INTRODUCTION:Long-standing persistent atrial fibrillation (LSPAF) is among the most challenging arrhythmia phenotypes to manage, due to extensive atrial remodeling, fibrosis, and the presence of complex non-pulmonary vein substrates and triggers. Conventional antiarrhythmic drug (AAD) therapy provides limited efficacy and is constrained by short- and long-term toxicity. Catheter ablation (CA) remains the cornerstone of rhythm control but offers modest single-procedure success. AREAS COVERED:This review examines current treatment strategies for LSPAF, including pharmacologic rhythm control, CA, and hybrid surgical - endocardial approaches. Evidence from major clinical trials and meta-analyses is summarized, highlighting the limitations of pulmonary vein isolation (PVI) as a stand-alone therapy and the role of adjunctive strategies. The article also discusses novel approaches, including pulsed field ablation (PFA), fibrosis-guided mapping, and insights from recent international guidelines. EXPERT OPINION:CA remains the most effective rhythm-control strategy for LSPAF, but durable arrhythmia-free survival often requires repeat or hybrid procedures. Hybrid ablation should be considered, particularly in patients with advanced atrial remodeling. Emerging technologies, including PFA, offer the potential for improved outcomes. Future progress will depend on dedicated LSPAF trials with standardized endpoints, long-term follow-up, and broader patient representation to refine selection, optimize lesion sets, and establish the role of next-generation technologies.

BACKGROUND:Renal denervation (RDN) according to the latest ESH guidelines can be considered as a treatment option for patients with resistant hypertension. However, excess sympathetic nervous system activity constitutes an underlying pathophysiological mechanism in many disorders other than arterial hypertension. AIMS:This systematic review and meta-analysis investigated the therapeutic effects of RDN beyond arterial hypertension. METHODS:A systematic review and meta-analysis were conducted following PRISMA guidelines. Electronic databases (PubMed, Embase, Cochrane) were searched for studies assessing RDN effects in atrial fibrillation (AF) recurrence, obstructive sleep apnea (OSA), metabolic parameters, heart failure (HF) and diastolic heart function. Inclusion criteria encompassed randomized controlled trials and observational studies with relevant outcome measures. Effect sizes were pooled using a random-effects model. RESULTS:A total of 16 studies comprising 818 patients were included. RDN was associated with a significant increase in freedom from AF when combined with pulmonary vein isolation (RR: 1.30, 95% CI: 1.04 to 1.61, I2 = 5%), an improvement in OSA severity as measured by the apnea-hypopnea index (MD: -4.80, 95% CI: -12.60 to 3.01, I2 = 39%), and decreased fasting blood glucose (MD: -10.04, 95% CI: -26.51 to 6.43, I2 = 0%). Additionally, RDN led to improvements in left ventricular diastolic function in terms of E/e' reduction (MD: -1.51, 95% CI: -2.71 to -0.31, I2 = 94%) and improved HF-related biomarkers, specifically NT pro-BNP (MD: -438.54, 95% CI: -1658.57 to 781.49, I2 = 92%) and 6-min walking distance (MD: +64.58, 95% CI: 0.11 to 129.05, I2 = 53%). CONCLUSION:This meta-analysis suggests that RDN exerts beneficial effects beyond hypertension, particularly in AF burden, OSA severity, metabolic parameters, and cardiac function. These findings support the broader role of RDN in autonomic regulation and cardiovascular health. Further large-scale trials are warranted to confirm these effects and refine patient selection criteria.

Background: Pulmonary vein isolation (PVI) constitutes the established strategy for atrial fibrillation (AF) ablation. With the advent of PV stenosis risk-free pulsed field ablation (PFA), we explored the feasibility and safety of additional ablation within PV sleeves (PVA). Moreover, we assessed the durability of PVI through PFA in a deep sedation setting, comparing a 3D Electroanatomical Mapping (3D-EAM)-based navigation approach with the standard fluoroscopy-based one. Methods: In this single-center, first-in-human study ([NCT07035288][1]), 40 AF patients underwent first time PFA-based PVI+PVA (4 additional applications inside the PVs) between November 2024 and April 2025 using a circular array PFA catheter (PulseSelect, Medtronic, Minneapolis, MN), randomized to either 3D-EAM-based (Carto3 prime, J&J, Irvine, CA) or fluoroscopy-based navigation, in a propofol-based deep sedation setting. Rate of conversion from 3D-EAM to fluoroscopy-based navigation was recorded. First-pass isolation was assessed immediately post-ablation. Venography and 3D-EAM were performed at remapping at 2 to 3 months after the index procedure. Results: No major procedure-related adverse events were noted, as well as no acute kidney injury, significant hemolysis or phrenic nerve palsy. First-pass isolation was successfully achieved in 95% of patients (3D-EAM: 95%, fluoroscopy: 95%, p=NS) and in 98.7% of PVs. Venography performed at remapping revealed no PV stenosis. PVI durability per patient was 92.5% (3D-EAM: 90%, fluoroscopy: 95%, p=NS) and per vein was 97.5% (3D-EAM: 97.5%, fluoroscopy: 97.5%, p=NS between navigation methods). Half of 3D-EAM cases were converted to fluoroscopy due to map shift. Conclusions: PFA-based PVA is safe. Catheter performance, as depicted by 97.5% durable PVI, was such that adding a 3D-EAM system was not associated with improved efficacy and exhibited high conversion rate to fluoroscopy-based navigation in a deep sedation setting. ### Competing Interest Statement Dimitris Tsiachris has been a member of advisory board for PulseSelect Catheter, received honoraria for lectures and presentations on PulseSelect Catheter and support for attending meetings Athanasios Kordalis and Konstantinos Tsioufis received honoraria for lectures and presentations on PulseSelect Catheter and support for attending meetings ### Clinical Trial NCT07035288 ### Funding Statement The present study was funded by Medtronic through the ERP-2024-13979 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Ethics Committee of General Hospital of Athens, Hippokratio I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data are available when required [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT07035288&atom=%2Fmedrxiv%2Fearly%2F2025%2F10%2F30%2F2025.10.22.25338592.atom

Background Prompt recognition of arrhythmogenic conditions in recreational and competitive athletes is essential for clinical management and for providing appropriate exercise recommendations. Case Summary We report the case of a 67-year-old athletic individual with a high burden of ventricular arrhythmias and a phenotype within the dilated/nondilated left ventricular cardiomyopathy spectrum. Genetic testing identified a likely causative variant in the Filamin C (FLNC) gene. An integrative evaluation incorporating advanced cardiac imaging, genetic analysis, and invasive electrophysiology was undertaken to optimize risk stratification and customize exercise counseling. Discussion In arrhythmogenic cardiomyopathy with confirmed or suspected genetic etiology, a multimodal evaluation is essential for accurate patient phenotyping. The impact of exercise on disease expression in specific gene variants associated with predominantly left-sided involvement remains insufficiently understood and requires further research and shared decision-making. Take-Home Message A comprehensive multidisciplinary evaluation is key for diagnosis, risk stratification, and management of athletes with ventricular arrhythmias.

Dilated cardiomyopathy (DCM) is one of the most common cardiomyopathy phenotypes. Moreover, sudden cardiac death (SCD) remains a leading cause of mortality in patients with DCM, predominantly driven by malignant ventricular arrhythmias (VAs). Current guideline-recommended risk stratification relies heavily on left ventricular ejection fraction (LVEF) to guide implantable cardioverter-defibrillator (ICD) therapy; however, attention has recently shifted toward a multiparametric strategy that integrates clinical characteristics with electrocardiographic markers, biomarkers, cardiac magnetic resonance (CMR) findings, genetic testing, and electrophysiological studies. This review summarizes current evidence on established and emerging tools for SCD risk stratification in DCM, highlights the limitations of single-parameter approaches, and discusses future directions toward more personalized, dynamic risk assessment to optimize SCD outcomes.

BACKGROUND Pulmonary vein (PV) isolation is the mainstay in atrial fibrillation (AF) ablation. However, additional arrhythmogenic foci seem to contribute to AF initiation and maintenance. A great proportion of those non-PV foci have been reported to be located in the superior vena cava (SVC). AIM To investigate the effectiveness of SVC as an adjunctive therapy to PV isolation. METHODS We performed a meta-analysis of MEDLINE and CENTRAL. Inclusion criteria were cohort studies with a control group or randomized clinical trials, comparing patients undergoing AF ablation without additional SVC isolation to those receiving ablation with concurrent SVC isolation, in effects of freedom from atrial tachycardia. RESULTS A total of 10 studies, incorporating 2176 patients, were included. The majority of the patients (91.5%) expressed paroxysmal AF. The additional SVC isolation strategy in patients undergoing AF ablation was more effective than the non-SVC isolation strategy [odds ratio (OR) = 0.71; 95% confidence interval (CI): 0.55-0.92]. In a subgroup analysis, radiofrequency ablation demonstrated effectiveness (OR = 0.69; 95%CI: 0.53-0.92). Conversely, the use of cryoablation did not alter clinical outcomes (OR = 0.69; 95%CI: 0.13-3.61). In a distinct subgroup analysis, SVC isolation guided by induction of SVC-originating AF triggers - vs no isolation when no AF-inducing triggers were observed - yielded no superiority (OR = 0.73; 95%CI: 0.46-1.16). CONCLUSION The outcomes of AF ablation are favorable when additional SVC isolation is conducted. In a tailored care approach, radiofrequency energy should be preferred. Periprocedural induction of SVC-originating AF triggers, either by isoproterenol infusion or burst atrial pacing, should not be used as a criterion for performing SVC isolation. These findings support integrating SVC isolation into individualized ablation strategies to optimize patient outcomes.

BACKGROUND:Resistant hypertension remains a major clinical challenge. This systematic review/meta-analysis evaluated whether the addition of a single pharmacological or device-based intervention (renal denervation [RDN]) can achieve effective blood pressure (BP) control in patients with true resistant hypertension. METHODS:A systematic search of MEDLINE/PubMed was performed to identify studies assessing the antihypertensive effects of adding a single pharmacological or device-based intervention in patients with true resistant hypertension. Primary analyses were conducted using a single-arm framework. RESULTS:Sixty-eight studies were included (n=6297; weighted mean age, 60 years; men 60%; diabetes 35%; smoking 16%; cardiovascular disease 27%). Participants received an average of 4.8 antihypertensive medications, with baseline office BP of 164/92 mm Hg and 24-hour ambulatory BP of 148/85 mm Hg. The median follow-up was 6 months. Meta-analysis of 58 studies (n=4579; 52% RDN) demonstrated a pooled mean 24-hour systolic ambulatory BP reduction from baseline of -11.3 mm Hg (95% CI, -12.3 to -10.2). Meta-analysis of 15 studies (n=2700; 15% RDN) showed a pooled hypertension control rate during follow-up of 35% (95% CI, 28-42). No significant differences were observed between RDN and pharmacotherapy or between randomized and nonrandomized studies. CONCLUSIONS:A single intervention-either pharmacological or RDN-on top of guideline-directed background therapy resulted in clinically meaningful BP reduction in patients with true resistant hypertension; however, only one-third of patients achieved BP control. Future clinical trials are needed to evaluate whether combination treatment strategies integrating optimized pharmacological regimens with RDN can provide more effective and durable BP control in this particularly challenging patient population.

BACKGROUND:Pulsed field ablation (PFA) has emerged as a tissue-selective modality for atrial fibrillation (AF) ablation. Early recurrence of any atrial tachyarrhythmia (ERAT) during the blanking period is considered transient; however, its association with late recurrence of any atrial tachyarrhythmia (LRAT) remains unclear. OBJECTIVE:This meta-analysis aimed to elucidate the association between ERAT and LRAT after PFA for different blanking cutoffs. METHODS:A search of MEDLINE, Scopus, and Cochrane (up to January 12, 2026) identified observational or randomized studies of PFA with ≥1-year follow-up. Double independent study selection, data extraction, and quality assessment were performed. Random-effects frequentist models were used to pool odds ratios, hazard ratios, proportions, and diagnostic accuracy measures with 95% confidence intervals (CIs). RESULTS:Seven observational cohort studies (3003 patients) were analyzed. ERATs within 0-90 days were strongly associated with LRATs (odds ratio, 8.98; 95% CI, 5.61-14.37; I2 = 68%; 7 studies), without subgroup differences by AF type, use of event recorders, or PFA technology. The positive predictive value of ERATs was 0.66 (95% CI, 0.55-0.76; I2 = 75%; 7 studies) within 0-90 days, 0.73 (95% CI, 0.63-0.81; I2 = 23%; 3 studies) within 0-60 days, and 0.56 (95% CI, 0.16-0.90; I2 = 85%; 2 studies) within 0-30 days. ERATs within 0-90 days demonstrated high specificity (0.93; 95% CI, 0.90-0.95) and positive likelihood ratio (5.83; 95% CI, 4.09-8.32) for LRATs. Age, heart failure, and non-pulmonary vein ablation were significant effect modifiers in meta-regression analysis. CONCLUSION:ERATs within 0-90 days and 0-60 days after PFA are robust LRAT predictors, whereas first-month ERATs remain insufficiently investigated. Further studies are required to define the optimal blanking period after PFA.

Several randomized controlled trials (RCTs) have examined catheter ablation (CA) and class III antiarrhythmic drugs (AAD) in secondary prevention of ventricular arrhythmias (VA) in patients with ischemic cardiomyopathy (ICM) and an implantable cardioverter-defibrillator (ICD). This study sought to evaluate the efficacy and safety of CA versus AADs (amiodarone, sotalol) in this population. MEDLINE (Pubmed), Scopus, Cochrane and ClinicalTrials.gov were searched until October 26, 2025 for RCTs. Double-independent study selection, data extraction and quality assessment were performed. Appropriate shock and electrical storm (ES) were the primary efficacy outcomes. Risk ratios (RR) with 95

Introduction:The PRESERVE EF study proposed a two-step algorithm for risk stratification in post-myocardial infarction (MI) patients with mid-range and preserved left ventricular ejection fraction (LVEF). This method assessed the performance of a two-step, programmed ventricular stimulation (PVS)-inclusive approach in identifying high-risk post-MI patients with LVEF ≥40%. This report presents findings from the 8-year follow-up. Methods:The primary endpoint was the occurrence of a major arrhythmic event, defined as sustained ventricular tachycardia/fibrillation, appropriate implantable cardioverter-defibrillator (ICD) activation, or sudden cardiac death (SCD). We included a total of 575 consecutive patients (mean age 57 years, LVEF 50.8%). Of them, 204 (35.5%) had at least one positive non-invasive risk factor. Forty-one of 152 patients undergoing PVS were inducible; 37 (90.2%) of them received an ICD. Results:During a mean follow-up of 106 ± 14.5 months, no SCDs were observed, while 12 ICDs (the major arrhythmic event prevalence in patients with ICD implantation reaching 29.3%) were appropriately activated. The updated performance metrics of the proposed approach were as follows: sensitivity 100% (95% CI: 73.5%-100%), specificity 94.8% (95% CI: 92.5-96.5%), positive predictive value 29.3% (95% CI: 17.2-45.0%), and negative predictive value 100% (95% CI: 99.3%-100%). Notably, events occurred only in patients with an LVEF 40%-50% and a history of ST-Elevation Myocardial Infarction. Conclusion:The PRESERVE EF study demonstrates that a simple, two-step, non-invasive risk factor-guided approach, followed by programmed ventricular stimulation, can effectively identify a subgroup of post-MI patients with preserved or mid-range LVEF ≥40 who are at high risk for major arrhythmic events. Clinical Trial Registration:Clinicaltrials.gov, identifier NCT02124018.

Currently efforts are being undertaken to establish and bring into clinical practice the field of virtual cardiac electrophysiology. The basic premise lies in acquiring an accurate whole-heart model based both on anatomy and electrophysiological properties of every myocardial voxel. Subsequently, one option is to perform a virtual electrophysiology study, with no constraints regarding site and number of extrasystoles in order to assess arrhythmogenic potential of the ventricle (ventricular arrhythmia risk prediction). The alternative, in cases with documented ventricular arrhythmia, would be to fine-tune the model into being able to simulate the clinical arrhythmia and then assess its mechanism, establishing vulnerable sites and thus ablation targets in order to guide the subsequent interventional procedure (virtual arrhythmia ablation targeting). Once clinical evidence supports vEP value in terms of accuracy and safety, it could be expected that even induced, nonclinical, arrhythmias could be targeted. Finally, advances in the field of computational power and artificial intelligence, including radiomics, along with stereotactic arrhythmia radioablation could render the future of arrhythmia management and treatment virtually unrecognizable in the not-so-distant future. The present mini review will attempt to familiarize clinicians with the tenets and current state of vEP, especially in the current phase where larger prospective clinical studies are required for further advancement, as well as offer a glimpse at potential future directions of this approach.

Atrial fibrillation (Afib) recurrence after catheter ablation (CA) remains a significant clinical challenge, driven by a complex and dynamic interplay of structural, electrical, and autonomic mechanisms. While pulmonary vein isolation (PVI) is the cornerstone of CA, recurrence rates remain substantial, highlighting the need to understand the evolving pathophysiology beyond PV reconnection. Post-ablation changes, including inflammation, edema, oxidative stress, and ischemia, create a transient proarrhythmic state that may contribute to early recurrence. Over time, atrial remodeling, fibrosis, and residual autonomic activity further sustain arrhythmogenicity. Additionally, epicardial adipose tissue promotes atrial myopathy, accelerating disease progression, particularly in patients with risk factors such as older age, female sex, obesity, hypertension, obstructive sleep apnea, and heart failure. The multifactorial nature of Afib recurrence underscores the limitations of a “one-size-fits-all” ablation strategy. Instead, a patient-specific approach integrating advanced mapping techniques, multimodal imaging, and computational modeling is essential. Artificial intelligence (AI) and digital twin models hold promise for predicting recurrence by simulating individualized disease progression and optimizing ablation strategies. However, challenges remain regarding the standardization and validation of these novel approaches. A deeper understanding of the dynamic interconnections between the mechanisms driving recurrence is crucial for improving long-term CA outcomes. This review explores the evolving nature of Afib recurrence, emphasizing the need for a precision medicine approach that accounts for the continuous interaction of pathophysiological processes in order to refine patient selection, ablation strategies, and post-procedural management.

Idiopathic premature ventricular complexes (PVCs) commonly originate from the right and left ventricular outflow tracts (RVOT and LVOT, respectively). The surface 12-lead ECG is commonly used to differentiate the anatomic site of origin, prior to catheter ablation. Multiple ECG algorithms have been published to assist preprocedural localization. We sought to evaluate the diagnostic performance of three commonly implemented algorithms. This study included 18 patients (47.4% women, mean age 52 ± 22.9 years), who underwent successful catheter ablation of outflow tract- originating idiopathic PVCs. The diagnostic algorithms evaluated were the V2S/V3R index, the transition zone index and the lead I R wave amplitude (an R wave amplitude ≥ 0.1 mV in lead I predicts LVOT origin). The diagnostic accuracy of the algorithms was assessed by the area under the receiver- operating characteristics curve (AUC). Specificity and sensitivity of each algorithm were measured. Electroanatomic 3D mapping depicted as site of origin the RVOT in 7 patients (42.9% women, mean age 33.9 ± 21.4 years) and the LVOT in 11 patients (54.5% women, mean age 64.1 ±14.7 years). The V2S/V3R index yielded a sensitivity of 0.86 and a specificity of 0.73. The AUC was 0.94 (Figure 1). As for the transition score index, sensitivity and specificity were 0.83 and 0.63, respectively, with an AUC 0.86. Lead I R wave amplitude demonstarted a sensitivity of 0.57 and a specificity of 0.9, respectively. The AUC was 0.7. Published diagnostic algorithms can reliably differentiate right ventricular from left ventricular originating outflow tract arrhythmias.ROC Curve of each algorithm

Background: Flecainide, a class Ic antiarrhythmic agent, has long been contraindicated in structural heart disease (SHD) due to findings of the Cardiac Arrhythmia Suppression Trial (CAST). However, its proven efficacy in patients without structural abnormalities and emerging safety data in selected SHD populations have prompted reconsideration of its role. Aim: This mini review evaluates recent evidence on the safety and efficacy of flecainide in atrial fibrillation (AF) and premature ventricular contractions (PVCs), particularly in patients with stable coronary artery disease (CAD), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Results: Modern imaging and improved risk stratification allow for more precise identification of patients who may safely receive flecainide, even in the presence of specific structural abnormalities. Observational studies have reported no mortality or ventricular arrhythmias incidence increase in stable CAD or ARVC when flecainide is administered under stringent criteria. While current guidelines remain cautious, clinical practice is beginning to reflect a more individualized approach. Conclusions: Flecainide use in selected SHD patients appears both feasible and safe when guided by comprehensive imaging and clinical judgment. The need for prospective randomized trials to confirm these findings and potentially inform future guideline updates is urgent and of utmost importance in the field of antiarrhythmic therapies.

Atrial fibrillation (Afib) is a common arrhythmia with significant public health implications, affecting millions of individuals worldwide. Catheter ablation (CA) is an established treatment for drug-resistant Afib, yet recurrence remains a major concern, impacting quality of life in a significant portion of patients. Inflammation plays a critical role in the recurrence of Afib after ablation, with systemic inflammatory markers such as C-reactive protein being linked to higher recurrence rates. In this editorial, we discuss the study by Wang et al, published in the latest issue, which investigates the predictive role of the systemic immune inflammation index (SII) in Afib recurrence following radiofrequency CA. Elevated pre-ablation SII levels are identified as an independent predictor of recurrence, significantly enhancing the predictive power of the APPLE score. Integration of SII improved the APPLE score's predictive performance, as shown by enhanced area under the curve, net reclassification improvement, and integrated discrimination improvement. This combined model highlights the importance of both structural and inflammatory factors in Afib recurrence, offering a more personalized approach to patient management. Additionally, the affordability and accessibility of SII enhance its practicality in clinical workflows. The study by Wang et al underscores the potential of integrating SII with existing scoring systems to refine risk stratification and optimize treatment strategies. Future research should validate these findings across diverse populations, explore limitations such as the potential influence of comorbidities on SII reliability, and investigate additional biomarkers to enhance predictive accuracy.

Diabetes mellitus and atrial fibrillation (AF) are two global epidemics that frequently coexist, with diabetes mellitus contributing to both an increased risk of new-onset AF and a worse prognosis. Pathophysiological mechanisms underlying this relationship include chronic inflammation, oxidative stress, atrial remodeling, autonomic dysfunction, advanced glycation end-products and epicardial adiposity. Management remains challenging; however, recent advances offer promise, including guideline-directed anticoagulation, tailored rate and rhythm control, and particularly, novel antidiabetic therapies, such as sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, may improve AF outcomes. A comprehensive, individualized approach is essential to mitigate morbidity and mortality in this high-risk population.