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The loss of semaphorin 3A (Sema3A), which is related to endothelial-to-mesenchymal transition (EndMT) in atrial fibrosis, is implicated in the pathogenesis of atrial fibrillation (AF). To explore the mechanisms by which EndMT affects atrial fibrosis and assess the potential of a Sema3A activator (naringin) to prevent atrial fibrosis by targeting transforming growth factor-beta (TGF-β)-induced EndMT, we used human atria, isolated human atrial endocardial endothelial cells (AEECs), and used transgenic mice expressing TGF-β specifically in cardiac tissues (TGF-β transgenic mice). We evaluated an EndMT marker (Twist), a proliferation marker (proliferating cell nuclear antigen; PCNA), and an endothelial cell (EC) marker (CD31) through triple immunohistochemistry and confirmed that both EndMT and EC proliferation contribute to atrial endocardial fibrosis during AF in TGF-β transgenic mice and AF patient tissue sections. Additionally, we investigated the impact of naringin on EndMT and EC proliferation in AEECs and atrial fibroblasts. Naringin exhibited an antiproliferative effect, to which AEECs were more responsive. Subsequently, we downregulated Sema3A in AEECs using small interfering RNA to clarify a correlation between the reduction in Sema3A and the elevation of EndMT markers. Naringin treatment induced the expression of Sema3A and a concurrent decrease in EndMT markers. Furthermore, naringin administration ameliorated AF and endocardial fibrosis in TGF-β transgenic mice by stimulating Sema3A expression, inhibiting EndMT markers, reducing atrial fibrosis, and lowering AF vulnerability. This suggests therapeutic potential for naringin in AF treatment., (© 2024 Wiley Periodicals LLC.)

We aimed to identify serum exosomal microRNAs (miRNAs) associated with the transition from atrial fibrillation (AF) to sinus rhythm (SR) and investigate their potential as biomarkers for the early recurrence of AF within three months post-treatment. We collected blood samples from eight AF patients at Chang Gung Memorial Hospital in Taiwan both immediately before and within 14 days following rhythm control treatment. Exosomes were isolated from these samples, and small RNA sequencing was performed. Using DESeq2 analysis, we identified nine miRNAs (16-2-3p, 22-3p, 23a-3p, 23b-3p, 125a-5p, 328-3p, 423-5p, 504-5p, and 582-3p) associated with restoration to SR. Further analysis using the DIABLO model revealed a correlation between the decreased expression of miR-125a-5p and miR-328-3p and the early recurrence of AF. Furthermore, early recurrence is associated with a longer duration of AF, presumably indicating a more extensive state of underlying cardiac remodeling. In addition, the reads were mapped to mRNA sequences, leading to the identification of 14 mRNAs ( AC005041.1 , ARHGEF12 , AMT , ANO8 , BCL11A , DIO3OS , EIF4ENIF1 , G2E3-AS1 , HERC3 , LARS , NT5E , PITX1 , SLC16A12 , and ZBTB21 ) associated with restoration to SR. Monitoring these serum exosomal miRNA and mRNA expression patterns may be beneficial for optimizing treatment outcomes in AF patients.

Atrial fibrosis is an essential contributor to atrial fibrillation (AF). It remains unclear whether atrial endocardial endothelial cells (AEECs) that undergo endothelial-mesenchymal transition (EndMT) are among the sources of atrial fibroblasts. We studied human atria, TGF-β-treated human AEECs, cardiac-specific TGF-β-transgenic mice, and heart failure rabbits to identify the underlying mechanism of EndMT in atrial fibrosis. Using isolated AEECs, we found that miR-181b was induced in TGF-β-treated AEECs, which decreased semaphorin 3A (Sema3A) and increased EndMT markers, and these effects could be reversed by a miR-181b antagomir. Experiments in which Sema3A was increased by a peptide or decreased by a siRNA in AEECs revealed a mechanistic link between Sema3A and LIM-kinase 1/phosphorylated cofilin (LIMK/p-cofilin) signaling and suggested that Sema3A is upstream of LIMK in regulating actin remodeling through p-cofilin. Administration of the miR-181b antagomir or recombinant Sema3A to TGF-β-transgenic mice evoked increased Sema3A, reduced EndMT markers, and significantly decreased atrial fibrosis and AF vulnerability. Our study provides a mechanistic link between the induction of EndMT by TGF-β via miR-181b/Sema3A/LIMK/p-cofilin signaling to atrial fibrosis. Blocking miR-181b and increasing Sema3A are potential strategies for AF therapeutic intervention.

Aldehyde dehydrogenase 2 (ALDH2) is an enzyme that detoxifies reactive oxygen species (ROS)-generated aldehyde adducts such as 4-hydroxy-trans-2-nonenal (4-HNE). Previous meta-analyses have shown an increase in the risk of atrial fibrillation (AF) in patients with chronic alcohol consumption. ALDH2*2 , a common dysfunctional polymorphism in the ALDH2 gene, has been linked to an increased risk of cancer and heart disease. We tested the effect of ALDH2 deficiency on alcohol-induced AF in a murine model of chronic-binge ethanol feeding, with ALDH2*2 knock-in (KI) mice generated by a CRISPR/CAS9 system. In addition, right atrial appendages were obtained from eight patients with AF undergoing open heart surgery. The results showed that burst atrial pacing induced a greater susceptibility to AF in ALDH2*2 KI mice exposed to chronic ethanol intoxication than in wild-type mice, resulting from a higher degree of 4-HNE accumulation and collagen deposition in their atria. Alda-1 attenuated transforming growth factor beta 1 (TGF-β1) expression and collagen deposition in the atria and reduced AF inducibility. Patients with AF and the ALDH2*2 allele exhibited greater oxidative stress and substrate remodeling in their atria than non-carriers. In conclusion, ALDH2 deficiency may increase the risk of chronic alcohol and tachypacing-induced AF through the accumulation of 4-HNE and increased ROS production.

Atrial fibrillation (AF) is associated with oxidative stress and Ca 2+ -handling abnormalities in atrial myocytes. Our prior study has demonstrated the involvement of CD44, a membrane receptor for hyaluronan (HA), in the pathogenesis of AF. This study further evaluated whether CD44 and its related signaling mediate atrial tachycardia-induced oxidative stress and Ca 2+ -handling abnormalities. Tachypacing in atrium-derived myocytes (HL-1 cell line) induced the activation of CD44-related signaling, including HA and HA synthase (HAS) expression. Blocking HAS/HA/CD44 signaling attenuated tachypacing-induced oxidative stress (NADPH oxidase [NOX] 2/4 expression) and Ca 2+ -handling abnormalities (oxidized Ca 2+ /calmodulin-dependent protein kinase II [ox-CaMKII] and phospho-ryanodine receptor type 2 [p-RyR2] expression) in HL-1 myocytes. Furthermore, a direct association between CD44 and NOX4 was documented in tachy-paced HL-1 myocytes and atrial tissues from AF patients. In vitro, Ca 2+ spark frequencies in atrial myocytes isolated from CD44 -/- mice were lower than those from wild-type mice. Furthermore, administration of an anti-CD44 blocking antibody in atrial myocytes isolated from wild-type mice diminished the frequency of Ca 2+ spark. Ex vivo tachypacing models of CD44 -/- mice exhibited a lower degree of oxidative stress and expression of ox-CaMKII/p-RyR2 in their atria than those of wild-type mice. In vivo, burst atrial pacing stimulated a less inducibility of AF in CD44 -/- mice than in wild-type mice. In conclusion, atrial tachypacing-induced Ca 2+ -handling abnormalities are mediated via CD44/NOX4 signaling, which provides a possible explanation for the development of AF., (Copyright © 2019. Published by Elsevier Ltd.)

Objective: The aim of this study was to explore the relationship between perioperative right ventricular (RV) function and postoperative atrial fibrillation (POAF) in the context of cardiac surgery., Design: Prospective, observational study., Setting: A single medical center setting., Participants: The study comprised 92 patients undergoing elective cardiac surgery., Interventions: None., Measurements and Main Results: Consecutive patients without previous history of atrial fibrillation referred for cardiac surgery were enrolled prospectively. Comprehensive transesophageal echocardiography was recorded at the following 2 specific timeframes: before sternotomy (T1) and after sternal closure (T2). Four RV measurements, including RV global longitudinal strain (RVGLS), were performed offline. POAF was defined as any sustained episode of atrial fibrillation recorded within 14 days postoperatively. Ninety-two patients (mean age 61.2 ± 10.8 yr, 63 men) were included in this study; 25 patients (27%) experienced POAF, with a median occurrence of 3 days after cardiac surgery. Multivariable logistic regression models demonstrated that RVGLS T1 (odds ratio 1.13, p = 0.047) and RVGLS T2 (odds ratio 1.38, p = 0.001) were associated independently with POAF. However, changes in RV indices were not correlated to POAF. The optimal cutoff points obtained from the receiver operating characteristic curve analysis were as follows: -16.7% of RVGLS T1 (positive likelihood ratio 2.21, negative likelihood ratio 0.59) and -16.1% of RVGLS T2 (positive likelihood ratio 2.68, negative likelihood ratio 0.38)., Conclusions: RV dysfunction is associated significantly with the occurrence of POAF in the context of cardiac surgery, and perioperative RVGLS measured using transesophageal echocardiography is a useful index to predict POAF in patients referred for cardiac surgery., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Inducible nitric oxide synthase (iNOS) plays an important role in the pathogenesis of atrial fibrillation (AF). The iNOS promoter has a CCTTT-repeat length polymorphism that can determine the level of gene transcription. This study enrolled 200 AF patients and 240 controls. The length of CCTTT-repeat polymorphism in the iNOS promoter region was examined by polymerase chain reactions, with the alleles with ≤11 repeats designated as S and alleles with ≥12 repeats designated as L alleles. AF patients carried significantly higher frequencies of the LL genotype than control subjects (40.0% versus 28.3%, P = 0.010). Multivariate analysis showed that the presence of LL genotype was significantly associated with AF (odds ratio: 1.87, 95% CI = 1.10-3.17, P = 0.021). In vitro, transient transfection assay in HL-1 atrial myocytes showed that the responsiveness of iNOS transcriptional activity to tachypacing was correlated with the length of the CCTTT-repeats. Right atrial tissues from patients with chronic AF were investigated with immunoconfocal microscopy. Patients with LL genotype exhibited greater oxidative stress and substrate remodeling in their atria than those with non-LL genotypes. Our results suggest that the iNOS microsatellite polymorphism may contribute to the genetic background of AF in Chinese-Taiwanese patients.

Background: Atrial fibrillation (AF) causes atrial remodeling, and the left atrium (LA) is the favored substrate for maintaining AF. It remains unclear if AF remodels both atria differently and contributes to LA arrhythmogenesis and thrombogenesis. Therefore, we wished to characterize the transcript profiles in the LA and right atrium (RA) in sinus rhythm (SR) and AF respectively., Methods: Paired LA and RA appendages acquired from patients receiving cardiac surgery were used for ion-channel- and whole-exome-based transcriptome analysis. The ultrastructure was evaluated by immunohistochemistry., Results: Twenty-two and twenty ion-channels and transporters were differentially expressed between the LA and RA in AF and SR, respectively. Among these, 15 genes were differentially expressed in parallel between AF and SR. AF was associated with increased LA/RA expression ratio in 9 ion channel-related genes, including genes related to calcium handling. In microarray, AF was associated with a differential LA/RA gene expression ratio in 309 genes, and was involved in atherosclerosis-related signaling. AF was associated with the upregulation of thrombogenesis-related genes in the LA appendage, including P2Y12, CD 36 and ApoE. Immunohistochemistry showed higher expressions of collagen-1, oxidative stress and TGF-β1 in the RA compared to the LA., Conclusions: AF was associated with differential LA-to-RA gene expression related to specific ion channels and pathways as well as upregulation of thrombogenesis-related genes in the LA appendage. Targeting the molecular mechanisms underlying the LA-to-RA difference and AF-related remodeling in the LA appendage may help provide new therapeutic options in treating AF and preventing thromboembolism in AF., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: It is difficult to achieve rhythm control in patients with long-standing persistent atrial fibrillation (AF). The radiofrequency maze procedure is an effective means in curing AF with a variable recurrence rate depending on patient characteristics and AF duration. In these patients, the characteristics of the atrial substrate have not been well investigated. Because the inflammatory process has been shown to be important in the pathogenesis of AF, we sought to characterize the proinflammatory gene expression in left atria obtained from patients with AF undergoing mitral valve surgery combined with the maze procedure to distinguish the changes associated with AF and its recurrence after the surgical ablation., Methods: Left atrial appendages from 35 patients receiving mitral valve surgery were used for study. Ten patients had sinus rhythm (SR) and 25 patients had persistent AF for more than 1 year and underwent the maze procedure. Among the AF patients, 13 patients remained in SR (AF-SR) and 12 patients had recurrent AF during the 1-year clinical follow-up (AF-AF). The nCounter Human Inflammation Array (NanoString Technologies, Seattle, Wash) was used for evaluating proinflammatory gene expression. Quantitative polymerase chain reaction, Western blot, and immunohistochemistry were applied for studying messenger RNA and protein expression., Results: Of 144 expressed proinflammatory genes, the inflammation array analysis revealed that 32 genes were differentially expressed between AF (including AF-SR and AF-AF) and SR. Thirteen genes were differentially expressed between AF-SR and AF-AF. The array and quantitative polymerase chain reaction produced parallel results in analyzing the expression of particular genes. Concordant with the gene expression difference between AF and SR patients, rapid pacing increased the expressions of SHC1, RHOA, PDGFA, and TRAF2 in HL-1 myocytes, implicating a causative effect of tachyarrhythmia on these genes. Compared with AF-SR, AF-AF expressed more intense oxidative stress, upregulations of collagen, transforming growth factor beta 1, and intranuclear nuclear factor of activated T-cells. Regression analysis showed that increased left atrial diameter was associated with the expression of RHOA and STAT1., Conclusions: Differential expression profiles of proflammatory genes were presented between SR and AF and between maintained SR and recurrent AF after the maze procedure. The identified inflammatory molecules associated with AF and failed surgical ablation may provide clues for developing new potential therapeutic targets to improve AF rhythm control., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Matrix metalloproteinase (MMP) plays an important role in the pathogenesis of atrial fibrillation (AF). The MMP9 promoter has a functional polymorphism rs3918242 that can regulate the level of gene transcription. This study recruited 200 AF patients and 240 controls. The MMP9 rs3918242 was examined by polymerase chain reactions. HL-1 atrial myocytes were cultured and electrically stimulated. Right atrial appendages were obtained from six patients with AF and three controls with sinus rhythm undergoing open heart surgery. The MMP9 expression and activity were determined using immunohistochemical analysis and gelatin zymography, respectively. Rapid pacing induces MMP9 secretion from HL-1 myocytes in a time- and dose-dependent manner. The responsiveness of MMP9 transcriptional activity to tachypacing was significantly enhanced by rs3918242. The expression of MMP9 was increased in fibrillating atrial tissue than in sinus rhythm. However, the distribution of rs3918242 genotypes and allele frequencies did not significantly differ between the control and AF groups. HL-1 myocyte may secrete MMP9 in response to rapid pacing, and the secretion could be modulated by rs3918242. Although the MMP9 expression of human atrial myocyte is associated with AF, our study did not support the association of susceptibility to AF among Taiwanese subjects with the MMP9 rs3918242 polymorphism.

Objectives: Traditional Cox maze III is the gold standard for treatment of atrial fibrillation (AF). Because of its invasiveness, it has been replaced by a simplified procedure involving radiofrequency ablation of modified Cox maze IV. Although the modified Cox maze IV has the advantages of simplicity and less morbidity, a lower rate of sinus rhythm conversion has been reported. We try to establish a scoring system to predict the outcome of this procedure., Methods and Results: The derivation group consisted of 287 patients with structural heart disease and chronic AF who underwent cardiac surgery and modified Cox-maze IV procedure between August 2005 and March 2013. Demographics, clinical and laboratory variables were retrospectively collected as sinus conversional predictors. Overall sinus conversion rate was 75.8%. The parameters of the Soft Markers Scoring system included AF duration, preoperative left atrial (LA) size, rheumatic pathology and postoperative LA remodeling. We compared 80 patients from another hospital between January 2004 and December 2011 as a validation group to evaluate the power of the scoring system. Soft Markers Score indicated a good discriminative power by using the areas under the receiver operating characteristic curve (AUROC: 0.759 ± 0.032). The score was further divided into three groups: low (0-2), intermediate (3-5), and high (6-10), with predicted sinus conversion rates of 92.4%, 74.2%, and 47.8%, respectively., Conclusions: In patients with chronic AF receiving modified Cox-maze IV procedure, the Soft Markers Score demonstrated good discriminative power of predicting sinus recovery in our patients and applied well to the other validation populations.

Background: Atrial fibrillation (AF) is associated with increased oxidative stress. Emerging evidence suggests that heme oxygenase-1 (HO-1) is a potent antioxidant system against various oxidative stress-related diseases. The human HO-1 promoter has a GT-repeat length polymorphism that can determine the level of gene transcription., Objective: The aim of this study is to assess the role of the GT-repeat polymorphism in the promoter region of the HO-1 gene in Chinese-Taiwanese patients with AF., Methods and Results: This study enrolled 200 AF patients and 240 controls, comparable for age and gender. In each subject, the length of GT-repeat polymorphism in the HO-1 promoter region was examined by polymerase chain reactions. The frequencies of long GT-repeat alleles (≧32) were significantly higher in AF patients than in controls. Multivariate analysis showed that the presence of long allele was significantly and independently associated with AF (odds ratio: 1.91, 95% CI 1.07-3.72; P = 0.028). Right atrial tissues from patients with chronic AF were investigated with immunoconfocal microscopy. Patients homozygous for shorter GT-repeat alleles exhibited greater HO-1 expression in their atria than those homozygous for longer alleles, which was reflected by less oxidative stress, myofibril degradation, and fibrosis in the atria of patients with shorter GT-repeat. In vitro, transient transfection assay in HL-1 atrial myocytes showed that the responsiveness of HO-1 transcriptional activity to tachypacing was inversely correlated with the length of the GT-repeats., Conclusion: Our results suggest that the HO-1 microsatellite polymorphism may contribute to the genetic background of AF in Chinese-Taiwanese patients.

Background: Previous studies have demonstrated that atrial regions contribute differently to atrial fibrillation (AF) substrate. Pulmonary vein and the surrounding left atrial junction (LA-PV junction) are crucial areas in AF substrates and important ablation targets., Objective: To identify regional differences in the left atria of patients with AF by using a genome-wide approach., Methods: Paired LA-PV junction and left atrial appendage (LAA) specimens were obtained from 16 patients with persistent AF and 3 with sinus rhythm who underwent valvular surgery. The paired specimens were sent for microarray comparison., Results: Of 54,675 expressed sequence tags, microarray analysis in patients with AF revealed that 391 genes were differentially expressed between the LA-PV junction and the LAA, including genes related to arrhythmia, cell death, fibrosis, hypertrophy, and inflammation. Microarray and real time-polymerase chain reaction produced parallel results in analyzing the expression of particular genes. In both patients with AF and sinus rhythm, the LA-PV junction exhibited greater paired-like homeodomain-2 and its target protein (short stature homeobox-2) expression than the LAA, which might contribute to arrhythmogenesis. Five genes related to thrombogenesis were upregulated in the LAA of patients with AF, which might implicate for the preferential thrombus formation in the LAA. Genes related to fibrosis were highly expressed in the LAA of patients with AF, which was reflected by intense ultrastructural changes in this region., Conclusions: We used a genome-wide approach to investigate region-specific gene expression in the left atria. Our findings provide important information relevant to region-specific arrhythmogenesis and thrombogenesis in AF pathogenesis., (Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Atrial fibrosis is an essential contributor to atrial fibrillation (AF). It remains unclear whether atrial endocardial endothelial cells (AEECs) that undergo endothelial-mesenchymal transition (EndMT) are among the sources of atrial fibroblasts. We studied human atria, TGF-β-treated human AEECs, cardiac-specific TGF-β-transgenic mice, and heart failure rabbits to identify the underlying mechanism of EndMT in atrial fibrosis. Using isolated AEECs, we found that miR-181b was induced in TGF-β-treated AEECs, which decreased semaphorin 3A (Sema3A) and increased EndMT markers, and these effects could be reversed by a miR-181b antagomir. Experiments in which Sema3A was increased by a peptide or decreased by a siRNA in AEECs revealed a mechanistic link between Sema3A and LIM-kinase 1/phosphorylated cofilin (LIMK/p-cofilin) signaling and suggested that Sema3A is upstream of LIMK in regulating actin remodeling through p-cofilin. Administration of the miR-181b antagomir or recombinant Sema3A to TGF-β-transgenic mice evoked increased Sema3A, reduced EndMT markers, and significantly decreased atrial fibrosis and AF vulnerability. Our study provides a mechanistic link between the induction of EndMT by TGF-β via miR-181b/Sema3A/LIMK/p-cofilin signaling to atrial fibrosis. Blocking miR-181b and increasing Sema3A are potential strategies for AF therapeutic intervention. [ABSTRACT FROM AUTHOR]