Identification of Potential Key Biomarkers of Atrial Fibrillation and Their Correlation with Immune Infiltration in Atrial Tissue.

Objective: To identify potential key biomarkers and characterize immune infiltration in atrial tissue of patients with atrial fibrillation (AF) through bioinformatics analysis. Methods: Differentially expressed genes (DEGs) were identified by the LIMMA package in Bioconductor, and functional and pathway enrichment analyses were undertaken using GO and KEGG. The LASSO logistic regression and BORUTA algorithm were employed to screen for potential novel key markers of AF from all DEGs. Gene set variation analysis was also performed. Single-sample gene set enrichment analysis was employed to quantify the infiltration levels for each immune cell type, and the correlation between hub genes and infiltrating immune cells was analyzed. Results: A total of 52 DEGs were identified, including of 26 downregulated DEGs and 26 upregulated DEGs. DEGs were primarily enriched in the Major Histocompatibility Complex class II protein complex, glucose homeostasis, protein tetramerization, regulation of synapse organization, cytokine activity, heart morphogenesis, and blood circulation. Three downregulated genes and three upregulated genes were screened by LASSO logistic regression and the BORUTA algorithm. Finally, immune infiltration analysis indicated that the atrial tissue of AF patients contained significant infiltration of APC_co_inhibition, Mast_cell, neutrophils, pDCs, T_cell_costimulation, and Th1_cells compared with paired sinus rhythm (SR) atrial tissue, and the three downregulated genes were negatively correlated with the six kinds of immune cells mentioned above. Conclusion: The hub genes identified in this study and the differences in immune infiltration of atrial tissue observed between AF and SR tissue might help to characterize the occurrence and progression of AF.

Ferroportin-mediated ferroptosis involved in new-onset atrial fibrillation with LPS-induced endotoxemia.

Sepsis is a known risk factor for new-onset atrial fibrillation (AF), and previous studies have demonstrated that ferroptosis participates in sepsis-induced organ injury development. Nevertheless, the role of ferroptosis in new-onset AF with sepsis remains largely unknown. This study aims to investigate the underlying mechanisms linking ferroptosis and AF caused by sepsis. LPS-induced endotoxemia is often used to model the acute inflammatory response associated with sepsis. Herein, we reported that ferroptosis was significantly activated in LPS-induced endotoxemia rat model. We also observed that ferroportin (Fpn), the only identified mammalian non-heme iron exporter, was downregulated in the atrium of endotoxemia model. Vulnerability to AF was also significantly increased in a endotoxemia rat model. Additionally, Fpn knockdown by shFpn further increased intracellular iron concentration and oxidative stress and exaggerated the AF vulnerability, which was alleviated by ferroptosis inhibition. Mechanistically, silencing Fpn worsened the alterations in calcium handling proteins expression in a endotoxemia rat model. These findings suggest that Fpn-mediated ferroptosis is involved in the new-onset AF with LPS-induced endotoxemia via worsening the calcium handling proteins dysregulation and provides a novel and promising strategy for preventing AF development in sepsis.

Exercising immune cells: The immunomodulatory role of exercise on atrial fibrillation.

Exercise training is generally beneficial for cardiovascular health, improving stroke volume, cardiac output, and aerobic capacity. Despite these benefits, some evidence indicates that endurance training may increase the risk of atrial fibrillation (AF), particularly in highly trained individuals. Among multiple mechanisms, autonomic tone changes and atrial remodeling have been proposed as main contributors for exercise-induced AF. However, the contribution of local and systemic immunity is poorly understood in the development of atrial arrhythmogenic substrates. Here we aim to update the field of immunomodulation in the context of exercise and AF by compiling and reconciling the most recent evidence from preclinical and human studies and rationalize the applicability of "lone" AF terminology in athletes.

Neutrophil degranulation interconnects over-represented biological processes in atrial fibrillation.

Despite our expanding knowledge about the mechanism underlying atrial fibrillation (AF), the interplay between the biological events underlying AF remains incompletely understood. This study aimed to identify the functionally enriched gene-sets in AF and capture their interconnection via pivotal factors, that may drive or be driven by AF. Global abundance of the proteins in the left atrium of AF patients compared to control patients (n = 3/group), and the functionally enriched biological processes in AF were determined by mass-spectrometry and gene set enrichment analysis, respectively. The data were validated in an independent cohort (n = 19-20/group). In AF, the gene-sets of innate immune system, metabolic process, cellular component disassembly and ion homeostasis were up-regulated, while the gene-set of ciliogenesis was down-regulated. The innate immune system was over-represented by neutrophil degranulation, the components of which were extensively shared by other gene-sets altered in AF. In the independent cohort, an activated form of neutrophils was more present in the left atrium of AF patients with the increased gene expression of neutrophil granules. MYH10, required for ciliogenesis, was decreased in the atrial fibroblasts of AF patients. We report the increased neutrophil degranulation appears to play a pivotal role, and affects multiple biological processes altered in AF.

Morpho-functional changes of cardiac telocytes in isolated atrial amyloidosis in patients with atrial fibrillation.

Telocytes are interstitial cells with long, thin processes by which they contact each other and form a network in the interstitium. Myocardial remodeling of adult patients with different forms of atrial fibrillation (AF) occurs with an increase in fibrosis, age-related isolated atrial amyloidosis (IAA), cardiomyocyte hypertrophy and myolysis. This study aimed to determine the ultrastructural and immunohistochemical features of cardiac telocytes in patients with AF and AF + IAA. IAA associated with accumulation of atrial natriuretic factor was detected in 4.3-25% biopsies of left (LAA) and 21.7-41.7% of right (RAA) atrial appendage myocardium. Telocytes were identified at ultrastructural level more often in AF + IAA, than in AF group and correlated with AF duration and mitral valve regurgitation. Telocytes had ultrastructural signs of synthetic, proliferative, and phagocytic activity. Telocytes corresponded to CD117+, vimentin+, CD34+, CD44+, CD68+, CD16+, S100-, CD105- immunophenotype. No significant differences in telocytes morphology and immunophenotype were found in patients with various forms of AF. CD68-positive cells were detected more often in AF + IAA than AF group. We assume that in aged AF + IAA patients remodeling of atrial myocardium provoked transformation of telocytes into "transitional forms" combining the morphological and immunohistochemical features with signs of fibroblast-, histiocyte- and endotheliocyte-like cells.

Inflammatory cell infiltration in left atrial appendageal tissues of patients with atrial fibrillation and sinus rhythm.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice and is known to be associated with significant morbidity and mortality. Previous studies suggested a link between inflammation and AF by findings of increased inflammatory markers in AF patients. However, it has not been finally clarified whether inflammation is a systemic or a local phenomenon reflecting an active inflammatory process in the heart. To address this subject, human left atrial appendage tissues were obtained from 10 patients who underwent cardiac surgery and subjected to immunohistochemical analysis. The number of inflammatory CD3-positive T cells significantly increased from patients with sinus rhythm to paroxysmal AF and persistent AF, respectively. Interestingly, in patients with persistent AF, these cells were frequently arranged in small clusters. Subsequently, the number of inflammatory CD3-positive T cells decreased and was significantly lower in patients with permanent AF than in patients with persistent AF. Inflammatory CD20-positive B cells could only be detected very occasionally in all AF subgroups and were not locatable in patients with SR. Hence, our data emphasize the potential prominent role of the cellular component of the immune system in the development and perpetuation of AF.

Epitope Mapping of SERCA2a Identifies an Antigenic Determinant That Induces Mainly Atrial Myocarditis in A/J Mice.

Sarcoplasmic/endoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA)2a, a critical regulator of calcium homeostasis, is known to be decreased in heart failure. Patients with myocarditis or dilated cardiomyopathy develop autoantibodies to SERCA2a suggesting that they may have pathogenetic significance. In this report, we describe epitope mapping analysis of SERCA2a in A/J mice that leads us to make five observations: 1) SERCA2a contains multiple T cell epitopes that induce varying degrees of myocarditis. One epitope, SERCA2a 971-990, induces widespread atrial inflammation without affecting noncardiac tissues; the cardiac abnormalities could be noninvasively captured by echocardiography, electrocardiography, and magnetic resonance microscopy imaging. 2) SERCA2a 971-990-induced disease was associated with the induction of CD4 T cell responses and the epitope preferentially binds MHC class II/IAk rather than IEk By creating IAk/and IEk/SERCA2a 971-990 dextramers, the T cell responses were determined by flow cytometry to be Ag specific. 3) SERCA2a 971-990-sensitized T cells produce both Th1 and Th17 cytokines. 4) Animals immunized with SERCA2a 971-990 showed Ag-specific Abs with enhanced production of IgG2a and IgG2b isotypes, suggesting that SERCA2a 971-990 can potentially act as a common epitope for both T cells and B cells. 5) Finally, SERCA2a 971-990-sensitized T cells were able to transfer disease to naive recipients. Together, these data indicate that SERCA2a is a critical autoantigen in the mediation of atrial inflammation in mice and that our model may be helpful to study the inflammatory events that underlie the development of conditions such as atrial fibrillation in humans.

Analysis of immune cell populations in atrial myocardium of patients with atrial fibrillation or sinus rhythm.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia and despite obvious clinical importance remains its pathogenesis only partially explained. A relation between inflammation and AF has been suggested by findings of increased inflammatory markers in AF patients. OBJECTIVE: The goal of this study was to characterize morphologically and functionally CD45-positive inflammatory cell populations in atrial myocardium of patients with AF as compared to sinus rhythm (SR). METHODS: We examined 46 subjects (19 with AF, and 27 in SR) undergoing coronary bypass or valve surgery. Peroperative bioptic samples of the left and the right atrial tissue were examined using immunohistochemistry. RESULTS: The number of CD3+ T-lymphocytes and CD68-KP1+ cells were elevated in the left atrial myocardium of patients with AF compared to those in SR. Immune cell infiltration of LA was related to the rhythm, but not to age, body size, LA size, mitral regurgitation grade, type of surgery, systemic markers of inflammation or presence of diabetes or hypertension. Most of CD68-KP1+ cells corresponded to dendritic cell population based on their morphology and immunoreactivity for DC-SIGN. The numbers of mast cells and CD20+ B-lymphocytes did not differ between AF and SR patients. No foci of inflammation were detected in any sample. CONCLUSIONS: An immunohistochemical analysis of samples from patients undergoing open heart surgery showed moderate and site-specific increase of inflammatory cells in the atrial myocardium of patients with AF compared to those in SR, with prevailing population of monocyte-macrophage lineage. These cells and their cytokine products may play a role in atrial remodeling and AF persistence.

ß1-Adrenergic and M2 Muscarinic Autoantibodies and Thyroid Hormone Facilitate Induction of Atrial Fibrillation in Male Rabbits.

Activating autoantibodies to the ß1-adrenergic and M2 muscarinic receptors are present in a very high percentage of patients with Graves' disease and atrial fibrillation (AF). The objective of this study was to develop a reproducible animal model and thereby to examine the impact of these endocrine-like autoantibodies alone and with thyroid hormone on induction of thyroid-associated atrial tachyarrhythmias. Five New Zealand white rabbits were coimmunized with peptides from the second extracellular loops of the ß1-adrenergic and M2 muscarinic receptors to produce both sympathomimetic and parasympathomimetic antibodies. A catheter-based electrophysiological study was performed on anesthetized rabbits before and after immunization and subsequent treatment with thyroid hormone. Antibody expression facilitated the induction of sustained sinus, junctional and atrial tachycardias, but not AF. Addition of excessive thyroid hormone resulted in induced sustained AF in all animals. AF induction was blocked acutely by the neutralization of these antibodies with immunogenic peptides despite continued hyperthyroidism. The measured atrial effective refractory period as one parameter of AF propensity shortened significantly after immunization and was acutely reversed by peptide neutralization. No further decrease in the effective refractory period was observed after the addition of thyroid hormone, suggesting other cardiac effects of thyroid hormone may contribute to its role in AF induction. This study demonstrates autonomic autoantibodies and thyroid hormone potentiate the vulnerability of the heart to AF, which can be reversed by decoy peptide therapy. These data help fulfill Witebsky's postulates for an increased autoimmune/endocrine basis for Graves' hyperthyroidism and AF.

IL-1 provokes electrical abnormalities in rat atrial myocardium.

Using a micro-electrode technique we studied the effects of interleukin 1α and interleukin 1ß on bio-electric activity of rat atrial myocardium under normal conditions and after gradual stretching. Perfusion with interleukin 1α increased the duration of the action potential at the level of 90% re-polarization. Stretch induced tachy-arrhythmia in the presence of interleukin 1α is mainly regulated via stretch increased nitric oxide production, while the ionotropic effect of the interleukin-1α during stretching is not pronounced. The perfusion with interleukin 1ß did not change the values of the duration of the action potentials at the levels of 25, 50 and 90% repolarization. The interleukin lß caused an appearance of extra-systolic patterns which turned into normal rhythm, alternating with periods of normal activity. The total intracellular nitric oxide level induced by both interleukin 1ß and stretching is balanced by interleukin-1ß induced cation influx.

Mechanisms of persistent atrial fibrillation.

PURPOSE OF REVIEW: Atrial fibrillation is the most common sustained arrhythmia, but its mechanisms are poorly understood. In particular, little is known about the factors that contribute to the establishment of persistent or permanent atrial fibrillation. This review addresses possible common signaling pathways that might promote both structural and electrical remodeling of the atria, thus contributing to atrial fibrillation perpetuation. RECENT FINDINGS: Sustained atrial fibrillation may trigger an inflammatory response leading to activation of myofibroblasts and to the release of cytokines such as transforming growth factor-ß and platelet-derived growth factor, as well as profibrotic proteins such as galectin-3. Activation of signaling cascades involving such proteins is critical for the development of fibrosis and may also lead to ion channel dysfunction, which, along with myocyte apoptosis and extracellular matrix generation and turnover, likely contributes to both electrical and structural remodeling and predisposes to atrial fibrillation. SUMMARY: Identifying upstream strategies targeting molecular pathways that are common to fibrosis and electrical remodeling leading to atrial fibrillation perpetuation is highly desirable. This would facilitate finding new target genes with pleiotropic effects on the expression of ion channel proteins in myocytes and profibrotic molecules in nonmyocyte cells that are important for pathologic remodeling, which could become an important goal in persistent atrial fibrillation therapy.

Development of autoimmune hair loss disease alopecia areata is associated with cardiac dysfunction in C3H/HeJ mice.

Alopecia areata (AA) is a chronic autoimmune hair loss disease that affects several million men, women and children worldwide. Previous studies have suggested a link between autoimmunity, stress hormones, and increased cardiovascular disease risk. In the current study, histology, immunohistology, quantitative PCR (qPCR) and ELISAs were used to assess heart health in the C3H/HeJ mouse model for AA and heart tissue response to adrenocorticotropic hormone (ACTH) exposure. Mice with AA exhibited both atrial and ventricular hypertrophy, and increased collagen deposition compared to normal-haired littermates. QPCR revealed significant increases in Il18 (4.6-fold), IL18 receptor-1 (Il18r1; 2.8-fold) and IL18 binding protein (Il18bp; 5.2-fold) in AA hearts. Time course studies revealed a trend towards decreased Il18 in acute AA compared to controls while Il18r1, Il18bp and Casp1 showed similar trends to those of chronic AA affected mice. Immunohistochemistry showed localization of IL18 in chronic AA mouse atria. ELISA indicated cardiac troponin-I (cTnI) was elevated in the serum and significantly increased in AA heart tissue. Cultures of heart atria revealed differential gene expression between AA and control mice in response to ACTH. ACTH treatment induced significant increase in cTnI release into the culture medium in a dose-dependent manner for both AA and control mice. In conclusion, murine AA is associated with structural, biochemical, and gene expression changes consistent with cardiac hypertrophy in response to ACTH exposure.

Three short perioperative infusions of n-3 PUFAs reduce systemic inflammation induced by cardiopulmonary bypass surgery: a randomized controlled trial.

BACKGROUND: Fish oil (FO) has antiinflammatory effects, which might reduce systemic inflammation induced by a cardiopulmonary bypass (CPB). OBJECTIVE: We tested whether perioperative infusions of FO modify the cell membrane composition, inflammatory responses, and clinical course of patients undergoing elective coronary artery bypass surgery. DESIGN: A prospective randomized controlled trial was conducted in cardiac surgery patients who received 3 infusions of 0.2 g/kg FO emulsion or saline (control) 12 and 2 h before and immediately after surgery. Blood samples (7 time points) and an atrial biopsy (during surgery) were obtained to assess the membrane incorporation of PUFAs. Hemodynamic data, catecholamine requirements, and core temperatures were recorded at 10-min intervals; blood triglycerides, nonesterified fatty acids, glucose, lactate, inflammatory cytokines, and carboxyhemoglobin concentrations were measured at selected time points. RESULTS: Twenty-eight patients, with a mean ± SD age of 65.5 ± 9.9 y, were enrolled with no baseline differences between groups. Significant increases in platelet EPA (+0.86%; P = 0.0001) and DHA (+0.87%; P = 0.019) were observed after FO consumption compared with at baseline. Atrial tissue EPA concentrations were higher after FO than after control treatments (+0.5%; P < 0.0001). FO did not significantly alter core temperature but decreased the postoperative rise in IL-6 (P = 0.018). Plasma triglycerides increased transiently after each FO infusion. Plasma concentrations of glucose, lactate, and blood carboxyhemoglobin were lower in the FO than in the control group on the day after surgery. Arrhythmia incidence was low with no significant difference between groups. No adverse effect of FO was detected. CONCLUSIONS: Perioperative FO infusions significantly increased PUFA concentrations in platelet and atrial tissue membranes within 12 h of the first FO administration and decreased biological and clinical signs of inflammation. These results suggest that perioperative FO may be beneficial in elective cardiac surgery with CPB.

Atrial tachycardia provoked in the presence of activating autoantibodies to ß2-adrenergic receptor in the rabbit.

BACKGROUND: A recent clinical study of patients with inappropriate sinus tachycardia reported that autoantibodies to ß-adrenergic receptors (ß2ARs) could act as agonists to induce atrial arrhythmias. OBJECTIVE: To test the hypothesis that activating autoantibodies to the ß2AR in the rabbit atrium are arrhythmogenic. METHODS: Five New Zealand white rabbits were immunized with a ß2AR second extracellular loop peptide to raise ß2AR antibody titers. A catheter-based electrophysiologic study was performed on anesthetized rabbits before and after immunization. Arrhythmia occurrence was determined in response to burst pacing before and after the infusion of acetylcholine in incremental concentrations of 10 µM, 100 µM, and 1 mM at 1 mL/min. RESULTS: In the preimmune studies when ß2AR antibody titers were undetectable, of a total of 20 events, only 3 episodes of nonsustained (<10 seconds) atrial arrhythmias were induced. In the postimmune studies when ß2AR antibody titers ranged from 1:160,000 to 1:1.28 million, burst pacing induced 10 episodes of nonsustained or sustained (≥10 seconds) arrhythmias in 20 events (P = .04 vs preimmune; χ(2) and Fisher exact test). Taking into account only the sustained arrhythmias, there were 6 episodes in 20 events in the postimmune studies compared with 0 episodes in 20 events in the preimmune studies (P = .02). Immunized rabbits demonstrated immunoglobulin G deposition in the atria, and their sera induced significant activation of ß2AR in transfected cells in vitro compared to the preimmune sera. CONCLUSIONS: Enhanced autoantibody activation of ß2AR in the rabbit atrium leads to atrial arrhythmias mainly in the form of sustained atrial tachycardia.

Programmed cell death-1 deficiency results in atrial remodeling in C57BL/6 mice.

Deficiency of the programmed cell death-1 (PD-1) gene enhances T-cell activation and increases inflammation levels. It has been reported that atrial fibrillation (AF) is closely related to inflammation. The aim of the present study was to investigate the role of PD-1 deficiency in the pathogenesis of AF. Two groups of mice were used in our experiment: the C57BL/6 and the C57BL/6-PD-(1-/-) group. The expression of the inflammatory cytokines interleukin (IL)-2, -4, -6, -10, -17, interferon-γ and tumor necrosis factor were detected. Furthermore, the levels of atrial myocyte oxidative stress, the atrial effective refractory period (AERP) and the atrial myocardial fibrosis levels were determined. Compared with the C57BL/6 group, we found that the inflammatory cytokines were significantly increased in the PD-1(-/-) group and the levels of atrial myocyte oxidative stress in the PD-1(-/-) group were also higher. The AERP became shorter and the dispersion of AERP was increased in the PD-1(-/-) group. Moreover, the PD-1(-/-) group presented significant atrial myocardial fibrosis but the C57BL/6 group did not. Our findings strongly suggest that the higher levels of inflammatory cytokines and atrial myocyte oxidative stress were present in the PD-1(-/-) mice and resulted in atrial electricity and structural remodeling. Due to the atrial remodeling, the PD-1(-/-) mice were more likely to develop AF.

Human cardiosphere-derived cells from patients with chronic ischaemic heart disease can be routinely expanded from atrial but not epicardial ventricular biopsies.

To investigate the effects of age and disease on endogenous cardiac progenitor cells, we obtained right atrial and left ventricular epicardial biopsies from patients (n = 22) with chronic ischaemic heart disease and measured doubling time and surface marker expression in explant- and cardiosphere-derived cells (EDCs, CDCs). EDCs could be expanded from all atrial biopsy samples, but sufficient cells for cardiosphere culture were obtained from only 8 of 22 ventricular biopsies. EDCs from both atrium and ventricle contained a higher proportion of c-kit+ cells than CDCs, which contained few such cells. There was wide variation in expression of CD90 (atrial CDCs 5-92 % CD90+; ventricular CDCs 11-89 % CD90+), with atrial CDCs cultured from diabetic patients (n = 4) containing 1.6-fold more CD90+ cells than those from non-diabetic patients (n = 18). No effect of age or other co-morbidities was detected. Thus, CDCs from atrial biopsies may vary in their therapeutic potential.

Role of anti-ß1 adrenergic antibodies from patients with periodontitis in cardiac dysfunction.

BACKGROUND: The presence of serum autoantibodies against ß(1) adrenoreceptors (ß(1)-ARs) in human gingival fibroblast from patients with periodontitis inhibits primary cell-specific growth and induces over-expression of pro-inflammatory mediators. Serum ß(1)-AR autoantibodies from patients with periodontitis react with myocardium and modify cardiac contractility. The relationship between the presence of serum ß(1)-AR autoantibodies and alterations in heart rate variability (HRV) was also studied. METHODS: An enzyme-linked immunosorbent assay (ELISA) using cardiac and gingival fibroblast membranes or synthetic peptides corresponding to the second extracellular loop of human ß(1)-AR was used to detect serum autoantibodies. The HRV was assessed from RR interval files generated from 22:00 to 08:00 hours. The autoantibody effects on contractility were measured on spontaneous rat isolated atria. RESULTS: Circulating autoantibodies from 36 patients with periodontitis and 20 healthy individuals (controls) interacted with fibroblasts, the cardiac surface, and ß(1)-AR synthetic peptides. The distributions of serum antibodies against gingival and myocardium membranes and ß(1)-AR synthetic peptide were 88.8%, 77.7%, and 92.8%, respectively. Moreover, 88.5% of patients with periodontitis whose sera were positive against ß(1)-AR synthetic peptide had decreased HRV. The corresponding affinity-purified anti-ß(1)-AR peptide IgG displayed partial agonist-like activity modifying the isolated atria contractility. CONCLUSION: This manuscript describes that patients with periodontitis showed increased levels of serum IgG with reactive activity against ß(1)-AR. Those patients demonstrated decrease in heart rate, and IgG derived from their sera induced aberrant contractility of heart atrium. We propose that periodontitis increases the risk of cardiovascular diseases, although it increases anti-ß(1)-AR autoantibody that alters myocardial contractility.

Inflammation abnormalities and inducibility of atrial fibrillation after epicardial ganglionated plexi ablation.

BACKGROUND: Epicardial ganglionated plexi (GP) ablation can prevent atrial fibrillation inducibility. However, the long-term effects of GP ablation on atrial fibrillation have not been elucidated. METHODS: Thirteen adult dogs of either sex, weighing 13-17kg, were randomly assigned to a sham-operated group (n=6) or a GP ablation group (n=7). After right thoracotomy, the atrial effective refractory period (AERP) was measured and atrial fibrillation was induced by right atrial rapid burst pacing. Atrial fibrillation and AERP were remeasured after anterior right and inferior right GP ablation in the GP ablation group. The animals were allowed to recover for 8 weeks, after which atrial fibrillation and AERP were measured again. Concentrations of C-reactive protein, tumour necrosis factor-alpha (TNF-α) and interleukin-6 were measured in the blood and atrial tissues. RESULTS: After 8 weeks, atrial fibrillation was induced in all animals in the GP ablation group. AERP and dispersion of AERP (dAERP; maximum AERP minus minimum AERP) were increased after GP ablation but AERP recovered after 8 weeks. There were no significant differences in the concentrations of C-reactive protein, TNF-α or interleukin-6 in venous blood between the two groups and the concentration of C-reactive protein in the atrium did not change before and after GP ablation. However, the concentrations of TNF-α and interleukin-6 in the atrium increased significantly 8 weeks after GP ablation (P<0.05). CONCLUSION: Increased concentrations of TNF-α and interleukin-6 in the atrium after GP ablation provide a new causative factor in terms of atrial fibrillation vulnerability.

Infiltration of macrophages through the atrial endocardium of inflammation-induced rats: contribution of fractalkine.

BACKGROUND: Inflammatory processes in the atria during systemic inflammation remain unclear, so this study tested the hypothesis that macrophages infiltrate the atrial myocardium mainly through the atrial endocardium with the contribution of fractalkine. METHODS AND RESULTS: Sprague-Dawley rats were injected with lipopolysaccharide (LPS) to simulate inflammation in the atria. Inflammation was immunohistologically assessed by the presence of macrophages. Macrophage infiltration was diffuse throughout the atrial myocardium after LPS injection. At an earlier phase after LPS injection, the number of macrophages dramatically increased, mainly in the atrial endocardium, and the expression of fractalkine protein was markedly increased by treatment with LPS in the atrial endocardium. The LPS-induced increase in atrial macrophage infiltration was significantly suppressed by neutralizing the fractalkine protein (P<0.01). CONCLUSIONS: In an experimental model of atrial inflammation, macrophages infiltrated the myocardium mainly through the atrial endocardium with the contribution of fractalkine. Inhibition of macrophage infiltration by suppressing chemokine expression could be a novel therapeutic approach to controling acute inflammation in the atria.