Substrate For Atrial Fibrillation Research Articles

Impact of Pirfenidone on arrhythmic and clinical outcomes in patients with idiopathic pulmonary fibrosis

Abstract Background/Introduction Atrial fibrosis is an important substrate in atrial fibrillation (AF), particularly in the setting of structural heart disease. Previous study reported that Pirfenidone, an antifibrotic agent, was beneficial at reducing myocardial fibrosis. Purpose The objective of the present study is to evaluate the effects of Pirfenidone on arrhythmic and clinical outcomes in patients with idiopathic pulmonary fibrosis (IPF). Methods Our database of patients diagnosed with IPF from 2008 to 2023 was used to obtain echocardiography, electrocardiogram, and 24hr-holter monitoring data. Inclusion criteria were all IPF patients with/without Pirfenidone. And we compared arrhythmic events including atrial fibrillation, atrial premature complex, atrial tachycardia, ventricular arrhythmia and clinical outcomes according to use of Pirfenidone. Results Among 257 patients with IPF (74.0±8.9 years), 106 (41.2%) patients took Pirfenidone. Difference in the baseline characteristics was not observed. During the median 36-month follow-up, a lower incidence of arrhythmic events (P=0.001) and diastolic dysfunction (P=0.025) was observed in the Pirfenidone group. In univariate analysis, hypertension, coronary artery disease, higher body weight, longer PR interval, QRS duration, and less use of Pirfenidone were associated with arrhythmic events. In multivariate analysis, higher body weight and less Pirfenidone use were independent risk factors for arrhythmic events. Conclusion(s) The use of Pirfenidone was associated with less arrhythmic events and lower diastolic dysfunction compared with no use of Pirfenidone in the long-term follow-up. And obesity was associated with higher incidence of arrhythmic events in IPF patients.Table

Peak frequency can be effectively used to characterize atrial remodelling in atrial fibrillation

Abstract Introduction Characterizing atrial fibrillation (AF) substrate can guide ablation strategies, particularly as current efficacy leaves room for substantial improvement. Low voltage zones (LVZs) correlate with atrial fibrosis and scar and can independently predict AF recurrence. Ablation of these zones improves freedom from arrhythmia, but the chaotic nature of atrial excitation frequently results in overestimation of LVZs limiting accurate substrate identification. Purpose While omnipolar voltage (OV) mapping has emerged to address this issue by closely correlating with sinus rhythm (SR) voltage maps, our study builds upon this by investigating a novel parameter, peak frequency (PF), to further refine AF substrate characterization. Methods Patients undergoing catheter ablation for persistent AF were enrolled. OV maps and PF maps were created during AF while bipolar voltage (BV) maps were created in SR with atrial pacing at pacing intervals (PIs) of 600ms and 250ms. Areas were classified as fixed scar (consistent LVZs across all maps), functional remodelling (LVZs in AF OV and SR BV 250ms maps) and non-LVZs (normal voltage across all maps). PF was assessed in these areas and defined as the highest frequency detected in the electrogram. Results Among 20 patients, the average voltage in AF OV maps differed significantly from SR BV 600ms (0.49±0.76mV in AF OV vs. 1.12±0.97mV SR BV 600ms, p<0.001) but not SR BV 250ms maps (0.49±0.76mV in AF OV vs. 0.52±0.84mV SR BV 250ms, p=0.10). Comparing co-registered points, there was a significant difference between AF OV and SR BV 600ms maps (0.21±0.09mV, p<0.001) but not between AF OV and SR BV 250ms maps (0.06±0.04mV, p=0.10). These findings were also consistent with regards to the proportion of LA area occupied by LVZs (42.4±8.2% AF OV, 24.3±7.4% SR BV 600ms and 39.4±6.7% SR BV 250ms; p=0.001). AF OV maps thereby correlated better with SR BV 250ms maps hence representing both fixed scar and functional remodelling. PF values ≥244Hz were predictive of non-LVZs (OR 3.91, 95% CI 3.77-4.07,) with an AUC of 0.71. A PF of ≤214Hz was predictive of fixed scar (OR 17.67, 95% CI 16.82-18.56, p<0.001) with an AUC of 0.90. A PF between 215-236Hz was predictive of functional remodelling (OR 2.83, 95% CI 2.71-2.95, p<0.001) with an AUC of 0.60. The majority of LVZs identified exclusively in AF OV maps exhibited PFs akin to those in non-LVZs highlighting the ability of PF to pinpoint potential overestimations in LVZs. Conclusions PF mapping can effectively discern between areas of fixed scar, functional remodelling, and potential overestimation of LVZs. PF may enhance substrate characterization in AF utilising data solely from electrograms.Trial Design and Zone AssignmentPeak Frequency and Voltage Zones

Clinical characteristics and genetic substrate of lone atrial fibrillation: a single center experience

Abstract Background Juvenile-onset lone atrial fibrillation (LAF) may be the initial manifestation of a concealed channelopathy or cardiomyopathy (CMP) or it may be due to an atrial specific genetic susceptibility. Clinical characteristics, genetic background and proper management are still largely unknown. Purpose Aim of the present study is to describe the clinical and genetic characteristics of patients with juvenile-onset LAF. Methods We enrolled patients referred to our center for ablation between 1/2018 and 11/2023 with a first diagnosis of LAF before the age of 60, a structurally normal heart (absence of known CMP, ischemic, valvular, congenital heart disease) and no overt channelopathy. A concealed Brugada syndrome was systematically excluded. Genetic testing was performed using Next Genome Sequencing and a dedicated gene panel. Results 89 patients were included (84% male, LAF onset 43 ± 8 years, BMI 25 ± 7 kg/m2): 32% had a first-degree family history of AF (including 15% below 60 years), 18% of sudden death, 8% of cardiac conduction disorders and 2% of CMP. Cardiovascular risk factors included arterial hypertension in 24%, smoking in 47% and obstructive sleep apnea syndrome in 4%; 20% were competitive athletes. Most patients (89%) presented with paroxysmal AF and 92% were symptomatic (mainly palpitations). At presentation LVEF was 61±5% and LAVI 35±14 ml/m2. Median follow-up time after the first AF episode was 6 years (IQR 4-10). Most patients (81, 91%) underwent at least one transcatheter ablation procedure after failed anti-arrhythmic drug (AAD) therapy (mostly IC). The first procedure (73% radiofrequency, 27% cryoablation) included pulmonary veins isolation (PVI) in all and additional lesions in 5%; the second procedure (n=18, 22% of the ablation group) included PV re-isolation in all (mostly due to multiple vein reconnections) and additional lesions in 17%; the third procedure (n=8, 10% of the ablation group) included PV re-isolation in 25% and additional lesions in 75%. The remaining 8 patients were treated with AAD only (mostly IC). By the last follow-up, 7% of patients in the ablation group and 25% in the AAD group had documented recurrences (even though 50% of those who received ablation were still on AAD). Among the 35 patients subjected to genetic investigation, 10 have available results: 30% tested positive for C4-C5 variants (2 for KCNQ1, 1 for TTN), 50% for C3 variants (RYR2, ABCC9, LMNA, KCNH2 and RMB20) and 20% were negative. Conclusions In the present single center cohort of patients with juvenile-onset LAF, a positive family history was found in almost one third of patients. Despite prompt diagnosis and treatment (including >1 ablation in 20% of patients), recurrences rate is not trivial. The yield of genetic test so far is high, supporting its use in this population.

Intermittent hypoxia is significantly associated with low-voltage areas in patients with atrial fibrillation complicated by obstructive sleep apnea

Abstract Background Obstructive sleep apnea (OSA) is one of risk factors for atrial fibrillation (AF); however, how OSA affects the structural and electrical atrial remodeling is not well described. This study aimed to determine the association of OSA with left atrial (LA) size and LA low-voltage area (LVA), a known arrhythmogenic substrate for AF. Methods Eighty-three patients undergoing catheter ablation of AF (forty-nine with OSA [apnea–hypopnea index: AHI ≥ 5/h] and thirty-four control patients without OSA by full polysomnography or portable monitor) were studied. In all cases, LA maps were created using a three-dimensional electro-anatomical mapping system in sinus rhythm or pacing from the right atrium. LVA was defined as a bipolar voltage < 0.5 mV. %LVA is defined as ratio of LVA to LA area. Results LVA and %LVA were larger in OSA group as compared to Control group (6.0 ± 6.6 vs. 2.6 ± 3.2 cm2, P = 0.003 and 7.5 ± 8.5 vs. 3.5 ± 4.6 %, P = 0.008, respectively). On the other hand, there was no difference in LA size between the two groups. In addition, 3% oxygen desaturation index (ODI) was significantly correlated with %LVA (r = 0.282, P = 0.010), but not with LA size (r = 0.053, P = 0.637). Multiple regression analysis demonstrated that 3%ODI ≥ 30 (3.088, 1.078-8.851, P = 0.036) was significantly associated with %LVA after adjustment. Conclusion In patients with AF complicated by OSA, significant enlargement of the LVA was observed, but there was no evidence of enlargement in LA size. Intermittent hypoxia may be one of the mechanisms of this atrial electro-anatomical remodeling.figure 1figure 2

Severity of tricuspid regurgitation predicts risk of atrial fibrillation recurrence after pulmonary vein isolation

Abstract Background Atrioventricular valve regurgitation (AVVR) results in atrial remodeling, thus promoting the formation of a substrate for atrial fibrillation (AF). On the other hand, AF may cause functional AVVR by annular dilatation of the atria. In this vicious circle, the identification of the leading pathomechanism and consequently the optimization of treatment can be challenging. Purpose Our aim was to investigate whether the presence of significant AVVR and especially of tricuspid regurgitation (TR) affects the efficacy of catheter-based pulmonary vein isolation (PVI) for AF. Furthermore, we evaluated whether rhythm control for AF through PVI could lead to an improvement of AVVR severity. Finally we examined the effect of concomitant right atrial flutter on the arrhythmic outcome in patients with significant TR . Methods We enrolled patients undergoing first-time PVI for symptomatic AF. We compared the severity of AVVR at the time of the procedure as well as after 6 months, using transthoracic echocardiography. Moderate to severe AVVR was defined as significant. Moreover, we evaluated whether the presence of significant AVVR, at baseline and 6 months after the procedure, could serve as an independent predictor for AF recurrence. Results Out of 320 consecutive patients (mean age 66.3 ± 10 years, 61.6% male, 60% paroxysmal AF) , significant TR at baseline was documented in 13.1%, while significant mitral regurgitation (MR) in 10.9%. Six months after PVI, the proportion of patients with moderate to severe TR (13.1% to 7.2%; p<0.001) and MR (10.9% to 6.6%; p<0.001) decreased significantly. Compared to patients with post-interventional improvement of significant TR, right atrial (RA) dilatation at baseline was more pronounced in patients with persistent significant TR (RA area 20.2 ± 4.4 vs. 26.6 ± 8.3 cm2; p=0.002). The presence of significant TR, particularly without improvement during the follow-up, independently increased the risk of atrial fibrillation recurrences. Even after propensity-score matching, TR at baseline remained an independent risk predictor regarding recurrent atrial fibrillation (HR 2.2 [95% CI, 1.1 - 4.9]; p=0.045). Among patients with significant TR, those with documented right atrial flutter were at high risk for recurrence of atrial arrhythmia (HR 2.69 [95% CI, 1.0 – 6.9]; p=0.039), despite the additional ablation of the cavo-tricuspid isthmus. Significant MR was not associated with increased risk of atrial arrhythmias. Conclusion In patients with symptomatic AF undergoing PVI, the presence of moderate to severe TR, particularly without improvement 6 months after the procedure, was associated with a worse arrhythmic outcome. Further investigations to enhance the understanding of the underlying electrophysiological substrate and the need for tailored ablation strategies are warranted.TR as predictor for AF(propensity score)AVVR improvement after PVI

Prevalence of diabetes mellitus diminished the efficacy of additional ablation following pulmonary vein isolation: a sub-analysis of the EARNEST-PVI trial

Abstract Introduction Diabetes mellitus (DM) is a well-known cause of atrial remodeling in patients with atrial fibrillation (AF). Although additional left atrial ablation following pulmonary vein isolation (PVI) is a strategy to modify AF substrate, its efficacy has not been well elucidated in patients with DM. We hypothesized that the efficacy of additional ablation was different in patients with DM and in those without. Purpose The purpose of this study was to investigate the efficacy of additional ablation following PVI in patients with or without DM. Methods The EARNEST-PVI was a multicenter, prospective, randomized controlled trial. In this sub-analysis, 493 consecutive patients of persistent AF (age, 65 ± 9 years; female, 120 [24%] patients) who underwent the initial radiofrequency catheter ablation were analyzed. Patients were randomized to be treated with PVI only (PVI-alone) or PVI plus linear and/or complex fractionated atrial electrogram ablation (PVI-plus). Primary outcome measure was defined as AF recurrence during the 12 months follow-up periods. Results In total, 84 (17%) patients had DM. Primary outcome occurred in 120 (24%) patients. In patients without DM, freedom from AF recurrence was significantly higher in PVI-plus group than in PVI-alone group (80.0% versus 71.1%, p=0.03) (Figure 1A). Conversely, in patients with DM, freedom from AF recurrence was similar between PVI-plus group and PVI-alone group (75.4% versus 72.9%, p=0.70) (Figure 1B). Conclusion Additional ablation following PVI reduced AF recurrence after radiofrequency catheter ablation only in patients without DM.Figure 1

Multielectrode catheter-based pulsed field ablation of persistent and long-standing persistent atrial fibrillation

Abstract Background Rhythm control of non-paroxysmal atrial fibrillation (AF) is significantly more challenging, as a result of arrhythmia perpetuation promoting atrial substrate changes and AF maintenance. Purpose We describe a tailored ablation strategy targeting multiple left atrial (LA) sites via the multielectrode FarawaveTM pulsed field ablation (PFA) catheter in patients with persistent AF sustained beyond 6 months (PerAF>6m) and long-standing persistent AF (LSPAF). Methods The ablation protocol included the following stages: pulmonary vein antral and posterior wall isolation plus anterior roof line ablation (Stage 1); electrogram-guided substrate ablation (Stage 2); atrial tachyarrhythmia (AT) regionalization and ablation (Stage 3). Results Seventy-two [age:68±10y, 61.1%males; AF history: 25 (18-45) months] patients with PerAF>6m (52.8%) and LSPAF (47.2%) underwent their first PFA via the FarapulseTM system. LA substrate ablation (Stage 1 and 2) led to AF termination in 95.8% of patients. AF termination occurred while ablating the mitral edge of the postero-lateral ridge (40.3%), the inferior left atrium above the proximal coronary sinus (27.4%), the interatrial septum (22.6%), the superior aspect of the postero-lateral ridge (6.5%), the base of the appendage (3.2%). AF organized into a left-sided atrial flutter (AFlu) in 46 (74.2%) patients. The FarawaveTM catheter was used to identify LA sites showing diastolic, low-voltage electrograms and entrainment from its splines was performed to confirm the pacing site was inside the AFlu circuit (Figure 1). Left AFlu termination was achieved in all cases via PFA delivery. Total procedural and LA dwell times were 112±25min and 59±22 min, respectively. Major complications occurred in 2 (2.8%) patients with pre-existing left ventricular systolic dysfunction (EF<35%) who required inotropic therapy due to acute heart failure. Hemodynamics normalized within 24h and both patients were discharged after 2 and 3 additional hospital days. Transient ST-segment elevation was documented in 4 patients after peri-mitral PFA; timely nitrate administration led to ECG normalization within 10 minutes. Single-procedure success rate was 81.8% after 13.3±1.9 months of follow-up; AF-free survival was 93.1% (Figure 2). A subgroup of 36 patients completed a follow-up transthoracic echocardiography study to assess left atrial mechanical contraction changes after ablation. Median A-wave velocity was 30 (IQR: 20-35) cm/s post-ablation and 50 (IQR: 41-70) cm/s after a mean of 7.3±1.8 months post-ablation. Conclusions In our cohort, PFA-based AF substrate ablation led to AF termination in 95.8% of cases. Very favorable clinical outcomes were observed at one year of follow-up.Entrainment from the PFA Catheter.Kaplan-Meier Analysis.

Inter-patient variability of local cycle length and duty cycle distribution of the atrial fibrillation substrate beyond pulmonary vein isolation

Abstract Appropriate targets for catheter ablation of atrial fibrillation (AFib) beyond pulmonary vein isolation (PVI) are still controversially discussed. Various approaches such as ablation of complex fractionated atrial electrograms (EGMs), areas with spatio-temporal dispersion, and areas with increased rotor density have not been reproducible or failed to improve clinical success rates. The local cycle length (CL) and duty cycle (DC) distribution during AFib offer novel measures to characterize the atrial substrate. This study aims at providing first insights into the inter-individual variability of observed CL and DC distributions, their interdependence, and their correlation to the duration of AFib episodes to improve the individual characterization of the AFib substrate and tailor ablation strategies in future. In patients with recurrence of AFib despite PVI, a high-resolution 3D map was recorded at baseline during AFib. Intracardiac EGMs were preprocessed to improve local signal quality and far field suppression. EGMs were recorded with the multipolar, basket-shaped high-density mapping catheter. Local CL and DC distribution were visualized using a scatter plot and histograms. CL quantifies the time between subsequent local activations, DC quantifies the fraction of CL with local EGM activity, and the confidence (conf) feature quantifies the spatiotemporal consistency of EGM morphology. Only EGMs with conf > 0.6 are analysed. Feature calculation does not only take into account single EGMs but a weighted conglomerate of all acquisitions within a series of beats. Adjustable CL and DC thresholds allow highlighting regions within the 3D map for individual spatial analysis. 14 patients (7x paroxysmal AFib, 7x persistent AFib) were enrolled. All subjects underwent repeat ablation after PVI due to recurrence of AFib. CL and DC histograms were of highly individual shape. The most prevalent feature value varied from 158ms to 263ms for CL and from 38% to 96% for DC; histogram widths (inter-quartile-range) from 10ms to 34ms and from 26% to 36%, respectively. Normal distributions, multimodal distributions, and skewed distributions exhibiting a dominant peak were observed for CL. Both the most prevalent CL and the width of the distribution were highly individual. DC was observed to be normally to equally distributed with mostly broad bandwidths. Linear regression revealed a positive dependency between the most prevalent CL and the width of CL distributions. The most prevalent value and the width of both CL and DC did not differ significantly for the paroxysmal and persistent subgroup. Compare figure for detailed results. CL and DC distributions can help to characterize the highly individual type of AFib. The presented results suggest that there will not be a one-size-fits-all ablation approach for the AFib substrate. Further research is needed to identify clusters of similar pattern and individually adjust the ablation strategy.

Activated factor X stimulates atrial endothelial cells and tissues to promote remodeling responses through AT1R/NADPH oxidases/SGLT1/2.

Atrial fibrillation (AF), the most common cardiac arrhythmia favoring ischemic stroke and heart failure involves left atrial remodeling, fibrosis and a complex interplay between cardiovascular risk factors. This study examined whether activated factor X (FXa) induces pro-remodeling and pro-fibrotic responses in atrial endothelial cells (AECs) and human atrial tissues and determined the underlying mechanisms. AECs were from porcine hearts and human right atrial appendages (RAA) from patients undergoing heart surgery. Protein expression levels were assessed by Western blot and immunofluorescence staining, mRNA levels by RT-qPCR, formation of reactive oxygen species (ROS) and NO using fluorescent probes, thrombin and angiotensin II generation by specific assays, fibrosis by Sirius red staining and senescence by senescence-associated beta-galactosidase (SA-β-gal) activity.In AECs, FXa increased ROS formation, senescence (SA-β-gal activity, p53, p21), angiotensin II generation and the expression of pro-inflammatory (VCAM-1, MCP-1), pro-thrombotic (tissue factor), pro-fibrotic (TGF-β and collagen-1/3a) and pro-remodeling (MMP-2/9) markers whereas eNOS levels and NO formation were reduced. These effects were prevented by inhibitors of FXa but not thrombin, protease-activated receptors antagonists (PAR-1/2) and inhibitors of NADPH oxidases, ACE, AT1R, SGLT1/SGLT2. FXa also increased expression levels of ACE1, AT1R, SGLT1/2 proteins which was prevented by SGLT1/2 inhibitors. Human RAA showed tissue factor mRNA levels that correlated with markers of endothelial activation, pro-remodeling and pro-fibrotic responses and SGLT1/2 mRNA levels. They also showed protein expression levels of ACE1, AT1R, p22phox, SGLT1/2, and immunofluorescence signals of nitrotyrosine and SGLT1/2 colocalized with those of CD31. FXa increased oxidative stress levels which were prevented by inhibitors of the AT1R/NADPH oxidases/SGLT1/2 pathway. FXa promotes oxidative stress triggering premature endothelial senescence and dysfunction associated with pro-thrombotic, pro-remodeling and pro-fibrotic responses in AECs and in human RAA involving the AT1R/NADPH oxidases/SGLT1/2 pro-oxidant pathway. Targeting this pathway may be of interest to prevent atrial remodeling and the progression of atrial fibrillation substrate.

Pulmonary Veins Function as Echo Chambers in Persistent Atrial Fibrillation: Circuitous Re-Entry Generates Outgoing Wavefronts.

Although the substrate in persistent atrial fibrillation (PeAF) is not limited to the pulmonary veins (PVs), PV isolation (PVI) remains the cornerstone ablation strategy. The aim of this study was to describe the mechanism of outgoing wavefronts (WFs) originating in the PVsleeves during PeAF. Eleven patients presenting for first-time PeAF ablation were recruited (mean age 63.1 ± 10.9 years, 91%men). A 64-electrode catheter (Constellation; 38mm) was positioned within the PV under fluoroscopic guidance. Aninverse mapping technique was used to reconstruct unipolar atrial electrograms on the PV surface, and the resulting phase maps were used to identify incoming and outgoing WFs at the PV junction and to classify focal and re-entrant activity within the PV sleeves. During PeAF, the PVs gave rise to outgoing WFs with a frequency of 3.7 s-1 (Q1-Q3: 3.4-5.4 s-1) compared with 3.6 s-1 (Q1-Q3: 2.8-4.2 s-1) for incoming WFs. Circuitous macroscopic re-entry was the dominant mechanism driving outgoing WFs (frequency of re-entry 2.7 s-1 [Q1-Q3: 2.0-3.3 s-1] compared with focal activity 1.4 s-1 [Q1-Q3: 1.1-1.5 s-1]; P< 0.006). This was initiated by incoming WFs in 80% of cases. Consecutive focal activation from the same location was infrequent (10.0% ± 6.6%, n=10). Rotors≥360° were never observed. The median ratio (R) of outgoing to incoming WF frequency was 1.14 (Q1-Q3: 0.84-1.75), with R > 1 in 6 of 11 PVs. Electric activity generated by PV sleeves during PeAF is due mainly to circuitous re-entry initiated by incoming waves, frequently with R > 1. That is, the PVs act less as drivers of atrial fibrillation than as "echo chambers" that sustain and amplify fibrillatory activity.

FIBROSIS AS AN ADDITIONAL RISK FACTOR FOR STROKE DEVELOPMENT IN HYPERTENSIVE PATIENTS WITH ATRIAL FIBRILLATION (RETROSPECTIVE STUDY)

Objective: Atrial fibrillation (AF) is a common issue that is increasingly prevalent, particularly in hypertensive patients and leads to severe complications, notably stroke. Several prothrombotic factors are elevated in AF, contributing to an increased risk of stroke. Tissue factor (TF) is the main initiator of the blood coagulation cascade, also involved in inflammation and fibrogenesis. Atrial fibrosis plays a central role in creating the substrate for AF, with the Transforming Growth Factor (TGF-B1) identified as a key cytokine involved in the pathogenesis of atrial fibrosis. The aim of this study is to investigate the relationship between atrial fibrosis and the risk of developing transient ischemic attack (TIA) or stroke in hypertensive patients with AF (retrospective study). Design and method: We observed 445 hypertensive patients with nonvalvular AF over three years (2017-2019). Clinical examination included a study of complaints, physical, laboratory, and instrumental examination, along with additional biochemical blood tests, such as TF, hsCRP, IL-6, and TGF-B1. Blood tests were determined using the ELISA method. Treatment regimens for all patients included standard therapy (anticoagulants, antiarrhythmic, and symptomatic medication). Studies were conducted based on open-label protocols, using the universal statistical packages SPSS 13.0. Results: The obtained results have shown that among the 445 hypertensive patients with AF within three years, TIA or stroke was detected in 128 patients (28.8%). We found that in these patients, the level of TF is statistically elevated compared to other patients with AF (1350±65 vs. 850±33 pg/ml). Hypertensive patients undergoing TIA or stroke exhibited a significant increase in levels of inflammatory and fibrosis markers compared with other hypertensive patients with AF. Significant differences between hsCRP levels were observed (8.6±1.4 vs. 4.2±1.6, p=0.002); IL-6 levels (6.4±0.8 vs. 3.6±1.2 pg/ml, p=0.043); and TGF-B1 levels (1240±75 vs. 900±43 pg/ml, p=0.02). Moreover, plasma levels of hs-CRP were higher among AF patients at high risk of stroke (3 or more) according to CHA2DS2-VASc (p=0.002). Conclusions: We have demonstrated that fibrosis and inflammation markers, along with coagulation cascade markers, are additional prognostic criteria contributing to the development of TIA or stroke in hypertensive patients with AF.

The SK4 channel allosteric blocker, BA6b9, reduces atrial fibrillation substrate in rats with reduced ejection fraction.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is strongly associated with several comorbidities including heart failure (HF). AF in general, and specifically in the context of HF, is progressive in nature and associated with poor clinical outcomes. Current therapies for AF are limited in number and efficacy and do not target the underlying causes of atrial remodeling such as inflammation or fibrosis. We previously identified the calcium-activated SK4 K+ channels, which are preferentially expressed in the atria relative to the ventricles in both rat and human hearts, as attractive druggable target for AF treatment. Here, we examined the ability of BA6b9, a novel allosteric inhibitor of SK4 channels that targets the specific calmodulin-PIP2 binding domain, to alter AF susceptibility and atrial remodeling in a systolic HF rat postmyocardial infarction (post-MI) model. Daily BA6b9 injection (20 mg/kg/day) for 3 weeks starting 1-week post-MI prolonged the atrial effective refractory period, reduced AF induction and duration, and dramatically prevented atrial structural remodeling. In the post-MI left atrium (LA), pronounced upregulation of the SK4 K+ channel was observed, with corresponding increases in collagen deposition, α-SMA levels, and NLRP3 inflammasome expression. Strikingly, BA6b9 treatment reversed these changes while also significantly reducing the lateralization of the atrial connexin Cx43 in the LA of post-MI rats. Our findings indicate that the blockade of SK4 K+ channels using BA6b9 not only favors rhythm control but also remarkably reduces atrial structural remodeling, a property that is highly desirable for novel AF therapies, particularly in patients with comorbid HF.

Sinus Rhythm Atrial Electrocardiographic Imaging in Patients With Mitral Regurgitation: Clues to the Substrate for Atrial Fibrillation.

Sinus Rhythm Atrial Electrocardiographic Imaging in Patients With Mitral Regurgitation: Clues to the Substrate for Atrial Fibrillation.

The autonomic nerves around the vein of Marshall: apostmortem study with clinical implications.

This study aims to analyze the vein of Marshall (VOM) in human autopsy hearts and its correlation with clinical data to elucidate the morphological substrates of atrial fibrillation (AF) and other cardiac diseases. Twenty-three adult autopsy hearts were studied, assessing autonomic nerves by immunohistochemistry with tyrosine hydroxylase (sympathetic nerves), choline acetyltransferase (parasympathetic nerves), growth-associated protein 43 (neural growth), and S100 (general neural marker) antibodies. Interstitial fibrosis was assessed by Masson trichrome staining. Measurements were conducted via morphometric software. The results were correlated with clinical data. Sympathetic innervation was abundant in all VOM-adjacent regions. Subjects with a history of AF, cardiovascular cause of death, and histologically verified myocardial infarction had increased sympathetic innervation and neural growth around the VOM at the mitral isthmus. Interstitial fibrosis increased with age and heart weight was associated with AF and cardiovascular cause of death. This study increases our understanding of the cardiac autonomic innervation in the VOM area in various diseases, offering implications for the development of new therapeutic approaches targeting the autonomic nervous system.

Isolevuglandins Promote Mitochondrial Dysfunction and Electrophysiologic Abnormalities in Atrial Cardiomyocytes.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, yet the cellular and molecular mechanisms underlying the AF substrate remain unclear. Isolevuglandins (IsoLGs) are highly reactive lipid dicarbonyl products that mediate oxidative stress-related injury. In murine hypertension, the lipid dicarbonyl scavenger 2-hydroxybenzylamine (2-HOBA) reduced IsoLGs and AF susceptibility. We hypothesized that IsoLGs mediate detrimental pathophysiologic effects in atrial cardiomyocytes that promote the AF substrate. Using Seahorse XFp extracellular flux analysis and a luminescence assay, IsoLG exposure suppressed intracellular ATP production in atrial HL-1 cardiomyocytes. IsoLGs caused mitochondrial dysfunction, with reduced mitochondrial membrane potential, increased mitochondrial reactive oxygen species (ROS) with protein carbonylation, and mitochondrial DNA damage. Moreover, they generated cytosolic preamyloid oligomers previously shown to cause similar detrimental effects in atrial cells. In mouse atrial and HL-1 cells, patch clamp experiments demonstrated that IsoLGs rapidly altered action potentials (AP), implying a direct effect independent of oligomer formation by reducing the maximum Phase 0 upstroke slope and shortening AP duration due to ionic current modifications. IsoLG-mediated mitochondrial and electrophysiologic abnormalities were blunted or totally prevented by 2-HOBA. These findings identify IsoLGs as novel mediators of oxidative stress-dependent atrial pathophysiology and support the investigation of dicarbonyl scavengers as a novel therapeutic approach to prevent AF.

Clinical Predictors of Device-Detected Atrial Fibrillation During 2.5 Years After Cardiac Surgery: Prospective RACE V Cohort

BackgroundPostoperative atrial fibrillation (POAF) is a frequent complication after cardiac surgery that is associated with late atrial fibrillation (AF) recurrences (late-POAF) and increased morbidity and long-term mortality. ObjectivesThis study sought to determine device-detected POAF incidence and to identify clinical variables associated with POAF, both in patients with and without preoperative AF history. MethodsA total of 133 consecutive patients undergoing cardiac surgery were prospectively enrolled and continuously monitored with an implantable loop recorder for 2.5 years after surgery. Preoperative transthoracic echocardiography, 12-lead electrocardiogram, blood biomarkers, and clinical data were analyzed to develop prediction models for early- and late-POAF. ResultsIn patients without preoperative AF history, early-POAF within the first 90 postoperative days occurred in 41 (47.1%) of 87 patients. Late-POAF after the first 90 postoperative days occurred in 22 (25%) of 87 patients, and 20 of these patients also had early-POAF during the first 90 days (20 of 22 [91%]). Increased right atrial minimum volume indexed for body surface area (RAVImin) and early-POAF were independently associated with late-POAF. A prediction model for late-POAF, which included RAVImin >11 mL/m2, age >65 years, and early-POAF, achieved an area under the curve of 0.82 (95% CI: 0.72-0.92). For patients with preoperative AF-history, late-POAF recurrences were frequent (22 of 33 [67%]). Increased RAVImin was independently associated with a higher incidence of late-POAF. ConclusionsIn patients with and without AF history, late-POAF recurrences are frequent, including in patients undergoing surgical AF ablation. In patients with no history of AF, late-POAF might be predicted with excellent accuracy by using a combination of preoperative variables. In patients with a history of AF, signs of advanced AF substrate (eg, increased right atrial volumes) were associated with long-term AF recurrences. [Reappraisal of Atrial Fibrillation: Interaction Between Hypercoagulability, Electrical Remodeling, and Vascular Destabilisation in the Progression of AF; NCT03124576]

Developments of ex vivo cardiac electrical mapping and intelligent labeling of atrial fibrillation substrates

Cardiac three-dimensional electrophysiological labeling technology is the prerequisite and foundation of atrial fibrillation (AF) ablation surgery, and invasive labeling is the current clinical method, but there are many shortcomings such as large trauma, long procedure duration, and low success rate. In recent years, because of its non-invasive and convenient characteristics, ex vivo labeling has become a new direction for the development of electrophysiological labeling technology. With the rapid development of computer hardware and software as well as the accumulation of clinical database, the application of deep learning technology in electrocardiogram (ECG) data is becoming more extensive and has made great progress, which provides new ideas for the research of ex vivo cardiac mapping and intelligent labeling of AF substrates. This paper reviewed the research progress in the fields of ECG forward problem, ECG inverse problem, and the application of deep learning in AF labeling, discussed the problems of ex vivo intelligent labeling of AF substrates and the possible approaches to solve them, prospected the challenges and future directions for ex vivo cardiac electrophysiology labeling.

Use of Atrial Fibrillation Electrograms and T1/T2 Magnetic Resonance Imaging to Define the Progressive Nature of Molecular and Structural Remodeling: A New Paradigm Underlying the Emergence of Persistent Atrial Fibrillation.

The temporal progression states of the molecular and structural substrate in atrial fibrillation (AF) are not well understood. We hypothesized that these can be detected by AF electrograms and magnetic resonance imaging parametric mapping. AF was induced in 43 dogs (25-35 kg, ≥1 year) by rapid atrial pacing (RAP) (3-33 weeks, 600 beats/min), and 4 controls were used. We performed high-resolution epicardial mapping (UnEmap, 6 atrial regions, both atria, 130 electrodes, distance 2.5 mm) and analyzed electrogram cycle length, dominant frequency, organization index, and peak-to-peak bipolar voltage. Implantable telemetry recordings were used to quantify parasympathetic nerve activity over RAP time. Magnetic resonance imaging native T1, postcontrast T1, T2 mapping, and extracellular volume fraction were assessed (1.5T, Siemens) at baseline and AF. In explanted atrial tissue, DNA oxidative damage (8-hydroxy-2'-deoxyguanosine staining) and percentage of fibrofatty tissue were quantified. Cycle length and organization index decreased (R=0.5, P<0.05; and R=0.5, P<0.05; respectively), and dominant frequency increased (R=0.3, P n.s.) until 80 days of RAP but not thereafter. In contrast, voltage continued to decrease throughout the duration of RAP (R=0.6, P<0.05). Parasympathetic nerve activity increased following RAP and plateaued at 80 days. Magnetic resonance imaging native T1 and T2 times increased with RAP days (R=0.5, P<0.05; R=0.6, P<0.05) in the posterior left atrium throughout RAP. Increased RAP days correlated with increasing 8-hydroxy-2'-deoxyguanosine levels and with fibrosis percentage (R=0.5, P<0.05 for both). A combination of AF electrogram characteristics and T1/T2 magnetic resonance imaging can detect early-stage AF remodeling (autonomic remodeling, oxidative stress) and advanced AF remodeling due to oxidative stress and fibrosis.

LNK/SH2B3 loss of function increases susceptibility to murine and human atrial fibrillation.

The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signaling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and hematologic disorders including stroke. In mice, deletion of Lnk causes inflammation and oxidative stress. We hypothesized that Lnk-/- mice are susceptible to atrial fibrillation (AF) and that rs3184504 is associated with AF and AF-related stroke in humans. During inflammation, reactive lipid dicarbonyls are a major component of oxidative injury, and we further hypothesized that these mediators are critical drivers of the AF substrate in Lnk-/- mice. Lnk-/- or wild-type (WT) mice were treated with vehicle or 2-hydroxybenzylamine (2-HOBA), a dicarbonyl scavenger, for 3 months. Compared to WT, Lnk-/- mice displayed increased AF duration that was prevented by 2-HOBA. In the Lnk-/- atria, action potentials were prolonged with reduced transient outward K+ current, increased late Na+ current, and reduced peak Na+ current, proarrhythmic effects that were inhibited by 2-HOBA. Mitochondrial dysfunction, especially for complex I, was evident in Lnk-/- atria, while scavenging lipid dicarbonyls prevented this abnormality. Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were elevated in Lnk-/- plasma and atrial tissue, respectively, both of which caused electrical and bioenergetic remodeling in vitro. Inhibition of soluble TNF-α prevented electrical remodeling and AF susceptibility, while IL-1β inhibition improved mitochondrial respiration but had no effect on AF susceptibility. In a large database of genotyped patients, rs3184504 was associated with AF, as well as AF-related stroke. These findings identify a novel role for LNK in the pathophysiology of AF in both experimental mice and in humans. Moreover, reactive lipid dicarbonyls are critical to the inflammatory AF substrate in Lnk-/- mice and mediate the proarrhythmic effects of pro-inflammatory cytokines, primarily through electrical remodeling.

Exerkine β-aminoisobutyric acid protects against atrial structural remodeling and atrial fibrillation in obesity via activating AMPK signaling and improving insulin sensitivity

Moderate exercise decreases the risk for atrial fibrillation (AF), an effect which is probably mediated via exercise-stimulated release of exerkines. β-Aminoisobutyric acid (BAIBA), a novel exerkine, has been reported to provide protective benefits against many cardiovascular diseases, yet its role in AF remains elusive. Herein, using a mouse model of obesity-related AF through high-fat diet (HFD) feeding, we found that 12-week drinking administration of BAIBA (170 mg/kg/day) decreased AF susceptibility in obese mice. Atrial remodeling assessment showed that BAIBA attenuated obesity-induced atrial hypertrophy and interstitial fibrosis, thereby ablating the substrate for AF. Of note, to our knowledge, this is the first report of the direct association of BAIBA and hypertrophy. BAIBA has been reported to be a key regulator of glucose and lipid metabolism, and we found that BAIBA alleviated insulin resistance in obese mice. Transcriptional analysis of metabolism-related genes showed that BAIBA increased the transcription of fatty acids metabolism-related genes in the atria of lean mice but not in that of obese mice. Mechanistic investigation showed that BAIBA stimulated AMP-activated protein kinase (AMPK) signaling in the atria of obese mice and palmitic acid (PA)-treated neonatal rat cardiomyocytes (NRCM), whereas inhibition of AMPK via Compound C attenuated BAIBA-conferred cardioprotection against hypertrophy and insulin resistance in PA-treated NRCM. Collectively, BAIBA attenuates AF susceptibility in obese mice via activated AMPK signaling and resultant improvement of insulin sensitivity, thereby providing perspectives on the potential therapeutic role of BAIBA in AF treatment.