Atrial Fibrosis Research Articles

Relationship Between Periodontitis and Atrial Fibrosis in Atrial Fibrillation: Histological Evaluation of Left Atrial Appendages.

Atrial fibrosis contributes to the onset and persistence of atrial fibrillation (AF) and AF-related stroke.Periodontitis, a common infectious and inflammatory disease, aggravates some systemic diseases. However, theassociation of periodontitis with AF and with atrial fibrosis has remained unclarified. The authors aimed to elucidate the relationship between periodontitis and atrial fibrosis by studying resected left atrial appendages (LAAs). Seventy-six patients with AF (55 with nonparoxysmal AF, 25 with mitral valve regurgitation, 18 with LAA thrombus) who were scheduled to undergo LAA excision during cardiac surgery were prospectively enrolled. All patients underwent an oral examination, and the remaining number of teeth, bleeding on probing, periodontal probing depth, and periodontal inflamed surface area (PISA) were evaluated as parameters of periodontitis. The degree of fibrosis in each LAA was quantified by Azan-Mallory staining. Bleeding on probing (R=0.48; P< 0.0001), periodontal probing depth of≥4mm (R=0.26; P=0.02), and PISA (R=0.46; P< 0.0001) were positively correlated with atrial fibrosis. Among patients with >10 remaining teeth, PISA was positively and strongly correlated with atrial fibrosis (R=0.57; P< 0.0001). After adjustments for age, AF duration, BMI, mitral valve regurgitation, and CHADS₂ (congestive heart failure, hypertension, age, diabetes, previous stroke/transient ischemic attack) score, PISA was significantly associated with atrial fibrosis (β=0.016; P=0.0002). The authors histologically revealed the association of periodontitis with atrial fibrosis. This indicates that periodontitis, which is modifiable, is likely a risk factor for AF.

The Role of Myocardial Fibrosis in the Pathogenesis of Atrial Fibrillation

The article discusses the role of atrial myocardial fibrosis in the occurrence and maintenance of atrial fibrillation (AF). The participation of such mechanisms as the profibrotic renin-angiotensin-aldosterone system (RAAS), transforming growth factor (TGF-β1) and their relationship to developing fibrosis was revealed. A relationship has been shown between atrial fibrosis and atrial remodeling.

Irisin attenuates angiotensin II-induced atrial fibrillation and atrial fibrosis via LOXL2 and TGFβ1/Smad2/3 signaling pathways.

Irisin was reported as a cardioprotective and anti-oxidative effector, while the effect on atrial fibrosis is unknown. The current research examined irisin's function in atrial fibrillation (AF); atrial fibrosis brought on by Ang II can be suppressed, thus lessening the risk of developing AF. 246 individuals were enrolled in the present case-control study. Chinese AF patients (n=126), 83 of whom were paroxysmal AF (PAF), 43 patients with persistent AF (PeAF), and 120 healthy controls. Saline or Ang II (2.0 mg/kg/day) was subcutaneously injected into healthy male C57BL/6 mice for four weeks. Once daily for four weeks, intraperitoneal injections of exogenous irisin (500 g/kg/day) were administered. In comparison to PAF patients and healthy controls (all P<0.05), PeAF patients had significantly higher rates of heart failure (HF), large left atrial size (LAD), hypertrophic protein B-type natriuretic peptide (BNP), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-terminal telopeptide of type I collagen (CTX-I), and transforming growth factor beta-1 (TGF-β1), while superoxide dismutase (SOD) level was low. Expression of irisin was decreased in AF patients' serum and Ang II-infused mice. Exogenous irisin dramatically reduced apoptosis, atrial fibrosis, atrial inflammation, and the susceptibility to AF caused by Ang II. In the atrial tissue, irisin inhibited Ang II-induced fibroblast transdifferentiation, LOXL2, TGF-β1, collagen production, and phosphorylation of Smad2/3. The study results speculated that irisin could be a potential AF target, and it inhibited atrial fibrosis and significantly impaired increased AF susceptibility through inactivation of LOXL2 and the TGF-β/Smad pathway.

Linggui Qihua Decoction Inhibits Atrial Fibrosis by Regulating TGF-β1/Smad2/3 Signal Pathway.

Myocardial fibrosis is a critical factor in the development of heart failure with preserved ejection fraction (HFpEF). Linggui Qihua decoction (LGQHD) is an experienced formula, which has been proven to be effective on HFpEF in clinical and in experiments. Objective. This study aimed to observe the effect of LGQHD on HFpEF and its underlying mechanism. Methods. Spontaneously hypertensive rats (SHR) were induced with high-glucose and high-fat to establish HFpEF models and were treated with LGQHD for 8 weeks. The heart structure was detected by echocardiography, and the histopathological changes of the myocardium were observed by hematoxylin-eosin (HE) and Masson staining. Reverse transcription PCR (RT-PCR) and western blot were used to detect mRNA and protein expression of the target gene in rat myocardium. Results. In this study, LGQHD improved cardiac morphology and atrial fibrosis in HfpEF rats, decreased tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA expression, up-regulated matrix metalloproteinase-9 (MMP-9) mRNA expression, and inhibited the expression of angiotensin II (Ang II), angiotensin II type 1 receptor (AT1), transforming growth factor β1 (TGF-β1), Smad2/3 mRNA, and protein in myocardial tissue of HFpEF rats. Conclusion. LGQHD can suppress atrial fibrosis in HFpEF by modulating the TGF-β1/Smad2/3 pathway.

Adipose Triglyceride Lipase Deficiency Aggravates Angiotensin II–Induced Atrial Fibrillation by Reducing Peroxisome Proliferator–Activated Receptor α Activation in Mice

Atrial fibrillation (AF) is a main risk factor for cerebrovascular diseases but lacks precision therapy. Adipose triglyceride lipase (ATGL) is a key enzyme involved in the intracellular degradation of triacylglycerol and plays an important role in lipid and energy metabolism. However, the role of ATGL in the regulation of AF remains unclear. In this study, AF was induced by infusion of angiotensin II (Ang II, 2000 ng/kg/min) for 3 weeks in male ATGL knockout (KO) mice and age-matched C57BL/6 wild-type mice. The atrial volume was measured by echocardiography. Atrial fibrosis, inflammatory cells, and superoxide production were detected by histologic examinations. The results showed that ATGL expression was significantly downregulated in the atrial tissue of the Ang II–infused mice. Moreover, Ang II–induced increase in the inducibility and duration of AF, atrial dilation, fibrosis, inflammation, and oxidative stress in wild-type mice were markedly accelerated in ATGL KO mice; however, these effects were dramatically reversed in the ATGL KO mice administered with peroxisome proliferator–activated receptor (PPAR)-α agonist clofibric acid. Mechanistically, Ang II downregulated ATGL expression and inhibited PPAR-α activity, activated multiple signaling pathways (inhibiting kappa B kinase α/β-nuclear factor-κB, nicotinamide adenine dinucleotide phosphate oxidase, and transforming growth factor-β1/SMAD2/3) and reducing Kv1.5, Cx40, and Cx43 expression, thereby contributing to atrial structural and electrical remodeling and subsequent AF. In summary, our results indicate that ATGL KO enhances AF inducibility, possibly through inhibiting PPAR-α activation and suggest that activating ATGL might be a new therapeutic option for treating hypertensive AF.

Atriopathy and atrial fibrillation. Part II

Atrial fibrillation is based on various forms of congenital and acquired pathology. When choosing a method of treatment, it is important to understand not only the causes of arrhythmia in a particular patient, but also the features of its mechanism and progression factors. Obviously, there is a difference in the mechanisms of paroxysmal and nonparoxysmal forms of atrial fibrillation. Criteria and methods for assessing the stage of possible reverse structural and functional changes in the atria after stabilization of the heart rate are of great clinical importance. The second part of the review reflects the immediate causes of atriopathy, including heart amyloidosis, mutations of the natriuretic peptide precursor A, hereditary myodistrophia, heart failure, obstructive sleep apnea, drug effect, myocarditis, genetic disorders of repolarization, aging, arterial hypertension, obesity, diabetes mellitus, heart defects, atrial fibrillation itself. Qualitative and quantitative methods of atrial fibrosis evaluation are described, as well as the possibilities of reverse remodeling. The potential role of fibrosis as a direct cause of systemic thromboembolism and ischemic stroke in atrial fibrillation patients is considered. Ways of atriopathy prevention and treatment are discussed. An algorithm for assessing the severity of atriopathy and the probability of maintaining sinus rhythm are presented.

Elevated fibrosis burden as assessed by MRI predicts cryoballoon ablation failure.

Late-gadolinium enhancement magnetic resonance (LGE-MRI) imaging is increasingly used in management of atrial fibrillation (AFib) patients. Here, we assess the usefulness of LGE-MRI-based fibrosis quantification to predict arrhythmia recurrence in patients undergoing cryoballoon ablation. Our secondary goal was to compare two widely used fibrosis quantification methods. In 102 AF patients undergoing LGE-MRI and cryoballoon ablation (mean age 62 years; 64% male; 59% paroxysmal AFib), atrial fibrosis was quantified using the pixel intensity histogram (PIH) and image intensity ratio (IIR) methods. PIH segmentations were completed by a third-party provider as part of the standard of care at our hospital; Image intensity ratio(IIR) segmentations of the same scans were carried out in our lab using a commercially available software package. Fibrosis burdens and spatial distributions for the two methods were compared. Patients were followed prospectively for recurrent arrhythmia following ablation. Average PIH fibrosis was 15.6 ± 5.8% of the left atrial (LA) volume. Depending on threshold (IIRthr ), the average IIR fibrosis (% of LA wall surface area) ranged from 5.0 ± 7.2% (IIRthr = 1.2) to 37.4 ± 10.9% (IIRthr = 0.97). An IIRthr of 1.03 demonstrated the greatest agreement between the methods, but spatial overlap of fibrotic areas delineated by the two methods was modest (Sorenson Dice coefficient: 0.49). Fourty-two patients (41.2%) had recurrent arrhythmia. PIH fibrosis successfully predicted recurrence (HR 1.07; p = .02) over a follow-up period of 362 ± 149 days; regardless of IIRthr , IIR fibrosis did not predict recurrence. PIH-based volumetric assessment of atrial fibrosis was modestly predictive of arrhythmia recurrence following cryoballoon ablation in this cohort. IIR-based fibrosis was not predictive of recurrence for any of the IIRthr values tested, and the overlap in designated areas of fibrosis between the PIH and IIR methods was modest. Caution must therefore be exercised when interpreting LA fibrosis from LGE-MRI, since the values and spatial pattern are methodology-dependent.

Atrial fibrillatory wave amplitude revisited: A predictor of recurrence after catheter ablation independent of the degree of left atrial structural remodeling.

The fibrillatory wave amplitude (FWA) during atrial fibrillation (AF) is thought to reflect structural atrial remodeling, but it remains unclear what determines the FWA. 114 consecutive patients were prospectively studied who underwent catheter ablation of AF. The mean FWA was computed by automated surface ECG analyses. The extent of the left atrial (LA) voltage-defined atrial fibrosis and conduction properties were estimated by a three-dimensional high-density electroanatomical mapping system. The LA size was evaluated by transthoracic echocardiography. The study patients were divided into 2 groups according to an FWA in lead V1 above the median value of 46 µV (high FWA group, n=57) or below 46 µV (low FWA group, n=57). There were no differences in the age, gender, CHADS2 score, prevalence of paroxysmal AF, medications, ablation strategy, and LA volume index between the two groups. The LA low voltage areas in the low FWA group were not different from those in the high FWA group. The total LA activation time and local LA conduction velocity did not differ between the two groups. During a median follow-up of 710 days, the recurrence rate after ablation was significantly higher in patients with a low FWA than a high FWA (log-rank P=0.02). In a multivariate analysis, non-paroxysmal AF, the LA volume index, and FWA were independent predictors of recurrence after ablation. The FWA was not correlated with the markers of atrial structural remodeling. Nevertheless, the FWA could still provide information for predicting the clinical outcome after AF ablation.

Novel preventive effect of isorhamnetin on electrical and structural remodeling in atrial fibrillation.

Isorhamnetin, a natural flavonoid, has strong antioxidant and antifibrotic effects, and a regulatory effect against Ca2+-handling. Atrial remodeling due to fibrosis and abnormal intracellular Ca2+ activities contributes to initiation and persistence of atrial fibrillation (AF). The present study investigated the effect of isorhamnetin on angiotensin II (AngII)-induced AF in mice. Wild-type male mice (C57BL/6J, 8 weeks old) were assigned to three groups: (1) control group, (2) AngII-treated group, and (3) AngII- and isorhamnetin-treated group. AngII (1000 ng/kg/min) and isorhamnetin (5 mg/kg) were administered continuously via an implantable osmotic pump for two weeks and intraperitoneally one week before initiating AngII administration, respectively. AF induction and electrophysiological studies, Ca2+ imaging with isolated atrial myocytes and HL-1 cells, and action potential duration (APD) measurements using atrial tissue and HL-1 cells were performed. AF-related molecule expression was assessed and histopathological examination was performed. Isorhamnetin decreased AF inducibility compared with the AngII group and restored AngII-induced atrial effective refractory period prolongation. Isorhamnetin eliminated abnormal diastolic intracellular Ca2+ activities induced by AngII. Isorhamnetin also abrogated AngII-induced APD prolongation and abnormal Ca2+ loading in HL-1 cells. Furthermore, isorhamnetin strongly attenuated AngII-induced left atrial enlargement and atrial fibrosis. AngII-induced elevated expression of AF-associated molecules, such as ox-CaMKII, p-RyR2, p-JNK, p-ERK, and TRPC3/6, was improved by isorhamnetin treatment. The findings of the present study suggest that isorhamnetin prevents AngII-induced AF vulnerability and arrhythmogenic atrial remodeling, highlighting its therapeutic potential as an anti-arrhythmogenic pharmaceutical or dietary supplement.

El fracaso de la ablación por catéter de la fibrilación auricular se asocia con mayor remodelado y menos eficacia de una posterior ablación toracoscópica

Introduction and objectivesRecent observations suggest that patients with a previous failed catheter ablation have an increased risk of atrial fibrillation (AF) recurrence after subsequent thoracoscopic AF ablation. We assessed the risk of AF recurrence in patients with a previous failed catheter ablation undergoing thoracoscopic ablation. MethodsWe included patients from 3 medical centers. To correct for potential heterogeneity, we performed propensity matching to compare AF freedom (freedom from any atrial tachyarrhythmia> 30 s during 1-year follow-up). Left atrial appendage tissue was analyzed for collagen distribution. ResultsA total of 705 patients were included, and 183 had a previous failed catheter ablation. These patients had fewer risk factors for AF recurrence than ablation naïve controls: smaller indexed left atrial volume (40.9± 12.5 vs 43.0±12.5 mL/m2, P=.048), less congestive heart failure (1.5% vs 8.9%, P=.001), and less persistent AF (52.2% vs 60.3%, P=.067). However, AF history duration was longer in patients with a previous failed catheter ablation (6.5 [4-10.5] vs 4 [2-8] years; P<.001). In propensity matched analysis, patients with a failed catheter ablation were at a 68% higher AF recurrence risk (OR, 1.68; 95%CI, 1.20-2.15; P=.034). AF freedom was 61.1% in patients with a previous failed catheter ablation vs 72.5% in ablation naïve matched controls. On histology of the left atrial appendage (n=198), patients with a failed catheter ablation had a higher density of collagen fibers. ConclusionsPatients with a prior failed catheter ablation had fewer risk factors for AF recurrence but more frequently had AF recurrence after thoracoscopic AF ablation than ablation naïve patients. This may in part be explained by more progressed, subclinical, atrial fibrosis formation.

812 FOLATES-RELATED ERYTHROCYTE DIVERSION LEAD TO ATRIAL CARDIOMYOPATHY/FIBRILLATION THROUGH EPCS DYSFUNCTION

Abstract Background Recent advances support the concept that pre-persistent Atrial Fibrillation (AF) and paradoxical embolism do not explain the wholeness of embolic strokes, thus suggesting a broad Atrial Cardiomyopathy (AC). Pathogenic mechanisms underlying AC are still largely unknown. Folate cycle disorders are a yet underrated dysmetabolism. MTHFR-inherited defects could hinder both endothelial and circulating endothelial progenitor cell (EPCs) functioning, therefore providing one-shot explanation to both atrial stasis (increasing atrial fibrosis and generating atrial hypocontractility even in sinus rhythm) and endothelial dysfunction (ED). Purpose This study aims to enquire for the hypothesis that: 1) atrial fibrosis (AFib – intended as a relative percentage of low voltage area in the context of left atrial endocavitary voltage mapping) would relate to folate cycle disorders (intended as both: a)MTHFR C677T inherited mutations and b)bone-marrow function disorders, here referring to erythropoiesis diversions) and 2) AF patients would show dysfunctional EPCs. Methods We studied 59 consecutive patients admitted to the cardiology Unit of the General Hospital “F.Miulli”, with preserved EF, subjected to AF ablation. AFib was quantified by bipolar peak-to-peak voltage areas (&amp;lt;0,5 mV) with respect to the wholeness of the picked voltage points. Blood count cell was evaluated by a commercial laboratory test. EPCs isolation and characterization were performed by Ficoll-Hypaque gradient and following flow cytometry analysis for cell surface antigens: CD45, CD34, CD133, VEGFR2 and KDR. EPCs functional wound healing assay was performed to determine the number of EPCs migrated to the “wound”, measuring the percentage of relative wound closure compared with matched-controls. Results Baseline characteristics did not differ between Sample and Control groups. % of Afib significantly differs between C677T MTHFR homozigosis patients (n=15) with respect to non-C&amp;//T MTHFR homozygosis patients (n=44 p &amp;lt; 0,02). Once univariate analysis was performed, subsequent multivariate analysis highlights highest fit once merged RBC, RDW-SD and folates values were inputed: Goodness of fit was proper, modelling good (Low figure - R2=0,39; p=0,0001). Either RBC, RDW-SD and folates coefficient reached significance (p &amp;lt; 0,0001; p &amp;lt; 0,01; p &amp;lt; 0,05 respectively). Number of EPCs significantly differs between AF patients and matched controls (p &amp;lt; 0,001). Conclusions Our findings support the hypothesis that genetically determined folates dysmetabolism (MTHFR dysfunction) promotes AFib via a complex cardiac-bone marrow networking involving circulating EPCs and unraveled by erythropoiesis diversions. Such results suggest a pathogenic role of folate cycle disorders in the AC development

545 INVESTIGATING THE RISK OF CARDIAC FIBROSIS IN RESPONSE TO HEAT-NOT-BURN CIGARETTES THROUGH HUMAN CARDIAC STROMAL CELLS

Abstract Background The use of alternative smoking devices, such as heat-not-burn cigarettes (HNBC), is increasing on a global scale, and their impact on health is still uncertain. Objective To investigate the effects of circulating molecules in HNBC chronic smokers on the fibrotic specification and paracrine function of cardiac stromal cells (CSCs). Methods Resident CSCs were isolated from the atrial tissue of non-smokers patients with cardiovascular diseases, and exposed to the serum pools derived from 60 young healthy subjects, stratified in exclusive HNBC smokers, traditional combustion cigarette (TCC) smokers, or non-smokers (NS) as reference. Results CSCs treated with TCC serum versus NS displayed impaired 3D growth (NS 568±24 vs. TCC 442±27 spheroids/well, p≤0,01) and reduced migration after 6h (NS 0,62±0,04 vs. TCC 0,80±0,03 normalized scratch area versus t0, p≤0,01) and 10h (NS 0,49±0,03 vs. TCC 0,36±0,03 normalized scratch area versus t0, p≤0,05), as well as significantly increased expression (IL-6, IL-8) and/or release of pro-inflammatory (e.g CRP, PAI-1, CD40L, CXCL4) and pro-fibrotic cytokines (PDGFA, MMP1). CSCs cultured with HNBC serum showed significantly increased mRNA levels of pro-fibrotic genes (PDGFA, THY1, COL1A1, p&amp;lt;0,01), and significantly reduced expression of the gap junction protein CX43 (p&amp;lt;0,05). Nonetheless, both TCC and HNBC sera reduced the release of angiogenic and protective factors (e.g. VEGF, Adiponectin, CHI3L1) from CSCs, as assessed by protein arrays and ELISA. In fact, their paracrine support to tube-formation by endothelial cells (NS 63,29±4,72 vs. TCC 41,43±6,64 vs. HNBC 37,29±5,67 mesh number per well, p≤0,05) and to preserved cell viability of neonatal rat cardiomyocytes (NS 0,60±0,04 vs. TCC 0,40±0,01 vs. HNBC 0,47±0,01 OD490 normalized OD versus t0, p≤0,001) were significantly impaired. Treatment with the sera of both types of smokers also increased the expression of NOX isoforms and the release of H2O2 (NS 1,76±0,09 vs. TCC 3,84±0,25 vs. HNBC 2,90±0,35 µM, p≤0,05) and significantly reduced the release of NO (NS 6,98±0,43 vs. TCC 4,65±0,07 vs. HNBC 5,06±0,13 µM, p≤0,01) by CSCs. Conclusion The circulating molecules in the serum of chronic HNBC smokers induce fibrotic specification in CSCs. They also reduce the beneficial paracrine effects of stromal cells on endothelial cells and cardiomyocytes, albeit to a reduced extent for some features. These results point to a potential risk for atrial fibrosis development triggered by chronic HNBC use.

Mechanisms and Management of Thyroid Disease and Atrial Fibrillation: Impact of Atrial Electrical Remodeling and Cardiac Fibrosis.

Atrial fibrillation (AF) is the most common cardiac arrhythmia associated with increased cardiovascular morbidity and mortality. The pathophysiology of AF is characterized by electrical and structural remodeling occurring in the atrial myocardium. As a source of production of various hormones such as angiotensin-2, calcitonin, and atrial natriuretic peptide, the atria are a target for endocrine regulation. Studies have shown that disorders associated with endocrine dysregulation are potential underlying causes of AF. The thyroid gland is an endocrine organ that secretes three hormones: triiodothyronine (T3), thyroxine (T4) and calcitonin. Thyroid dysregulation affects the cardiovascular system. Although there is a well-established relationship between thyroid disease (especially hyperthyroidism) and AF, the underlying biochemical mechanisms leading to atrial fibrosis and atrial arrhythmias are poorly understood in thyrotoxicosis. Various animal models and cellular studies demonstrated that thyroid hormones are involved in promoting AF substrate. This review explores the recent clinical and experimental evidence of the association between thyroid disease and AF. We highlight the current knowledge on the potential mechanisms underlying the pathophysiological impact of thyroid hormones T3 and T4 dysregulation, in the development of the atrial arrhythmogenic substrate. Finally, we review the available therapeutic strategies to treat AF in the context of thyroid disease.

Acetyltransferase p300 regulates atrial fibroblast senescence and age-related atrial fibrosis through p53/Smad3 axis.

Atrial fibrosis induced by aging is one of the main causes of atrial fibrillation (AF), but the potential molecular mechanism is not clear. Acetyltransferase p300 participates in the cellular senescence and fibrosis, which might be involved in the age-related atrial fibrosis. Four microarray datasets generated from atrial tissue of AF patients and sinus rhythm (SR) controls were analyzed to find the possible relationship of p300 (EP300) with senescence and fibrosis. And then, biochemical assays and in vivo electrophysiological examination were performed on older AF patients, aging mice, and senescent atrial fibroblasts. The results showed that (1) the left atrial tissues of older AF patients, aging mouse, and senescence human atrial fibroblasts had more severe atrial fibrosis and higher protein expression levels of p300, p53/acetylated p53 (ac-p53)/p21, Smad3/p-Smads, and fibrosis-related factors. (2) p300 inhibitor curcumin and p300 knockdown treated aging mouse and senescence human atrial fibroblasts reduced the senescence ratio of atrial fibroblasts, ameliorated the atrial fibrosis, and decreased the AF inducibility. In contrast, over-expression of p300 can lead to the senescence of atrial fibroblasts and atrial fibrosis. (3) p53 knockdown decreased the expression of aging and fibrosis-related proteins. (4) Co-immunoprecipitation and immunofluorescence showed that p53 forms a complex with smad3 and directly regulates the expression of smad3 in atrial fibroblasts. Our findings suggest that the mechanism of atrial fibrosis induced by aging is, at least, partially dependent on the regulation of p300, which provides new sights into the AF treatment, especially for the elderly.

Catheter ablation of symptomatic atrial fibrillation: Sex, ethnicity, and socioeconomic disparities.

Catheter ablation for treatment of atrial fibrillation (AF), AF ablation, is more effective than antiarrhythmic drugs in reducing AF burden, reducing symptoms and increasing health-related quality of life. Although females more often experience AF-related symptoms, and have more severe symptoms, have lower quality of life, and experience more serious adverse effects of antiarrhythmic drugs than males, they are less likely to undergo AF ablation. Potential explanations for the disparity include older age at diagnosis, longer AF duration, a greater number of comorbidities, more extensive atrial fibrosis, and presumed lower success rate and more complications after AF ablation in women. Studies have failed to show sex-related differences in AF recurrence or serious complications following AF ablation but show more nuisance bleeds in women. Ethnic minorities, such as African Americans and Latin Americans, and individuals of low socioeconomic status are also less likely to undergo AF ablation, possibly associated with greater numbers of comorbidities, lack of patient advocacy, healthcare costs, and inadequate insurance coverage. Inclusion of marginalized patient groups in clinical trials of AF treatment and a personalized, patient-centered approach may expand equality in utilization of AF ablation.

Biomimetic design of bioartificial scaffolds for the in vitro modelling of human cardiac fibrosis.

In vitro models of pathological cardiac tissue have attracted interest as predictive platforms for preclinical validation of therapies. However, models reproducing specific pathological features, such as cardiac fibrosis size (i.e., thickness and width) and stage of development are missing. This research was aimed at engineering 2D and 3D models of early-stage post-infarct fibrotic tissue (i.e., characterized by non-aligned tissue organization) on bioartificial scaffolds with biomimetic composition, design, and surface stiffness. 2D scaffolds with random nanofibrous structure and 3D scaffolds with 150µm square-meshed architecture were fabricated from polycaprolactone, surface-grafted with gelatin by mussel-inspired approach and coated with cardiac extracellular matrix (ECM) by 3weeks culture of human cardiac fibroblasts. Scaffold physicochemical properties were thoroughly investigated. AFM analysis of scaffolds in wet state, before cell culture, confirmed their close surface stiffness to human cardiac fibrotic tissue. Following 3weeks culture, biomimetic biophysical and biochemical scaffold properties triggered the activation of myofibroblast phenotype. Upon decellularization, immunostaining, SEM and two-photon excitation fluorescence microscopy showed homogeneous decoration of both 2D and 3D scaffolds with cardiac ECM. The versatility of the approach was demonstrated by culturing ventricular or atrial cardiac fibroblasts on scaffolds, thus suggesting the possibility to use the same scaffold platforms to model both ventricular and atrial cardiac fibrosis. In the future, herein developed in vitro models of cardiac fibrotic tissue, reproducing specific pathological features, will be exploited for a fine preclinical tuning of therapies.

Atrial contractile function and fibrosis in patients with paroxysmal atrial fibrillation in sinus rhythm

The aim of the study was to investigate atrial contractile function in patients with paroxysmal atrial fibrillation (AF) in sinus rhythm using transthoracic echocardiography (EchoCG). Thirty-five patients with paroxysmal AF and arterial hypertension (mean age 62 ± 10 years, 43% male) in sinus rhythm were enrolled in the study. The control group was composed of comparable patients with arterial hypertension without heart rhythm disturbances. EchoCG was performed during sinus rhythm according to an extended protocol, which included the ejection fraction (EF) of the left atrium (LA) and tissue Doppler measurements. Myocardial fibrosis was assessed quantitatively by videodensitometry in intraventricular and intraatrial (IAS) septa using an original image post-processing algorithm. We found a significant decrease in the left atrial contraction function during sinus rhythm in patients with AF when compared to controls. LA EF (34 ± 14 vs. 54 ± 17, p = 0.03) and A' velocity (0.17 ± 0.04 vs. 0.22 ± 0.04, p = 0.008) decreased while A/A' ratio (2.7 ± 0.2 vs. 1.9 ± 0.1, p = 0.006) increased. Peak A velocity was not affected. Videodensitometric analysis revealed a 2.3-fold increase in IAS fibrosis fraction in AF patients compared with controls (p = 0.01). Patients with AF in sinus rhythm have markedly depressed atrial contractile function. Videodensitometry of IAS has the potential to be used as inexpensive method of atrial fibrosis assessment in patients with AF.

CircCAMTA1 facilitates atrial fibrosis by regulating the miR-214-3p/TGFBR1 axis in atrial fibrillation.

Circular RNAs (circRNAs) have been shown to be associated with cardiac fibrosis. Atrial fibrosis is an important pathophysiological event in the progression of atrial fibrillation (AF). Although a novel circRNA calmodulin binding transcription activator 1 (circCAMTA1) has been reported to be related with the development of AF, the detailed molecular mechanisms remain largely unknown. In this study, we found that circCAMTA1 was upregulated in atrial muscle tissues of AF patients and angiotensin-II (Ang-II)-treated human atrial fibroblasts (HAFs). Moreover, circCAMTA1 expression was positively correlated with the expression of collagen (I and III) and α-SMA in atrial muscle tissues of AF patients. In vitro experiments, knockdown of circCAMTA1 significantly suppressed Ang-II-induced HAFs proliferation and reduced the expression of atrial fibrosis-associated genes, but overexpression of circCAMTA1 exhibited opposite results. In vivo experiments, circCAMTA1 knockdown ameliorated Ang-II-induced atrial fibrosis by reducing AF incidence, AF duration, and collagen synthesis. Functionally, circCAMTA1 facilitated Ang-II-induced atrial fibrosis in vitro and in vivo via downregulating the inhibitory effect of miR-214-3p on transforming growth factor β receptor 1 (TGFBR1) expression. In conclusions, circCAMTA1 knockdown alleviated atrial fibrosis through downregulating TGFBR1 expression intermediated by miR-214-3p in AF, suggesting circCAMTA1/miR-214-3p/TGFBR1 axis may be a novel therapeutic target for AF treatment in clinic.

Adenosine and Adenosine Receptors: Advances in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia in the world. Because the key to developing innovative therapies that limit the onset and the progression of AF is to fully understand the underlying molecular mechanisms of AF, the aim of the present narrative review is to report the most recent advances in the potential role of the adenosinergic system in the pathophysiology of AF. After a comprehensive approach describing adenosinergic system signaling and the mechanisms of the initiation and maintenance of AF, we address the interactions of the adenosinergic system's signaling with AF. Indeed, adenosine release can activate four G-coupled membrane receptors, named A1, A2A, A2B and A3. Activation of the A2A receptors can promote the occurrence of delayed depolarization, while activation of the A1 receptors can shorten the action potential's duration and induce the resting membrane's potential hyperpolarization, which promote pulmonary vein firing, stabilize the AF rotors and allow for functional reentry. Moreover, the A2B receptors have been associated with atrial fibrosis homeostasis. Finally, the adenosinergic system can modulate the autonomous nervous system and is associated with AF risk factors. A question remains regarding adenosine release and the adenosine receptors' activation and whether this would be a cause or consequence of AF.

Knockdown of Ift88 in fibroblasts causes extracellular matrix remodeling and decreases conduction velocity in cardiomyocyte monolayers.

Background: Atrial fibrosis plays an important role in the development and persistence of atrial fibrillation by promoting reentry. Primary cilia have been identified as a regulator of fibroblasts (FB) activation and extracellular matrix (ECM) deposition. We hypothesized that selective reduction of primary cilia causes increased fibrosis and facilitates reentry. Aim: The aim of this study was to disrupt the formation of primary cilia in FB and examine its consequences on ECM and conduction in a co-culture system of cardiomyocytes (CM) and FB. Materials: Using short interfering RNA (siRNA), we removed primary cilia in neonatal rat ventricular FB by reducing the expression of Ift88 gene required for ciliary assembly. We co-cultured neonatal rat ventricular cardiomyocytes (CM) with FB previously transfected with Ift88 siRNA (siIft88) or negative control siRNA (siNC) for 48h. We examined the consequences of ciliated fibroblasts reduction on conduction and tissue remodeling by performing electrical mapping, microelectrode, and gene expression measurements. Results: Transfection of FB with siIft88 resulted in a significant 60% and 30% reduction of relative Ift88 expression in FB and CM-FB co-cultures, respectively, compared to siNC. Knockdown of Ift88 significantly increased the expression of ECM genes Fn1, Col1a1 and Ctgf by 38%, 30% and 18%, respectively, in comparison to transfection with siNC. Conduction velocity (CV) was significantly decreased in the siIft88 group in comparison to siNC [11.12 ± 4.27cm/s (n = 10) vs. 17.00 ± 6.20 (n = 10) respectively, p < 0.05]. The fraction of sites with interelectrode activation block was larger in the siIft88 group than in the siNC group (6.59 × 10-2 ± 8.01 × 10-2 vs. 1.18 × 10-2 ± 3.72 × 10-2 respectively, p < 0.05). We documented spontaneous reentrant arrhythmias in two cultures in the siIft88 group and in none of the siNC group. Action potentials were not significantly different between siNC and siIft88 groups. Conclusion: Disruption of cilia formation by siIft88 causes ECM remodeling and conduction abnormalities. Prevention of cilia loss could be a target for prevention of arrhythmias.