Characteristics of immune clusters and cell abundance in patients with different subtypes of nonparoxysmal atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice. Inflammation plays an important role in the initiation and perpetuation of AF. The present study was conducted to characterize immune clusters in nonparoxysmal AF and to distinguish immune subtypes of nonparoxysmal AF. Immune-related algorithms (CIBERSORT, ESTIMATE, and ssGSEA) were used to evaluate the immune cluster characterization and cell abundance, and multivariable logistics analysis was performed to determine the most relevant immune cells. We identified differentially expressed genes (DEGs) and used consensus clustering analysis to identify nonparoxysmal AF subtypes. Weighted gene coexpression network analysis (WGCNA) was used for finding highly correlated gene sets and attach to external sample traits. And it was conducted twice to identify the immune- and subtype- related modules. Finally, Metascape was used to compare the biological functions of the two nonparoxysmal AF subtypes we obtained. CytoHubba was used to identify the hub genes of these two subtypes. Based on the results of bioinformatics analysis, regulatory T cells, resting NK cells, active mast cells and neutrophils were considered to be closely related to nonparoxysmal AF. The brown module was identified as the most relevant module to the above immune cells by WGCNA. We identified two major nonparoxysmal AF subtypes by consensus clustering analysis and their enriched biological functions by Metascape. The hub genes are TYROBP, PTPRC, ITGB2, SPI1, PLEK, and CSF1R in permanent AF and JAM3, S100P, ARPC5, TRIM34, and GREB1L in persistent AF. This study revealed two major nonparoxysmal AF subtypes and eleven hub genes, which provide potential therapeutic targets for anti-inflammatory treatments of nonparoxysmal AF.

Colchicine attenuates the electrical remodeling of post-operative atrial fibrillation through inhibited expression of immune-related hub genes and stabilization of microtubules.

Rationale: Acute inflammation is a major risk factor for post-operative atrial fibrillation (POAF), and epicardial adipose tissue (EAT) is considered as a source of inflammatory mediators. However, underlying mechanisms and pharmacological targets of POAF are poorly understood. Methods: Integrative analysis of array data from EAT and right atrial appendage (RAA) samples was conducted to identify potential hub genes. Lipopolysaccharide (LPS)-stimulated inflammatory models in mice and in induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) were used to examine the exact mechanism underlying POAF. Electrophysiological analysis, multi-electrode array, and Ca2+ imaging was employed to explore the alterations of electrophysiology and Ca2+ homeostasis under inflammation. Flow cytometry analysis, histology and immunochemistry were performed to investigate immunological alterations. Results: We observed electrical remodeling, enhanced atrial fibrillation (AF) susceptibility, immune cell activation, inflammatory infiltration, and fibrosis in LPS-stimulated mice. LPS-stimulated iPSC-aCMs showed arrhythmias, abnormal Ca2+ signaling, reduced cell viability, disrupted microtubule network and increased α-tubulin degradation. VEGFA, EGFR, MMP9 and CCL2 were identified as hub genes simultaneously targeted in the EAT and RAA of POAF patients. Notably, treatment of colchicine in LPS-stimulated mice resulted in a U-shape dose-response curve, where greatly improved survival rates were observed only at doses between 0.10-0.40 mg/kg. At this therapeutic dose level, colchicine inhibited the expression of all the identified hub genes and effectively rescued the pathogenic phenotypes observed in LPS-stimulated mice and iPSC-aCM models. Conclusions: Acute inflammation promotes α-tubulin degradation, induces electrical remodeling, and both recruits and facilitates the infiltration of circulating myeloid cells. A certain dose of colchicine attenuates electrical remodeling and decreases the recurrence of AF.

Corrigendum: Impact of Serum Uric Acid Lowering and Contemporary Uric Acid-Lowering Therapies on Cardiovascular Outcomes: A Systematic Review and Meta-Analysis.

[This corrects the article DOI: 10.3389/fcvm.2021.641062.].

Impact of Serum Uric Acid Lowering and Contemporary Uric Acid-Lowering Therapies on Cardiovascular Outcomes: A Systematic Review and Meta-Analysis.

Objective: This study aimed to evaluate the potential association between uric acid (UA) lowering and cardiovascular risk reduction among UA-lowering therapies in adults. Methods: A systematic search for randomized controlled trials (RCTs) was conducted according to the protocol pre-registered in PROSPERO (No. CRD42020199259). We search for RCTs in PubMed, Embase, Web of Science, the Cochrane Library, and ClinicalTrials.gov up to July 1, 2020. A meta-analysis was performed using a fixed- or random-effects model. Results: In total, 30 studies involving 18,585 hyperuricaemic patients were included. Xanthine oxidase inhibitor (XOI) therapy produced a 6.0% reduction in relative risk (RR) for major adverse cardiovascular events (MACEs). The use of febuxostat was associated with a higher risk of cardiovascular events (CVEs) (RR: 1.09, 95% CI 0.998-1.19, I 2 = 0.0%), but the difference was not statistically significant. Allopurinol treatment was associated with a lower CVE risk (RR: 0.61, 95% CI 0.46-0.80, I 2 = 21.0%). Among the UA-lowering therapies, the drug treatments were associated with all-cause mortality (RR: 1.20, 95% CI 1.02-1.41, I 2 = 0.0%). The subgroup with a UA endpoint <7 mg/dl was not associated with a higher CVE risk (RR: 0.57, 95% CI 0.35-0.92, I 2 = 0.0%), and in the subgroup with a UA endpoint <5 mg/dl group, a lower risk of CVEs was not observed (RR: 0.99, 95% CI 0.69-1.44, I 2 = 0.0%). Conclusions: UA reduction caused by XOIs reduced the incidence of MACEs. UA-lowering medicines were associated with changes in all-cause mortality but not cardiovascular outcomes. The lower UA endpoint was not associated with reduced cardiovascular risk.

Selective Interventricular Septal Radiofrequency Ablation in Patients With Hypertrophic Obstructive Cardiomyopathy: Who Can Benefit?

Introduction: Septal mass reduction is beneficial for hypertrophic obstructive cardiomyopathy (HOCM) patients with severe left ventricular outflow (LVOT) gradient and symptoms, with surgical myectomy or alcohol septal ablation (ASA) currently recommended in selected patients. Radiofrequency (RF) ablation of hypertrophied septum has been published as a novel method to alleviate LVOT obstruction in small populations. This study aims to investigate factors influencing clinical outcomes of radiofrequency septum ablation. Methods and Results: In this study, 20 patients with HOCM who underwent endocardial ablation were included. Echocardiography and cardiac MRI (CMR) data was collected and analyzed pre- and (or) post- procedure. Nineteen patients underwent ablation successfully, while ablation was aborted in one patient with prior RBBB due to transient complete atrioventricular block (AVB). After 6 months of follow-up, NYHA heart functional class improved from III (2 - 3) to II (1 - 2) (p < 0.001), and resting LVOT gradient was significantly reduced (87.6 ± 29.5 mmHg vs. 48.1 ± 29.7, p < 0.001). LVOT gradient reduction was significantly higher in patients with limited basal septal hypertrophy (60.9 ± 8.3 vs. 27.9 ± 7.1, p = 0.01), shorter anterior mitral leaflet (56.1 ± 6.4 vs. 20.4 ± 5.0, p < 0.01), and normally positioned papillary muscle (36.9 ± 7.1 vs. 75.0 ± 6.3, p < 0.05). Conclusions: Endocardial septal ablation appears to be a safe and effective procedure for alleviating LVOT gradient in patients with HOCM, especially in those with limited basal septal hypertrophy, shorter anterior mitral leaflet, and normal positioned papillary muscle.