-state drug concentrations in plasma were measured at 0 h (C trough ), 3 h (C 3h ), and 12 h post-dosing in thirty-four patients treated with 20 mg rivaroxaban daily. The clinical data were compared against "virtual twins" generated with a novel IVIVP model that combined drug dissolution modeling, mechanistic description of gastric drug transit, and population pharmacokinetics defining the variability of drug disposition. The nonresponders had significantly lower C 3h and C trough than the responders (p < 0.001) and the covariates included in the population pharmacokinetic submodel did not fully explain this difference. Simulations involving varied gastrointestinal parameters in the "virtual twins" revealed that lower small intestinal effective permeability (P eff ), rather than a slower stomach emptying rate, could explain low rivaroxaban exposure in the nonresponders. IVIVP modeling was effectively used for exploring pharmacotherapy failure. Low P eff , found as a major determinant of ineffective rivaroxaban treatment, encourages further research to find (pato)physiological factors influencing suboptimal absorption., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: The impact of unhealthy lifestyles on clinical outcomes among patients with atrial fibrillation (AF) who are at low risk of stroke remains uncertain. The study objective was to evaluate the association between unhealthy lifestyles and clinical outcomes among low-risk AF patients with 0-1 non-sex risk factor of the CHA 2 DS 2 -VASc (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, prior Stroke or transient ischemic attack [TIA], Vascular disease, Age 65-74 years, female Sex;) score., Methods: A total of 52,451 low-risk AF patients (mean age 51.6 ± 10.4 years) were evaluated with the National Health Insurance Service of the Republic of Korea database between 2009 and 2016. Using the survey on health habits, an unhealthy lifestyle score (ULS) was calculated by adding one point each if a respondent had a sedentary lifestyle, drinking, or smoking. The primary outcome was the composite of myocardial infarction, ischemic stroke, heart failure, and all-cause death. Multivariable Cox regression analysis was used to estimate the risk of the study outcome according to the ULS., Results: There was a total of 12,792 (24.4%), 24,785 (47.3%), 11,602 (22.1%), and 3272 (6.2%) low-risk AF patients with 0 to 3 points of the ULS, respectively. The median follow-up period was 4.1 (2.1-6.1) years. Compared with the healthiest-lifestyle group (ULS 0), the other groups were associated with significantly higher risks of the primary outcome, with a gradually increasing trend according to the ULS (adjusted hazard ratio [95% confidence interval] =1.17 [1.05-1.31], 1.37 [1.21-1.56], 1.82 [1.53-2.17], for the groups with ULS 1, 2, and 3, respectively)., Conclusion: Unhealthy lifestyles, including a sedentary lifestyle, drinking, and smoking, may synergistically impact poor clinical outcomes in AF patients who are deemed to be at low risk of stroke., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is a cardiac disease characterized by disordered atrial electrical activity. Atrial inflammation and fibrosis are involved in AF progression. Costunolide (COS) is a sesquiterpene lactone containing anti-inflammatory and anti-fibrotic activities. This study aims to explore the underlying mechanisms by which COS protects against AF. Male C57BL/6 mice (8- to 10-week-old) were infused with angiotensin (Ang) II for 3 weeks. Meanwhile, different doses of COS (COS-L: 10 mg/kg, COS-H: 20 mg/kg) were administered to mice by intragastric treatment. The results showed irregular and rapid heart rates in Ang II-treated mice. Moreover, the levels of inflammatory cytokines and fibrotic factors were elevated in mice. COS triggered a reduction of Ang II-induced inflammation and fibrosis, which conferred a protective effect. Mechanistically, mitochondrial dysfunction with mitochondrial respiration inhibition and aberrant ATP levels were observed after Ang II treatment. Moreover, Ang-II-induced excessive reactive oxygen species caused oxidative stress, which was further aggravated by inhibiting Nrf2 nuclear translocation. Importantly, COS diminished these Ang-II-mediated effects in mice. In conclusion, COS attenuated inflammation and fibrosis in Ang-II-treated mice by alleviating mitochondrial dysfunction and oxidative stress. Our findings represent a potential therapeutic option for AF treatment., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Although direct oral anticoagulants' (DOACs) prescriptions have experienced immense growth in the last decade, the proportion of discontinuers is still common yielding an increased risk of ischemic stroke (IS) onset., Aims: We aimed to estimate the association between DOACs discontinuation and risk of IS among patients with non-valvular atrial fibrillation (NVAF)., Methods: We used data from a cohort of new DOACs users, followed patients from the first DOAC prescription date up to IS (index date) and conducted a nested case-control analysis using conditional logistic regression. Adjusted odds ratios, 95% confidence intervals were calculated for discontinuation of DOACs (current use compared with past use). The latter, subdivided among those stopping treatment 3 to 2 months and 6 and 3 months prior to index date. The effect of naïve current users against IS onset compared with non-naïve current users was also evaluated., Results: DOACs discontinuation showed an OR of IS of 1.47 (95% CI: 1.02-2.12); estimates were 2.51 (95% CI: 1.84-3.42) for whom discontinued treatment within months 3 and 2 and 1.43 (95% CI: 0.96-2.13) for those between months 6 and 3 prior to index date. Analyzing DOACs individually, risk of IS associated with past users compared with current users: 1.98 (95% CI: 1.25-3.12) for apixaban, 1.38 (95% CI: 0.40-4.72) for edoxaban, 1.98 (95% CI: 1.24-2.65) for dabigatran and 1.87 (95% CI: 1.26-2.76) for rivaroxaban. Similar results were found when stratified by naïve and non-naïve users., Conclusions: DOACs' discontinuation is associated with higher risk of IS, especially in the second and third months following interruption., (© 2023 John Wiley & Sons Ltd.)

Whether thrombocytopenia substantively increases the risk of hemorrhage associated with anticoagulation in patients with atrial fibrillation (AF) is not established. The purpose of this study was to compare rates of bleeding in patients with AF and thrombocytopenia (platelet count < 100 000/μL) to patients with AF and normal platelet counts (>150 000/μL). We performed a propensity score-matched, retrospective cohort study of adults (n = 1070) with a new diagnosis of AF who received a prescription for an oral anticoagulant between 2015 and 2020. The thrombocytopenia cohort was defined as having at least 2 platelet counts <100 000/μL on separate days in the period spanning the 12 weeks preceding the initiation of anticoagulation to 6 weeks after the initiation of anticoagulation. The primary end point was the 1-year cumulative incidence of major bleeding; secondary end points included clinically relevant bleeding, arterial and venous thrombotic events, and all-cause mortality. Patients with AF and thrombocytopenia experienced a higher 1-year cumulative incidence of major bleeding (13.3% vs 5.7%; P < .0001) and clinically relevant bleeding (24.5% vs 16.7%; P = .005) than the controls. Thrombocytopenia was identified as an independent risk factor for major bleeding (hazard ratio, 2.20; confidence interval, 1.36-3.58; P = .001), with increasing risk based on the severity of thrombocytopenia. The cumulative incidence of arterial thrombosis at 1 year was 3.6% in the group with thrombocytopenia and 1.5% in controls (Gray test, P = .08). These findings suggest that baseline platelet counts are an important biomarker for hemorrhagic outcomes in AF and that the degree of thrombocytopenia is an important factor in determining the level of risk., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Aims: The clinical relevance of common pharmacokinetic interactions with non-vitamin K antagonist oral anticoagulants (NOACs) often remains unclear. Therefore, the impact of P-glycoprotein (P-gp) and CYP3A4 inhibitors and inducers on clinical outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated., Methods and Results: AF patients were included between 2013 and 2019 using Belgian nationwide data. Concomitant use of P-gp/CYP3A4-interacting drugs at the time of NOAC initiation was identified. Among 193 072 NOAC-treated AF patients, 46 194 (23.9%) and 2903 (1.5%) subjects concomitantly used a P-gp/CYP3A4 inhibitor or inducer, respectively. After multivariable adjustment, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding [adjusted hazard ratio (aHR) 1.24, 95% confidence interval (CI) (1.18-1.30)] and all-cause mortality risks [aHR 1.07, 95% CI (1.02-1.11)], but not with thromboembolism in NOAC-treated AF patients. A significantly increased risk of major bleeding was observed with amiodarone [aHR 1.27, 95% CI (1.21-1.34)], diltiazem [aHR 1.28, 95% CI (1.13-1.46)], verapamil [aHR 1.36, 95% CI (1.03-1.80)], ticagrelor [aHR 1.50, 95% CI (1.20-1.87)], and clarithromycin [aHR 1.55, 95% CI (1.14-2.11)]; and in edoxaban [aHR 1.24, 95% CI (1.06-1.45)], rivaroxaban [aHR 1.25, 95% CI (1.16-1.34)], and apixaban users [aHR 1.27, 95% CI (1.16-1.39)], but not in dabigatran users [aHR 1.07, 95% CI (0.94-1.23)]. Concomitant use of P-gp/CYP3A4 inducers (e.g. antiepileptic drugs like levetiracetam) was associated with a significantly higher stroke risk [aHR 1.31, 95% CI (1.03-1.68)], but not with bleeding or all-cause mortality., Conclusion: Concomitant use of P-gp/CYP3A4 inhibitors was associated with higher bleeding and all-cause mortality risks in NOAC users, whereas the use of P-gp/CYP3A4 inducers was associated with higher stroke risks., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Pulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular remodeling that triggers fibrosis and excessive myocardium apoptosis, ultimately facilitating atrial fibrillation (AF). In various rat models, Pinocembrin has anti-fibrotic and anti-apoptotic effects, reducing arrhythmia vulnerability. However, whether pinocembrin alleviates to AF in a PAH model remains unclear. The experiment aims to investigate how pinocembrin affects AF susceptibility in PAH rats and the possible mechanisms involved., Methods: The PAH model was induced by monocrotaline (MCT; i. p. 60 mg/kg). Concurrently, rats received pinocembrin (i.p.50 mg/kg) or saline. Hemodynamics parameters, electrocardiogram parameters, lung H.E. staining, atrial electrophysiological parameters, histology, Western blot, and TUNEL assay were detected., Results: Compared to the control rats, MCT-induced PAH rats possessed prominently enhancive mPAP (mean pulmonary artery pressure), pulmonary vascular remodeling, AF inducibility, HRV, right atrial myocardial fibrosis, apoptosis, atrial ERP, APD, and P-wave duration. Additionally, there were lowered protein levels of Cav1.2, Kv4.2, Kv4.3, and connexin 40 (CX40) in the MCT group in right atrial tissue. However, pinocembrin reversed the above pathologies and alleviated the activity of the Rho A/ROCKs signaling pathway, including the expression of Rho A, ROCK1, ROCK2, and its downstream MYPT-1, LIMK2, BCL-2, BAX, cleaved-caspase3 in right atrial and HL-1 cells., Conclusion: Present data exhibited pinocembrin attenuated atrial electrical, ion-channel, and autonomic remodeling, diminished myocardial fibrosis and apoptosis levels, thereby reducing susceptibility to AF in the MCT-induced PAH rats. Furthermore, we found that pinocembrin exerted inhibitory action on the Rho A/ROCK signaling pathway, which may be potentially associated with its anti-AF effects., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Although older patients with atrial fibrillation are at heightened risk of thromboembolic and bleeding events, their optimal treatment choice remains uncertain., Methods and Results: This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the PubMed, EMBASE, and Cochrane databases for randomized controlled trials that compared thromboembolic or bleeding outcomes between a direct oral anticoagulant (DOAC) and a vitamin K antagonist (VKA) and reported outcomes for patients aged ≥75 years with atrial fibrillation. The efficacy outcome was the composite of stroke and systemic embolism. Safety outcomes included major bleeding, any clinically relevant bleeding, and intracranial hemorrhage. Each DOAC and VKA was compared pairwise in a network meta-analysis. High- and low-dose regimens and factor IIa and Xa inhibitors were also compared. Seven randomized controlled trials were included in the analysis. Stroke and systemic embolism risks did not differ significantly among DOACs. There were no significant differences in major bleeding between each DOAC and VKA. Intracranial hemorrhage risk was significantly lower with dabigatran, apixaban, and edoxaban than with VKA and rivaroxaban, which had similar risks. High-dose regimens led to lower risks of stroke or systemic embolism compared with VKA and low-dose regimens, with both doses having similar bleeding risks., Conclusions: In patients aged ≥75 years with atrial fibrillation, DOACs were associated with fewer thromboembolic events compared with VKA, whereas dabigatran, apixaban, and edoxaban were associated with lower risks of intracranial hemorrhage compared with VKA and rivaroxaban., Registration: URL: www.crd.york.ac.uk/prospero/. Unique identifier: CRD42022329557.

Background: An increased risk of recurrent stroke is noted in patients with atrial fibrillation despite direct oral anticoagulant (DOAC) use. We investigated the efficacy and safety of treatment with each of 4 different DOACs or warfarin after DOAC failure., Methods and Results: We retrospectively analyzed patients with atrial fibrillation with ischemic stroke despite DOAC treatment between January 2002 and December 2016. The different outcomes of patients with DOAC failure were compared, including recurrent ischemic stroke, major cardiovascular events, intracranial hemorrhage and subarachnoid hemorrhage, mortality, and net composite outcomes according to switching to different DOACs or vitamin K antagonist after index ischemic stroke. We identified 3759 patients with DOAC failure. A total of 84 patients experienced recurrent ischemic stroke after switching to different oral anticoagulants, with a total follow-up time of 14 years. Using the vitamin K antagonist group as a reference, switching to any of the 4 DOACs was associated with a 69% to 77% reduced risk of major cardiovascular events (adjusted hazard ratio [aHR], 0.25 [95% CI, 0.16-0.39] for apixaban, 0.23 [95% CI, 0.14-0.37] for dabigatran, 0.23 [95% CI, 0.09-0.60] for edoxaban, and 0.31 [95% CI, 0.21-0.45] for rivaroxaban), and a 69% to 83% reduced risk of net composite outcomes (aHR, 0.25 [95% CI, 0.18-0.35] for apixaban, 0.17 [95% CI, 0.11-0.25] for dabigatran, 0.31 [95% CI, 0.17-0.56] for edoxaban, and 0.31 [95% CI, 0.23-0.41] for rivaroxaban)., Conclusions: In Asian patients with DOAC failure, continuing DOACs after index stroke was associated with fewer undesirable outcomes than switching to a vitamin K antagonist. Alternative pharmacologic and nonpharmacologic strategies warrant investigation.

Background: Oxidative stress is an essential component participating in the development and maintenance of atrial fibrillation (AF). Dapagliflozin, a SGLT2 inhibitor, has been shown to exert cardioprotective effects by ameliorating oxidative stress in multiple heart disease models. However, its potential to attenuate lipopolysaccharide (LPS)-induced myocardial injury in rats remains unknown., Aim: This study aims to investigate the role of dapagliflozin in LPS-induced myocardial injury and the potential mechanisms involved., Methods: Rats were intraperitoneally administered LPS to induce sepsis-like condition. The intervention was conducted with intraperitoneal injection of dapagliflozin or saline 1 h in advance. The effects of dapagliflozin were detected by electrophysiological recordings, western blot, qPCR, ELISA, HE staining, immunohistochemistry and fluorescence. We further validated the mechanism in vitro using HL-1 cells., Results: Dapagliflozin significantly improved LPS-induced myocardial injury, reduced susceptibility to AF, and mitigated atrial tissue inflammatory cell infiltration and atrial myocyte apoptosis. These were correlated with the Nrf2/HO-1 signaling pathway, which subsequently reduced oxidative stress. Subsequently, we used a specific inhibitor of the Nrf2/HO-1 pathway in vitro, reversed the anti-oxidative stress effects of dapagliflozin on HL-1 cells, further confirming the Nrf2/HO-1 pathway's pivotal role in dapagliflozin-mediated cardioprotection., Conclusion: Dapagliflozin ameliorated myocardial injury and susceptibility to AF induced by LPS through anti-oxidative stress, which relied on upregulation of the Nrf2/HO-1 pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: The use of flecainide and propafenone for medical cardioversion of atrial fibrillation (AF) and atrial flutter/intra-atrial reentrant tachycardia (IART) is well-described in adults without congenital heart disease (CHD). Data are sparse regarding their use for the same purpose in adults with CHD and in adolescent patients with anatomically normal hearts and we sought to describe the use of class IC drugs in this population and identify factors associated with decreased likelihood of success., Methods: Single center retrospective cohort study of patients who received oral flecainide or propafenone for medical cardioversion of AF or IART from 2000 to 2022. The unit of analysis was each episode of AF/IART. We performed a time-to-sinus rhythm analysis using a Cox proportional hazards model clustering on the patient to identify factors associated with increased likelihood of success., Results: We identified 45 episodes involving 41 patients. As only episodes of AF were successfully cardioverted with medical therapy, episodes of IART were excluded from our analyses. Use of flecainide was the only factor associated with increased likelihood of success. There was a statistically insignificant trend toward decreased likelihood of success in patients with CHD., Conclusions: Flecainide was more effective than propafenone. We did not detect a difference in rate of conversion to sinus rhythm between patients with and without CHD and were likely underpowered to do so, however, there was a trend toward decreased likelihood of success in patients with CHD. That said, medical therapy was effective in >50% of patients with CHD with AF., (© 2023 Wiley Periodicals LLC.)

Introduction: The best therapeutic strategy for patients with mechanical heart valves (MHVs) having acute ischemic stroke during treatment with vitamin K antagonists (VKAs) remain unclear. Being so, we compared the outcomes for: (i) full dose heparin along with VKA (bridging therapy group) and (ii) restarting VKA without heparin (nonbridging group)., Patients and Methods: For this multicenter observational cohort study, data on consecutive acute ischemic stroke patients with MHV was retrospectively collected from prospective registries. Propensity score matching (PSM) was adopted to adjust for any treatment allocation confounders. The primary outcome was the composite of stroke, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding at 90 days., Results: Overall, 255 out of 603 patients (41.3%) received bridging therapy: 36 (14.1%) had combined outcome, compared with 28 (8.0%) in the nonbridging group (adjusted OR 1.83; 95% CI 1.05-3.18; p  = 0.03). Within the bridging group, 13 patients (5.1%) compared to 12 (3.4%) in the nonbridging group had an ischemic outcome (adjusted OR 1.71; 95% CI 0.84-3.47; p  = 0.2); major bleedings were recorded in 23 (9.0%) in the bridging group and 16 (4.6%) in the nonbridging group (adjusted OR 1.88; 95% CI 0.95-3.73; p  = 0.07). After PSM, 36 (14.2%) of the 254 bridging patients had combined outcome, compared with 23 (9.1%) of 254 patients in the nonbridging group (OR 1.66; 95% CI 0.95-2.85; p  = 0.07)., Conclusion: Acute ischemic stroke patients with MHV undergoing bridging therapy had a marginally higher risk of ischemic or hemorrhagic events, compared to nonbridging patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Paciaroni received honoraria as a member of the speaker bureau of Sanofi-Aventis, Bristol Meyer Squibb, Daiiki Sankyo and Pfizer. Becattini received honoraria as a member of the speaker bureau of Bristol Meyer Squibb and Bayer. Michel received research grant by Swiss National Science Foundation, Swiss Heart Foundation and University of Lausanne. Tsivgoulis has received funding for travel or speaker’s honoraria from Bayer, Pfizer, and Boehringer Ingelheim. He has served on scientific advisory boards for Bayer, Boehringer Ingelheim, and Daiichi Sankyo. Toni has received personal fees from Abbott, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Medtronic, and Pfizer. Caso received honoraria as a member of the speaker bureau of Boehringer Ingelheim, Bayer, and Daiichi Sankyo (all fees were paid to Associazione Ricerca Stroke, Umbria). She received honoraria as consultant or advisory board member of Boehringer Ingelheim, Bayer, Daiichi Sankyo, and Pfizer. Ntaios reports speaker fees/advisory board/ research support from Bayer, Pfizer, Boehringer Ingelheim and Elpen. All fees are paid to his institution. Sacco has received personal fees as speaker or advisor from Abbott, Allergan, Astra Zeneca, Eli Lilly, Lundbeck, Novartis, NovoNordisk, Teva and research grants from Allergan, Novartis, and Uriach. Vanacker received honoraria as a member of the speaker bureau and as advisory board of Boehringer Ingelheim, Bristol Meyer Squibb, Daiichi Sankyo, Medtronic, EG and Pfizer. Del Sette has received honoraria for speaking from Bayer and Boehringer Ingelheim. Zedde received speaking and consulting fees from Daiichi Sankyo, Amicus Therapeutics, Sanofi Genzyme, Abbott, and Takeda. Cappellari has received consulting fees from Boehringer Ingelheim, Pfizer – Bristol Meyer Squibb, and Daiichi Sankyo. Flomin has received personal fees from Boehringer Ingelheim, Bayer and Takeda, grants, personal fees and nonfinancial support from Pfizer, personal fees and nonfinancial support from Sanofi Genzyme. Ornello has received nonfinancial support from Novartis, Allergan, and Teva. Giannopoulos has received funding for travel from Bayer and speaker’s honoraria from Pfizer. Zini has received consulting fees from Boehringer Ingelheim, CSL Behing and Alexion, Astra Zeneca. The other authors report no conflicts.

Amiodarone is an antiarrhythmic drug with a significant adverse effect profile, including neurotoxicity. While ataxia, neuropathy, and tremors are more commonly seen forms of amiodarone neurotoxicity, very few cases of nystagmus are reported. We report the case of an 86-year-old man who presented with abrupt-onset ataxia, dizziness, and inability to ambulate, 10 days after initiating amiodarone for atrial fibrillation. His examination revealed gaze-evoked nystagmus along with features of cerebellar dysfunction. After excluding other etiologies, amiodarone was stopped. His nystagmus resolved, and his ataxia improved within 48 h of stopping amiodarone. Due to the rarity of this drug-induced adverse effect, we performed a systematic review of available case reports in the literature (PubMed and Scopus) using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and presented our findings. Nystagmus is a rarely reported adverse effect of amiodarone, which can occur within days to months of starting the medication. Treatment includes stopping the drug and monitoring for resolution of nystagmus., (© 2023, The American College of Clinical Pharmacology.)

The disparities in atrial fibrillation (AF) care are partially attributed to inadequate access to providers with specialized training in AF. Primary care providers (PCPs) are often the sole providers of AF care in under-resourced regions. As such, we sought to create a virtual education intervention for PCPs and to evaluate its impact on the use of stroke risk reduction strategies in patients with AF. A multidisciplinary team mentored PCPs on AF management over 6 months using a virtual case-based training format. Surveys of participant knowledge and confidence in AF care were compared before and after the intervention. Hierarchical logistic regression modeling was used to evaluate change in oral anticoagulation (OAC) therapy in the patients seen by participants before or after training. Of 41 participants trained, 49% worked in family medicine, 41% internal medicine, and 10% general cardiology. Participants attended a mean of 14 1-hour sessions. Overall, the appropriate use of OAC (for CHA 2 DS 2 -VASc score ≥1 man, ≥2 women) increased from 37% to 46% (p <0.001) comparing the patients seen before (n = 1,739) versus after (n = 610) intervention. The factors independently associated with appropriate OAC use included participant training (odds ratio [OR] 1.4, p = 0.002) and participant competence in AF management. The factors associated with decreased OAC use included patient age (OR 0.8 per 10 year, p = 0.008) and nonwhite race (OR 0.7, p = 0.028). Provider knowledge and confidence in AF care improved (p <0.001). In conclusion, we show that a virtual PCP training intervention improves the use of stroke risk reduction therapy in outpatients with AF and could be a widely scalable intervention to improve AF care in under-resourced communities., Competing Interests: Declaration of Competing Interest Dr. Gehi reports financial support was provided by Bristol-Myers Squibb Foundation. Anil Gehi reports a relation with Abbott that includes consulting or advisory. Dr. Gehi reports a relation with ZOLL Medical Corporation that includes consulting or advisory. Dr. Gehi reports a relation with iRhythm Technologies Inc that includes consulting or advisory. Dr. Sears reports a relation with Medtronic that includes consulting or advisory. Dr. Sears reports a relation with Abbott that includes consulting or advisory. Dr. Sears reports a relation with Milestone Pharmaceuticals that includes consulting or advisory. Dr. Sears reports a relation with BIOTRONIK Inc that includes speaking and lecture fees. Dr. Sears reports a relation with ZOLL Medical Corporation that includes speaking and lecture fees. Dr. Rosman reports a relation with National Heart Lung and Blood Institute that includes funding grants. Dr. Rosman reports a relation with Pfizer that includes consulting or advisory. Dr. Rosman reports a relation with BIOTRONIK Inc. that includes consulting or advisory. Dr. Walker reports a relation with Bristol-Myers Squibb Foundation that includes funding grants. The remaining authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Brugada syndrome (BrS) is an inherited disease associated with an increased risk of ventricular arrhythmias. Recent studies have reported the presence of an altered atrial phenotype characterized by abnormal P-wave parameters. The aim of this study was to identify BrS based exclusively on P-wave features through an artificial intelligence (AI)-based model., Methods and Results: Continuous 5 min 12-lead ECG recordings were obtained in sinus rhythm from (i) patients with spontaneous or ajmaline-induced BrS and no history of AF and (ii) subjects with suspected BrS and negative ajmaline challenge. The recorded ECG signals were processed and divided into epochs of 15 s each. Within these epochs, P-waves were first identified and then averaged. From the averaged P-waves, a total of 67 different features considered relevant to the classification task were extracted. These features were then used to train nine different AI-based supervised classifiers. A total of 2228 averaged P-wave observations, resulting from the analysis of 33 420 P-waves, were obtained from 123 patients (79 BrS+ and 44 BrS-). Averaged P-waves were divided using a patient-wise split, allocating 80% for training and 20% for testing, ensuring data integrity and reducing biases in AI-based model training. The BrS+ patients presented with longer P-wave duration (136 ms vs. 124 ms, P < 0.001) and higher terminal force in lead V1 (2.5 au vs. 1.7 au, P < 0.01) compared with BrS- subjects. Among classifiers, AdaBoost model had the highest values of performance for all the considered metrics, reaching an accuracy of over 81% (sensitivity 86%, specificity 73%)., Conclusion: An AI machine-learning model is able to identify patients with BrS based only on P-wave characteristics. These findings confirm the presence of an atrial hallmark and open new horizons for AI-guided BrS diagnosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

To assess whether Roberts' age-adjusted warfarin loading protocol is effective in Chinese patients and whether the SAMeTT2R2 score can predict international normalized ratio (INR) control. Roberts' protocol for warfarin titration was applied to patients with non-valvular atrial fibrillation (NVAF) complicated with ischemic stroke at the Department of Neurology between 2014 and 2019. Clinical and sociodemographic variables were recorded. A minimum of 1-year follow-up was used to calculate the time in therapeutic range (TTR) of the INR. A total of 94 acute ischemic stroke patients with NVAF were included in the study. Seventy-seven (81.9%) of the patients had attained stable INR (2.0-3.0) at the fifth dose, and 90.0% of the patients had achieved stable INR on the ninth day. Seventeen (18.1%) of the patients had an INR > 4 during dose-adjustment period. Patients with INR > 4 had significantly lower body weight (53.8 vs. 63.1 kg, P = 0.014), lower rate of achievement of stable INR (35.3% vs. 92.2%, P = 0.000), and lower rate of TTR ≥ 65% (23.5% vs. 70.1%, P = 0.001), but with no significant increase in bleeding risk. A total of 89 patients underwent long-term INR follow-up, of which 58 (65.2%) patients achieved TTR ≥ 65%. Patients with poor TTR had significantly lower body weight (56.3 vs. 63.7 kg, P = 0.020) and lower rate of stable INR achievement (64.5% vs. 89.7%, P = 0.002). All 94 patients had SAMeTT2R2 score ≥ 2. There was no linear association between SAMeTT2R2 score and the rate of TTR ≥ 65% (P trend  = 0.095). Chinese ischemic stroke patients with NVAF on warfarin can safely and quickly achieve therapeutic INR using Roberts' age-adjusted protocol and can obtain a good TTR. Lower body weight may be a predictor of poor TTR and INR > 4. Patients who have not attained stable INR after adjusting the dose five times are at high risk for poor TTR. SAMeTT2R2 score may not predict TTR in Chinese ischemic stroke patients with NVAF., (© 2023. Springer Nature Limited.)

Both unhealthy lifestyle factors and ambient air pollution have been closely linked with the risk of atrial fibrillation (AF). We retrieved 250,898 participants without AF at baseline from UK Biobank. LE8 was determined by 8 metrics, and was characterized as low, moderate and high cardiovascular health (CVH). Exposure to PM 2.5 was estimated at the geocoded residential address of each participant. During a median follow-up of 12.46 years, we identified 14,743 (5.9%) incident AF cases. Participants with moderate and high CVH showed a decreased risk of incident AF compared to those with low CVH. Of the LE8 metrics, ideal body mass index (BMI) and blood pressure (BP) were associated with a decrease of 11.57% and 11.46% AF cases. High PM 2.5 exposure was associated with an 8% increased risk of AF as compared to low PM 2.5 exposure. Compared with those who had low CVH and high PM 2.5 exposure, participants with a high CVH and low PM 2.5 exposure had the lower AF incidence. Our study found higher CVH is protective, while higher PM 2.5 might be one risk factor of AF. Adherence to the LE8 guidelines may help reduce the incidence of AF, especially in those with lower PM 2.5 exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cartilage oligomeric matrix protein (COMP) regulates transforming growth factor-β (TGF-β) signaling pathway, which has been proved to be associated with skin fibrosis and pulmonary fibrosis. Atrial fibrosis is a major factor of atrial fibrillation (AF). Nevertheless, the interaction between COMP and TGF-β as well as their role in AF remains undefined. The purpose of this study is to clarify the role of COMP in AF and explore its potential mechanism. The hub gene of AF was identified from two datasets using bioinformatics. Furthermore, it was verified by the downregulation of COMP in angiotensin-II (Ang-II)-induced AF in mice. Moreover, the effect on AF was examined using CCK8 assay, ELISA, and western blot. The involvement of TGF-β pathway was further discussed. The expression of COMP was the most significant among all these hub genes. Our experimental results revealed that the protein levels of TGF-β1, phosphorylated Smad2 (P-Smad2), and phosphorylated Smad3 (P-Smad3) were decreased after silencing COMP, which indicated that COMP knockdown could inhibit the activation of TGF-β pathway in AF cells. However, the phenomenon was reversed when the activator SRI was added. COMP acts as a major factor and can improve Ang-II-induced AF via TGF-β signaling pathway. Thus, our research enriches the understanding of the interaction between COMP and TGF-β in AF, and provides reference for the pathogenesis and diagnosis of AF., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)