Atrial Fibrillation Progression Research Articles

Mechanisms of Quercetin against atrial fibrillation explored by network pharmacology combined with molecular docking and experimental validation

Atrial fibrillation (AF) is a common atrial arrhythmia for which there is no specific therapeutic drug. Quercetin (Que) has been used to treat cardiovascular diseases such as arrhythmias. In this study, we explored the mechanism of action of Que in AF using network pharmacology and molecular docking. The chemical structure of Que was obtained from Pubchem. TCMSP, Swiss Target Prediction, Drugbank, STITCH, Pharmmapper, CTD, GeneCards, DISGENET and TTD were used to obtain drug component targets and AF-related genes, and extract AF and normal tissue by GEO database differentially expressed genes by GEO database. The top targets were IL6, VEGFA, JUN, MMP9 and EGFR, and Que for AF treatment might involve the role of AGE-RAGE signaling pathway in diabetic complications, MAPK signaling pathway and IL-17 signaling pathway. Molecular docking showed that Que binds strongly to key targets and is differentially expressed in AF. In vivo results showed that Que significantly reduced the duration of AF fibrillation and improved atrial remodeling, reduced p-MAPK protein expression, and inhibited the progression of AF. Combining network pharmacology and molecular docking approaches with in vivo studies advance our understanding of the intensive mechanisms of Quercetin, and provide the targeted basis for clinical Atrial fibrillation treatment.

Atrial fibrillation progression and the importance of early treatment for improving clinical outcomes.

Over time, atrial fibrillation (AF) naturally progresses from initially paroxysmal to persistent/permanent AF caused by structural and electrical remodelling with a complex underlying pathogenesis. It has been demonstrated that this progression of AF itself is linked to negative cardiovascular outcomes (stroke, systemic embolism, and hospitalization due to heart failure). Consequently, there is a profound rationale for early treatment of AF as a cornerstone of AF management. Recent randomized trials produced evidence that early rhythm control is effective in maintaining sinus rhythm, lower the risk of cardiovascular outcomes, and that catheter ablation of AF is effective to delay AF progression. This review will illuminate current evidence regarding the hypothesis of early AF treatment to prevent AF progression and improve clinical outcomes.

The role of alcohol consumption on echocardiographic and electrophysiologic changes in atrial fibrillation.

A wealth of evidence suggests that alcohol consumption is a risk factor for atrial fibrillation (AF); however, the mechanisms underlying this association are unclear. This makes it challenging to develop therapeutic strategies in patients with AF attributed to alcohol consumption. To investigate the echocardiographic and electrophysiologic changes caused by alcohol consumption in patients with AF. The study was registered in Chinese Clinical Trial Registry (Registration number ChiCTR2000041575). Data on 134 consecutive non-valvular AF patients who underwent radiofrequency catheter ablation in our center was collected from April 1, 2019 to June 30, 2020. Patients were divided into no-alcohol (72) and alcohol groups [categorized into light (34), moderate (11) and heavy (17) alcohol consumption]. All patients underwent echocardiographic and electrophysiologic examinations for the assessment of left atrial (LA) strain, inter-atrial conduction, intra-atrial conduction, and atrial effective refractory period (ERP). Overall, the mean age was 61 ± 11 years and 87 (65%) were males. Compared with the no-alcohol group, impaired peak LA longitudinal strain, obvious inter-atrial conduction delay and increasing ERP dispersion were observed in the alcohol group. Intra-atrial conduction delay and ERP dispersion increased with increasing amounts of alcohol consumption. Alcohol consumption was associated with substantial abnormal echocardiographic and electrophysiologic changes in AF patients. These changes may contribute to the occurrence and progression of AF attributed to alcohol consumption, which may help in the development of new strategies for the prevention and management of AF. However further investigation is required.

Characteristics of successful reactive atrial-based antitachycardia pacing in patients with cardiac implantable electronic devices: History of catheter ablation of atrial fibrillation as a predictor of high treatment efficacy.

Reactive atrial-based antitachycardia pacing (rATP) in patients with cardiac implantable electronic devices (CIEDs) suppresses the progression of atrial fibrillation (AF) to the persistent form. However, the clinical factors associated with successful reactive atrial-based antitachycardia pacing (rATP) treatment are unknown. This study aimed to examine the predictors of high rATP efficacy in patients with CIEDs. The data of 101,325 rATP-treated atrial tachyarrhythmia (AT/AF) episodes in 51 patients, obtained through remote monitoring and device interrogation, were analyzed. The study population was divided into the high and low efficacy groups based on the overall median success rate of rATP. Clinical characteristics were compared between the two groups. During a follow-up period of 28.6 ± 8.6 months, the median success rate was 43.7% (31.5%-64.9%). The prevalence of a history of catheter ablation of AF was significantly higher in the high efficacy group than in the low efficacy group (73.0% vs. 44.0%, p = .048) and was the only independent predictor of high rATP efficacy (odds ratio, 3.45; p = .038). The rATP success rate in patients with (n = 30) and without (n = 21) a history of catheter ablation was 53.9% (40.0%-67.5%) and 36.4% (22.2%-47.7%), respectively (p = .012). The effect of rATP after ablation was more pronounced in patients with long cycle length episodes (≥75% of AT/AF sequences having a cycle length of 200-449 ms) (67.3% [46.0%-73.6%] vs. 30.6% [18.1%-60.3%], p = .027). The high efficacy group had a significantly lower incidence of AT/AF lasting ≥1, ≥7, and ≥30 days than the low efficacy group. rATP combined with catheter ablation therapy is effective in suppressing AT/AF.

The impact of different fat depots in the body on the progression of atrial fibrillation - data from RACE V

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation, Medtronic Background Paroxysmal atrial fibrillation (PAF) progression is associated with cardiovascular complications and worse outcome. Obesity is independently associated with AF prevalence and progression. The association between different fat depots in the body with AF is unclear. Aim We aim to systematically investigate the association of different fat depots in the body with AF. Methods 417 patients with PAF and continuous rhythm monitoring (implantable loop recorder or pacemaker) were included in the prospective RACE V study. In addition to extensive phenotyping at baseline including calculating BMI and measuring waist circumference (WC) epicardial and pericardial fat were measured on non-contrast enhanced cardiac CT scans by tracing the pericardium manually on every slice and afterwards fat automatically summed between -50 and -150 HU. Epicardial fat was defined as fat within the pericardium, pericardial fat as fat inside the pericardium and adjacent to the pericardium and thoracic fat as adjacent fat outside the pericardium. AF progression was defined as (1) progression to persistent or permanent AF, or (2) progression of PAF with >3% burden increase within 2.2years of follow-up. Multivariable logistic regression analysis was used to analyse the association of different fat pads with AF progression. Results Six percent of patients per year showed AF progression (51/417) after a median follow-up of 2.2 (1.6-2.8) years. Multivariate analysis identified WC (odds ratio [OR] 1.03, 95% confidence intervals [CI] 1.01-1.06, p=.014) to be associated with AF progression. Epicardial fat (OR 1.00, 95%CI .99-1.01, p=.407), pericardial fat (OR 1.00, 95%CI .99-1.01, p=.311), thoracic fat (OR 1.00, 95%CI .99-1.01, p=.372), and BMI (OR 1.03, 95%CI .97-1.10, p=.328) showed no relation with AF progression. Conclusion AF progression occurred in 6% per year in patients with PAF. In contrast to epicardial, pericardial and thoracic fat measured in a semiautomatic way, WC was the only fat depot associated with AF progression. Whether a more different assessment of obesity and epicardial fat may demonstrate an association with AF progression warrants further study.

Replicated gene expression changes in patients with atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union Horizon 2020 CATCH ME; Cardiovascular Research Netherlands RACE V Background Little is known about changes in the atrial transcriptome associated with paroxysmal and persistent atrial fibrillation (AF). Purpose To identify major molecular mechanisms in AF, we determined consistent differential expression (DE) between atrial tissue samples from well-characterized patients with paroxysmal or persistent AF and patients without a history of AF (no AF) in two independent patient cohorts. Methods Poly-A tailed RNA from left and right atrial appendage tissue samples from independent discovery and replication cohorts CATCH ME (n=192) and RACE V (n=122) was sequenced and analyzed according to patient AF history. Analyses were performed stratified by atrial side, adjusting for age, sex, heart failure and a combination of clinical characteristics determined by principal component analysis. Transcripts were considered DE in CATCH ME if their fold change reached transcriptome-wide significance (false discovery rate (FDR) < 0.05). DE transcripts in each rhythm comparison were replicated in RACE V if we observed a concordant direction of effect and a within-set FDR < 0.05 in the same comparison. Results Persistent AF compared to no AF was associated with 184 left atrial DE transcripts in CATCH ME of which 85 (46%) were replicated in RACE V, and with 208 right atrial DE transcripts in CATCH ME of which 86 (41%) were replicated in RACE V. Overall, 26 transcripts were discovered and replicated in both atria. Discovered but non-replicated transcripts often did exhibit concordant direction of effect (left: 78%, right: 83%). Replicated transcripts consisted of protein coding genes, antisense and non-coding RNAs. Protein coding genes showed involvement in pathways linking persistent AF to cardiomyocyte structure, conduction properties, fibrosis, inflammation, molecule trafficking, and endothelial dysfunction. Interestingly, paroxysmal AF was not consistently associated with DE transcripts in any comparison. Principal component analysis of the expression of the 26 transcripts strongly associated with persistent AF did however reveal a distinct paroxysmal AF expression profile in-between no AF and persistent AF patients in the first principal component scores (Figure 1). Conclusion RNA sequencing of human atrial tissue samples identified many transcripts associated with persistent AF in left and/or right atria, discovered and replicated using two independent cohorts. These consistent findings of AF-induced changes provide a starting point for targeted proteomic analysis and single-nucleus sequencing to further unravel the molecular mechanisms underlying AF progression to persistent AF, and biomarker development to quantify AF progression and enable precision medicine in individual patients.

Left atrium hemodynamic in atrial fibrillation and normal subjects

Abstract Funding Acknowledgements Type of funding sources: None. Background A computational fluid-dynamics (CFD) model previously developed with the aim of evaluating cardioembolic risk in patient affected by atrial fibrillation (AF) was used for the characterization of the left atrium (LA) hemodynamic in normal subjects (NL), patients affected by paroxysmal atrial fibrillation (PAR-AF) and patients affected by persistent atrial fibrillation (PER-AF). Based on the fluid-dynamics simulations results, we aimed at enhancing differences in blood flow in AF patients and NL and at better understanding the relationship between AF progression and stroke risk on a patient-specific basis. Methods 3D patient-specific anatomical and motion models were derived from ECG-gated coronary artery CT acquired with retrospective protocol. These models represented the computational domain for CFD simulations in which inflow initial conditions were derived from PW Doppler at the mitral valve and at the pulmonary veins. Velocity field and vortex structures both within the LA and left atrial appendage (LAA) were assessed in 10 NL, 5 PAR-AF and 4 PER-AF. Blood stasis was evaluated by populating the LAA with 500 particles and counting the number of particles still present after five cardiac cycles. Results Velocities inside the LA and in the LAA presented different amplitude and distribution in the 3 groups (peak velocity – NL: 50÷60 cm/s, PAR-AF: 40÷50 cm/s, PER-AF: 15÷25 cm/s). The mean velocity resulted lower in the PER-AF compared with PAR-AF (mean velocity – PAR-AF: 25÷35 cm/s, PER-AF: 8÷20 cm/s) at the LAA ostium and inside the LAA, in which the wash-out effect was strongly reduced (Figure 1). On the other hand, the mean velocity in the NL was higher with respect of AF patients (mean velocity – NL: 40÷45 cm/s). A higher number of vortex structures was observed in NL compared with AF patients, thus favouring the hypothesis of a more efficient wash-out of the LA and of the LAA. Blood stasis in terms of number of particles in the LAA after five cardiac cycles confirmed these results (NL: 5±2, PAR-AF: 18±3, PER-AF: 41±10). Conclusions The developed approach quantifies differences in LA hemodynamic between AF and NL patients, also allowing a stratification of the atrial disease progression in terms of variations in the blood velocity, organization of blood flow and quantification of blood stasis.

The role of the autonomous nervous system in atrial fibrillation progression. Data from the RACE V study

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): We acknowledge the support from the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation, CVON 2014-9: Reappraisal of Atrial Fibrillation: interaction between hyperCoagulability, Electrical remodelling, and Vascular destabilisation in the progression of AF (RACE V). Unrestricted grant support from Medtronic Trading NL B.V. Background Atrial fibrillation (AF) progression is associated with adverse outcome. The autonomic nervous system plays a yet unsettled role in initiation and progression of AF. Purpose To assess in patients with paroxysmal selfterminating AF differences in phenotype and AF progression depending on the role of the autonomic nervous system in triggering AF episodes. Methods Patients with paroxysmal AF included in the Reappraisal of AF: Interaction Between HyperCoagulability, Electrical Remodelling, and Vascular Destabilisation in the Progression of AF (RACE V) study were analysed. Patients were extensively phenotyped at baseline and received continuous rhythm monitoring with an implantable loop recorder (ILR).To adequately define the role of the autonomic nervous system in triggering AF only patients with at least 3 selfterminating AF episodes were included. ILR data were used to assess whether AF was mainly vagally induced (>80% of episodes starting during night time) or mainly adrenergically induced (>80% starting during daytime), and to assess the development of AF progression. If a patient could not be identified as either vagal or adrenergic, they were classified as mixed AF. Primary outcome were differences in AF progression between the three groups. AF progression was defined as (1) progression to persistent or permanent AF, or (2) progression of PAF with >3% burden increase. Follow-up was 2.2 (1.6-2.8) years. Results 278 patients were included, median was age 66 (59-71) years, 117 (42%) were women (Table 1). Patients with vagally or adrenergically induced AF had less comorbidities compared to mixed AF patients (median 2 versus 2 versus 3, respectively, p=0.012). In the mixed group, compared to either the vagal or adrenergic group the estimated glomerular filtration rate was slightly worse (median 78 versus 84 versus 82 mL/min*1.73m2 in the mixed versus vagal and adrenergic group, respectively, p=0.018), diabetes was more common (12% versus 5% versus 0%, respectively, p=0.031). Obesity was most often present in the vagal group (38% versus 12% versus 27%, in the vagal versus adrenergic versus mixed group, respectively p=0.028). Progression rates in the vagal versus adrenergic versus mixed groups were 5% versus 5% versus 24%, respectively (p=0.013 vagal versus mixed and p=0.008 adrenergic versus mixed group, respectively)(Figure). Conclusion Important differences exist between AF patients depending on their autonomic nervous system associated triggering mechanisms. Patients with either vagally or adrenergically induced AF have less comorbidities as compared to those with a mixed initiation type of AF and showed lower AF progression rates.

The features of atrial fibrillation occurrence in patients who have undergone COVID-19

Funding AcknowledgementsType of funding sources: None.COVID-19 pandemic has a rather negative effect on patients with cardiovascular pathology, also in patients without cardiovascular disease because its pathogenesis is based on generalized vascuities of the microvasculature with the development of multiple thrombosis and thromboembolism. Atrial fibrillation (AF) is one of the major cardiac arrhythmias and accounts for almost one third of all arrhythmias. Changes in electrical, structural, and contractile properties of cardiac tissue that are thought to underlie AF maintenance and progression are reviewed. The aim of this study is to identify the features and predictors that contribute to the onset or development of AF in patients who have had COVID -19.MethodsThis was a three-center prospective study, conducted in the coronary care unit during the period of February 2020 to June 2021. This study included 196 patients with AF who underwent COVID-19 at different times of this period (I group). For comparison, the data of similar 203 AF patients without COVID (II group) were analyzed in the period from February 2018 to February 2019 from the same centers... Medical history, clinical, instrumental and laboratory data, including troponin-1, tissue factor (TF), and hsCRP were studied in all patients. The data obtained was analyzed for statistical significance including multivariable logistic regression using analyses by SPSS 16.ResultsThe compared results showed that the first-onset AF in patients from first group was observed in 18.7% compared with 8.1% in second group. In intensive care units, AF were registered in 44.2% of patients in I group vs. 7.1% of patients in II group. In first group among patients with ACS, AF occurred in 12.7% of cases vs. similar patients in II group- 8.4%. In first group hypokalemia was observed in 67.8% of cases vs. 28.6% in II group... Multivariable logistic regression was shown that among tested biomarkers, hsCRP, troponin‐I and TF were more higher in patients undergoing COVID in compared patients with AF without COVID (odds ratio, 3.48; p<0.001, 2.36 p<0.017 and 2.48 p<0.01 accordingly).ConclusionsSome features of the onset or development of AF were identified in patients undergoing COVID. So, In these patients compared with AF patients without COVID, AF more often occurs in clinically severe patients, with ACS, as well as in patients with severe hypokalemia, higher hsCRP, TF and troponin values.

The impact of a structured polygraphy screening incorporated in a novel remote mobile health pathway on sleep apnoea prevalence in patients with atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Background Untreated obstructive sleep apnoea (OSA) contributes to progression of atrial fibrillation (AF) and reduces the success rate of heart rhythm control strategies. OSA remains one of the most frequently underdiagnosed modifiable risk factors in AF patients due to a lack of standardized screening methods and low awareness. Purpose To assess the impact of implementation of a structured remote OSA screening and management pathway on the prevalence of OSA in AF patients scheduled for AF ablation procedures. Methods In October 2020, a novel remote OSA screening and management pathway (VIRTUAL-SAFARI) was introduced in two AF outpatient clinics in the Netherlands. Consecutive patients scheduled for AF ablation were offered OSA screening consisting of sending a portable home sleep test to patients’ homes to perform a remote sleep recording for one night, analysis by a sleep physician, discussion of results with the patient, and initiation of treatment (when applicable). The impact of this structural screening strategy was assessed by comparing the prevalence of concomitant OSA (defined as apnoea-hypopnoea index ≥5) for patients scheduled for AF ablation in the year before and after introduction of the OSA management pathway. Results A total of 733 patients was studied, 308 in the year before (Oct ’19 - Sep ’20) and 425 in the year after (Oct ’20 - Sep ’21) introduction of the VIRTUAL-SAFARI pathway. Median age was 65 [58-71], 64% was male and median body mass index (BMI) was 27 [25-30] kg/m2. Baseline characteristics were comparable for the groups before and after introduction of the pathway (Table 1). In the cohort before pathway introduction, OSA had been diagnosed in 26 patients (8%, Figure 1) and was treated with positive airway pressure in 10 cases (3%). In the cohort after pathway introduction, OSA had previously been diagnosed in 53 patients (12%). Eighty-eight percent of patients without previous OSA screening was referred via the remote pathway. Results of the sleep recordings were available for 213 (59%) at the time of this analysis. Previously unknown OSA was diagnosed in 184 patients (86% of available recordings), increasing the prevalence of confirmed OSA to 237 (55%). For 22% of patients, results of sleep recordings are pending. Absence of OSA was confirmed in 9%, and 13% of patients had not been screened (e.g. because of patient preference or logistical reasons). After pathway introduction, 82 patients (19%) were treated or received advice to start treatment with positive airway pressure. Treatment decisions are pending for 9% of the cohort. Conclusion After the implementation of structured remote OSA screening in a well characterized cohort of consecutive patients scheduled for AF ablation, the prevalence of diagnosed OSA increased from 8% to 55%. Whether appropriate risk factor management, including treatment of OSA identified by structured screening, will improve AF outcomes needs to be tested in future studies.

The impact of an atrial septal defect on the progression of atrial tachypacing-induced atrial fibrillation in a Danish Landrace pig: A case report.

The impact of an atrial septal defect on the progression of atrial tachypacing-induced atrial fibrillation in a Danish Landrace pig: A case report.

Blood pressure response during treadmill exercise testing and the risk for future development of atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Aims Hypertension is a well-established risk factor for the onset and progression of atrial fibrillation (AF). Blood pressure (BP) response during routine exercise stress testing (EST) may identify subjects at increased risk for developing AF. Methods A retrospective analysis of treadmill EST performed by the Bruce protocol in patients aged ≥40 years without a history of AF (n=17,617; 42% women). BP was measured at rest, peak exercise, and 2-minute recovery, and was analyzed for association with the risk for developing AF. Results AF was documented in 4.5% of patients during mean follow-up of 7 years. The incidence rate of AF per 1000 person-years increased with the rise in CHA2DS2VASc score (3.26 in score=0 to 19.78 in scores≥6). Adjusting for CHA2DS2VASc score and exercise capacity, a multivariate analysis of systolic BP at rest (≥130 vs. ≤110 mmHg), peak-exercise (&amp;gt;170 vs. ≤150 mmHg), and recovery (&amp;gt;150 vs. ≤130 mmHg), were associated with increased risk for AF: hazard ratio (HR) 1.68 (95% CI, 1.40-2.01), 1.38 (1.15-1.64), 1.54 (1.27-1.86), respectively. Similarly, diastolic BP analysis at rest (≥90 vs. &amp;lt;80 mmHg), peak-exercise (≥100 vs. &amp;lt;90 mmHg), and recovery (&amp;gt;90 vs. ≤80 mmHg), were associated with increased risk for AF: 1.78 (1.34-2.35), 2.22 (1.37-3.59), 1.73 (0.90-3.25). The association with AF was also observed when BPs were analyzed as continuous variables, including after additional adjustment of exercise and recovery measurements to resting BP. Conclusions Systolic and diastolic BP at rest, peak-exercise and recovery phases of EST may provide independent predictive information regarding future risk for developing AF.

Atrial fibrillation progression and burden after the first clinical episode: a prospective observational study via implantable loop recorders

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Medtronic Inc Background The progression of atrial fibrillation (AF) after the first clinical AF episode is not well known. AF burden is of clinical significance as it may have clinical implications concerning the long-term management of the arrhythmia and the decision-making on AF patients. Continuous rhythm monitoring via implantable loop recorders (ILRs) can precisely evaluate the AF recurrence profile. Purpose To observe the AF progression and AF burden in patients after their first clinical AF episode. Methods Thirty consecutive patients (age 66.9 ± 10 years; 14 men) received an ILR after their first clinical AF episode. We recorded the AF recurrences and burden during a follow-up period of three years. We excluded patients with persistent or permanent AF and patients with an episode of AF attributed to reversible or transient causes. Results Three patients (10%) had no AF recurrence, whereas 4 patients (13.3%) presented only one episode. Almost half of the patients (46.7%) had a low recurrence rate (&amp;lt;5 episodes/year), whereas the majority of patients (19/30) suffered from episodes with maximum duration ≤24 hours. Eleven patients (36.7%) presented either no episode or a low recurrence rate with episodes lasting ≤24 hours. In 16 patients (53.3%) the AF burden was increased during the second year of follow-up period while in 9 patients (30%) the AF burden was decreased. During the third year of follow-up period the AF burden was increased in 19 patients (63.3%), decreased in 7 patients (23.3%) and remained almost the same in 4 patients (13.3%). Five patients (16.6%) presented at least one episode of persistent AF during the follow-up period. Seven patients (23.3%) suffered only from symptomatic AF episodes, while in nine patients (30%) only asymptomatic AF episodes were recorded. Eleven patients (36.7%) had both types of AF episodes (symptomatic and asymptomatic). Conclusions The AF recurrences and burden increased in most AF patients. However, a significant percentage of patients either suffer no AF recurrence after their first symptomatic episode or show a low recurrence rate. Most patients present episodes of short duration. Paroxysmal AF clinical profile differed significantly among the patients. If these findings are confirmed in larger studies, they could have clinical implications ensuring individualized management of the arrhythmia in the future in newly diagnosed AF patients.

Lifestyle Modification and Atrial Fibrillation: Critical Care for Successful Ablation.

Management of atrial fibrillation (AF) requires a comprehensive approach due to the limited success of medical or procedural approaches in isolation. Multiple modifiable risk factors contribute to the development and progression of the underlying substrate, with a heightened risk of progression evident with inadequate risk factor management. With increased mortality, stroke, heart failure and healthcare utilisation linked to AF, international guidelines now strongly support risk factor modification as a critical pillar of AF care due to evidence demonstrating the efficacy of this approach. Effective lifestyle management is key to arrest and reverse the progression of AF, in addition to increasing the likelihood of freedom from arrhythmia following catheter ablation.

Effect of PCSK9 Monoclonal Antibody Versus Placebo/Ezetimibe on Atrial Fibrillation in Patients at High Cardiovascular Risk: A Meta-Analysis of 26 Randomized Controlled Trials.

Patients at high cardiovascular risk are closely associated with an increased risk of atrial fibrillation (AF). Whether proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9 mAbs) can attenuate AF progression remains unknown. To compare PCSK9 mAbs with placebo or ezetimibe to explore the effect of PCSK9 mAbs therapy on the end-point of incidence of AF, we searched PubMed, Embase, and ClinicalTrials.gov for articles. We used Mantel-Haenszel risk ratio (RR) with corresponding 95% CI for the categorical data, including the incidence of AF and predefined other outcomes of interest. We included 21 articles consisting of 26 randomized controlled trials with a total of 95,635 participants. Quantitative synthesis revealed that PCSK9 mAbs significantly reduce the incidence of AF events (RR 0.84; 95% CI 0.72-0.98; p = 0.03), whereas no obvious differences were seen between the PCSK9 mAbs group and the ezetimibe group (RR 0.90; 95% CI 0.29-2.76; p = 0.85). PCSK9 mAbs also markedly decreased the incidence of cerebrovascular events (RR 0.75; 95% CI 0.66-0.85; p < 0.0001) and new-onset hypertension (RR 0.92; 95% CI 0.87-0.97; p = 0.003), but not the risk of cardiovascular death (RR 0.95; 95% CI 0.85-1.07; p = 0.40) and new-onset diabetes mellitus (RR 1.01; 95% CI 0.95-1.08; p = 0.67). Overall, the PCSK9 mAbs therapy reduced AF and presented certain cardiovascular benefits in patients at high cardiovascular risk. Further big-scale and long follow-up duration randomized controlled trials that compare PCSK9 mAbs with ezetimibe are required to evaluate the effect of PCSK9 mAbs versus ezetimibe on AF.

Slow Conduction Corridors and Pivot Sites Characterize the Electrical Remodeling in Atrial Fibrillation.

This study aimed to evaluate the progression of electrophysiological phenomena in a cohort of patients with paroxysmal atrial fibrillation (PAF) and persistent atrial fibrillation (PsAF). Electrical remodeling has been conjectured to determine atrial fibrillation (AF) progression. High-density electroanatomic maps during sinus rhythm of 20 patients with AF (10 PAF, 10 PsAF) were compared with 5 healthy control subjects (subjects undergoing ablation of a left-sided accessory pathway). A computational postprocessing of electroanatomic maps was performed to identify specific electrophysiological phenomena: slow conductions corridors, defined as discrete areas of conduction velocity<50cm/s, and pivot points, defined as sites showing high wave-front curvature documented by a curl module >2.5 1/s. A progressive decrease of mean conduction velocity was recorded across the groups (111.6 ± 55.5cm/s control subjects, 97.1 ± 56.3cm/s PAF, and 84.7 ± 55.7cm/s PsAF). The number and density of slow conduction corridors increase in parallel with the progression of AF (8.6 ± 2.2 control subjects, 13.3 ± 3.2 PAF, and 20.5 ± 4.5 PsAF). In PsAF the atrial substrate is characterized by a higher curvature of wave-front propagation (0.86 ± 0.71 1/s PsAF vs 0.74 ± 0.63 1/s PAF; P = 0.003) and higher number of pivot points (25.1 ± 13.8 PsAF vs 9.5 ± 6.7 PAF; P< 0.0001). Slow conductions: corridors were mostly associated with pivot sites tending to cluster around pulmonary veins antra. The electrical remodeling hinges mainly on corridors of slow conduction and higher curvature of wave-front propagation. Pivot points associated to SC corridors may be the major determinants for functional localized re-entrant circuits creating the substrate for maintenance of AF.

PO-712-05 TEMPORAL TRENDS IN USING CATHETER ABLATION AS FIRST-LINE THERAPY IN PATIENTS DIAGNOSED WITH PAROXYSMAL ATRIAL FIBRILLATION IN THE UNITED STATES

More than a decade ago, randomized clinical trials have demonstrated clinical benefits of catheter ablation compared to antiarrhythmic drugs (AAD) in patients with symptomatic paroxysmal atrial fibrillation (AF) refractory or intolerant to AAD. More recently, superiority of catheter ablation as first-line treatment vs AAD has been demonstrated as well. In addition, early AF ablation has been shown to delay AF progression. However, data are limited on contemporary trends of real-world catheter ablation practice as first-line therapy in patients diagnosed with paroxysmal AF. To explore the temporal trends in catheter ablation as first-line therapy in patients diagnosed with paroxysmal AF in the US. A retrospective analysis was conducted in adult patients who had a diagnosis of paroxysmal AF and underwent a catheter ablation of AF by pulmonary vein isolation during 2016-2020 from the IBM MarketScan® Commercial Database. The proportion of catheter ablation as first-line therapy in patients diagnosed with paroxysmal AF was calculated according to the calendar year of the catheter ablation procedure. Logistic regression models evaluated the association between the calendar year of the catheter ablation procedure and first-line therapy choice. There was a significant 61% increase in the proportion of catheter ablation as first-line therapy in patients diagnosed with paroxysmal AF from 2016 (25%) to 2020 (35%) (2020 vs 2016: odds ratio, 1.61; 95% confidence interval, 1.42-1.83) (p for trend <0.0001). The increasing trend was similar by sex, age, and setting of care, but the proportion was slightly higher in younger patients than in older patients and was more pronounced in the inpatient vs outpatient setting of care (Figure 1). There was an increasing trend in using catheter ablation as first-line therapy in patients diagnosed with paroxysmal AF in the US. This finding may reflect increasing comfort level with catheter ablation due to multiple demonstrated clinical benefits compared to AAD as first-line treatment for symptomatic paroxysmal AF.

Blood pressure measurements during treadmill exercise testing and the risk for the future development of atrial fibrillation.

Hypertension is a well-established risk factor for the onset and progression of atrial fibrillation (AF). Blood pressure (BP) measurements during routine exercise stress testing (EST) may identify subjects at increased risk for developing AF. We performed a retrospective analysis of treadmill EST carried out using the Bruce protocol in patients aged ≥40 years without a history of AF (n = 17,617; 42% women). BP was measured at rest, peak exercise, and 2-min recovery and analyzed for its association with the risk for developing AF. During a mean follow-up of 7 years, AF was documented in 4.5% of the patients. The incidence rate of AF per 1000 person-years increased with the rise in CHA2DS2VASc scores (3.26 for a Score=0 to 19.78 for scores ≥6). In a multivariate analysis, adjusting for risk score components and exercise capacity, systolic BP measurements taken at rest (≥130 vs. ≤110 mmHg), peak exercise (>170 vs. ≤150 mmHg), and recovery (>150 vs. ≤130 mmHg) were associated with an increased risk for AF: the hazard ratios (HRs) were 1.56 (95% CI, 1.30-1.87), 1.21 (1.01-1.45), and 1.33 (1.10-1.62), respectively. Similarly, diastolic BP measurements taken at rest (≥90 vs. <80 mmHg), peak exercise (≥100 vs. <90 mmHg), and recovery (>90 vs. ≤80 mmHg) were associated with an increased risk for AF: the HRs were 1.80 (1.36-2.38), 2.08 (1.28-3.37), and 1.56 (0.81-3.02), respectively. The association of exercise BP with AF was further observed when the BPs were analyzed as continuous variables and in subjects without a baseline diagnosis of hypertension. In conclusion, systolic and diastolic BP taken at the rest, peak exercise and recovery phases of EST may provide independent predictive information regarding future risk for developing AF.

Ameliorative Impact of Liraglutide on Chronic Intermittent Hypoxia-Induced Atrial Remodeling.

Atrial fibrillation (AF) is the most frequent form of clinical cardiac arrhythmias. Previous evidence proved that atrial anatomical remodeling (AAR) and atrial electrical remodeling (AER) are crucial for the progression and maintenance of AF. This study is aimed at investigating the impact of the glucagon-like peptide-1 (GLP-1) receptor agonist, Liraglutide (Lir), on atrial remodeling (AR) mouse model induced by chronic intermittent hypoxia (CIH). C57BL/6 mice were categorized randomly into the control, Lir, CIH, and CIH+Lir groups. CIH was performed in CIH and CIH+Lir groups for 12 weeks. Lir (0.3 mg/kg/day, s.c) was administered to the Lir and CIH+Lir groups for four weeks, beginning from the ninth week of CIH. Meanwhile, echocardiography and right atrial endocardial electrophysiology via jugular vein, as well as induction rate and duration of AF, were evaluated. Masson and Sirius red staining assays were utilized to assess the extent of fibrosis in the atrial tissue of the mice. Immunohistochemical staining, RT-qPCR, and Western blotting were performed to evaluate the marker levels of AAR and AER and the expression of genes and proteins of the miR-21/PTEN/PI3K/AKT signaling pathway, respectively. ELISA was also performed to evaluate the changes of serum inflammatory factor levels. The CIH group exhibited significant AR, increased atrial fibrosis, and a higher incidence rate of AF compared to the control group. Lir could significantly downregulate the protein expression level in the PI3K/p-AKT pathway and upregulated that of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Moreover, Lir downregulated the expression of miR-21. However, the protein expressions of CACNA1C and KCNA5 in atrial tissue were not changed significantly. In addition, Lir significantly attenuated the levels of markers of inflammation (TNF-α and IL-6) in the serum. In the mouse model of CIH, Lir treatment could ameliorate AR by the miR-21/PTEN/PI3K/AKT signaling pathway and modulation of inflammatory responses.

The good, the bad and the ugly: the impact of extracellular vesicles on the cardiovascular system.

Cardiovascular diseases (CVDs), which encompass a myriad of pathological conditions that affect the heart and/or the blood vessels, remain the major cause of morbidity and mortality worldwide. By transferring a wide variety of bioactive molecules, including proteins and microRNAs (miRNAs), extracellular vesicles (EVs) are recognized as key players in long-range communication across the cardiovascular system. It has been demonstrated that these highly heterogeneous nanosized vesicles participate both in the maintenance of homeostasis of the heart and vessels, and contribute to the pathophysiology of CVDs, thus emerging as promising tools for diagnosis, prognosis and treatment of multiple CVDs. In this review, we highlight the beneficial roles of EV-mediated communication in regulating vascular homeostasis, and inter-organ crosstalk as a potential mechanism controlling systemic metabolic fitness. In addition, the impact of EV secretion in disease development is described, particularly focusing on cardiac remodelling following ischaemia, atherogenesis and atrial fibrillation progression. Finally, we discuss the potential of endogenous and bioengineered EVs as therapeutic tools for CVDs, as well as the suitability of assessing the molecular signature of circulating EVs as a non-invasive predictive marker of CVD onset and progression. This rapidly expanding field of research has established the role of EVs as key conveyors of both cardioprotective and detrimental signals, which might be of relevance in uncovering novel therapeutic targets and biomarkers of CVDs.