Remodeling In Atrial Fibrillation Research Articles

Implications of Inflammation and Fibrosis in Atrial Fibrillation Pathophysiology

Inflammation and fibrosis have been implicated in the pathophysiology of atrial fibrillation. Atrial fibrosis causes conduction disturbances and is a central component of atrial remodeling in atrial fibrillation. Cardiac fibroblasts, the cells responsible for fibrosis formation, are activated by inflammatory mediators and growth factors associated with systemic inflammatory conditions. Thus, inflammation contributes to atrial fibrosis; the complex interplay of these maladaptive components creates a vicious cycle of atrial remodeling progression, maintaining atrial fibrillation and increasing thrombogenicity. This review provides up-to-date knowledge regarding inflammation and fibrosis in atrial fibrillation pathophysiology and their potential as therapeutic targets.

Atrial Remodeling in Atrial Fibrillation. Comorbidities and Markers of Disease Progression Predict Catheter Ablation Outcome.

Atrial fibrillation is the most common supraventricular arrhythmia affecting an increasing proportion of the population in which mainstream therapy, i.e. catheter ablation, provides freedom from arrhythmia in only a limited number of patients. Understanding the mechanism is key in order to find more effective therapies and to improve patient selection. In this review, the structural and electrophysiological changes of the atrial musculature that constitute atrial remodeling in atrial fibrillaton and how risk factors and markers of disease progression can predict catheter ablation outcome will be discussed in detail.

Inhibiting microRNA-155 attenuates atrial fibrillation by targeting CACNA1C

BackgroundReduction in L-type Ca2+ current (ICa,L) density is a hallmark of the electrical remodeling in atrial fibrillation (AF). The expression of miR-155, whose predicted target gene is the α1c subunit of the calcium channel (CACNA1C), was upregulated in atrial cardiomyocytes (aCMs) from patients with paroxysmal AF.The study is to determine miR-155 could target the gene expression of ICa,L and contribute to electrical remodeling in AF. MethodsThe expression of miR-155 and CACNA1C was assessed in aCMs from patients with paroxysmal AF and healthy control. ICa,L properties were observed after miR-155 transfection in human induced pluripotent stem cell derived atrial cardiomyocytes (hiPSC-aCMs). Furthermore, an miR-155 transgene (Tg) and knock-out (KO) mouse model was generated to determine whether miR-155 was involved in ICa,L-related electrical remodeling in AF by targeting CACNA1C. ResultsThe expression level of miR-155 was increased, while the expression level of CACNA1C reduced in the aCMs of patients with AF. miR-155 transfection in hiPSC-aCMs produced changes in ICa,L properties qualitatively similar to those produced by AF. miR-155/Tg mice developed a shortened action potential duration and increased vulnerability to AF, which was associated with decreased ICa,L and attenuated by an miR-155 inhibitor. Finally, the genetic inhibition of miR-155 prevented AF induction in miR-155/KO mice with no changes in ICa,L properties. ConclusionsThe increased miR-155 expression in aCMs was sufficient for the reduction in the density of ICa,L and the underlying electronic remodeling. The inhibition of miR-155 prevented ICa,L-related electric remodeling in AF and might constitute a novel anti-AF approach targeting electrical remodeling.

The association between impairment of HDL cholesterol efflux capacity and atrial remodeling in atrial fibrillation

This cross-sectional study enrolled 202 patients with atrial fibrillation (AF) who had undergone catheter ablation and evaluated the association between high-density lipoprotein (HDL) functionality, cholesterol efflux capacity (CEC) of HDL, and the pathophysiology of left atrial structural remodeling. Participants were divided into two groups, based on their left atrial volume index (LAVI) (< 34 mL/m2, n = 60 vs. LAVI ≥ 34 mL/m2, n = 142). We quantified three types of HDL CECs by the presence or absence of cyclic-AMP, as entire, and CEC dependent or not dependent on ATP binding cassette transporter A1 (ABCA1) and termed them Global CEC, ABCA1 CEC, and Non-ABCA1 CEC, respectively. Consequently, Global and Non-ABCA1 CECs were significantly impaired in patients with an enlarged LA (Global CEC: p = 0.039, Non-ABCA1 CEC: p = 0.022). Logistic regression analyses demonstrated that Non-ABCA1 CEC was significantly associated with an enlarged LA after adjusting for the conventional risk factors of AF. Furthermore, the association of higher Non-ABCA1 CEC with an enlarged LA was independent of serum levels of HDL cholesterol and serum myeloperoxidase (Odds ratio of 1 standard deviation higher: 0.64, 95% confidence interval: 0.43–0.95, p = 0.027). The findings of this study indicate the potential contribution of reduced Non-ABCA1 CEC in HDL to the pathophysiology in left atrial structural remodeling of patients with AF.

Treating atrial fibrillation with radiofrequency ablation to reverse changes in microRNAs regulating the ion-channel proteins.

To investigate the possible molecular mechanisms of radiofrequency ablation (RFA) for treating atrial fibrillation (AF) and the microRNA (miRNA) target for intervention in the future. We examined the changes in miRNAs regulating the atrial ion-channel proteins across the whole genome. We compared findings from 90 AF patients with those from 90 healthy subjects before RFA and three months after RFA. Twenty-one miRNAs regulating ion-channel proteins were differentially expressed more than ten-fold, and the findings were completely reversed after RFA as compared with the pre-RFA results. The colonial regulating effects of miRNAs regulating the outward K+ current channels such as those for the ultra-rapid delayed rectifier potassium current (Ikur), voltage-dependent delayed rectifier potassium current (Ikr), and delayed rectifier potassium channel current (Iks) were more unanimous and stronger, while this was not the case for miRNAs regulating the L-type Ca2+ current and INa current channels. Generally, miR-1266 levels were increased in the blood but down-regulated in the rheumatic atrial tissue, while a dual luciferase test indicated that SCN5A was the direct target gene of miR-1266. Using RFA to treat AF may have an impact via reversing the changes in miRNAs regulating the ion-channel proteins, especially for outward K+ current channels such as Ikur, Ikr, and Iks, which may play a major role in electrical remodeling in AF. It may be that miR-1266 is an antiarrhythmic miRNA and an AF intervention target in the future (Tab. 2, Fig. 4, Ref. 46).

Relaxin abrogates genomic remodeling of the aged heart.

"Healthy" aging drives structural and functional changes in the heart including maladaptive electrical remodeling, fibrosis and inflammation, which lower the threshold for cardiovascular diseases such as heart failure (HF) and atrial fibrillation (AF). Despite mixed results in clinical trials, Relaxin-therapy for 2-days reduced mortality by 37% at 180-days post-treatment, in patients with acute decompensated HF. Relaxin's short lifespan (2-3h) but long-lasting protective actions suggested that relaxin acts at a genomic level to reverse maladaptive remodeling in AF, HF and aging. Our recent studies showed that a 2-week treatment with Relaxin (0.4mg/kg/day) of aged (24months old F-344 rats) increases the expression of voltage-gated Na+ channels (mRNA, Nav1.5 and INa), connexin-43, abrogates inflammatory and immune responses and reverses myocardial fibrosis and cellular hypertrophy of the aged hearts. Relaxin acts directly at a wide range of cell types in the cardiovascular system that express its cognate GPCR receptor, RXFP1. RNA-seq analysis of young and aged hearts with and without Relaxin treatment revealed that "normal" aging altered the expression of ~10% of genes expressed in the ventricles, including: ion channels, components of fibrosis, hemodynamic biomarkers, immune and inflammatory responses which were reversed by Relaxin. The extensive cardiovascular remodeling caused by Relaxin was mediated through the activation of the Wnt/β-catenin signaling pathway which was otherwise suppressed by in adult cardiomyocytes intracellular by cytosolic Dickkopf1 (Dkk1). Wnt/β-catenin signaling is a mechanism that can explain the pleiotropic actions of Relaxin and the marked reversal of genomic changes that occur in aged hearts.

Decreased bioavailability of hydrogen sulfide links vascular endothelium and atrial remodeling in atrial fibrillation

Oxidative stress drives the pathogenesis of atrial fibrillation (AF), the most common arrhythmia. In the cardiovascular system, cystathionine γ-lyase (CSE) serves as the primary enzyme producing hydrogen sulfide (H2S), a mammalian gasotransmitter that reduces oxidative stress. Using a case control study design in patients with and without AF and a mouse model of CSE knockout (CSE-KO), we evaluated the role of H2S in the etiology of AF. Patients with AF (n = 51) had significantly reduced plasma acid labile sulfide levels compared to patients without AF (n = 65). In addition, patients with persistent AF (n = 25) showed lower plasma free sulfide levels compared to patients with paroxysmal AF (n = 26). Consistent with an important role for H2S in AF, CSE-KO mice had decreased atrial sulfide levels, increased atrial superoxide levels, and enhanced propensity for induced persistent AF compared to wild type (WT) mice. Rescuing H2S signaling in CSE-KO mice by Diallyl trisulfide (DATS) supplementation or reconstitution with endothelial cell specific CSE over-expression significantly reduced atrial superoxide, increased sulfide levels, and lowered AF inducibility. Lastly, low H2S levels in CSE KO mice was associated with atrial electrical remodeling including longer effective refractory periods, slower conduction velocity, increased myocyte calcium sparks, and increased myocyte action potential duration that were reversed by DATS supplementation or endothelial CSE overexpression. Our findings demonstrate an important role of CSE and H2S bioavailability in regulating electrical remodeling and susceptibility to AF.

Abstract 17251: Knockdown of NOX2 Reduces Rotational Drivers in AF - A New Gene Therapy Approach for Atrial Fibrillation?

Introduction: Oxidative Stress (OS) is thought to be a mediator of atrial fibrillation (AF). However, the precise role of OS in electrical remodeling in AF is unknown. We assessed the effect of a novel gene-based strategy by performing knockdown of NOX2 in a clinically relevant large animal on the maintenance of rotational drivers in AF. Hypothesis: We hypothesized that the gene-based strategy by performing knockdown of NOX2 reduces rotational activities in AF. Methods: 1 week after pacemaker implantation, open-chest sub-epicardial gene injection of NOX2 shRNA was performed in the LA (PLA, LAFW, LAA), to significantly knockdown NOX2 in 6 dogs and 10 controls were also used. Epicardial high-density mapping was performed (117 electrodes, inter-elec.-distance 2.5mm) at day1 (gene injection) and at terminal day (up to 12weeks RAP) in 6 atrial regions. Number and stability of rotational activities were detected based on activation maps and CL was analyzed. Results: AF developed in controls (&gt;30 min) in 4-9 days, compared to &gt;21 days in NOX2 shRNA animals (p&lt;0.01). The stability of observed rotational drivers decreased (baseline gene delivery vs terminal day) in all left atrial regions: in the LAA (315.88±123.53ms, median 300.00ms vs 282.55±175.04ms, median 270ms), PLA (462.46±477.04ms, median 360ms vs 280.39±101.55ms, median 240ms), LAFW (416.67±162.50ms, median 405ms vs 241.67±92.63ms, median 195ms) (Figure A). Number of rotational activities reduced by 36.58% (P=0.14) after gene delivery. CL increased in the PLA from (93.74±30.11ms, median 85.00ms to 102.15±33.07ms, median 92.00ms after gene delivery (Figure C). Conclusions: Gene injection by NOX2 shRNA reduced the stability of rotational activities in AF. OS may be an important, dynamic mechanism underlying the formation and maintenance of the AF disease state. Targeted disruption of NOX2-dependent oxidative injury with a new gene therapy approach prevents onset as well as the perpetuation of AF.

Long Noncoding RNA HOTAIR Functions as a Competitive Endogenous RNA to Regulate Connexin43 Remodeling in Atrial Fibrillation by Sponging MicroRNA-613.

Several studies have indicated that long noncoding RNAs (lncRNAs)-HOX transcript antisense RNA (HOTAIR) is involved in some cardiovascular diseases by regulating gene expression as a competitive endogenous RNA (ceRNA). GJA1 encoding Cx43 is one potential target gene of microRNA-613 (miR-613). Meanwhile, there is a potential target regulatory relationship between HOTAIR and miR-613. The present study is aimed at investigating whether HOTAIR functions as a ceRNA to regulate the Cx43 expression in atrial fibrillation (AF) by sponging miR-613. The expressions of HOTAIR, miR-613, and Cx43 were detected in the right atrial appendages of 45 patients with heart valve disease, including 23 patients with chronic AF. The HOTAIR overexpressed and underexpressed HL-1 cell model were constructed to confirm the effect of HOTAIR on Cx43. Then, the Cx43 expression was detected to testify the interplay between HOTAIR and miR-613 after cotransfecting HOTAIR and miR-613. Furthermore, luciferase assays were performed to verify that HOTAIR could regulate Cx43 remolding as a ceRNA by sponging miR-613. The expression of HOTAIR and Cx43 was significantly downregulated in chronic AF group. HOTAIR regulated positively the Cx43 expression in HL-1 cells. The upregulated effect of HOTAIR on the Cx43 expression could be remarkably attenuated by miR-613. Moreover, the inhibitory effect of miR-613 on the Cx43 expression could be obviously mitigated by HOTAIR. At last, luciferase assays confirmed HOTAIR functioned as a ceRNA in the Cx43 expression by sponging miR-613. Our study suggests that HOTAIR, functioning as a ceRNA by sponging miR-613, is an important contributor to Cx43 remolding in AF.

Abstract 15011: Association of Pulmonary Hemodynamics and Right Ventricular Function With Incident Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Higher pulmonary artery systolic pressure (PASP) and right ventricular (RV) dysfunction are associated with higher risk of heart failure (HF) and mortality. Whether higher PASP and lower RV function are associated with risk of atrial fibrillation (AF) is unclear. Hypothesis: Higher PASP, higher pulmonary vascular resistance (PVR), and lower RV function are associated with incident AF after accounting for left atrial (LA) size and function, and left ventricular (LV) systolic and diastolic function. Methods: ARIC participants free of prevalent coronary heart disease (CHD), HF, AF, and with LA volume index (LAVi) &lt;34ml/m 2 and average E/e’ ratio &lt;14 in 2011-13 were included. We measured PASP, PVR, RV fractional area change (RVFAC), and RV-PA coupling (defined as RVFAC/PASP ratio) from 2D-echocardiograms. Incident AF (through 2018) was ascertained from hospital discharge codes and death certificates. We used Cox proportional hazards regression in our analysis. Results: We included 1915 participants (mean age 75 years, 69% female, 24% black) of whom 176 developed AF over a median follow-up of 6.3 years. PASP, PVR, and RV-PA coupling were significantly associated with incident AF after adjusting for measures of LA and LV structural and functional remodeling. RVFAC was not significantly associated with incident AF. Conclusions: In persons without CHD, HF, and LA enlargement, higher PASP and lower RV-PA coupling are associated with higher risk of AF after accounting for LA and LV structural and functional remodeling. This finding, which suggests a possible etiological role of RV remodeling for AF, needs further confirmation.

Serum interleukin-17A/interferon-gamma ratio as a predictor for the severity of atrial low voltage in atrial fibrillation: from FIB-MARK study

Abstract Background Atrial fibrosis is hallmark of structural remodeling in atrial fibrillation (AF), but the inflammatory mechanism remains unclear. The purpose of the present study was to identify the specific inflammatory biomarkers to atrial fibrosis evaluated by atrial low voltage (LV) in AF patients for clarification of the mechanism. Methods Forty inflammatory biomarkers were quantified in 16 consecutive AF patients measured left atrial low voltage during catheter ablation. Results Median %LV area was 17%. In Pearson's correlation analysis, interleukin (IL)-17A and interferon (IFN)-γ was the most significant positive and negative correlation with %LV (R=0.35 and 0.43, P&amp;lt;0.001). Furthermore, there was a significant correlation between IL-17A/IFN-γ ratio and %LV (R=0.65, P=0.007). The area under the receiver operator characteristics curve of IL-17A/IFN-γ ratio for significant LV (%LV &amp;gt;10% as a reference standard) was 0.88. IL-17A/IFN-γ ratio was significantly higher in patients with significant LV than those without (1.41 versus 0.97, P=0.01), Furthermore, the sensitivity, specificity, and accuracy for detecting significant LV were 60%, 100%, and 75.0% at the cutoff value of 1.3. The event free survival from recurrent atrial tachyarrhythmias was not significantly different between patients with and without IL-17A/IFN-γ ratio &amp;gt;1.3 (83.3% versus 80.0% at 1-year, P=0.81). Conclusions Among inflammatory biomarkers, IL-17A/IFN-γ ratio was a significant predictor for the severity of left atrial low voltage n AF patients. Further study is needed to reveal the association between IL-17A and IFN-γ for development of fibrosis in AF. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): JSPS KAKENHI GrantNumber JP19K17594

Atrial matrix remodeling in atrial fibrillation patients with aortic stenosis

BackgroundThis study aimed to evaluate atrium extracellular matrix remodeling in atrial fibrillation (AF) patients with severe aortic stenosis, through histological fibrosis quantification and extracellular matrix gene expression analysis, as well as serum quantification of selected protein targets.MethodsA posthoc analysis of a prospective study was performed in a cohort of aortic stenosis patients. Between 2014 and 2019, 56 patients with severe aortic stenosis submitted to aortic valve replacement surgery in a tertiary hospital were selected.ResultsFibrosis was significantly increased in the AF group when compared to sinus rhythm (SR) patients (p = 0.024). Moreover, cardiomyocyte area was significantly higher in AF patients versus SR patients (p = 0.008). Conversely, collagen III gene expression was increased in AF patients (p = 0.038). TIMP1 was less expressed in the atria of AF patients. MMP16/TIMP4 ratio was significantly decreased in AF patients (p = 0.006). TIMP1 (p = 0.004) and TIMP2 (p = 0.012) were significantly increased in the serum of AF patients. Aortic valve maximum (p = 0.0159) and mean (p = 0.031) gradients demonstrated a negative association with serum TIMP1.ConclusionsAtrial fibrillation patients with severe aortic stenosis present increased atrial fibrosis and collagen type III synthesis, with extracellular matrix remodelling demonstrated by a decrease in the MMP16/TIMP4 ratio, along with an increased serum TIMP1 and TIMP2 proteins.

Enhanced monocyte migratory activity in the pathogenesis of structural remodeling in atrial fibrillation.

Pathophysiological roles of monocytes in atrial fibrillation (AF), particularly for the progression of structural remodeling of the left atrium (LA), remain elusive. This study examined the association between the characteristics of circulating and local monocytes and extent of structural remodeling in LA, gauged by LA size, in AF patients. First, 161 AF patients who were referred for catheter ablation were enrolled and divided into two groups according to the median of LA diameter (≤39 mm: normal LA group, >39 mm: enlarged LA group). As a control group, 22 patients underwent catheter ablation for paroxysmal supraventricular tachycardia (PSVT) without history of AF were analyzed. Blood samples were collected for flow cytometric analyses to evaluate monocyte subsets based on the levels of CD14 and CD16. Moreover, monocytes were isolated from blood to measure CC chemokine receptor 2 (CCR2) transcripts and protein levels, and migratory activity toward monocyte chemoattractant protein 1 (MCP-1). Second, to characterize the local monocytes in the atrial wall in AF, the resected left atrial appendages (LAA) in AF patients underwent cardiac surgery were histologically evaluated (n = 20). The proportions of monocyte subsets based on CD14 and CD16 expressions were not significantly different between the normal and enlarged LA group. Both transcripts and total protein levels of CCR2 in monocytes were higher in the enlarged LA group compared to those in the normal LA group. In the enlarged LA group, monocytes exhibited more enhanced migratory activity than the normal LA group. Moreover, we found a significantly higher number of CCR2-positive monocytes/macrophages in the LAA in the enlarged LA group. Enhanced migratory activity in circulating and local monocytes may play a pivotal role in the pathogenesis of progression in atrial remodeling in AF patients.

Attenuation of Oxidative Injury With Targeted Expression of NADPH Oxidase 2 Short Hairpin RNA Prevents Onset and Maintenance of Electrical Remodeling in the Canine Atrium: A Novel Gene Therapy Approach to Atrial Fibrillation.

Atrial fibrillation (AF) is the most common heart rhythm disorder in adults and a major cause of stroke. Unfortunately, current treatments of AF are suboptimal because they are not targeted to the molecular mechanisms underlying AF. Using a highly novel gene therapy approach in a canine, rapid atrial pacing model of AF, we demonstrate that NADPH oxidase 2 (NOX2) generated oxidative injury causes upregulation of a constitutively active form of acetylcholine-dependent K+ current (IKACh), called IKH; this is an important mechanism underlying not only the genesis, but also the perpetuation of electric remodeling in the intact, fibrillating atrium. To understand the mechanism by which oxidative injury promotes the genesis and maintenance of AF, we performed targeted injection of NOX2 short hairpin RNA (followed by electroporation to facilitate gene delivery) in atria of healthy dogs followed by rapid atrial pacing. We used in vivo high-density electric mapping, isolation of atrial myocytes, whole-cell patch clamping, in vitro tachypacing of atrial myocytes, lucigenin chemiluminescence assay, immunoblotting, real-time polymerase chain reaction, immunohistochemistry, and Masson trichrome staining. First, we demonstrate that generation of oxidative injury in atrial myocytes is a frequency-dependent process, with rapid pacing in canine atrial myocytes inducing oxidative injury through the induction of NOX2 and the generation of mitochondrial reactive oxygen species. We show that oxidative injury likely contributes to electric remodeling in AF by upregulating IKACh by a mechanism involving frequency-dependent activation of PKCε (protein kinase C epsilon). The time to onset of nonsustained AF increased by >5-fold in NOX2 short hairpin RNA-treated dogs. Furthermore, animals treated with NOX2 short hairpin RNA did not develop sustained AF for up to 12 weeks. The electrophysiological mechanism underlying AF prevention was prolongation of atrial effective refractory periods, at least in part attributable to the attenuation of IKACh. Attenuated membrane translocation of PKCε appeared to be a likely molecular mechanism underlying this beneficial electrophysiological remodeling. NOX2 oxidative injury (1) underlies the onset, and the maintenance of electric remodeling in AF, as well, and (2) can be successfully prevented with a novel, gene-based approach. Future optimization of this approach may lead to a novel, mechanism-guided therapy for AF.

The Association of Cardio-Ankle Vascular Index (CAVI) with Biatrial Remodeling in Atrial Fibrillation.

Aim: Arterial stiffness results in elevated left ventricular filling pressure and can promote atrial remodeling due to chronic pressure overload. However, the impact of arterial stiffness on the process of atrial remodeling in association with atrial fibrillation (AF) has not been fully evaluated. Methods: We enrolled 237 consecutive patients diagnosed with AF who had undergone ablation; data from 213 patients were analyzed. Cardio-ankle vascular index (CAVI) was used as a marker of arterial stiffness. The left atrial (LA) and right atrial (RA) volumes were determined by computed tomography imaging; atrial conduction and voltage amplitude were evaluated using a three-dimensional electromapping system used to guide the ablation procedure. Result: In univariate analysis, CAVI significantly correlated with atrial structural and electrical remodeling (LA volume index, r =0.297, P =0.001; RA volume index, r =0.252, P =0.004; LA conduction velocity, r =0.254, P = 0.003; LA mean voltage, r =−0.343, P =0.001, RA mean voltage; r =−0.245, P =0.015). Multivariate regression analysis revealed that CAVI and plasma levels of N-terminal B-type natriuretic peptide were independent determinants of LA and RA remodeling, respectively. On the other hand, age and LA conduction velocity were independent variables with respect to CAVI. Age-adjusted CAVI was highest in long-standing persistent AF when compared with measures of persistent or paroxysmal AF. Conclusion: CAVI was closely associated with biatrial remodeling in patients diagnosed with AF. These results suggest that arterial stiffness may play a significant role with respect to disease progression.

Adverse remodeling in atrial fibrillation following isolated aortic valve replacement surgery.

Atrial fibrillation (AF) is the most common arrhythmia with adverse clinical outcomes. Aortic valve replacement (AVR) is one of the most frequently performed cardiac surgeries, although there is scarce evidence on arrhythmic outcomes. We aimed to evaluate AF during the first year post- isolated aortic valve replacement surgery and its clinical, analytical, and echocardiographic predictors. Severe aortic stenosis patients with no prior atrial fibrillation submitted to isolated aortic valve replacement surgery were included in our study, of which 316 remained in sinus rhythm and 24 developed AF. We performed logistic regression searching for AF predictors and a longitudinal comparison between pre and post-operative echocardiographic data. Postoperative AF (POAF), diabetes, and follow-up indexed Left Atrium Diameter (iLAD) were significantly higher in the group of patients developing AF. POAF and iLAD were independent AF predictors at follow-up. No differences between groups were found regarding baseline and follow-up echocardiographic data except for indexed Left Ventricle End-diastolic Diameter (LVED), which failed to decrease after surgery in the AF group. POAF and iLAD independently predicted AF at 1 year following isolated AVR surgery in aortic stenosis patients with no AF history. iLVED did not decrease significantly at follow-up in AF patients, possibly reflecting adverse ventricular remodeling.

P333Left atrial function by echocardiography is independent of degree of left atrial electrical scar

Abstract Introduction Assessment of left atrial function via transthoracic echocardiography (TTE) is performed most commonly by measuring the transmitral A wave in sinus rhythm. Left atrial (LA) fibrosis plays an important role in the pathogenesis and perpetuation of Atrial Fibrillation (AF). It may be identified by bipolar voltage (BiV) mapping, which can easily be performed at the beginning of a Pulmonary Vein Isolation (PVI) procedure. The relationship between the degree of LA fibrosis, characterised with mapping, and LA function, determined by echocardiography, has not previously been elucidated. Methods Patients were enrolled in a project to evaluate the degree of fibrosis during PVI procedures. Pre-procedure TTEs of those presenting in sinus rhythm were assessed and the transmitral A wave was measured and compared to the degree of scarring seen. The high density electroanatomic maps (HD-EAMs) created during the PVIs were analysed using a novel VHA algorithm after the procedure. All points with voltages &amp;lt; 0.5mV were defined to have electrical scar. Patients were classified into 4 quartiles based on the levels of scar seen (Figure 1). Results 39 patients were included in the evaluation. Average age was 60.6 +/- 13.2 years. 32 (82.0%) of the patients were male. Mean CHADS2VASc score was 1.5. The mean percentage of scar was calculated as 19.6 +/- 15.9%. The average A wave was 0.62 +/- 0.18 ms-1. Pearson’s correlation coefficient showed no relationship between LA scar and either A wave velocities (r = 0.26, p = 0.11) or E:A ratio (r=-0.02, p = 0.91). A significant correlation between A wave velocity and CHADS2VASc was observed (r = 0.49, p = 0.001). Conclusion Our study demonstrates no relationship between degree of LA scarring and reduced LA function on TTE as assessed by the A wave. It has been established that structural remodelling in AF (such as atrial dilatation) may occur independently of the electrical remodelling. A potential explanation for our findings is that the electrical scarring in AF, which results in alterations in refractory periods, precedes the negative remodelling which ultimately results in reduced atrial function. This hypothesis would need to be further evaluated in larger studies. Abstract Figure 1

Omentin-1 is associated with atrial fibrillation in patients with cardiac valve disease

BackgroundEpicardial adipose tissue (EAT) remodeling and adipocytokines are associated with structural remodeling in atrial fibrillation (AF). However, the role of omentin-1, a novel adipocytokine, in structural remodeling remains unknown.MethodsHematoxylin and eosin (H&E) and Masson’s trichrome stains were used to investigate the histology of EAT and right atrial appendages. The expression levels of adipocytokines in these human samples were determined by immunohistochemical assay and western blotting. Models of transforming growth factor (TGF)-β1-induced activation of cardiac fibroblasts (CFs) and TGF-β1-induced endothelial-mesenchymal transition (EndMT) of human umbilical vein endothelial cell (HUVEC) were established to explore roles of omentin-1 in these processes. To determine changes in adipocytokines secretion under hypoxia conditions, adipocytes were treated with 5% O2 and 95% N2, and then CFs and HUVECs were co-cultured with the conditioned medium of adipocytes to determine the effects of hypoxia-treated adipocytes on these cells.ResultsExpression of omentin-1 was downregulated in the EAT and right atrial appendages from patients with AF compared to samples from patients without AF, while the TGF-β1 level was upregulated in EAT from patients with AF. EAT from patients with AF exhibited adipocyte hypertrophy and severe interstitial fibrosis. Omentin-1 inhibited TGF-β1-induced CF activation and reversed TGF-β1-induced HUVEC EndMT. Adipocytes treated with hypoxia exhibited downregulation of omentin-1 and partly activated CFs.ConclusionsThis study demonstrated that omentin-1 was an antifibrotic adipocytokine and was downregulated in patients with AF, which was partly mediated by hypoxia.

Understanding tricuspid valve remodelling in atrial fibrillation using three-dimensional echocardiography.

Atrial fibrillation (AF) has been associated with tricuspid annulus (TA) dilation in patients with severe functional tricuspid regurgitation (TR); however, the impact of AF is less clear in patients without severe TR. Our aim was to characterize TA remodelling in patients with AF in the absence of severe TR using 3D transoesophageal echocardiography (TOE). Ninety patients underwent clinically indicated transthoracic and TOE: non-structural (NS)-AF (n = 30); AF with left heart disease (LHD) (n = 30), and controls in sinus rhythm (n = 30). Three-dimensional TOE datasets were analysed to measure TA dimensions using novel dedicated tricuspid valve software. The NS-AF group showed biatrial dilatation and normal right ventricular (RV) size with decreased longitudinal function compared to controls, whereas the LHD-AF group showed biatrial dilatation, RV enlargement, decreased biventricular function, and higher systolic pulmonary artery pressure compared with the other groups. Indexed TA area, minimum diameter, maximum diameter, and total perimeter were significantly larger in the NS-AF group than in controls (measurements in end-diastole: 6.4 ± 1.1 vs. 5.0 ± 0.6 cm2/m2, 1.8 ± 0.3 vs. 1.6 ± 0.2 cm/m2, 2.1 ± 0.3 vs. 1.9 ± 0.2 cm/m2, and 6.6 ± 0.9 vs. 5.9 ± 0.7 cm/m2, respectively, all P < 0.05). There was no significant difference in any indexed TA parameter between AF groups. TA circularity index (ratio between minimum and maximal diameters) and TA fractional area change between end-diastole and end-systole were no different among the three groups. AF is associated with right atrial and tricuspid annular remodelling independent of the presence of LHD in patients with intrinsically normal tricuspid leaflets without severe TR.

DACT2 regulates structural and electrical atrial remodeling in atrial fibrillation.

BackgroundAtrial fibrillation (AF) is the most common sustained arrhythmia. DACT2 is a novel and important mediator of signaling pathways. The aim of this study was to investigate the clinical significance and functions of DACT2 expression in AF.MethodsImmunohistochemistry was used to detect the DACT2 expression pattern in valvular disease patients. DACT2 was overexpressed in HL-1 cells and primary atrial fibroblasts. The expression levels of the potassium channel, the L-type calcium current channel, sodium ion channel proteins and collagen proteins were detected by real-time polymerase chain reaction (RT-PCR). The proteins involved in the Wnt and TGF-β signaling pathways were detected after DACT2 overexpression by western blotting.ResultsDACT2 expression was significantly associated with AF (P=0.016). The fibrosis ratio in the strong DACT2 expression group was significantly lower than that in the weak DACT2 expression group (weak: 0.198±0.091, strong: 0.129±0.064, P=0.048), and a negative correlation between DACT2 expression levels and fibrosis severity was observed (Spearman rho =−0.476, P=0.010). DACT2 significantly increased the expression levels of KCNE5 and decreased the levels of KCNH2 and SCN5A. Overexpression of DACT2 significantly inhibited the expression of collagen I and collagen III in primary rat atrial fibroblasts. DACT2 could facilitate β-catenin accumulation by reducing its phosphorylation at Thr41/Ser45 in HL-1 cells and inhibit the TGF-β signaling pathway in primary atrial fibroblasts.ConclusionsDACT2 played a role in AF by regulating both structural and electrical atrial remodeling and by affecting β-catenin accumulation and TGF-β signaling, and it could serve as a protective factor against AF in valvular heart disease.