Atrial Fibrosis Research Articles

CE-452780-1 LEFT ATRIAL VOLUME IS THE STRONGEST PREDICTOR OF ATRIAL ARRHYTHMIA RECURRENCE AFTER PULMONARY VEIN ISOLATION ALONE IN PERSISTENT AF: A DECAAF II SUBSTUDY

Left atrial volume (LAV) is a known predictor of atrial arrhythmia recurrence (AAR) after pulmonary vein isolation (PVI). We sought to assess the role of LAV in predicting AAR in pts with persistent atrial fibrillation (PrAF) undergoing PVI alone as the initial procedure. The DECAAF II Trial was a prospective randomized trial of pts with PrAF undergoing initial ablation. Baseline demographics and risk factors were collected for all pts, who also underwent late gadolinium enhanced magnetic resonance imaging for calculation of baseline LAV and atrial fibrosis. Of 408 pts in the control group (PVI alone), 47 were excluded predominantly due to receiving additional LA ablation. The remaining 361 pts constituted the study population. Pts provided single-lead home ECG strips once daily and during symptoms. The primary endpoint was single-procedure success, defined as freedom from AAR (AF, flutter or atrial tachycardia > 30 sec) following a 90-day blanking period through 365 days post-procedure. A receiver operating curve (ROC) was performed to identify the optimal LAV predicting success. A covariate adjusted Cox regression model was performed to identify independent predictors of outcome. At baseline, the mean pt age was 62±9 yrs, and 80% were male. Mean fibrosis was 19±8%, and median LAV was 129 cc (IQR: 104-154). ROC analysis identified LAV < 114 cc as the optimal cut-point. In the Cox model, LAV < 114 cc was the only significant predictor of procedural success (p=0.004) with a hazard ratio of 0.53 (95% CI 0.35-0.82,table). Pts with LAV < 114 cc had one year freedom from RAA of 73% (95% CI 65-81%) vs 53% (95% CI 47-60%) in pts with larger LAV (p=0.00043,log-rank,figure). Baseline LAV < 114 cc was present in 120/361 pts (33%). LAV is the strongest predictor of RAA in pts with PrAF undergoing PVI alone as the first ablation procedure. PVI may be a reasonable initial approach for PrAF ablation in pts with small LAV.Tabled 1Left Atrial (LA) volume as a predictor of AF recurrence using Cox regression analysis. CHF: Congestive Heart Failure. HTN: Hypertension. BMI: Body Mass Index.Variable (Ref)Estimatep-valueHazard ratio [95% CI]Age (Years)0.012±0.00110.2581.01 [0.99 - 1.03]Sex (Male)-0.291±0.2240.1950.75 [0.48 - 1.16]Baseline Fibrosis-0.006±0.0130.6590.99 [0.97 - 1.02]Antiarrhythmics history (Yes)-0.068±0.1980.7300.93 [0.63 - 1.38]CHF (Yes)0.151±0.2400.5291.16 [0.73 - 1.86]HTN (Yes)0.103±0.1930.5941.11 [0.76 - 1.62]History of Stroke (Yes)0.188±0.3110.5461.21 [0.66 - 2.22]Tobacco (Yes)0.264±0.1830.1491.30 [0.91 - 1.87]Failed antiarrhythmics treatment (Yes)0.107±0.1990.5931.11 [0.75 - 1.64]BMI0.026±0.0160.0941.03 [1.00 - 1.06]LA Volume (<114)-0.631±0.2190.0040.53 [0.35 - 0.82] Open table in a new tab

PO-01-095 REGIONAL DIFFERENCES IN ATRIAL FIBER STRAINS IN HEART FAILURE PATIENTS WITH AND WITHOUT ATRIAL FIBRILLATION

Left atrial (LA) strain is inhibited by atrial fibrosis, which is a hallmark of atrial fibrillation (AF). Retrospective gated computed tomography (CT) imaging with feature tracking (FT) can measure three-dimensional (3D) local LA strain. Atrial myocardial fiber directions may play an important role in preferred deformation, and therefore atrial fiber strains should be considered. Using the average endocardial fiber architecture from seven hearts imaged ex vivo with high resolution diffusion-tensor magnetic resonance imaging (DT-MRI), the endocardial fiber strain can be measured. To investigate regional and global differences in atrial endocardial fiber strains between heart failure (HF) patients with and without AF. 30 HF patients underwent 10-frame gated CT imaging, and FT was used to measure local endocardial fiber strain (Fig. A). The LA body was classified into five regions using Universal Atrial Coordinates (Fig. B). Global and regional strains were reported as the mean strain over the entire LA body surface and within each region, respectively. The fiber strain range over the cardiac cycle was used to stratify between HF patients with and without AF. The left ventricular ejection fraction (LVEF) and left atrial ejection fraction (LAEF) were calculated from the gated CT images. HF patients with AF had smaller global fiber strain ranges than those without AF (5.9 ± 3.7 % vs 14.2 ± 8.9 %, p = 0.011) (Fig. C). All regions had higher strain ranges in HF patients without AF and the anterior wall exhibited the most significant difference between groups (7.8 ± 4.1 vs 17.9 ± 10.6, p = 0.009). ROC analysis using global strain range to stratify between patient groups gave an AUC of 0.853 (Fig. D). The anterior wall was the region with the highest AUC of 0.842. LVEF was similar between patient groups (p=0.682), however LAEF differed (p=0.002) (Fig. E). Patients with AF had decreased fiber strain ranges globally and regionally compared to those without AF. Strain range in the anterior wall most significantly decreased in the presence of AF, which may suggest a regionally higher fibrosis burden. The LVEF was similar between HF patients with and without AF, however the LAEF differed, which suggests strain differences were driven by LA dysfunction.

Atrial cardiomyocytes orchestrate the development of profibrotic inflammatory profile associated with atrial fibrillation vulnerability

Atrial fibrillation (AF) is the most common type of arrhythmia encountered clinically. AF risk factors include hypertension, respiratory diseases, obesity, or heart failure. Right heart disease (RHD) has also been described among AF risk factors associated with an atrial inflammatory profile leading to AF. Studies focusing on the cardiomyocytes (CM) orchestration of the tri-factorial relation between RHD, inflammation, and AF are rare. This project aims to characterize the proarrhythmogenic remodeling affecting atrial cardiomyocyte in a rat model of RHD induced by permanent pulmonary trunk constriction. Characterize RHD induced electrophysiological and morphological CM remodeling leading to atrial inflammation and fibrosis, responsible for increased AF susceptibility. Pulmonary artery banding (PAB) was performed on Wistar rats weighing 225–275 g to induce right-sided cardiac hypertrophy and dilation. Sham animals did not receive the PAB surgery. Cardiac echography and electrophysiological studies were performed in vivo on all animals before sacrifice, 21 days post-surgery. Optical mapping was performed ex-vivo on Langendorff-perfused hearts. Freshly isolated right ventricular (RV), as well as right and left atrial (RA and LA) CM, underwent contractility recording in vitro. Histological analyses were performed to assess myocardial fibrosis and Connexin-43 levels. Genes and protein levels were obtained by qPCR and Western-blot analyses respectively. PAB animals developed severe ventricular and atrial myocardial hypertrophy and dilation compared to Sham, as assessed by echocardiography. PAB animals were significantly more susceptible to AF compared to Sham. Freshly isolated CM revealed that overall CM size was increased in PAB animals, and contractile activity of CM was increased compared to the Sham rats. Analyses of targeted protein and gene expression levels by immunohistochemistry and qPCR analyses showed enhanced expression of fibrosis and inflammation-related compounds in whole-RA and RA CM from PAB, compared to Sham. RHD induces electro-physiological remodeling influencing the RA CM contractile machinery which in turn, leads to the development of pro-arrhythmogenic substrate including atrial inflammation, fibrosis, and enhanced AF inducibility.

PO-02-243 IMPACT OF PARTIAL CONSTRICTION OF THE ARTERIAL PULMONARY TRUNK ON THE DEVELOPMENT OF SUSCEPTIBILITY TO ATRIAL FIBRILLATION IN RATS

Atrial Fibrillation (AF) is the most frequent and clinically important form of cardiac arrhythmia. It has been demonstrated that cardiovascular comorbidities such as myocarditis, myocardial infarction, obesity, or pulmonary hypertension (PH) promote cardiac remodeling associated with the development of atrial arrhythmogenic substrates. Right-heart disease (RHD), characterized by chronic right-sided cardiac structural and functional anomalies, has also been designated among AF risk factors. Inflammation is one of the common denominators between cardiovascular risk factors and AF vulnerability. However, no study has described the progression of the molecular and cellular changes involved in the causal link relating RHD, the activation of atrial inflammation, and the development of AF substrate. This study aims to establish the characterization of the progression of atrial arrhythmogenic inflammation in a rat model of RHD. Hypothesis Permanent constriction of the pulmonary artery trunk (PAT) provokes severe RHD associated with progressive atrial inflammation and fibrosis responsible for enhanced AF vulnerability. Pulmonary Artery Banding (PAB) reducing the PAT diameter to 1 mm, was surgically performed on 225-275g Wistar rats to induce permanent PH and severe RHD. Sham animals received PAB-mimicking intervention without ligation. Echocardiography and electrophysiological studies (EPS) were performed in vivo, on all the animals at Day0, Day7, Day14 and Day21 post-surgery. The atrial tissues were analyzed by optical mapping, histology (Masson's Trichrome), qPCR and immunoblotting. Within three weeks, PAB rats developed severe right heart remodeling characterized by progressive ventricular and atrial hypertrophy and dilation. Right atrial (RA) optical mapping revealed a reduction in conduction velocity and refractory periods in PAB rats compared to Sham. PAB rats were more vulnerable to AF than Sham starting at 7th-day until the 21st-day post-surgery. Histological analysis shows that since the 14th day until the 21st-day post-surgery RA fibrosis significantly increased in PAB rats compared to sham. Quantitative polymerase chain reaction performed on inflammation and fibrosis-related genes such as IL6, Tgfb1 or Col1a1 revealed a progressive aggravation of RA inflammatory and fibrotic status in PAB rats from Day7, Day14 to Day2 Severe RHD is associated with progressive and unresolved RA inflammation and fibrosis provoking an aggravation of AF vulnerability overtime

PO-02-197 PREDICTORS OF ATRIAL FLUTTER RECURRENCE AFTER ATRIAL FIBRILLATION ABLATION: THE CRUCIAL ROLE OF STRUCTURAL AND MORPHOLOGICAL LEFT ATRIAL REMODELING

Recurrence of supraventricular tachyarrhythmias after catheter ablation of atrial fibrillation (AF) is common, representing 30% of patients. Although AF recurrence occurs mostly, 10% of the patients face arrhythmia recurrence through atypical atrial flutter (AFL). The diagnostic and therapeutic management of atypical AFL is challenging. Predicting atypical AFL after AF catheter ablation is critical. To identify morphological and structural predictors of recurrence in the form of atypical AFL compared to AF based on Late Gadolinium Enhancement Cardiac Magnetic Resonance (LGE-CMR). From January 2013 to December 2021, 56 patients facing post-AF-CA atypical AFL were included in the monocentric and retrospective cohort. 112 patients with AF recurrence were randomly included in the cohort from the general database. Pre-procedure LGE-CMR was post-processed for every patient to assess global and regional left and right atrial (LA, RA) fibrosis quantification using an image intensity ratio > 1.32 as fibrosis. Sphericity was calculated as the percentage of similarity with respect to a sphere, and the volume of LA and RA were calculated. 168 patients who had faced supraventricular arrhythmia recurrence after AF-CA were included in the monocentric retrospective cohort. They were mainly male (72.1%), with a median CHADS-VASc score of 1.4 +/- 1.3, a number of previous CA of 2,2 +/- 0.4, and a biatrial dilation (LA volume index of 53.5 ml/m2, RA volume index of 59.6 ml/m2). An age superior to 65 (OR=6.61, CI95%:2.18-14.41, p<0.01), the number of previous CA procedures (OR=3.03, CI95%:1.17-7.81, p=0.02), a history of management of invasive additional lines (OR=2.48, CI95%:1.01-6.27, p=0.05), an elevated LA sphericity (OR=1.33, CI95%:1.11-1.59, p<0.01) and an increased LA fibrotic burden (OR=1.03, CI95%:1.00-1.07, p=0.04) independently predicted the occurrence of atypical AFL compared with AF recurrence after AF-CA (Figure). Specifically, an increased amount of fibrosis in the lateral LA zone area (OR=1.03, CI95%:1.01-1.04, p<0.01)] was an independent predictor of recurrence in the form of atypical AFL compared with AF recurrence (Table). The structural LA remodeling of AE, including LA fibrosis and LA sphericity, is a predictor of recurrence in the form of atypical atrial flutter compared with AF recurrence after AF-CA.

Impact of Resolvin-D1 in the resolution of atrial inflammation and arrhythmogenic cardiac remodelling in a rat model of myosin light chain 4 (MYL-4) mutation

Atrial fibrillation (AF) is the most common heart rhythm disorder. AF risk factors include age, hypertension, obesity, or myocardial infarction. AF can cause severe complications such as stroke and sudden death. Hence, AF is a major public health issue. Proteins called actins and myosins interact to allow myocardial contractions. A mutation affecting the gene encoding a myosin light chain type 4 (MYL-4) protein is associated with a genetically inheritable form of AF. Furthermore, we have recently demonstrated that MYL-4 rats develop atrial inflammation and fibrosis. Conventional anti-inflammatory medications are ineffective against AF. Bioactive endogenous autacoids, called specialized proresolving mediators, including resolvin-D1: RvD1, have been described to promoting inflammation-resolution and potentially reduce AF occurrence. To elucidate the impact of a triggered resolution of inflammation in the prevention of AF. Resolution of atrial inflammation by daily treatment with RvD1 prevents the development of AF in a rat model of MYL-4 mutation. We have developed a colony of male and female Sprague-Dawley Knock-In rats, mutated on the Myl-4 gene. A dose of 2 μg/kg/d RvD1 (or equivalent dose of vehicle) was administered to wild-type (WT) and MYL-4 rats for 21 days. AF was assessed by in vivo electrophysiological study. The structure of the atria was studied by echocardiography, histology and electron microscopy. The expression levels of proteins (by western blotting) and genes (by qPCR) involved in inflammation and cellular apoptosis have been assessed in the right and left atria of MYL-4 rats compared to WT. Compared to WT rat, MYL-4 mutation causes an increased risk of AF, associated with an inflammatory and apoptotic profile in the atria. We observed that daily treatment with RvD1 prevents atrial inflammation (IL-1β), reduces cell death (Bax, Bcl2) and attenuates atrial structural remodelling (dilation, hypertrophy). Inflammation plays a crucial role in the development of arrhythmogenic atrial remodeling observed in rats carrying MYL4 mutation. In addition, this project contributes to highlight the potential therapeutic effects of the RvD1 treatment, to resolve inflammation and prevent AF in the context of a rhythm disturbances provoked by cardiac mutations.

PO-01-204 AN ARTIFICIAL INTELLIGENCE (AI)-ASSISTED END-TO-END COMPUTATIONAL PLATFORM FOR PREDICTION OF EXTRA-PULMONARY VEIN (EXTRA-PVI) ABLATION TARGETS IN ATRIAL FIBRILLATION (AF) PATIENTS WITH FIBROSIS REMODELING

Existing strategies targeting the extra-PVI AF substrate have failed to improve outcomes, as shown by clinical trials. There is an urgent need to establish new approaches that overcome existing limitations. We have shown previously, in a feasibility study, that bi-atrial personalized computational modeling can guide ablation in patients with fibrosis detected on late gadolinium enhancement MRI (LGE-MRI). However, the approach had laborious aspects, such as segmentation of both atria and fibrosis distribution, and determining substrate locations capable of sustaining rotors. These prevented the approach from being directly implementable in clinical workflows. To develop an AI-assisted computational platform for personalized extra-PVI substrate ablation target prediction in patients with atrial fibrosis detected by LGE-MRI, as part of an FDA-approved randomized clinical trial. We designed an AI-assisted platform enabling end-to-end modeling workflow for predicting extra-PVI ablation targets. The platform consists of 3 main components (Figure): i) personalized bi-atrial model construction from LGE-MRI, ii) personalized simulation of substrate AF inducibility, and iii) personalized extra-PVI ablation strategy implementable in the clinical workflow. For the first component, we developed, validated, and tested a deep learning approach to bi-atrial geometry and fibrosis segmentation, which consisted of a cascade of 4 neural networks (NNs). Extra-PVI substrate rotor inducibility was probed by pacing from numerous sites; locations capable of sustaining persistent drivers were determined using a novel NN approach and ablated. Each ablation was followed by the inducibility test, repeated until full substrate non-inducibility from any pacing site was achieved. The platform was successfully tested on 17 AF patients by multiple operators of differing expertise, with consistent results. Atrial geometry/fibrosis segmentation was achieved in 15 min, as compared to 5 hours pre-AI implementation. Using the NN approach for targeted substrate ablation ensured robustness and reproducibility of the predicted targets. Finally, a seamless import of atrial geometry and the optimal set of targets was achieved in a number of EAM systems. We developed a robust AI-assisted computational platform for prediction of extra-PVI atrial substrate ablation targets in AF patients with fibrosis, enabling our FDA-approved randomized clinical trial.

PO-04-030 PREDICTORS OF LOW VOLTAGE IN POSTERIOR WALL AND ASSOCIATION WITH ABLATION OUTCOMES

Areas of low voltage electrograms (<0.5 mV) (LVA) are known to correlate with areas of atrial fibrosis and are related to clinical outcomes after ablation for atrial fibrillation (AF). To identify predictors of posterior wall (PW) LVA and associate PW LVA with ablation outcomes. Patients with AF who underwent PW and PVI ablation were included. Pre-ablation voltage map data was obtained from CARTO and LVA was recorded. Patients were considered to have LVA if there was any voltage <0.5 mV in the PW. Patient characteristics and outcomes were also recorded. Time to ablation was defined as time from AF diagnosis to ablation. Recurrence <1 year was noted if AF was detected between 3 months and 1 year, to allow for 3-month blanking period. A total of 80 patients were included: 38 (47.5%) had PW LVA with a mean area of 3.54 + 5.76 cm2 (median 1.1, IQR .5-3.6), 42 (52.5%) had no PW LVA. Duration of AF was associated with presence of PW LVA: 18.42% of patients with paroxysmal AF had low voltage area, 21.05% for persistent AF, 60.53% for longstanding persistent (p = 0.036). Predictors of PW LVA are included in figure 2. Patients who sought ablation greater than 1 year after diagnosis of AF had larger PW LVA (2.2 + 5.19 cm2 vs 0.67 + 1.2, p = 0.13). Seventy-five patients had 1-year follow up at 366.52 + 69.23 days after ablation. Mean follow up was 899.98 + 453.72 days. Recurrence rates were higher in those with PW LVA compared to those without PW LVA at both <1 year (26.32% vs 9.52%, p = 0.048) and >1 year (42.11% vs 23.81%, p = 0.08). Respective odds ratios for recurrence at <1 year and >1 year based on presence of PW LVA was 3.39 (p = 0.05) and 2.32 (p = 0.08). Patients without PW LVA had higher incidence of atrial flutter before 1-year follow up (21.43% vs 5.26%, p = 0.036). CHADS2-VAsc score, vascular disease and duration of AF are positive predictors of PW LVA. Presence of PW LVA is associated with higher recurrence rates after ablation, however lower incidence of atrial flutter.

PO-02-144 ETIOLOGICAL AND MOLECULAR DETERMINANTS OF ATRIAL ENDOMYSIAL FIBROSIS: RESULTS FROM THE CATCH ME CONSORTIUM

We recently demonstrated that, in human atria, endomysial fibrosis causes conduction disturbances during atrial fibrillation (AF), while overall connective tissue content (over-all fibrosis) has no effect. Etiological and molecular determinants of endomysial fibrosis are largely unknown. To study transcriptional changes associated with increased endomysial fibrosis. We quantified over-all and endomysial atrial fibrosis using staining with WGA in left (LAA, n=95) and right (RAA, n=76) atrial appendages sampled from a European cohort (CATCH ME) of patients undergoing cardiac surgery. The contributions of AF, heart failure (HF), sex, age, and 4 principal components accounting for confounding clinical characteristics to over-all and endomysial fibrosis were determined in a multivariate model. RNA sequencing was performed to explore biological pathways associated with the two types of fibrosis. Over-all and endomysial fibrosis were moderately correlated (LAA: r=0.69, RAA: 0.61, both p<0.001) and more pronounced in RAA than in LAA samples (p<0.001). In LAA, persistent AF, female sex, and HF were independently associated with endomysial fibrosis, while over-all fibrosis was only associated with sex and HF. Likewise, in RAA, persistent AF was associated with endomysial fibrosis, while over-all fibrosis was not. Expression of 18 genes was univariately associated with endomysial fibrosis in LAA but only 1 in RAA. There were no genes associated with over-all fibrosis. After correction for relevant clinical traits, BMP10 showed the strongest association with endomysial fibrosis amongst coding genes (p=3.16E-04, LAA). In an independent validation cohort (RACE V Tissue Bank Project, n=162 pts undergoing cardiac surgery), out of 11 biomarkers reflecting inflammation, fibrosis, vascular dysfunction, or ischemia, BMP10 plasma levels were most strongly associated with endomysial fibrosis (p<0.001), but not with over-all fibrosis. In summary, female sex, HF, and AF are the main drivers of fibrosis in human atria. However, endomysial fibrosis is independently associated with AF whereas over-all fibrosis is not. BMP10 is a specific marker of endomysial fibrosis. Our findings suggest that distinct mechanisms are involved in the development of over-all versus endomysial fibrosis in human atria.

Molecular mechanisms of postoperative atrial fibrillation in patients with obstructive sleep apnea.

Obstructive sleep apnea (OSA) promotes atrial remodeling and fibrosis, providing a substrate for atrial fibrillation (AF). Herein, we investigate the pathophysiological mechanisms of AF in association with OSA in a cohort of cardiac surgery patients. A prospective study including patients undergoing cardiac surgery. Biomarkers reflective of AF pathophysiology (interleukin [IL-6], C-reactive protein [CRP], von Willebrand factor [vWF], N-terminal pro-brain natriuretic peptide [NT-proBNP], high-sensitivity Troponin T [hs-TnT], and Galectin-3 [Gal-3]) was assessed by functional or immunological assays. miRNAs involved in AF were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Using atrial tissue samples, fibrosis was assessed by Masson's trichrome. Connexin 40 and 43 (Cx40; Cx43) were evaluated by immunolabeling. Fifty-six patients (15 with OSA and 41 non-OSA) were included in this hypothesis-generating pilot study. OSA group had a higher incidence of postoperative AF (POAF) (46.7% vs. 19.5%; p = .042), presented an increased risk of POAF (OR 3.61, 95% CI 1.01-12.92), and had significantly higher baseline levels of NT-proBNP (p = .044), vWF (p = .049), Gal-3 (p = .009), IL-6 (p = .002), and CRP (p = .003). This group presented lower levels of miR-21 and miR-208 (both p < .05). Also, lower Cx40 levels in POAF and/or OSA patients (50.0% vs. 81.8%, p = .033) were found. The presence of interstitial fibrosis (according to myocardial collagen by Masson's trichrome) was raised in OSA patients (86.7% vs. 53.7%, p = .024). Several biomarkers and miRNAs involved in inflammation and fibrosis were dysregulated in OSA patients, which together with a higher degree of interstitial fibrosis, altered miRNA, and Cxs expression predisposes to the development of a substrate that increases the AF risk.

Role of echocardiography on early diagnosis of atrial remodelling and fibrosis in elite athletes.

There is emerging data indicating that long-standing vigorous exercise may be associated with atrial structural remodelling. This remodelling process is may be the cause of the increasing frequency of atrial arrythmias in athletes. Early diagnosis of atrial remodelling by atrial imaging could have a role in management of atrial arrythmias in elite athletes. In this study we aimed to diagnose early phases of atrial remodelling in elite athletes. Two groups of athletes including professional weight lifters (n = 33), professional marathoners (n = 32) and sedentary participants (n = 30) were enrolled. We also studied patients who received cardiotoxic chemotherapy (n = 10) for comparison. Serum TGF-beta level as a marker of fibrosis was measured. Both left atrial (LA) 3D volume and strain values were analysed. There was a positive correlation between serum TGF-beta levels and LA volumes and negative correlation between TGF-beta levels and strain values. TGF-beta levels were higher among chemotherapy and weight lifter groups, compared to control and marathoner groups [mean 0.57 ± 0.3 and 0.55 ± 0.2 vs. 0.45 ± 0.2 and 0.47 ± 0.2, respectively, p = 0.005]. LA volumes were higher among chemotherapy and weight lifter groups [median 33 (26-38) and 31 (23-36) respectively, p = 0.005], and strain values were lower in these two groups [mean 20.3 ± 2.5 and 24.6 ± 4.5, respectively, p < 0.005] compared to control and marathoner groups. Total exercise volume was higher in weight lifter group compared to marathoners [13,780 (2496-36,400) vs. 4732 (780-44928), respectively, p = 0.001]. There wasn't any difference between any group regarding left ventricular systolic and diastolic functions. Vigorous exercise causes atrial remodelling and fibrosis in elite athletes. Strength exercise carries higher risk for atrial fibrosis than endurance exercise. Burden of exercise is correlated with the severity of cardiac fibrosis. Echocardiographic evaluation of the left atrium and TGF-beta levels may help to detect subclinical cardiac remodelling and fibrosis.

Mechanism of myocardial fibrosis regulation by IGF-1R in atrial fibrillation through the PI3K/Akt/FoxO3a pathway.

Atrial structural remodeling takes on a critical significance to the occurrence and maintenance of atrial fibrillation (AF). As revealed by recent data, insulin-like growth factor-1 receptor (IGF-1R) plays a certain role in tissue fibrosis. In this study, the mechanism of IGF-1R in atrial structural remodeling was examined based on in vivo and in vitro experiments. First, cluster analysis of AF hub genes was conducted, and then the molecular mechanism was proposed by which IGF-1R regulates myocardial fibrosis via the PI3K/Akt/FoxO3a pathway. Subsequently, the mentioned mechanism was verified in human cardiac fibroblasts (HCFs) and rats transduced with IGF-1 overexpression type 9 adeno-associated viruses. The results indicated that IGF-1R activation up-regulated collagen Ⅰ protein expression and Akt phosphorylation in HCFs and rat atrium. The administration of LY294002 reversed the above phenomenon, improved the shortening of atrial effective refractory period, and reduced the increased incidence of AF and atrial fibrosis in rats. The transfection of FoxO3a siRNA reduced the anti-fibrotic effect of LY294002 in HCFs. The above data revealed that activation of IGF-1R takes on a vital significance to atrial structural remodeling by facilitating myocardial fibrosis and expediting the occurrence and maintenance of AF through the regulation of the PI3K/Akt/FoxO3a signaling pathway.

Epigallocatechin-3-Gallate Inhibits Atrial Fibrosis and Reduces the Occurrence and Maintenance of Atrial Fibrillation and its Possible Mechanisms.

Atrial fibrosis is one of the main causes of the onset and recurrence of atrial fibrillation (AF), for which there is no effective treatment. The aim of this study was to investigate the effect and mechanism of epigallocatechin-3-gallate (EGCG) on AF in rats. The rat model of AF was established by rapid pacing induction after angiotensin-II (Ang-II) induced atrial fibrosis to verify the relationship between atrial fibrosis and the AF. The expression levels of TGF-β/Smad3 pathway molecules and lysyl oxidase (LOX) in AF were detected. Subsequently, EGCG was used to intervene Ang-II-induced atrial fibrosis to explore the role of EGCG in the treatment of AF and its inhibitory mechanism on fibrosis. It was further verified that EGCG inhibited the production of collagen and the expression of LOX through the TGF-β/Smad3 pathway at the cellular level. The results showed that the induction rate and maintenance time of AF in rats increased with the increase of the degree of atrial fibrosis. Meanwhile, the expressions of Col I, Col III, molecules related to TGF-β/Smad3 pathway, and LOX increased significantly in the atrial tissues of rats in the Ang-II induced group. EGCG could reduce the occurrence and maintenance time of AF by inhibiting the degree of Ang-induced rat atrial fibrosis. Cell experiments confirmed that EGCG could reduce the synthesis of collagen and the expression of LOX in cardiac fibroblast induced by Ang-II. The possible mechanism is to down-regulate the expression of genes and proteins related to the TGF-β/Smad3 pathway. EGCG could downregulate the expression levels of collagen and LOX by inhibiting the TGF-β/Smad3 signaling pathway, alleviating Ang-II-induced atrial fibrosis, which in turn inhibited the occurrence and curtailed the duration of AF.

High-phosphate diet causes atrial remodeling and increases atrial fibrillation vulnerability via STAT3/NF-κB signaling and oxidative stress.

Hyperphosphatemia is associated with adverse cardiovascular outcomes in both the general population and patients with end-stage renal disease. We evaluated whether high inorganic phosphate (Pi) intake causes atrial remodeling and increased atrial fibrillation (AF) risk. The 5/6 nephrectomized chronic kidney disease (CKD) mice were fed a high-Pi (2%) diet for 10 weeks. AF vulnerability was evaluated through transesophageal burst atrial pacing. Phosphoproteomic, Western blotting, and immunohistochemistry were used to evaluate the effects of high Pi in atrial fibroblasts, atrial myocytes, and HL-1 myocytes. CKD and sham mice fed a high-Pi diet exhibited increased AF vulnerability, atrial fibrosis, and oxidative stress compared with mice fed a normal diet. Compared with normal (1 mM) Pi, high (2 mM) Pi significantly increased the activity of atrial fibroblasts and mitochondrial oxidative stress. Phosphoproteomic analysis revealed that compared with normal Pi, high Pi considerably increased the phosphorylation of intracellular proteins in atrial fibroblasts, including proteins related to NF-κB signaling and STAT3. Inhibition of NF-κB, STAT3, and Nox4 by small interfering RNA reduced the high-Pi-induced expression of collagen. In HL-1 myocytes, the high Pi induced the degradation of myofibril proteins and hyperphosphorylation of RyR2, which was abolished by Nox4 and CaMKII inhibition. Switching back to a normal-Pi diet improved the atrial abnormalities induced by high-Pi diet. High-Pi intake causes atrial structural and electrical remodeling and increases AF vulnerability, which is mediated through STAT3/NF-κB signaling and oxidative stress. High dietary Pi intake can exert detrimental effects on atria and may increase AF risk.

Electro-Mechanical Alterations in Atrial Fibrillation: Structural, Electrical, and Functional Correlates.

Atrial fibrillation is the most common arrhythmia encountered in clinical practice affecting both patients' survival and well-being. Apart from aging, many cardiovascular risk factors may cause structural remodeling of the atrial myocardium leading to atrial fibrillation development. Structural remodelling refers to the development of atrial fibrosis, as well as to alterations in atrial size and cellular ultrastructure. The latter includes myolysis, the development of glycogen accumulation, altered Connexin expression, subcellular changes, and sinus rhythm alterations. The structural remodeling of the atrial myocardium is commonly associated with the presence of interatrial block. On the other hand, prolongation of the interatrial conduction time is encountered when atrial pressure is acutely increased. Electrical correlates of conduction disturbances include alterations in P wave parameters, such as partial or advanced interatrial block, alterations in P wave axis, voltage, area, morphology, or abnormal electrophysiological characteristics, such as alterations in bipolar or unipolar voltage mapping, electrogram fractionation, endo-epicardial asynchrony of the atrial wall, or slower cardiac conduction velocity. Functional correlates of conduction disturbances may incorporate alterations in left atrial diameter, volume, or strain. Echocardiography or cardiac magnetic resonance imaging (MRI) is commonly used to assess these parameters. Finally, the echocardiography-derived total atrial conduction time (PA-TDI duration) may reflect both atrial electrical and structural alterations.

Left atrial volume affects the correlation of voltage map with magnetic resonance imaging.

The low-voltage area detected by electroanatomic mapping (EAM) is a surrogate marker of left atrial fibrosis. However, the correlation between the EAM and late gadolinium enhancement magnetic resonance imaging (LGE-MRI) has been inconsistent among studies. This study aimed to investigate how LA size affects the correlation between EAM and LGE-MRI. High-density EAMs of the LA during sinus rhythm were collected in 22 patients undergoing AF ablation. The EAMs were co-registered with pre-ablation LGE-MRI models. Voltages in the areas with and without LGE were recorded. Left atrial volume index (LAVI) was calculated from MRI, and LAVI > 62ml/m2 was defined as significant LA enlargement (LAE). Atrial bipolar voltage negatively correlates with the left atrial volume index. The median voltages in areas without LGE were 1.1mV vs 2.0mV in patients with vs without significant LAE (p = 0.002). In areas of LGE, median voltages were 0.4mV vs 0.8mV in patients with vs without significant LAE (p = 0.02). A voltage threshold of 1.7mV predicted atrial LGE in patients with normal or mildly enlarged LA (sensitivity and specificity of 74% and 59%, respectively). In contrast, areas of voltage less than 0.75mV correlated with LGE in patients with significant LA enlargement (sensitivity 68% and specificity 66%). LAVI affects left atrial bipolar voltage, and the correlation between low-voltage areas and LGE-MRI. Distinct voltage thresholds according to the LAVI value might be considered to identify atrial scar by EAM.

Quantification of left atrial appendage fibrosis by cardiac magnetic resonance: an accurate surrogate for left atrial fibrosis in atrial fibrillation patients?

Quantification of left atrial appendage fibrosis by cardiac magnetic resonance: an accurate surrogate for left atrial fibrosis in atrial fibrillation patients?

Effects of Sex on the Susceptibility for Atrial Fibrillation in Pigs with Ischemic Heart Failure.

Atrial fibrillation (AF) is the most prevalent arrhythmia, often caused by myocardial ischemia/infarction (MI). Men have a 1.5× higher prevalence of AF, whereas women show a higher risk for new onset AF after MI. However, the underlying mechanisms of how sex affects AF pathophysiology are largely unknown. In 72 pigs with/without ischemic heart failure (IHF) we investigated the impact of sex on ischemia-induced proarrhythmic atrial remodeling and the susceptibility for AF. Electrocardiogram (ECG) and electrophysiological studies were conducted to assess electrical remodeling; histological analyses were performed to assess atrial fibrosis in male and female pigs. IHF pigs of both sexes showed a significantly increased vulnerability for AF, but in male pigs more and longer episodes were observed. Unchanged conduction properties but enhanced left atrial fibrosis indicated structural rather than electrical remodeling underlying AF susceptibility. Sex differences were only observed in controls with female pigs showing an increased intrinsic heart rate, a prolonged QRS interval and a prolonged sinus node recovery time. In sum, susceptibility for AF is significantly increased both in male and female pigs with ischemic heart failure. Differences between males and females are moderate, including more and longer AF episodes in male pigs and sinus node dysfunction in female pigs.

TRIM21 deficiency protects against atrial inflammation and remodeling post myocardial infarction by attenuating oxidative stress

Atrial remodeling is a major contributor to the onset of atrial fibrillation (AF) after myocardial infarction (MI). Tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin protein ligase, is associated with pathological cardiac remodeling and dysfunction. However, the role of TRIM21 in postmyocardial infarction atrial remodeling and subsequent AF remains unclear. This study investigated the role of TRIM21 in post myocardial infarction atrial remodeling using TRIM21 knockout mice and explored the underlying mechanisms by overexpressing TRIM21 in HL-1 atrial myocytes using a lentiviral vector. The expression of TRIM21 in the left atrium of the mouse MI model was significantly elevated. TRIM21 deficiency alleviated MI-induced atrial oxidative damage, Cx43 downregulation, atrial fibrosis and enlargement, and abnormalities in electrocardiogram parameters (prolongation of the P-wave and PR interval). TRIM21 overexpression in atrial myocyte HL-1 cells further enhanced oxidative damage and Cx43 downregulation, whereas these effects were reversed by the reactive oxygen species scavenger N-acetylcysteine. The findings suggest that TRIM21 likely induces Nox2 expression mechanistically by activating the NF-κB pathway, which in turn leads to myocardial oxidative damage, inflammation, and atrial remodeling.

Relationship Between Fibrosis, Endocardial Endothelial Damage, and Thrombosis of Left Atrial Appendage in Atrial Fibrillation

BackgroundLeft atrial appendage (LAA) thrombus (LAAT) and ischemic stroke are considered important in atrial cardiomyopathy with progressive atrial fibrosis and endocardial endothelial damage. ObjectivesThis study aimed to obtain histological evidence to clarify the association between LAA fibrosis and endocardial endothelial damage with LAAT, ischemic stroke, and clinical risk factors. MethodsNinety-six patients with atrial fibrillation (AF) scheduled to undergo LAA excision during surgery were enrolled. They underwent transesophageal echocardiography before the surgery to validate the LAA function/morphology and LAAT presence or absence. The resected LAAs were subjected to Azan-Mallory staining and CD31 immunohistochemistry to quantify the degree of fibrosis and endocardial endothelial damage staged as F1-F4 and E1-E4 per the quantiles. ResultsPatients with an LAAT and/or ischemic stroke history had higher fibrosis degrees (18.4% ± 9.9% vs 10.4% ± 7.0%, P < 0.0001) and lower CD31 expressions (0.27 [IQR: 0.05-0.57] vs 1.02 [IQR: 0.49-1.65]; P < 0.0001). Also, higher CHADS2 was associated with a higher degree of fibrosis and lower CD31 expression. Multivariate logistic regression analysis revealed that endothelial damage (E4) was associated with an LAAT and/or ischemic stroke history independent of AF type (paroxysmal or nonparoxysmal) with an OR of 3.47. Among patients with nonparoxysmal AF, fibrosis (F4, OR: 3.66), endothelial damage (E4, OR: 4.62), and LAA morphology (non–chicken-wing, OR: 3.79) were independently associated with LAAT and/or stroke. The degree of fibrosis correlated significantly with endothelial damage (R = −0.38, P = 0.0001). ConclusionsThese histological findings may be essential in considering the pathophysiology of LAAT and stroke within the atrial cardiomyopathy context.