Electrical, structural, and autonomic atrial remodeling underlies atrial fibrillation in inflammatory atrial cardiomyopathy.

Background: There is growing evidence indicating a close relationship between inflammation and atrial fibrillation (AF). Although underlying inflammatory atrial cardiomyopathy may contribute to the development of AF, the arrhythmogenic remodeling caused by atrial inflammation has not been elucidated in detail. Herein, we examined electrical, structural, and autonomic changes in the atria in a mouse model of autoimmune myocarditis. Methods: BALB/c mice were immunized with cardiac myosin peptide (MyHC-α614-629) conjugated with complete Freund's adjuvant on days 0 and 7. Susceptibility to AF was assessed using right-atrial burst pacing. Results: The mice immunized with MyHC-α614-629 showed an inflammatory atrial cardiomyopathy phenotype, with enlarged atria; a high degree of inflammatory cell infiltration primarily consisting of CD4+ T cells, CD8+ T cells, Ly6GlowCD11b+ macrophages, and CD11c+ dendritic cells; and severe interstitial fibrosis with collagen deposition. These mice demonstrated significantly enhanced susceptibility to AF, as indicated by their increased AF induction rate and duration. In addition, the expression of potassium channels (Kcnh2, Kcnd3, and Kcnj2) and calcium handling-associated genes (Cacna1c, Camk2, Ryr2, and Atp2a2) was downregulated. Connexin 40 expression was significantly downregulated, leading to frequent lateralization to the inflamed atrium. Sympathetic and parasympathetic innervation and neurotrophin expression (nerve growth factor and brain-derived neurotrophic factor) were upregulated in the inflamed atria. Conclusion: Inflammatory atrial cardiomyopathy promotes susceptibility to AF via arrhythmogenic electrical, structural, and autonomic remodeling of the atria.

Uremic Toxins and Atrial Fibrillation: Mechanisms and Therapeutic Implications.

Atrial fibrillation (AF) is the most prevalent arrhythmia in the general population. There is a close association between chronic kidney disease (CKD) and AF. In recent years, attention has been focused on the relationship between AF and uremic toxins, including indoxyl sulfate (IS). Several animal studies have shown that IS promotes the development and progression of AF. IS has been shown to cause fibrosis and inflammation in the myocardium and exacerbate AF by causing oxidative stress and reducing antioxidative defense. Administration of AST-120, an absorbent of uremic toxins, decreases uremic toxin-induced AF in rodents. We have recently reported that patients with a higher serum IS level exhibit a higher rate of AF recurrence after catheter ablation, with serum IS being a significant predictor of AF recurrence. In this review, we discuss the possible mechanisms behind the AF-promoting effects of uremic toxins and summarize the reported clinical studies of uremic toxin-induced AF.

Initial Result of Antrum Pulmonary Vein Isolation Using the Radiofrequency Hot-Balloon Catheter With Single-Shot Technique.

OBJECTIVES: This study sought to determine the feasibility of a novel simplified ablation protocol targeting only the pulmonary vein antrum using the radiofrequency hot-balloon catheter in patients with paroxysmal atrial fibrillation. BACKGROUND: Radiofrequency hot-balloon (RHB) catheter has been recently introduced into clinical practice for pulmonary vein isolation (PVI). The authors hypothesized that a novel simplified ablation protocol targeting only the PV antrum with energy application for a longer time (single-shot technique) could be an alternative approach to achieve PVI, while avoiding unnecessary energy application at the PV ostium. METHODS: A total of 61 consecutive paroxysmal atrial fibrillation patients (age 64.1 ± 10.9 years, 48 male) who underwent antrum RHB-PVI were enrolled. Energy applications were performed following the pre-specified protocol only targeting the PV antrum. If the PVI was not achieved after 2 energy applications using the RHB, a touch-up ablation was performed. RESULTS: Of 241 PV, including 3 left common PV, 194 (80%) were isolated exclusively using the RHB. The target PVI average per group of 15 consecutive procedures improved from 75% (initial 15) to 89% (last 16) of patients. The injected volume was greatest in the right superior PV (13.1 ± 2.0 ml) and the smallest in the left inferior PV (10.8 ± 1.1 ml), and 23 PV (9.5%) required over 15 ml (estimated balloon diameter of 30 mm). Periprocedural complications were noted in 3 patients (4.9%), but phrenic nerve injury was not observed. Sinus rhythm maintenance at 12-month follow-up was achieved in 57 patients (93%). CONCLUSIONS: A novel simplified antrum RHB-PVI appears to be a feasible technique for the treatment of paroxysmal atrial fibrillation.

Indoxyl Sulphate is Associated with Atrial Fibrillation Recurrence after Catheter Ablation.

Renal dysfunction results in the accumulation of various uremic toxins, including indoxyl sulphate (IS), and is a major risk factor for atrial fibrillation (AF). Experimental studies have demonstrated that IS exacerbates atrial remodelling via oxidative stress, inflammation, and fibrosis. However, its clinical impact on AF-promoting cardiac remodelling has not been described. Therefore, the purpose of this study was to clarify the relationship between basal IS levels and the 1-year outcomes after catheter ablation for the treatment of AF. Our prospective observational study included data from 125 patients with AF who underwent catheter ablation. Over a 1-year follow-up period, AF recurrence was identified in 21 patients. The 1-year AF-free survival was significantly lower in patients with high serum IS levels (≥0.65 µg/mL) than in those with low IS levels (60.1 ± 10.4% versus 85.2 ± 3.9%, P = 0.007). Univariable analysis identified that an IS concentration ≥ 0.65 µg/mL was associated with AF recurrence (hazard ratio [HR] = 3.10 [1.26-7.32], P = 0.015), and this association was maintained in multivariate analysis (HR = 3.67 [1.13-11.7], P = 0.031). Thus, in patients undergoing AF ablation, serum IS levels at baseline independently predict the recurrence of arrhythmia.

Rev-erb agonist improves adverse cardiac remodeling and survival in myocardial infarction through an anti-inflammatory mechanism.

Rev-erb α, known as nuclear receptor 1D1 (NR1D1), regulates circadian rhythm, modulates glucose and lipid metabolism, and inflammatory response. However, little is known about the effect of Rev-erb agonist on the progression of myocardial infarction (MI) and heart failure. To investigate it, wild-type male mice underwent sham-operation or permanent ligation of the left anterior descending coronary artery to create MI model. Rev-erb agonist SR9009 (100 mg/kg/day) or vehicle was intraperitoneally administered. Echocardiography was performed to evaluate cardiac function 1 week after surgery. The gene and protein expression levels in the left ventricles (LVs) were determined with real-time PCR, western blotting, and immunofluorescence. Moreover, immune cell infiltration into the LVs was analyzed by flow cytometry. Survival rate and reduced LV function were significantly improved by the treatment with SR9009 after MI. The expression level and plasma concentration of brain natriuretic peptide were significantly lower in MI mice treated with SR9009 (MI+SR) than in MI mice treated with vehicle (MI+V). Moreover, the mRNA expression levels of inflammatory-related molecules such as Il6, Mcp1, Ly6g, Cd11b, matrix metallopeptidase (Mmp)9, and the protein expression levels of phosphorylated NF-κB p65, phosphorylated ERK, and phosphorylated p38 were also significantly lower in MI+SR than in MI+V. Immunofluorescence intensity for MMP-9 was enhanced in the LVs, but was less so in MI+SR than in MI+V. Furthermore, infiltrations of neutrophils and proinflammatory macrophages in the LVs were dramatically increased in MI+V and were significantly suppressed in MI+SR. Rev-erb agonist SR9009 treatment inhibited post-MI mortality and improved cardiac function through modulating inflammation and remodeling process.