Pathophysiology Of Atrial Fibrillation Research Articles

Heterogenous atrial conduction in patients with hypertrophic cardiomyopathy and atrial fibrillation

Abstract Background/Introduction Hypertrophic cardiomyopathy (HCM) is characterised by myocardial thickening, fibrosis, and disarray, affecting both ventricles and atria. This pathology extends to atrial tissue, potentially influencing conductivity and contributing to arrhythmias, notably atrial fibrillation (AF). Pulmonary vein isolation to treat AF in HCM patients yields less satisfactory results compared to other patient groups. Improved understanding of the pathophysiology of AF in HCM patients could improve treatment stratification and delivery. Purpose This study aims to analyse atrial conduction properties in HCM patients with AF, compared to age, body mass index and sex-matched control patients. Methods Pre-ablation electroanatomic mapping data from 10 HCM patients and a matched control group of patients with structurally normal hearts undergoing AF ablation was retrospectively analysed. All patients underwent pre-ablation electroanatomic mapping during proximal coronary sinus pacing. This data was analysed using OpenEP software to quantify voltage mapping, conduction velocity and wave collision points. Conduction velocity was calculated using both plane fitting and triangulation methods. Wave collisions were identified by calculating the percentage of points with conduction velocity field divergence values less than -1.5. Results HCM patients exhibited significantly reduced mean left atrial bipolar voltage and greater low voltage burden <0.5mV than matched control patients (1.43mV vs. 2.14mV, p=0.0177; and 38.28% vs. 15.68%, p<0.0001), (Figure 1A and B). Wave collision points were significantly more prevalent in the HCM group (5.4% vs. 1.6%, p=0.0004), indicating more heterogeneous conduction (Figure 1C). Figure 2 shows example of divergence map with local electrograms around wave collision points. Both methods of quantifying conduction velocity showed comparable results. While average conduction velocity showed no statistically significant difference (plane fitting method - 0.61m/s in HCM group vs. 0.64m/s in control group, p = 0.465; triangulation method - 0.61m/s in HCM group, 0.64m/s in control group, p=0.393), a trend toward lower velocities in HCM patients was observed (Figure 1D and 1E). Conclusion HCM patients demonstrate significantly lower bipolar voltage and significantly greater low voltage areas than matched control patients. Atrial conduction in patients with HCM is significantly more heterogenous than matched control patients. These findings highlight marked conduction abnormalities in HCM patients which are likely to contribute to AF pathogenesis.

Spontaneous atrial fibrillation occurrence following transesophageal atrial burst pacing in rats

Abstract Purpose Animal models play a crucial role in elucidating the complex pathophysiology of atrial fibrillation (AF) and in identifying and testing novel antiarrhythmic strategies. We aimed to develop and characterize a new experimental rat model of AF, induced by long-term transesophageal atrial electrical stimulation, and to investigate whether the "AF begets AF" concept applies to small rodent hearts. Method Twelve adult male Wistar rats were randomized into two groups: Sham (n = 5) and AF (n = 7). All rats were implanted at the beginning of the study with ECG radiotelemetry devices and underwent continuous ECG monitoring throughout the study. To induce AF, the rats in the AF group underwent atrial pacing for 10 consecutive days (15 successive cycles of stimulation/day, 20 s each, with a free interval of 5 min between cycles; 4,000 stimuli/min, stimulus duration 6 ms, voltage 3 V above the diastolic threshold). A similar procedure was applied to the Sham group, but without performing the actual electrical stimulation. The number and duration of spontaneous AF episodes were evaluated based on continuous ECG monitoring prior to, during, and for one week after transesophageal atrial pacing. The inducibility of AF and the occurrence and duration of spontaneous AF episodes were evaluated and compared between the two groups. Results Atrial fibrillation was induced in 85.7% of the rats subjected to atrial electrical pacing (Figure, A), with an average global inducibility of 44.0% ± 16.9% and a mean AF duration of 123.2 ± 96.3 s. No induced or spontaneous AF episodes were recorded in any of the Sham animals. In the AF group, none of the animals presented spontaneous AF before transesophageal atrial pacing. However, in the AF rats, after atrial electrical stimulation initiation, the number of atrial premature beats significantly increased (21.3 ± 6.8 / 24-h post-stimulation vs. 7.3 ± 6.5 / 24-h at baseline; p< 0.01; Figure, B), and all rats presented spontaneous AF episodes (Figure, C). At the end of the study, AF rats presented a total number of 23.9 ± 2.3 AF episodes / 24-h (Figure, D), with a mean AF burden of 337.7 ± 25.06 s / 24-h. Conclusions Our data demonstrate that, despite the small size of the atria, the "AF begets AF" concept is applicable in small rodents. The study presents a novel rat model of AF, in which spontaneous AF occurs following long-term atrial electrical stimulation. Given that the model is relatively rapid and easy to implement, it provides a setup for further investigation of AF pathophysiology, and for identifying and testing novel therapeutic strategies for AF.Figure 1

Downregulation of miR-568 in Atrial Fibrillation Leads to Increased Expression of NAPMT and TRMP7

Aim: Atrial fibrillation (AF) is known as the most common permanent cardiac arrhythmia worldwide with its incidence and prevalence gradually increase with age and cause significant morbidity and mortality. However, the epigenetic alterations underlying the development of this disease remains less understood. MicroRNAs (miRNAs), as one of the epigenetic regulators, are small non-coding RNAs that can target multiple genes to modulate proteins in different signaling pathways. Current studies have demonstrated that miRNAs, which are pivotal regulators of gene expression, may be involved in the pathophysiology of AF. The current study aims to clarify the miRNA regulated cellular signaling in atrial fibrillation. Material and Method: An AF model was generated by providing external electrical stimulation to the HL-1 mouse cardiomyocyte cell line for 24 hours in this study. To understand the molecular mechanisms of miRNAs underlying the AF model, miRNA microarray analysis was performed. The gene sets obtained from the microarray analysis and the bioinformatically obtained putative targets were intersected and pathway enrichment analysis was performed. qRT-PCR was performed for validation of the selected miRNAs and potential targets. Results: miRNA expression profile changes between the control group without external stimulation and the samples at the end of 3-, 6-, 12- and 24-hour stimulation were compared with microarray analysis. In particular, our transcriptomic analysis showed 5 distinctively expressed miRNAs (DEmiRNAs) whose target genes are associated with cardiovascular development within the stimulated groups in HL-1 cells. Additionally, our bioinformatics analysis revealed that targets of these miRNAs are concentrated in biological processes associated with cardiovascular development: smooth muscle cell proliferation, muscle cell proliferation, cell morphogenesis involved in differentiation and regulation of cell differentiation. Specifically, qPCR-based analyses confirmed the inverse correlation of miR-568 and potential targets of this miRNA. While miR-568 expression decreased with prolonged stimulation, expression of its potential targets, NAMPT and TRPM7, increased during prolonged stimulation. Conclusion: This study supported the potential regulative role of miRNAs and their targets in the development of AF.

Synergistic Effects of Weight Loss and Catheter Ablation: Can microRNAs Serve as Predictive Biomarkers for the Prevention of Atrial Fibrillation Recurrence?

In atrial fibrillation (AF), multifactorial pathologic atrial alterations are manifested by structural and electrophysiological changes known as atrial remodeling. AF frequently develops in the context of underlying cardiac abnormalities. A critical mechanistic role played by atrial stretch is played by abnormal substrates in a number of conditions that predispose to AF, including obesity, heart failure, hypertension, and sleep apnea. The significant role of overweight and obesity in the development of AF is known; however, the differential effect of overweight, obesity, cardiovascular comorbidities, lifestyle, and other modifiable risk factors on the occurrence and recurrence of AF remains to be determined. Reverse remodeling of the atrial substrate and subsequent reduction in the AF burden by conversion into a typical sinus rhythm has been associated with weight loss through lifestyle changes or surgery. This makes it an essential pillar in the management of AF in obese patients. According to recently published research, microRNAs (miRs) may function as post-transcriptional regulators of genes involved in atrial remodeling, potentially contributing to the pathophysiology of AF. The focus of this review is on their modulation by both weight loss and catheter ablation interventions to counteract atrial remodeling in AF. Our analysis outlines the experimental and clinical evidence supporting the synergistic effects of weight loss and catheter ablation (CA) in reversing atrial electrical and structural remodeling in AF onset and in recurrent post-ablation AF by attenuating pro-thrombotic, pro-inflammatory, pro-fibrotic, arrhythmogenic, and male-sex-associated hypertrophic remodeling pathways. Furthermore, we discuss the promising role of miRs with prognostic potential as predictive biomarkers in guiding approaches to AF recurrence prevention.

Effect of an Intensive Lifestyle Intervention on Circulating Biomarkers of Atrial Fibrillation-Related Pathways among Adults with Metabolic Syndrome: Results from a Randomized Trial.

Background: Lifestyles influence atrial fibrillation (AF) risk. Determining the effect of lifestyle interventions on blood concentrations of biomarkers of AF-related pathways could help understand AF pathophysiology and contribute to AF prevention. Methods: We studied 532 participants enrolled in the PREDIMED-Plus trial, a Spanish randomized trial conducted in adults (55-75 years) with metabolic syndrome and body mass index between 27-40 kg/m2. Eligible participants were randomized 1:1 to an intensive lifestyle intervention, emphasizing physical activity, weight loss, and adherence to an energy-reduced Mediterranean diet or to a control group. Serum biomarkers [carboxy-terminal propeptide of procollagen type I (PICP), high-sensitivity troponin T (hsTnT), high-sensitivity C reactive protein (hsCRP), 3-nitrotyrosine (3-NT), and N-terminal propeptide of B-type natriuretic peptide (NT-proBNP)] were measured at baseline, 3 and 5 years after randomization. Mixed models were used to evaluate the effect of intervention on changes in biomarkers through year 5. Mediation analysis was performed to examine the proportion mediated by each component of the intervention. Results: At baseline, participants' mean age was 65, 40% were female, and 50% were assigned to the intervention. After five years, mean changes in log-transformed biomarkers were -0.01 (PICP), 0.20 (hsTnT), -0.17 (hsCRP), 0.12 (3-NT), and 0.27 (NT-proBNP). Compared to the control group, participants in the intervention group experienced greater decreases in hsCRP (-14%, 95% confidence interval (CI) -26%, 0%) or smaller increases in 3-NT (-16%, 95% CI -25%, -5%) and NT-proBNP (-12%, 95% CI -23%, 1%). The intervention had minimal impact on hsTnT (-3%, 95% CI -7%, 2%) or PICP concentrations (-2%, 95% CI -9%, 6%). The effect of the intervention on hsCRP was primarily mediated by weight loss (89% at year 5). Conclusions: Over five years, a dietary and lifestyle intervention for weight-loss favorably affected concentrations of hsCRP, 3-NT, and NT-proBNP, pointing to specific mechanisms in pathways linking lifestyles and AF.

Exercise-Dependent Modulation of Immunological Response Pathways in Endurance Athletes With and Without Atrial Fibrillation.

Atrial fibrillation (AF) is a common arrhythmia characterized by uncoordinated atrial electrical activity. Lone AF occurs in the absence of traditional risk factors and is frequently observed in male endurance athletes, who face a 2- to 5-fold higher risk of AF compared with healthy, moderately active males. Our understanding of how endurance exercise contributes to the pathophysiology of lone AF remains limited. This study aimed to characterize the circulating protein fluctuations during high-intensity exercise as well as explore potential biomarkers of exercise-associated AF. A prospective cohort of 12 male endurance cyclists between the ages of 40 and 65 years, 6 of whom had a history of exercise-associated AF, were recruited to participate using a convenience sampling method. The circulating proteome was subsequently analyzed using multiplex immunoassays and aptamer-based proteomics before, during, and after an acute high-intensity endurance exercise bout to assess temporality and identify potential markers of AF. The endurance exercise bout resulted in significant alterations to proteins involved in immune modulation (eg, growth/differentiation factor 15), skeletal muscle metabolism (eg, α-actinin-2), cell death (eg, histones), and inflammation (eg, interleukin-6). Subjects with AF differed from those without, displaying modulation of proteins previously known to have associations with incident AF (eg, C-reactive protein, insulin-like growth factor-1, and angiopoietin-2), and also with proteins having no previous association (eg, tapasin-related protein and α2-Heremans-Schmid glycoprotein). These findings provide insights into the proteomic response to acute intense exercise, provide mechanistic insights into the pathophysiology behind AF in athletes, and identify targets for future study and validation.

IMPACT OF THYROID DYSFUNCTION IN PATIENTS WITH ATRIAL FIBRILLATION

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice, affecting approximately 2% of the general population and increasing the risk of stroke, heart failure and mortality. AF is often associated with several clinical conditions, including thyroid dysfunction, which can alter metabolism, function and cardiac structure. Thyroid dysfunction can be classified as hypothyroidism (low production of thyroid hormones) or hyperthyroidism (excess production of thyroid hormones), both of which can cause or worsen AF. The mechanism by which thyroid dysfunction affects AF is complex and involves electrophysiological, hemodynamic, inflammatory and structural changes in the atria. Appropriate diagnosis and treatment of thyroid dysfunction can improve AF control and reduce thromboembolic and hemorrhagic complications. However, the prevalence, incidence, risk factors, prognosis and management of AF in patients with thyroid dysfunction are still controversial topics in the literature. Objective: to evaluate the impact of thyroid dysfunction in patients with AF, addressing the following aspects: epidemiology, pathophysiology, diagnosis, treatment and clinical outcomes. Methodology: This review was carried out in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) protocol. The PubMed, Scielo and Web of Science databases were searched, using the following descriptors: "atrial fibrillation", "thyroid dysfunction", "hypothyroidism", "hyperthyroidism" and "thyrotoxicosis". Articles published in the last 10 years, in Portuguese, English or Spanish, that addressed the proposed topic were included. Articles that were not original, did not have sufficient data or were not relevant to the research question were excluded. Results: 18 studies were selected. The diagnosis of AF in patients with thyroid dysfunction requires confirmation of the heart rhythm by electrocardiogram (ECG) and assessment of serum thyroid hormone levels (TSH, free T4 and free T3). Treatment of AF in patients with thyroid dysfunction aims to restore and maintain sinus rhythm, control ventricular rate, prevent thromboembolic events, and correct thyroid dysfunction. Therapeutic options include antiarrhythmic drugs, antithyroid drugs, anticoagulant drugs, electrical cardioversion, catheter ablation, and surgical thyroid treatment. The clinical outcomes of AF in patients with thyroid dysfunction are influenced by the type, severity and duration of thyroid dysfunction, as well as rhythm, frequency and anticoagulation control. AF in patients with thyroid dysfunction is associated with a higher risk of arrhythmia recurrence, heart failure, stroke and mortality. Conclusion: Thyroid dysfunction is a frequent and important clinical condition in patients with AF, as it can cause or worsen arrhythmia, as well as increase the risk of complications. Appropriate diagnosis and treatment of thyroid dysfunction can improve AF control and reduce adverse outcomes. However, there are still gaps in knowledge about the epidemiology, pathophysiology, prognosis and management of AF in patients with thyroid dysfunction, which require further studies of high quality and clinical relevance.

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.

Identification of Atrial Transmural Conduction Inhomogeneity Using Unipolar Electrogram Morphology.

(1) Background: Structural remodeling plays an important role in the pathophysiology of atrial fibrillation (AF). It is likely that structural remodeling occurs transmurally, giving rise to electrical endo-epicardial asynchrony (EEA). Recent studies have suggested that areas of EEA may be suitable targets for ablation therapy of AF. We hypothesized that the degree of EEA is more pronounced in areas of transmural conduction block (T-CB) than single-sided CB (SS-CB). This study examined the degree to which SS-CB and T-CB enhance EEA and which specific unipolar potential morphology parameters are predictive for SS-CB or T-CB. (2) Methods: Simultaneous endo-epicardial mapping in the human right atrium was performed in 86 patients. Potential morphology parameters included unipolar potential voltages, low-voltage areas, potential complexity (long double and fractionated potentials: LDPs and FPs), and the duration of fractionation. (3) Results: EEA was mostly affected by the presence of T-CB areas. Lower potential voltages and more LDPs and FPs were observed in T-CB areas compared to SS-CB areas. (4) Conclusion: Areas of T-CB could be most accurately predicted by combining epicardial unipolar potential morphology parameters, including voltages, fractionation, and fractionation duration (AUC = 0.91). If transmural areas of CB indeed play a pivotal role in the pathophysiology of AF, they could theoretically be used as target sites for ablation.

Diagnosis and management of atrial fibrillation in primary care: a case study

This critically reflective case study will look at a 65-year-old male presenting with dyspnoea and an incidental diagnosis of atrial fibrillation (AF) in a primary care setting. The article critically analyses the diagnosis and management of the patient, considers potential differential diagnoses, current guidelines, and areas for service improvement. The author, a trainee advanced clinical practitioner (ACP) prescriber with a paramedic background, discusses the complexity of managing AF and the need for collaboration with a general practitioner. AF is a common cardiac arrhythmia associated with a significantly increased risk of stroke. The primary focus of AF management is stroke prevention. This article delves into the pathophysiology of AF, discussing its various causes and classifications, emphasising the role of left atrial appendage (LAA) in stroke risk. The limitations of AF screening methods, especially for paroxysmal AF, are also discussed. Recent advancements in opportunistic screening, including the use of artificial intelligence (AI) and smartwatches, show promise but require further research and validation. This article explores stroke risk assessment tools like CHA2DS2VASc and ATRIA, bleeding risk assessment using HAS-BLED and ORBIT scores, as well as rhythm control in newly diagnosed AF cases. Finally, the importance of lifestyle modifications and regular patient follow-up are underscored. AF diagnosis and management are multifaceted, involving stroke prevention, rate or rhythm control, and lifestyle modifications. Technological advancements hold promise in improving early AF detection. Collaborative efforts between healthcare providers and adherence to current guidelines are crucial in achieving optimal patient outcomes, while future practice may benefit from enhanced diagnostic screening and treatment options as further research unfolds.

Consensus on Stroke Prevention in Atrial Fibrillation and Utilization of NOACs in the Real-World Setting in India

Atrial fibrillation (AF) is the most frequent cardiac arrhythmia. Prevention of stroke and systemic thromboembolism remainsthe cornerstone of the management of AF. Even today, there are unresolved knowledge gaps in AF pathophysiology, screeningand therapeutic strategies and stroke prevention. The modified DELPHI method was used to develop the best practicerecommendations for the management of AF in a real-world setting with the participation of 500 cardiologists across India.The experts concurred that the decision to initiate antithrombotic treatment in patients with transient AF could be based onthe duration of transient AF, the co-existence of the risk factor for stroke and echocardiographic abnormalities impact thedecision. The decision to initiate anticoagulant therapy in device-detected atrial high-rate episodes (AHRE) can be decidedbased on the duration of AHRE, the burden of AHRE and the individual’s risk of stroke and thromboembolism. The benefitof early anticoagulation should be balanced with the risk of intracerebral hemorrhage (ICH), especially in elderly patientsand in severe strokes. Apixaban is the preferred drug in patients with concomitant ischemic heart disease (IHD), patientswith a history of gastrointestinal (GI) bleeding, patients with underlying malignancy, elderly patients with AF, patients withcomorbid diseases and patients with hepatic disease or renal disease. Apixaban was considered to be an affordable noveloral anticoagulant (NOAC) for Indian patients for primary and secondary stroke prophylaxis in AF patients

Pathophysiology of Atrial Fibrillation and Approach to Therapy in Subjects Less than 60 Years Old.

Atrial fibrillation (AF) is an arrhythmia that affects the left atrium, cardiac function, and the patients' survival rate. Due to empowered diagnostics, it has become increasingly recognized among young individuals as well, in whom it is influenced by a complex interplay of autoimmune, inflammatory, and electrophysiological mechanisms. Deepening our understanding of these mechanisms could contribute to improving AF management and treatment. Inflammation is a complexly regulated process, with interactions among various immune cell types, signaling molecules, and complement components. Addressing circulating antibodies and designing specific autoantibodies are promising therapeutic options. In cardiomyopathies or channelopathies, the first manifestation could be paroxysmal AF; persistent forms tend not to respond to antiarrhythmic drugs in these conditions. Further research, both in vitro and in vivo, on the use of genomic biotechnology could lead to new therapeutic approaches. Additional triggers that can be encountered in AF patients below 60 years of age are systemic hypertension, overweight, diabetes, and alcohol abuse. The aims of this review are to briefly report evidence from basic science and results of clinical studies that might explain the juvenile burden of the most encountered sustained supraventricular tachyarrhythmias in the general population.

The role of cellular senescence in profibrillatory atrial remodelling associated with cardiac pathology.

Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to (i) evaluate AF susceptibility and senescence marker expression in rat models of aging and myocardial infarction (MI), (ii) study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI rats, and (iii) assess senescence markers in human atrial tissue as a function of age and the presence of AF. AF susceptibility was studied with programmed electrical stimulation. Gene and protein expression was evaluated by immunoblot or immunofluorescence (protein) and digital polymerase chain reaction (PCR) or reverse transcriptase quantitative PCR (messenger RNA). A previously validated senolytic combination, dasatinib and quercetin, (D+Q; or corresponding vehicle) was administered from the time of sham or MI surgery through 28 days later. Experiments were performed blinded to treatment assignment. Burst pacing-induced AF was seen in 100% of aged (18-month old) rats, 87.5% of young MI rats, and 10% of young control (3-month old) rats (P ≤ 0.001 vs. each). Conduction velocity was slower in aged [both left atrium (LA) and right atrium (RA)] and young MI (LA) rats vs. young control rats (P ≤ 0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young MI (LA) vs. young control rats (P < 0.05 for each). Senolytic therapy reduced AF inducibility in MI rats (from 8/9 rats, 89% in MI vehicle, to 0/9 rats, 0% in MI D + Q, P < 0.001) and attenuated LA fibrosis. Double staining suggested that D + Q acts by clearing senescent myofibroblasts and endothelial cells. In human atria, senescence markers were upregulated in older (≥70 years) and long-standing AF patients vs. individuals ≤60 and sinus rhythm controls, respectively. Our results point to a potentially significant role of cellular senescence in AF pathophysiology. Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.

The autonomic nervous system in atrial fibrillation-pathophysiology and non-invasive assessment.

The autonomic nervous system plays a crucial role in atrial fibrillation pathophysiology. Parasympathetic hyperactivity result in a shortening of the action potential duration, a reduction of the conduction wavelength, and as such facilitates reentry in the presence of triggers. Further, autonomic remodeling of atrial myocytes in AF includes progressive sympathetic hyperinnervation by increased atrial sympathetic nerve density and sympathetic atrial nerve sprouting. Knowledge on the pathophysiological process in AF, including the contribution of the autonomic nervous system, may in the near future guide personalized AF management. This review focuses on the role of the autonomic nervous system in atrial fibrillation pathophysiology and non-invasive assessment of the autonomic nervous system.

Developing Pharmacological Therapies for Atrial Fibrillation Targeting Mitochondrial Dysfunction and Oxidative Stress: A Scoping Review.

Atrial fibrillation (AF) is a cardiac arrhythmia caused by electrophysiological anomalies in the atrial tissue, tissue degradation, structural abnormalities, and comorbidities. A direct relationship exists between AF and altered mitochondrial activity resulting from membrane potential loss, contractile dysfunction, or decreased ATP levels. This review aimed to elucidate the role of mitochondrial oxidative mechanisms in AF pathophysiology, the impact of mitochondrial oxidative stress on AF initiation and perpetuation, and current therapies. This review followed the Preferred Reporting Items for Systematic Reviews and the Meta-Analysis Extension for Scoping Reviews. PubMed, Excerpta Medica Database, and Scopus were explored until June 2023 using "MESH terms". Bibliographic references to relevant papers were also included. Oxidative stress is an imbalance that causes cellular damage from excessive oxidation, resulting in conditions such as AF. An imbalance in reactive oxygen species production and elimination can cause mitochondrial damage, cellular apoptosis, and cardiovascular diseases. Oxidative stress and inflammation are intrinsically linked, and inflammatory pathways are highly correlated with the occurrence of AF. AF is an intricate cardiac condition that requires innovative therapeutic approaches. The involvement of mitochondrial oxidative stress in the pathophysiology of AF introduces novel strategies for clinical treatment.

Clinician-Created Video Education for Patients With AF

ImportancePatient education is a critical aspect of atrial fibrillation (AF) management. However, there is limited time to provide effective patient education during routine care, and resources available online are of variable quality.ObjectiveTo determine whether clinician-led creation of video-based AF education is feasible and improves knowledge of AF.Design, Setting, and ParticipantsThis single-center randomized clinical trial was conducted between 2020 and 2022. Outcomes were assessed prior to their clinic visit and 2 and 90 days after the visit by blinded assessors. Participants included adults with AF and congestive heart failure, hypertension, age at least 75 years (doubled), diabetes, prior stroke or transient ischemic attack or thromboembolism (doubled), vascular disease, age 65 to 74 years, and sex category scores of 1 or greater presenting for routine care at publicly funded outpatient cardiology clinics within a tertiary teaching hospital. Individuals too unwell to participate or with limited English were excluded. Data were assessed as intention to treat and analyzed from December 2022 to October 2023.InterventionIntervention participants viewed a series of 4 videos designed and narrated by clinicians that aimed to improve understanding of AF pathophysiology, clinical presentation, diagnosis, and management. After viewing the videos, participants received weekly email links to review the videos. The control group received usual care.Main Outcomes and MeasuresThe prospectively selected primary outcome was AF knowledge at 90 days, measured by the validated Jessa Atrial Fibrillation Knowledge Questionnaire (JAFKQ).ResultsAmong 657 individuals screened, 208 adults with AF were randomized (mean [SD] age, 65.0 [12.2] years; 133 [65.2%] male) and included in analysis. Participants were randomized 1-to-1, with 104 participants in the control group and 104 participants in the video intervention group. At 90 days after the baseline clinic visit, intervention participants were more likely to correctly answer JAFKQ questions than control participants (odds ratio [OR], 1.23 [95% CI, 1.01-1.49]). The difference was greater in participants who remotely accessed videos on 3 or more occasions during the study (OR, 1.46 [95% CI, 1.14-1.88]).Conclusions and RelevanceIn this randomized clinical trial of patients with AF, remotely delivered, clinician-created video education improved medium-term AF knowledge beyond usual care of standard in-clinic education. The improvement demonstrated in this study provides support for the implementation of clinician-created educational resources across the care continuum. Further work is needed to assess for impact on clinical outcomes.Trial Registrationanzctr.org.au Identifier: ANZCTRN12620000729921

The Correlation of Inflammation, Oxidative Stress, and Hippocampal Perfusion in Patients with Atrial Fibrillation.

Atrial fibrillation (AF) is closely related to abnormal cerebral blood flow. Inflammation and oxidative stress have always been important factors in the pathophysiology of AF. It remains unknown whether inflammation and oxidative stress are correlated to hippocampal perfusion in patients with AF.Sixty-three patients with AF with normal hippocampal blood perfusion (NHBP) were compared to 71 patients with AF with abnormal hippocampal blood perfusion (AHBP) using a case-control study design. The serum levels of inflammation and oxidative stress were measured. The hippocampal perfusion was detected. (1) The serum levels of high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and oxidized low-density lipoprotein (ox-LDL) were statistically higher in the AHBP group than in the NHBP group. In the AHBP subgroup analysis, the serum levels of hs-CRP and IL-6 were statistically higher in patients with persistent AF than those with paroxysmal AF. (2) The relative cerebral blood volume (rCBV), mean transit time (MTT), and the time-to-peak (TTP) were statistically higher in the AHBP group than in the NHBP group. Moreover, cerebral blood flow (rCBF) was statistically lower in the AHBP group than in the NHBP group. (3) relative cerebral blood volume (rCBV), rCBF, MTT, and TTP were passively associated with serum hs-CRP and IL-6; rCBV, rCBF, and MTT were positively associated with ox-LDL. The serum levels of hs-CRP, IL-6, and ox-LDL were associated with AHBP in patients with AF after multivariate logistic regression analysis.Oxidative stress and inflammatory biomarkers were increased in patients with AF with AHBP, in which the serum levels of hs-CRP and IL-6 in the persistent AF group were statistically higher than those in the paroxysmal AF group. The serum levels of hs-CRP, IL-6, and ox-LDL were associated with AHBP in patients with AF.

Atrial Fibrillation Prevalence and Its Management in Transfusion-Dependent Thalassemias: The Fathal Study

Atrial fibrillation (AF) represents an emerging issue in the thalassemia population related to increased life expectancy. However, data on AF in these patients are limited, and the current management is based on the guidelines for the general population. Nevertheless, AF in these patients has distinctive features that could require specific management. We conducted a multicentric retrospective study supported by the Italian Society of Thalassemia and Hemoglobinopathies (SITE) to elucidate the prevalence of AF in transfusion-dependent thalassemia (TDT) adults in Italy and to study its management, particularly the use of transcatheter ablation and anticoagulation management. Patients followed between June 1, 2003 and May 31, 2023 with a diagnosis of alpha- or beta-transfusion-dependent thalassemia with at least one episode of AF were included in the study. Clinical data of patients have been retrospectively collected with dedicated digital case report form (CRF). So far, 3 centers (Cagliari, Ferrara, Milano) have participated in the study. Eight-hundred-sixty-one adult TDT patients are regularly followed in the participating centers. Data from 130 adult TDT with AF were included. At enrollment, 119 patients were alive (71 males, 60%), the mean age at enrollment was 51.9 years, and 71% were splenectomized. Almost all (98%) had beta-thalassemia, of which 20% had thalassemia intermedia and became transfusion dependent during their life. The mean age at the first AF episode was 39.7 yr. Overall, AF prevalence in TDT was 13.8%, with a significant rise above the age of 50 (age 51-65: prevalence 26.4%, age&amp;gt;65 33.3%), differently from the general population in which the prevalence is 2-4%, and patients are older. As in the general population, prevalence was higher in males (18.2% vs 10.2%). Among the known risk factors for AF, the most frequent were diabetes (16%, n=111) and previous heart failure (22%, n=111). Regarding disease-specific factors contributing to the pathophysiology of AF, cardiac iron overload, defined as at least one between T2*&amp;lt;20 ms and serum ferritin&amp;gt;2500 ng/ml, was present in half of the patients (48.7%, n=76) at any time before AF and in approximately one-third (29%, n=93) at the time of the first event. Thirty-eight patients did not show cardiac iron overload before or at the time of the first AF episode. Most subjects had left atrial dilatation (58.1%), which can result from chronically increased cardiac output due to anemia. In most patients (87%), a rhythm control strategy was chosen at any time. Amiodarone was the most widely used drug. Transcatheter ablation was performed in 29 patients (22%), with a total of 39 procedures, and 20 (77%) patients reported improvement in symptoms after the last ablation. CHA 2DS 2-VASc score at the first AF episode detected a low risk of thromboembolism in 66 (50.8%) patients and a high risk in 19 (14.6%). However, 72 patients, including 40 low-risk subjects, initiated anticoagulation after the first episode. Four patients had a hemorrhagic event (3.1%), but only one had major bleeding during anticoagulant therapy without significant sequelae. Interestingly, management was heterogenous between different centers for both transcatheter ablation use and anticoagulation strategy. The prevalence of stroke in TDT AF patients was 5%, rising to 7.6% when also considering transient ischemic attacks. Compared to the literature, this prevalence is at least 10-fold higher than the general TDT population. Of note, splenectomy, a well-known risk factor for thrombosis, was present in all patients with stroke at the time of the event. In conclusion, AF represents significant morbidity in adult TDT, and its management is heterogeneous. It generally occurs at a younger age than the general population, and iron overload and atrial dilatation play a central role in its genesis. For symptomatic patients, we propose a rhythm control strategy to improve their quality of life, among which ablation could be the best option. Moreover, because stroke represents a major and frequent complication in TDT patients with AF, early detection of AF and prompt initiation of anticoagulant therapy, irrespective of CHA 2DS 2-VASc, which does not capture potential disease-specific risk factors, including splenectomy, should be considered. Further studies to support our approach are needed.

How sex affects the sinus rhythm heartbeat

BackgroundThere is increasing awareness of sex-specific differences in epidemiology and pathophysiology of atrial fibrillation (AF). It is, however, unknown whether males and females differ in atrial electrophysiological properties during sinus rhythm (SR). The aim of this study was therefore to investigate sex-based (regional) differences in electrophysiological properties during SR of the right (RA) and left (LA) atrium including Bachmanns Bundle (BB) and pulmonary vein region (PVA). MethodsIntra-operative, high resolution mapping during SR was performed in 53 matched females with males (without a history of AF), to measure lines of conduction block (CB), continuous conduction delay and block (cCDCB), conduction velocities (CV), total atrial activation times (TAT), unipolar potential voltages and percentage of low voltage areas (LVA). ResultsCompared to males, females have significantly 1) lower unipolar potential voltages and slower CV at both RA and BB, 2) more LVAs, CB and cCDCB lines and longer CB and cCDCB lines at the RA only (all P < 0.05). ConclusionsElectrophysiological properties of the atria during SR differ between males and females. These sex-based differences are particularly present at the RA and to a lesser degree at BB. In females, both the RA and BB contained more areas of conduction disorders and low voltage potentials. Future studies are required to investigate whether these areas play a role in sex-based differences in vulnerability to arrhythmias such as atrial fibrillation.

The transcription factor ETV1 regulates expression of the atrial specific potassium channel TASK-1 and modulates cardiac action potentials

Abstract Background In recent years, the two-pore domain potassium channel TASK-1 has been identified to play an important role in the pathophysiology of atrial fibrillation (AF). In cardiac tissue, TASK-1 is almost exclusively expressed in the atria and significantly upregulated in AF patients. Moreover, it has been characterized as a key player in action potential (AP) shortening observed during AF, making it a promising target for antiarrhythmic therapy. However, the underlying transcriptional mechanisms responsible for TASK-1 upregulation during AF are still unclear. A few years ago, the transcription factor ETV1 has been described to induce atrial remodeling and arrhythmia. Similar to TASK-1, ETV1 is predominantly expressed in the atria and upregulated in AF patients. Therefore, investigating possible interactions between ETV1 and TASK-1 is crucial to further understand atrial remodeling and develop new antiarrhythmic strategies. Purpose The purpose of this study was to investigate the effects of ETV1 regulation on TASK-1 expression. For that, electrophysiological effects of ETV1 modulation on TASK-1 currents and action potential formation were studied on HL-1 cardiomyocytes. Methods ETV1 modulation was achieved either through application of the pharmacological ETV1-inhibitor BRD32048 (1 µM) or transfection of HL-1 cells with a specific ETV1-siRNA. Electrophysiological effects of ETV1 inhibition were assessed using two-electrode voltage clamp experiments on Xenopus laevis oocytes heterologously expressing TASK-1 as well as whole-cell patch clamp measurements on HL-1 cells after pharmacological- and siRNA-mediated ETV1 inhibition. Chromatin immunoprecipitation combined with real-time qPCR (ChIP-qPCR) and ATAC-seq experiments were performed to identify the epigenetic interaction between ETV1 and the KCNK3 gene encoding TASK-1. Results TASK-1 currents were markedly reduced in Xenopus laevis oocytes after inhibition of ETV1. Furthermore, both pharmacological inhibition and siRNA-mediated knockdown of ETV1 caused a significant decrease of TASK-1 currents in HL-1 cells by 35.8% and 39.3%, respectively. These effects were associated with a statistically significant prolongation of the action potential duration at 90% repolarization (APD90) by 28.5% after functional inhibition and 24.9% after siRNA-knockdown. This correlated with a significant decrease of TASK-1 expression on mRNA and protein level. In addition, ATAC-seq data and ChIP-qPCR revealed an enrichment of ETV1 binding within accessible regulatory elements at the KCNK3 gene locus. Conclusions ETV1-knockdown shows strong inhibitory effects on TASK-1 while ChIP-qPCR and ATAC-seq data suggest that ETV1 acts as a direct transcriptional activator of KCNK3. The finding that ETV1 is involved in the regulation of TASK-1 improves our understanding of the pathomechanisms underlying AF and will hopefully help to advance TASK-1-based AF therapy.