Pathophysiology Of Atrial Fibrillation Research Articles

Procedural findings and follow-up results of catheter ablation of atrial fibrillation in patients after radiation therapy for breast cancer

Abstract Backround Data on breast cancer radiation therapy (RT) associated atrial cardiomyopathy and its potential role in the pathophysiology of atrial fibrillation (AF) is very limited. Objectives To investigate the effect of breast cancer radiotherapy (RT) on atrial cardiomyopathy and its possible role in the pathophysiology of atrial fibrillation. What is the therapeutic success of antral pulmonary vein isolation (PVI) with possible substrate modifications (CFAE) in patients with breast cancer radiation therapy and paroxysmal or persistent atrial fibrillation. Methods We searched the institution’s data base for patients who received RT for breast cancer and underwent subsequently 3D mapping guided AF ablation. Intraprocedural mapping data and short- and long-term results of ablation were evaluated according to "no low voltage" and "low voltage" present. Low voltage amplitudes in bipolar electrograms were defined as <0.5 mV for endocardial maps created during SR and <0.3mV during AF. Ablation strategy comprised pulmonary vein isolation (PVI) ± additional substrate modification according to the mapping results. Follow Up (FU) was evaluated using repetitive 7-days Holter ECG and clinical visits. Results We included 45 patients (all female, 70.9±7.2 years) with paroxysmal or persistent AF (n=18 and n=27). In 3D mapping, 60% of the patients (27/45) showed left atrial low voltage (LV group) with the majority showing low voltage in the anterior wall of the left atrium (LA) in 18 of 45 patients (40%). PVI with ablation of complex fractionated signals (CFAE) was predominantly performed (18/27). After one ablation, 33.3% (9) of the patients in the LV group were recurrence-free and after an average of 1.9 ablations, freedom from recurrence was achieved in 21 patients with low voltage (77.8%). In 18 patients, no low voltage was detected (NLV group) and PVI only was performed in the majority (14/18). In this NLV group, 61.1% (11) of the patients were recurrence-free after one ablation and freedom from recurrence was achieved in 72.2% (13) after an average of 1.2 ablations. Conclusion Thoracic radiation therapy in patients with breast cancer can lead to low voltage in the LA with the predominant low voltage location being the anterior wall of the LA. An extended ablation strategy (PVI & CFAE) can show good treatment options in these patients with atrial fibrillation, with high freedom from recurrence after a mean of two ablation procedures.Freedom from recurrence after ablationCharacteristics of left atrium (LA)

Sex differences in the substrate of atrial fibrillation and the outcome of thoracoscopic ablation

Abstract Background Women with atrial fibrillation (AF) suffer more from AF symptoms, a lower quality of life, and have an enhanced risk of stroke. The AF recurrence after ablation is higher in women than in men. We hypothesize that sex specific differences in the atrial fibrotic substrate underlie these differences in clinical outcome. Here, we sought to characterize atrial fibrosis and fibrosis formation in the left atrial appendage (LAA) of women and men undergoing thoracoscopic ablation of AF. Methods We used the excised LAA of 30 female and 30 male patients with persistent AF undergoing thoracoscopic AF ablation. Patients were matched for age. In addition propensity score matching was also conducted for adjusting intermediary variables such as AF duration, Age ≥ 75, Body mass index (BMI), and CHA2DS2-VASc score ≥ 4. LAAs were stained with picrosirius red to quantify collagen and with vimentin for fibroblasts. Images were analyzed automatically (Image J version 1.50i) using color deconvolution to identify the area fraction of collagen and fibroblast. Results Women had similar age as men (66.4±7.76 vs 66.1 ±7.57, P= 0.85) but had a trend toward more cardiovascular risk factors [CHA2DS2-VASc score ≥ 4, (23.3 vs 6.7)%, P=0.07]. The total percentage of fibroblasts was larger in women 14.98 (9.79-24.95) % than men 13 (5.85-17.46) %, P=.018. In addition, in women fibroblasts were located more in epicardially and endocardially than in the interstitium.[women 8.18 (5.06-13.36) % vs men 6.49 (2.73-9.92) % , P=0.005].There was not a remarkable differences in total amount of collagen between the groups [women 16.03 (9.67-26.98) % vs men 15.50 (9.50-20.90) %, P=0.57 ], but there was a trend towards more epicardial and endocardial collagen in women than men [11.81(5.75-22.11)% vs 10.24 (6.06-15.10) % , P=0.06]. Conclusion We demonstrate more epicardial and endocardial fibroblasts in the LAA of women compared to men with persistent AF. There was similarly a trend towards more epicardia and endocardial but not interstitial collagen deposition. These findings may –at least in part- underlie sex specific differences in AF pathophysiology and ablation outcome.

Atrial Fibrillation in Elite Athletes: A Comprehensive Review of the Literature.

Although the benefits of exercise training have been shown repeatedly in many studies, its relationship with the occurrence of atrial fibrillation (AF) in competitive athletes still remains controversial. In the present review, we sought to demonstrate a comprehensive report of the incidence, pathophysiology, and therapeutic approaches to AF in elite athletes. A 2 to 10 times higher frequency of AF has been shown in many studies in high-intensity endurance athletes compared to individuals who do not exercise. Moreover, a U-shaped relationship between male elite athletes and AF is demonstrated through this finding, while the type and the years of physical activity seem to relate to AF development. A strong correlation seems to exist among the type of exercise (endurance sports), age (>55 years), gender (males), and the time of exercise training, all contributing to an increased risk of AF. The pathophysiology of AF still remains unclear; however, several theories suggest that complex mechanisms are involved, such as bi-atrial dilatation, pulmonary vein stretching, cardiac inflammation, fibrosis, and increased vagal tone. Elite athletes with AF require a comprehensive clinical evaluation and risk factor optimization, similar to the approach taken for nonathletes. Although anticoagulation and rate or rhythm control are cornerstones of AF management, there are still no specific guidelines for elite athletes.

Amlexanox reduces new-onset atrial fibrillation risk in sepsis by downregulating S100A12: a Mendelian randomization study.

Sepsis is characterized by high morbidity and mortality rates, alongside limited therapeutic efficacy. Atrial fibrillation (AF), the most common arrhythmia, has been closely linked to sepsis in prior research. However, the specific mechanisms through which sepsis leads to new-onset AF remain poorly understood. This study focuses on identifying critical genes that are dysregulated in the development of new-onset AF within the context of sepsis, with the goal of uncovering new potential targets for its diagnosis and prevention. Our study began by applying Mendelian Randomization (MR) to assess the causal link between sepsis and AF. We then sourced sepsis and AF datasets from the Gene expression Omnibus (GEO) database. Using Weighted Gene Co-expression Network Analysis (WGCNA), we pinpointed key modules and genes associated with both sepsis and AF conditions. Protein-protein interaction (PPI) network was constructed. The Transcriptional Regulatory Relationships Unravelled by Sentence-based Text-mining (TRRUST) database helped build the transcription factor (TF) interaction network. Key genes were scrutinized through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) to delve into their roles in new-onset AF's pathophysiology during sepsis. We employed the CIBERSORT algorithm to evaluate immune infiltration and the association between key genes and immune cells. The Connectivity Map (CMap) database facilitated the prediction of potential small molecule compounds targeting key genes. To culminate, an acute sepsis mouse model was developed to validate the implicated mechanisms of key genes involved in new-onset AF during sepsis, and to assess the prophylactic effectiveness of identified drug candidates. MR revealed potential independent risk factors for new-onset AF in sepsis. S100A12 was identified as a core interaction gene with elevated levels in sepsis and AF, underscoring its diagnostic and predictive significance. S100A12, along with associated genes, was mainly linked to immune and inflammatory response signaling pathways, correlating with immune cell levels. Targeting S100A12 identifies five potential small molecule therapeutics: amlexanox, balsalazide, methandriol, olopatadine, and tiboloe. In animal studies, acute sepsis increased S100A12 expression in serum and atrial tissues, correlating positively with inflammatory markers (IL-1β, IL-6, TNF-α) and negatively with heart rate, indicating a predisposition to AF. Early amlexanox administration can reduced S100A12 expression, dampened inflammation, and lessened new-onset AF risk in sepsis. This study demonstrates that sepsis may independently increase the risk of new-onset AF. We identified S100A12 as a key gene influencing the new-onset AF in sepsis through immune regulation, presenting considerable diagnostic and predictive value. Notably, amlexanox, by targeting S100A12 emerges as the most clinical relevant intervention for managing new-onset AF in sepsis patients.

Exploration of the shared gene signatures and comorbidity mechanisms of primary aldosteronism and atrial fibrillation.

Primary aldosteronism (PA) is a prevalent cause of endocrine hypertension characterized by an excess of aldosterone that can induce proinflammatory, prooxidant, and profibrotic effects on the heart. Emerging evidence indicates a heightened incidence of atrial fibrillation (AF) in patients with PA, suggesting a significant association between the two conditions. However, the underlying mechanisms remain unclear. The purpose of this study was to investigate the molecular networks associated with the development of both PA and AF. Datasets were obtained from the Gene Expression Omnibus (GEO) database. Hub genes were identified by enrichment and protein‒protein interaction analysis. These hub genes were subsequently validated via two independent external datasets: GSE60042 and GSE41177. Following the identification of shared genes, quantitative real-time polymerase chain reaction (qPCR) was employed to verify the reliability of the dataset and to further confirm the presence of shared genes in clinical samples. The results of the common gene analysis revealed that immune and inflammatory responses may be shared features in the pathophysiology of PA and AF. One hub gene, specifically tumor necrosis factor superfamily member 10 (TNFSF10), was identified through various analyses and subsequently validated via qPCR. Compared with that in healthy controls, the expression level of TNFSF10 was lower in PA patients with AF. Our findings indicate that TNFSF10 may play a role in the pathophysiology of AF complications associated with PA conditions, suggesting that it could serve as a potential target for the diagnosis or treatment of PA patients complicated with AF.

Atrial Fibrillation and Underlying Structural and Electrophysiological Heterogeneity.

As atrial fibrillation (AF) progresses from initial paroxysmal episodes to the persistent phase, maintaining sinus rhythm for an extended period through pharmacotherapy and catheter ablation becomes difficult. A major cause of the deteriorated treatment outcome is the atrial structural and electrophysiological heterogeneity, which AF itself can exacerbate. This heterogeneity exists or manifests in various dimensions, including anatomically segmental structural features, the distribution of histological fibrosis and the autonomic nervous system, sarcolemmal ion channels, and electrophysiological properties. All these types of heterogeneity are closely related to the development of AF. Recognizing the heterogeneity provides a valuable approach to comprehending the underlying mechanisms in the complex excitatory patterns of AF and the determining factors that govern the seemingly chaotic propagation. Furthermore, substrate modification based on heterogeneity is a potential therapeutic strategy. This review aims to consolidate the current knowledge on structural and electrophysiological atrial heterogeneity and its relation to the pathogenesis of AF, drawing insights from clinical studies, animal and cell experiments, molecular basis, and computer-based approaches, to advance our understanding of the pathophysiology and management of AF.

The effect of fixed and functional remodelling on conduction velocity, wavefront propagation, and rotational activity formation in atrial fibrillation.

Pathophysiology of atrial fibrillation (AF) remains unclear. Interactions between scar and conduction velocity (CV) and their impact on wavefront propagation in sinus rhythm (SR) and rotational activity burden in AF were evaluated. Local activation times (LATs) and voltage data were obtained from patients undergoing ablation for persistent AF. Omnipolar voltage (OV) and bipolar voltage (BV) data were obtained during AF and SR at pacing intervals of 600 and 250 ms. Local activation times were used to determine CV dynamics and their relationship to the underlying voltage and pivot points in SR. Computational modelling studies were performed to evaluate the impact of CVs and fibrosis on rotational activity burden in AF. Data from 60 patients with a total of 2 768 400 LAT and voltage points were analysed (46 140 ± 5689 points/patient). Voltage determined CV dynamics. Enhanced CV heterogeneity sites were predominantly mapped to low-voltage zones (LVZs) (0.2-0.49 mV) (128/168, 76.2%) rather than LVZs (<0.2 mV) and frequently co-located to pivot points (151/168, 89.9%). Atrial fibrillation OV maps correlated better with SR BV 250 ms than 600 ms maps, thereby representing fixed and functional remodelling. Sinus rhythm maps at 250 ms compared with 600 ms harboured a greater number of pivot points. Increased CV slowing and functional remodelling on computational models resulted in a greater rotational activity burden. Conduction velocity dynamics are impacted by the degree of scar. Conduction velocity heterogeneity and functional remodelling impacts wavefront propagation in SR and rotational activity burden in AF. This study provides insight into the pathophysiology of AF and identifies potential novel ablation targets.

Leveraging 3D Atrial Geometry for the Evaluation of Atrial Fibrillation: A Comprehensive Review.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia associated with significant morbidity and mortality. Managing risk of stroke and AF burden are pillars of AF management. Atrial geometry has long been recognized as a useful measure in achieving these goals. However, traditional diagnostic approaches often overlook the complex spatial dynamics of the atria. This review explores the emerging role of three-dimensional (3D) atrial geometry in the evaluation and management of AF. Advancements in imaging technologies and computational modeling have enabled detailed reconstructions of atrial anatomy, providing insights into the pathophysiology of AF that were previously unattainable. We examine current methodologies for interpreting 3D atrial data, including qualitative, basic quantitative, global quantitative, and statistical shape modeling approaches. We discuss their integration into clinical practice, highlighting potential benefits such as personalized treatment strategies, improved outcome prediction, and informed treatment approaches. Additionally, we discuss the challenges and limitations associated with current approaches, including technical constraints and variable interpretations, and propose future directions for research and clinical applications. This comprehensive review underscores the transformative potential of leveraging 3D atrial geometry in the evaluation and management of AF, advocating for its broader adoption in clinical practice.

Targeting the NLRP3 inflammasome signalling for the management of atrial fibrillation.

Inflammatory signalling via the nod-like receptor (NLR) family pyrin domain-containing protein-3 (NLRP3) inflammasome has recently been implicated in the pathophysiology of atrial fibrillation (AF). However, the precise role of the NLRP3 inflammasome in various cardiac cell types is poorly understood. Targeting components or products of the inflammasome and preventing their proinflammatory consequences may constitute novel therapeutic treatment strategies for AF. In this review, we summarise the current understanding of the role of the inflammasome in AF pathogenesis. We first review the NLRP3 inflammasome pathway and inflammatory signalling in cardiomyocytes, (myo)fibroblasts and immune cells, such as neutrophils, macrophages and monocytes. Because numerous compounds targeting NLRP3 signalling are currently in preclinical development, or undergoing clinical evaluation for other indications than AF, we subsequently review known therapeutics, such as colchicine and canakinumab, targeting the NLRP3 inflammasome and evaluate their potential for treating AF.

Association between Epicardial Adipose Tissue and Atrial Fibrillation in Patients with Transfusion-Dependent β-Thalassemia.

Background: Modern treatments for transfusion-dependent β-thalassemia (TDβT) have allowed patients to reach high life expectancy with no iron overload. Despite survival improvement, atrial fibrillation (AF) has emerged as a relevant issue. AF pathophysiology and characteristics in TDβT are different than in the general population. Epicardial adipose tissue (EAT) may play a role but its relationship with AF in patients with TDβT has not been explored. Methods: A monocentric, cross-sectional study, enrolling consecutive patients with TDβT. Epicardial adipose tissue (EAT) was evaluated at magnetic resonance. Characteristics of patients with and without history of AF were investigated. Factors independently associated with AF prevalence were analyzed. Results: A total of 116 patients were enrolled. All patients were treated with regular chelation therapy. The prevalence of AF was 29.3% (34/116). Cardiac T2* and liver iron concentration were no different between patients with and without AF. EAT thickness was significantly higher in patients with AF at left atrium, right atrium and right ventricle (5.0 vs. 4.0 mm, p < 0.01, 4.4 vs. 4.0, p = 0.02 and 5.0 vs. 4.3, p = 0.04). Patients with AF presented with older age, (53 vs. 49 years, p < 0.01), more hypothyroidism (44.1 vs. 20.7%, p = 0.01), pulmonary hypertension (23.5 vs. 2.4% p < 0.01), splenectomy (88.2 vs. 64.6%, p = 0.01), higher right and left atrial volume (61 vs. 40 and 74 vs. 43 mL, both p < 0.01). At multivariable analysis, hypothyroidism, left atrial volume and left atrial EAT were independently associated with AF (odds ratio 9.95, 1.09 and 1.91, respectively). Conclusions: In a contemporary cohort of patients with TDβT, treated with regular chelation therapy, prevalence of AF was unrelated to iron overload. EAT was independently associated with AF.

Exploring the association between atrial fibrillation and coeliac disease: A comprehensive review

Objective: This paper aims to provide a comprehensive overview of the pathophysiology of Atrial Fibrillation (AF) and Coeliac Disease (CD) individually, while also exploring the emerging evidence of a potential association between the two conditions. Methods: The pathophysiology of AF, the most prevalent arrhythmia globally, and CD, an autoimmune condition triggered by gluten consumption, is examined. Genetic, structural, electrophysiological, and inflammatory factors contributing to their development are explored. Results: AF involves irregular atrial activity leading to electrical and structural remodeling of the atrium. CD is characterized by an immune response to gluten, primarily associated with HLA-DQ2 and HLA-DQ8 genetic mutations, resulting in damage to intestinal tissue. Emerging research suggests a link between AF and CD, possibly mediated through inflammation, fibrosis, and electromechanical delays in the atrium. Conclusion: Understanding the association between AF and CD carries significant clinical implications. Recognition of this relationship can assist in identifying individuals at higher risk for AF and inform proactive management strategies. Additionally, it underscores the importance of comprehensive care for CD patients, considering potential cardiac implications. Further research is warranted to elucidate precise mechanisms and explore potential therapeutic interventions targeting common pathways, opening avenues for enhanced patient care and future investigations.

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 &amp;lt;0.5mV than matched control patients (1.43mV vs. 2.14mV, p=0.0177; and 38.28% vs. 15.68%, p&amp;lt;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&amp;lt; 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.

The Role of Ferroptosis in Atrial Fibrillation: A Promising Future.

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias, with its diagnosis being closely tied to higher rates of cardiovascular morbidity and mortality. AF is associated with a range of dangerous complications including stroke and heart failure, making it a key driver of healthcare spending and a major threat to global public health. The precise mechanisms that govern AF incidence and the onset of related complications, however, remain uncertain. Ferroptotic cell death has been the focus of rising interest in the cardiac arrhythmias, and there is recent evidence supporting a role for atrial ferroptosis as a mediator of AF development. Interventional strategies focused on ferroptotic activity, such as novel ferroptosis inhibitors, have also shown promise as a means of protecting against AF through their ability to reduce iron overload. In this review, we provide a summary of the proposed mechanisms whereby ferroptosis contributes to the pathophysiology of AF and their therapeutic implications.

Emerging Role of Renal Sympathetic Denervation as an Adjunct Therapy to Atrial Fibrillation Ablation.

The central anatomical locus in the context of atrial fibrillation (AF) ablation has been the pulmonary veins. Despite the attainment of a modest long-term success rate through pulmonary vein isolation (PVI), the pursuit of achieving a therapeutic efficacy nearing a definitive cure has spurred an investigation into alternative strategies and anatomical loci beyond the pulmonary veins. Despite extensive exploration, none of these alternative targets have succeeded in establishing themselves as routine ablation sites comparable to the pulmonary veins. Consequently, there exists an imperative for further inquiry and refinement of ablation strategies to propel advancements within the domain of AF ablation, thereby augmenting patient outcomes. Simultaneously, the examination of the autonomic system's role in AF pathophysiology introduces an additional ablation target aimed at rectifying sympathovagal imbalance. This discourse presents a contemporary review of renal denervation (RDN) as an emergent and auspicious technique poised to complement PVI, thereby contributing substantively to the augmentation of long-term success within the ambit of AF rhythm-control strategies.

Focus on the Role of Inflammation as a Bridge between Ferroptosis and Atrial Fibrillation: A Narrative Review and Novel Perspective.

In this comprehensive review, we examine the intricate interplay between inflammation, ferroptosis, and atrial fibrillation (AF), highlighting their significant roles in AF pathophysiology and pathogenesis. Augmented inflammatory responses are pivotal to AF, potentially leading to atrial remodeling and reentry phenomena by impacting calcium channels and atrial tissue fibrosis. A strong correlation exists between inflammatory cytokines and AF, underscoring the importance of inflammatory signaling pathways, such as NOD-like receptor thermal protien domain associated protein 3 (NLRP3) inflammasome, Nuclear Factor kappa B (NF- B) signaling, and Tumor necrosis factor- (TNF- ) signaling in AF development. Ferroptosis, a non-apoptotic regulated mode of cell death, has been widely studied in relation to cardiovascular diseases including heart failure, myocardial infarction, cardiomyopathy, and reperfusion injury. The interaction between ferroptosis and inflammation is complex and mutually influential. While significant progress has been made in understanding the inflammation-AF relationship, the role of inflammation as a conduit linking ferroptosis and AF remains underexplored. The specific pathogenesis and key molecules of atrial fibrosis caused by ferroptosis are still not fully understood. Here we review the role of inflammatory signaling in ferroptosis and AF. We elucidated the association between ferroptosis and AF, aiming to unveil mechanisms for targeted inhibition of atrial cell fibrosis and to propose novel therapeutic strategies for AF. This exploration is vital for advancing our knowledge and developing more effective interventions for AF, a condition deeply intertwined with inflammatory processes and ferroptotic pathways.

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.