Identification of key differentially expressed immune related genes in patients with persistent atrial fibrillation: an integrated bioinformation analysis.

OBJECTIVE: We aimed to investigate key differentially expressed immune related genes in persistent atrial fibrillation. METHODS: Gene expression profiles were downloaded from Gene Expression Omnibus (GEO) using "GEO query" package. "limma" package and "sva" package were used to conduct normalization and eliminate batch effects, respectively. We screened out differentially expressed genes (DEGs) based on "limma" package with the standard of |log fold change (FC)| ≥ 1.5 and false discovery rate (FDR) < 0.05. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed by "clusterProfler" package. We further applied LASSO to select key DEGs, and intersected key DEGs with immune related genes from ImmPort database. The ROC curve of each DEIRG was constructed to evaluate its diagnostic efficiency for AF. RESULTS: A total of 103 DEGs we were screened out, of them, 48 genes were down-regulated and 55 genes were up-regulated. Result of functional enrichment analysis show that, most of DEGs were related to immune response, inflammation, and oxidative stress. Ultimately, CYBB, RORB, S100A12, and CHGB were determined as key DEIRGs, each of which displayed a favor efficiency for diagnosing persistent AF. CONCLUSION: CYBB, RORB, S100A12, and CHGB were identified as key DEIRGs in persistent AF, and future studies are needed to further explore the underlying roles of CYBB, RORB, S100A12, and CHGB in persistent AF.

The association between systemic inflammation markers and paroxysmal atrial fibrillation.

BACKGROUND: Systemic inflammation markers have recently been identified as being associated with cardiac disorders. However, limited research has been conducted to estimate the pre-diagnostic associations between these markers and paroxysmal atrial fibrillation (PAF). Our aim is to identify potential biomarkers for early detection of PAF. METHODS: 91 participants in the PAF group and 97 participants in the non-PAF group were included in this study. We investigated the correlations between three systemic inflammation markers, namely the systemic immune inflammation index (SII), system inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI), and PAF. RESULTS: The proportion of patients with PAF gradually increased with increasing logSII, logSIRI, and logAISI tertiles. Compared to those in the lowest tertiles, the PAF risks in the highest logSII and logSIRI tertiles were 3.2-fold and 2.9-fold, respectively. Conversely, there was no significant correlation observed between logAISI and PAF risk within the highest tertile of logAISI. The restricted cubic splines (RCS) analysis revealed a non-linear relationship between the elevation of systemic inflammation markers and PAF risk. Specifically, the incidence of PAF is respectively increased by 56%, 95%, and 150% for each standard deviation increase in these variables. The ROC curve analysis of logSII, logSIRI and logAISI showed that they had AUC of 0.6, 0.7 and 0.6, respectively. It also demonstrated favorable sensitivity and specificity of these systemic inflammation markers in detecting the presence of PAF. CONCLUSIONS: In conclusion, our study reveals significant positive correlations between SII, SIRI, and AISI with the incidence of PAF.

Co-expression and interaction network analysis identifies neutrophil-related genes as the core mediator of atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and can cause serious complications. Several studies have shown that neutrophils may influence AF progression. However, the key genes related to neutrophils in AF have not been fully elucidated. Here, we downloaded microarray expression data of AF, and screened differentially expressed genes. Key immune cells in AF were identified by immune cell infiltration analysis. Weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) analysis were used to construct gene co-expression modules and identify hub genes. The association between key genes and neutrophils was then verified. Our results showed that 303 differentially expressed genes (DEGs) were screened in AF and sinus rhythm (SR), of which 194 were up-regulated and 109 were down-regulated. DEGs were mainly enriched in functions and pathways of neutrophil activation and biological functions of neutrophil activation-mediated immune response. Immune infiltration analysis revealed elevated levels of neutrophil infiltration in AF. WGCNA analysis revealed that the modules in dark red were associated with neutrophils. PPI analysis of these modules yielded 10 hub genes. S100A12, FCGR3B and S100A8 are 3 potential key genes related to neutrophils in AF, which are significantly positively correlated with neutrophils. These genes deserve further investigation and may be potential therapeutic targets for AF.

The systemic-immune-inflammation index predicts the recurrence of atrial fibrillation after cryomaze concomitant with mitral valve surgery.

BACKGROUND AND AIMS: Inflammation plays a key role in the initiation and progression of atrial fibrillation (AF). The systemic inflammation indexes are easily evaluated and predict AF development. However, it's role in prediction of recurrence of AF is unknown. We aim to explore the association between the systemic inflammation indexes and recurrence of AF in patients underwent cryoablation (CryoMaze) concomitant with mitral valve surgery. METHODS: We examined systemic inflammation indexes during perioperative period in 122 patients between 2015 and 2018. Systemic inflammation indexes were developed by systemic immune-inflammation index (SII), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocytes to monocytes ratio. Univariate and multivariate analyses were performed to examine the association of each markers with recurrence of AF. RESULTS: Of the 122 patients included in this study, 22 patients (18%) experienced AF recurrence after CryoMaze concomitant with mitral valve surgery. There is no significant difference between each systemic inflammation indexes before surgery and recurrence of AF. In univariate analysis, MLR after surgery 3 days, PLR, MPLR, NLR, SII after surgery 7 days were able to predict recurrence of AF. In multivariate analyses, SII ≥ 1696 independently predicted recurrence (OR, 3.719; 95% CI, 1.417-9.760). Interestingly, baseline SII showed no significant in prediction of recurrence. It was sharply elevated after surgery and dropped slowly. In patients of recurrence, SII after 7 days of surgery increased again. CONCLUSIONS: The raised SII again was associated with an increased risk of the postoperative recurrence of AF and independently predicted the late recurrence of AF after CryoMaze concomitant with mitral valve surgery.

Predictive value of lymphocyte-to-monocyte ratio in critically Ill patients with atrial fibrillation: A propensity score matching analysis.

BACKGROUND: Inflammation plays a key role in the initiation and progression of atrial fibrillation (AF). Lymphocyte-to-monocyte ratio (LMR) has been proved to be a reliable predictor of many inflammation-associated diseases, but little data are available on the relationship between LMR and AF. We aimed to evaluate the predictive value of LMR in predicting all-cause mortality among AF patients. METHODS: Data of patients diagnosed with AF were retrieved from the Medical Information Mart for Intensive Care-III (MIMIC-III) database. X-tile analysis was used to calculate the optimal cutoff value for LMR. The Cox regression model was used to assess the association of LMR and 28-day, 90-day, and 1-year mortality. Additionally, a propensity score matching (PSM) method was performed to minimize the impact of potential confounders. RESULTS: A total of 3567 patients hospitalized with AF were enrolled in this study. The X-tile software indicated that the optimal cutoff value of LMR was 2.67. A total of 1127 pairs were generated, and all the covariates were well balanced after PSM. The Cox proportional-hazards model showed that patients with the low LMR (≤2.67) had a higher 1-year all-cause mortality than those with the high LMR (>2.67) in the study cohort before PSM (HR = 1.640, 95% CI: 1.437-1.872, p < 0.001) and after PSM (HR = 1.279, 95% CI: 1.094-1.495, p = 0.002). The multivariable Cox regression analysis for 28-day and 90-day mortality yielded similar results. CONCLUSIONS: The lower LMR (≤2.67) was associated with a higher risk of 28-day, 90-day, and 1-year all-cause mortality, which might serve as an independent predictor in AF patients.

The impact of CD4+CD28null T lymphocytes on atrial fibrillation: a potential pathophysiological pathway.

INTRODUCTION: Atrial fibrillation (AF) represents the most common cardiac arrhythmia in daily clinical practice and substantially impacts affected patients by elevation of both morbidity and mortality. Previous investigations proved that inflammatory processes are closely linked to this multifactorial pathogenesis-especially autoreactive CD4+CD28null T cells received in-depth attention. PURPOSE: Consequently, a potential pathophysiological pathway of the impact of CD4+CD28null T lymphocytes on the development and progression AF can be outlined. CONCLUSION: Considering the available data in the literature, it needs to be assumed that CD4+CD28null T lymphocytes are mainly involved in the development of AF and disease progression. Of utmost importance, it can be considered as the result of a T-cell-mediated auto-immune reaction among myocardial tissue. However, mechanisms which recruit CD4+CD28null cells in cardiac tissue remain unclear and need further investigation.

Comprehensive analysis of autophagy-related genes and patterns of immune cell infiltration in valvular atrial fibrillation.

BACKGROUND: The development of atrial fibrillation (AF) following valvular heart disease (VHD) remains a common disease and is associated with substantial adverse complications. However, valid molecular diagnostic and therapeutic tools for post-VHD AF have not been fully established. This study was conducted to discover the molecular mechanisms and immune microenvironment underlying AF following VHD. METHODS: Gene expression profiles of the GSE41177 dataset were assessed to construct a protein-protein interaction network, and then, autophagy-related hub genes were identified. In addition, to determine the functions of immune cell infiltration in valvular AF, we used the CIBERSORT algorithm to estimate the composition of 22 immune cell types in valvular heart disease. Finally, correlation analysis was carried out to identify the relationship between differentially expressed autophagy-related genes (DEARGs) and significant immune cell subpopulations to reveal potential regulatory pathways. RESULTS: A total of 153 DEARGs were identified in AF-VHD patients compared with controlled donors. Moreover, we screened the top ten hub nodes with the highest degrees through a network analysis. The ten hub nodes were considered hub genes related to AF genesis and progression. Then, we revealed six significant immune cell subpopulations through the CIBERSORT algorithm. Finally, correlation analysis was performed, and six DEARGs (BECN1, GAPDH, ATG7, MAPK3, BCL2L1, and MYC) and three immune cell subpopulations (T cells CD4 memory resting, T cells follicular helper, and neutrophils) were identified as the most significant potential regulators. CONCLUSION: The DEARGs and immune cells identified in our study may be critical in AF development following VHD and provide potential predictive markers and therapeutic targets for determining a treatment strategy for AF patients.

The first case of COVID-19 treated with the complement C3 inhibitor AMY-101.

Acute respiratory distress syndrome (ARDS) is a devastating clinical manifestation of COVID-19 pneumonia and is mainly based on an immune-driven pathology. Mounting evidence suggests that COVID-19 is fueled by a maladaptive host inflammatory response that involves excessive activation of innate immune pathways. While a "cytokine storm" involving IL-6 and other cytokines has been documented, complement C3 activation has been implicated as an initial effector mechanism that exacerbates lung injury in preclinical models of SARS-CoV infection. C3-targeted intervention may provide broader therapeutic control of complement-mediated inflammatory damage in COVID-19 patients. Herein, we report the clinical course of a patient with severe ARDS due to COVID-19 pneumonia who was safely and successfully treated with the compstatin-based complement C3 inhibitor AMY-101.

Atopic dermatitis and risk of atrial fibrillation or flutter: A 35-year follow-up study.

BACKGROUND: Atopic dermatitis is characterized by chronic inflammation, which is a risk factor for atrial fibrillation. OBJECTIVE: To examine the association between hospital-diagnosed atopic dermatitis and atrial fibrillation. METHODS: Using linked population-based Danish registries, we identified persons with an inpatient or outpatient hospital diagnosis of atopic dermatitis during 1977-2013 and a comparison cohort individually matched to the atopic dermatitis cohort. We followed cohorts until death, emigration, atrial fibrillation diagnosis, or end of study (January 1, 2013). We compared 35-year risk of atrial fibrillation and estimated hazard ratios with 95% confidence intervals using Cox regression, adjusting for birth year and sex. We validated 100 atopic dermatitis diagnoses from a dermatologic department through medical record review. RESULTS: We included 13,126 persons with atopic dermatitis and 124,211 comparators and followed them for a median of 19.3 years. The 35-year risk of atrial fibrillation was 0.81% and 0.67%, respectively. The positive predictive value of atopic dermatitis diagnoses was 99%. The hazard ratio was 1.2 (95% confidence interval 1.0-1.6) and remained increased after adjusting for various atrial fibrillation risk factors. LIMITATIONS: Analyses were limited to persons with moderate-to-severe atopic dermatitis, and we had no lifestyle data. CONCLUSION: Patients with hospital-diagnosed atopic dermatitis have a 20% increased long-term risk of atrial fibrillation, but the absolute risk remains low.

Critical inflammatory mechanisms underlying arrhythmias.

During the past few decades, cardiovascular research has increasingly focused on systemic inflammatory mechanisms, particularly in the field of atherosclerosis but also in association with cardiac arrhythmogenesis. Objective inflammatory markers including C­reactive protein and cytokines, also called "biomarkers," seem to serve as predictors of onset and prognosis of cardiac arrhythmias. This review gives an overview of potential mechanisms underlying inflammatory processes and arrhythmias, especially atrial fibrillation, which is the most common sustained arrhythmia in daily clinical routine. The association between inflammatory pathways and cardiac arrhythmia is highly complex and includes direct as well as indirect pathways. While past research into arrhythmia focused on fibrosis, altered action potential properties, and ischemia, novel concepts include coagulation and inflammation in cardiac tissue. The underlying mechanisms are altered electrophysiological properties, including ion channel disturbance, early and late afterdepolarizations, as well as enhanced fibrosis and structural remodeling in cardiomyopathies. These pathophysiological factors favor the occurrence of ectopic pacemakers as well as re-entry tachycardia. Further studies are essential to better understand the main inflammatory signal cascades and the exact proarrhythmic effect of interacting key mediators. This will facilitate the evaluation of future anti-inflammatory therapeutic approaches for arrhythmias, analogous to recent developments in atherosclerosis.

TGFß Is Specifically Upregulated on Circulating CD14++ CD16+ and CD14+ CD16++ Monocytes in Patients with Atrial Fibrillation and Severe Atrial Fibrosis.

BACKGROUND/AIMS: Fibrotic remodeling of the atria plays a key role in the pathogenesis of atrial fibrillation (AF). As little is known about the contribution of circulating monocytes in atrial remodeling and the pathophysiology of AF, we investigated profibrotic factors in different subsets of circulating monocytes obtained from patients with atrial fibrillation undergoing catheter ablation. METHODS: A 3D high density voltage mapping was performed in sinus rhythm to evaluate the extent of low-voltage areas (LVAs) in the atria of 71 patients with persistent AF. Low-voltage was defined as signals of < 0.5mV during sinus rhythm. Prior to ablation, blood was drawn and monocytes were analyzed by FACS. Based on the expression of CD14 and CD16, three subgroups including CD14++ CD16- ('classical'), CD14++ CD16+ ('intermediate'), and CD14+ CD16++ ('non-classical') were analyzed for the expression of TGFb, CD147, and MMP-9, representing pivotal profibrotic pathways in myocardial remodeling. RESULTS: Expression of TGFb was increased in CD14+ monocytes of patients with extensive LVAs compared to patients with a low extend of LVAs. While CD14++ CD16- monocytes showed no difference, CD14++ CD16+ and CD14+ CD16++ monocytes showed a strong increase of TGFb abundance. Although CD147 and MMP-9 are strongly associated with myocardial fibrosis, we found no difference in expression between the two groups in any monocyte subsets. CONCLUSION: TGFb is specifically upregulated on CD14++ CD16+ and CD14+ CD16++ monocytes in patients with extensive LVAs undergoing catheter ablation.

Lower soluble Klotho and higher fibroblast growth factor 23 serum levels are associated with episodes of atrial fibrillation.

AIMS: The proarrhythmic effect of fibroblast growth factor 23 (FGF23) was observed in patients with end stage kidney disease (ESKD). However, there is no data on the role of FGF23 and soluble Klotho (sKlotho) in the pathogenesis of atrial fibrillation (AF) beyond ESKD. The aim of the study was to assess the peripheral vein and left atrial (LA) serum levels of FGF23 and sKlotho along with calcium-phosphates parameters in patients with AF undergoing percutaneous radiofrequency pulmonary vein isolation (PVI). METHODS AND RESULTS: Sixty-nine consecutive patients (mean age: 55.8 ±â€¯9.7 years, F/M: 26/43, CHA2DS2-Vasc: 1.7 ±â€¯1.1) with paroxysmal/persistent AF undergoing PVI were included into the study. Blood samples were taken during PVI - baseline from the peripheral vein, then from the LA immediately after a septal puncture. RESULTS: There were significant differences in the concentrations of peripheral and LA serum sKlotho, intact FGF23 (iFGF23), calcium and phosphates; peripheral FGF23, calcium and phosphates levels were significantly higher, and sKlotho levels were significantly lower than the LA concentrations. Serum sKlotho levels correlated with the CHADS2-VASc score (r = 0.254, p = 0.034) and glucose level (r = 0.300, p = 0.005). Serum sKlotho gradient (LA - peripheral vein) correlated with the baseline AF burden in the Holter monitoring (r = -0.389, p = 0.003). PVI efficacy was confirmed in 52 (75%) patients. There was a significant difference in the iFGF23 gradient between patients with AF and without AF (80.3 vs. -47.6 pg/ml, p = 0.009) in the six-month follow-up. A receiver operating characteristic (ROC) analysis revealed that an iFGF23 gradient >28.7 pg/ml (AUC = 0.742, p = 0.002) was a predictor for AF recurrence. CONCLUSIONS: There is a gradient between the LA and peripheral vein in the markers of calcium-phosphate metabolism in patients undergoing PVI. Lower sKlotho and higher iFGF23 serum levels are associated with episodes of AF. Serum iFGF23 gradient is a potent predictor for the recurrence of AF.

Reduction of atrial fibrillation burden by pulmonary vein isolation leads to a decrease of CD11b expression on inflammatory cells.

Aims: It is hypothesized that inflammation could promote structural and electrical remodelling processes in atrial fibrillation (AF). Atrial infiltration of monocytes and granulocytes has been shown to be dependent on CD11b expression. The aim of this study was to investigate whether treatment of AF by pulmonary vein isolation (PVI) may lead to reduced inflammation, as indicated by a decrease of CD11b expression on monocytes and granulocytes. Methods and results: Flow-cytometric quantification analysis and determination of systemic inflammatory markers of peripheral blood were performed in 75 patients undergoing PVI 1 day before and 6 months after PVI. The extent of activation of monocytes and granulocytes was measured by quantifying the cell adhesion molecule CD11b. The mean expression of CD11b on monocytes (20.9 ± 2.5 vs. 10.2 ± 1.4; P < 0.001) and granulocytes (13.9 ± 1.6 vs. 6.8 ± 0.5; P < 0.001), as well as the relative count of CD11b-positive monocytes (P < 0.05) and CD11b-positive granulocytes (P < 0.01) were significantly reduced when comparing the identical patients before and 6 months after PVI. Systemic inflammatory parameters showed only a declining tendency after 6 months. Patients with unsuccessful PVI and ongoing AF on the day of follow-up showed no decrease in CD11b expression. Conclusions: A significant reduction of CD11b expression on monocytes and granulocytes, as a sign of reduced cellular inflammation, was achieved by treatment of AF using PVI. These data strongly support that AF is not only a consequence of but also a cause for inflammatory processes, which, in turn, may contribute to atrial remodelling.

Toll-Like Receptors 2 and 4 Predict New-Onset Atrial Fibrillation in Acute Myocardial Infarction Patients.

Myocardial infarction (MI) can cause new-onset atrial fibrillation (AF) due to cardiac remodeling. As a recent study has shown, inflammatory factors are closely tied to cell death and survival in myocardial ischemia injury. Toll-like receptors (TLRs) have been shown to participate in the process of myocardial infarction as innate immune factors.The subjects were divided into 3 groups: healthy controls (n = 82), MI patients (n = 84), and AFMI (new-onset atrial fibrillation after myocardial infarction) patients (n = 85). Peripheral blood mononuclear cell (PBMC) TLR mRNA expression was detected by rt-PCR. Western blot was used to analyze PBMC TLRs and their downstream signal protein expression. PBMCs were presented as TLR2 expression or TLR4 expression using flow cytometry.From mRNA to protein detection, PBMC TLR2 and TLR4 were significantly higher in the AFMI group than in the control group and MI group. A similar tendency was also observed in the expression of downstream signaling proteins. When further analyzed with TLR2 and TLR4 antibodies by flow cytometry, PBMC levels also appeared to be higher in AFMI patients than those in MI patients and the healthy control group.In our study, PBMC TLRs and their downstream signaling proteins were significantly higher in the acute myocardial infarction patients with new-onset atrial fibrillation compared with healthy people and acute myocardial infarction patients without new-onset atrial fibrillation. They have the potential to be novel biomarkers for new-onset atrial fibrillation after acute myocardial infarction.

Circulating intermediate CD14++CD16+monocytes are increased in patients with atrial fibrillation and reflect the functional remodelling of the left atrium.

AIMS: A recent large clinical study demonstrated the association between intermediate CD14++CD16+monocytes and cardiovascular events. However, whether that monocyte subset contributes to the pathogenesis of atrial fibrillation (AF) has not been clarified. We compared the circulating monocyte subsets in AF patients and healthy people, and investigated the possible role of intermediate CD14++CD16+monocytes in the pathophysiology of AF. METHODS AND RESULTS: This case-control study included 44 consecutive AF patients without systemic diseases referred for catheter ablation at our hospital, and 40 healthy controls. Patients with systemic diseases, including structural heart disease, hepatic or renal dysfunction, collagen disease, malignancy, and inflammation were excluded. Monocyte subset analyses were performed (three distinct human monocyte subsets: classical CD14++CD16-, intermediate CD14++CD16+, and non-classical CD14+CD16++monocytes). We compared the monocyte subsets and evaluated the correlation with other clinical findings. A total of 60 participants (30 AF patients and 30 controls as an age-matched group) were included after excluding 14 AF patients due to inflammation. Atrial fibrillation patients had a higher proportion of circulating intermediate CD14++CD16+monocytes than the controls (17.0 ± 9.6 vs. 7.5 ± 4.1%, P < 0.001). A multivariable logistic regression analysis demonstrated that only the proportion of intermediate CD14++CD16+monocytes (odds ratio: 1.316; 95% confidence interval: 1.095-1.582, P = 0.003) was independently associated with the presence of AF. Intermediate CD14++CD16+monocytes were negatively correlated with the left atrial appendage flow during sinus rhythm (r= -0.679, P = 0.003) and positively with the brain natriuretic peptide (r = 0.439, P = 0.015). CONCLUSION: Intermediate CD14++CD16+monocytes might be closely related to the pathogenesis of AF and reflect functional remodelling of the left atrium.

Class I Histone Deacetylase Inhibition for the Treatment of Sustained Atrial Fibrillation.

Current therapies are less effective for treating sustained/permanent versus paroxysmal atrial fibrillation (AF). We and others have previously shown that histone deacetylase (HDAC) inhibition reverses structural and electrical atrial remodeling in mice with inducible, paroxysmal-like AF. Here, we hypothesize an important, specific role for class I HDACs in determining structural atrial alterations during sustained AF. The class I HDAC inhibitor N-acetyldinaline [4-(acetylamino)-N-(2-amino-phenyl) benzamide] (CI-994) was administered for 2 weeks (1 mg/kg/day) to Hopx transgenic mice with atrial remodeling and inducible AF and to dogs with atrial tachypacing-induced sustained AF. Class I HDAC inhibition prevented atrial fibrosis and arrhythmia inducibility in mice. Dogs were divided into three groups: 1) sinus rhythm, 2) sustained AF plus vehicle, and 3) sustained AF plus CI-994. In group 3, the time in AF over 2 weeks was reduced by 30% compared with group 2, along with attenuated atrial fibrosis and intra-atrial adipocyte infiltration. Moreover, group 2 dogs had higher atrial and serum inflammatory cytokines, adipokines, and atrial immune cells and adipocytes compared with groups 1 and 3. On the other hand, groups 2 and 3 displayed similar left atrial size, ventricular function, and mitral regurgitation. Importantly, the same histologic alterations found in dogs with sustained AF and reversed by CI-994 were also present in atrial tissue from transplanted patients with chronic AF. This is the first evidence that, in sustained AF, class I HDAC inhibition can reduce the total time of fibrillation, atrial fibrosis, intra-atrial adipocytes, and immune cell infiltration without significant effects on cardiac function.

Mast Cells Play an Important Role in the Pathogenesis of Hyperglycemia-Induced Atrial Fibrillation.

BACKGROUND AND OBJECTIVES: Recently, it was reported that mast cells (MCs) could underlie the mechanisms of several cardiovascular diseases. However, the role of MCs in diabetes-induced atrial fibrillation (AF) has not been notably investigated. We tested the hypothesis that MC deficiency attenuates hyperglycemia-induced AF in mice. METHODS AND RESULTS: Mast cell-deficient W/W(v)  mice, and congenic +/+ littermates (WT) were divided into either the vehicle (VEH)-injection group or the streptozotocin (STZ)-injection group (MCKO-VEH, MCKO-STZ, WT-VEH, and WT-STZ groups). On day 28 of our studies, we observed that (1) STZ-induced hyperglycemia increased MC infiltration in the left atrium (LA) in WT mice (P < 0.01), (2) atrium isolated from the WT-STZ group showed inhomogeneous interstitial fibrosis, abundant infiltration of macrophages, and enhanced apoptosis compared to the WT-VEH group (P < 0.01, P < 0.01, P < 0.05, respectively). However, the changes observed in the WT-STZ group were significantly attenuated in the MCKO-STZ mice. In addition, we observed that (3) messenger RNA levels of tumor necrosis factor-α, monocyte chemoattractant protein-1, interleukin-1ß, transforming growth factor-ß, and collagen-1 in the LA were increased in the WT-STZ group, but not in the MCKO-STZ group, (4) STZ-induced hyperglycemia increased AF induction and prolonged interatrial conduction time in the WT mice, which were not observed in the MCKO mice, and that (5) hyperglycemia-enhanced atrial production of reactive oxygen species (ROS) was equally observed in the WT and MCKO mice. CONCLUSIONS: Our results suggest that MCs contribute to the pathogenesis of hyperglycemia-induced AF via enhancement of inflammation and fibrosis.

Association of ß1-Adrenergic, M2-Muscarinic Receptor Autoantibody with Occurrence and Development of Nonvalvular Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia and is independently associated with increased risk of stroke and death. Although the exact mechanisms of AF are not completely elucidated, a large number of evidences demonstrate that autoimmunity may play an important role in the initiation, the progression, and the maintenance of AF. In this study, we aimed to compare anti-ß1-adrenergic receptor autoantibody (anti-ß1-R) and anti-M2-muscarinic receptor autoantibody (anti-M2-R) levels between nonvalvular AF patients and healthy control subjects. METHODS: The levels of serum anti-ß1-R, antinuclear antibodies, and anti-M2-R were measured in both groups by enzyme-linked immunosorbent assay (ELISA). High-sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6 concentration were measured, respectively, by immunoturbidimetry and chemiluminescence. RESULTS: Anti-ß1-R and anti-M2-R levels were significantly higher in patients with nonvalvular AF than in healthy controls (anti-ß1-R 221.11 [132.38-291.69] ng/mL vs 198.14 [125.70-278.40] ng/mL, P < 0.01; anti-M2-R 271.81 [144.99-378.20] ng/mL vs 235.01 [121.53-358.99] ng/mL, P < 0.01). Compared with the control group, the serum levels of IL-6 and hs-CRP were higher in the nonvalvular AF group (IL-6 19.65 ± 5.6 pg/mL vs 6.79 ± 1.09 pg/mL, hs-CRP 6.03 ± 1.35 mg/L vs 2.73 ± 0.63 mg/L, P < 0.05). Antinuclear antibody (ANA) levels were similar between two groups (ANA 10.55 [1.86-271.8] U/mL vs 10.49 [1.303-161.7] U/mL, P > 0.05). The baseline value of serum anti-ß1-R (odds ratio [OR]: 13.176, P < 0.001), anti-M2-R (OR: 4.41, P < 0.001), IL-6 (OR: 6.126, P < 0.05) levels, and left atrial diameter (OR: 5.781, P < 0.05) were independent predictors of nonvalvular AF by multivariable analyses. CONCLUSION: We found a significant association between circulating serum anti-ß1-R, anti-M2-R, IL-6 levels, and nonvalvular AF. We presume that the autoimmunity and inflammation might take part in electrical remodeling and structural remodeling of left atrium.