Jonathan M. Kalman

Introduction: Young‐onset atrial fibrillation (AF) is increasingly recognized as a clinically distinct entity and heritable mechanisms may contribute to disease onset. Although pathogenic monogenic variants are increasingly identified in this population, their clinical phenotype and prognostic significance remain incompletely defined. Aims: We sought to characterize the spectrum of genetic variants in patients with young‐onset AF diagnosed at age 45 years or younger, identify clinical predictors of pathogenic variants, and evaluate their association with long‐term clinical outcomes. Methods: This multicentre retrospective cohort study included adults with AF first diagnosed at age 45 years or younger who underwent clinical genetic testing across three tertiary centers in Melbourne, Australia. Variants were re‐assessed using contemporary American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria and classified as pathogenic/likely pathogenic (P/LP) or negative/variant of uncertain significance (VUS). Baseline clinical characteristics, electrocardiographic findings, cardiac imaging, and long‐term outcomes were compared between groups. Results: Among 58 patients who underwent genetic testing, 30 (52%) had a pathogenic or likely pathogenic monogenic variant. The most frequent variants involved TTN ( n = 8, 13.8%) and LMNA ( n = 6, 10.3%), followed by MYBPC3 and MYH7 (each n = 3, 5.2%). Family history of AF or cardiomyopathy was more common in the P/LP than the negative/VUS group (76.7% vs. 46.4%, p = 0.030) and was independently associated with a pathogenic variant (OR 3.90; 95% CI 1.28–13.0; p = 0.020). Patients with pathogenic variants more frequently had first‐degree atrioventricular block (20.0% vs. 0.0%; p = 0.024). Implantable cardioverter‐defibrillator implantation was more frequent in P/LP patients (53.6% vs. 25.0%; p = 0.05), whereas mortality, stroke, post‐ablation AF recurrence, and pacemaker implantation were similar. Conclusions: In this highly selected young‐onset AF cohort referred for genetic testing, pathogenic monogenic variants were common. There was a significant proportion of patients suffering adverse long‐term events.

Background: Atrial fibrillation (AF) is becoming increasingly recognised in younger patients. While both anti‐arrhythmic drug therapy and catheter ablation are recognised treatment options, their comparative effects on long‐term mortality in younger patients are not known. Aims: To describe an association between all‐cause mortality, pharmacotherapy and pulmonary vein isolation in young patients with AF. Methods: We conducted a retrospective observational cohort study using the Alfred Hospital's electronic medical records. Adults aged 18–65 at the time of first AF diagnosis were included and stratified into pharmacotherapy‐led and catheter ablation‐led groups. Inverse probability of treatment weighting was applied across a number of demographic and cardiometabolic covariates, achieving strict balance (standardised mean differences P = 0.002) subject to significant residual confounding and selection bias. Over a 10‐year RMST, the PVI‐led strategy conferred an absolute survival benefit of 0.76 years. Neither strategy significantly reduced the risk of incident heart failure (adjusted HR 1.11; 95% CI: 0.58–2.11; P = 0.761). Conclusions: In younger patients and subject to significant residual confounding and selection bias, PVI was associated with significantly lower all‐cause mortality than pharmacotherapy. These findings must only be considered hypothesis generating and require prospective validation.

Atrial fibrillation (AF) prevalence rises sharply with age due to two independent mechanisms. Ageing produces irreversible arrhythmogenic substrate changes through progressive fibrosis, cellular senescence and mitochondrial dysfunction, while modifiable risk factors such as obesity, hypertension, sleep apnoea, diabetes and alcohol use promote atrial remodelling through inflammatory, haemodynamic and metabolic pathways. These comorbidities accumulate with age but operate through distinct mechanisms. Late gadolinium enhancement magnetic resonance imaging now quantifies fibrosis burden, while circulating biomarkers track inflammation, fibrosis and disease activity, and these measures respond to treatment, providing objective evidence of substrate modification. Landmark trials have transformed management. Weight loss of 10% or more when maintained is associated with reduced AF burden. Structured risk‐factor management may improve ablation outcomes and is associated with regression of AF type, with some patients moving from persistent back to paroxysmal patterns. These benefits occur across age groups, preventing arrhythmogenic substrate formation in younger patients and likely enabling reduction in AF burden in older adults. Collectively, this evidence positions risk‐factor management as the fourth pillar of AF care and shifts AF from an inevitable consequence of ageing to a modifiable chronic disease when delivered effectively.

Background: Atrial fibrillation is a leading cause of emergency medical services (EMS) use, but sex differences across prehospital, hospital, and postdischarge care remain poorly characterized. Methods: We performed a population‐based linked cohort study of adults attended by EMS for atrial fibrillation in Victoria, Australia, from January 1, 2015, to June 30, 2019. EMS records were linked to emergency department, hospital admission, and death data sets. Multivariable models evaluated sex differences in care and outcomes. Results: Among 16 415 atrial fibrillation EMS attendances, 9329 (56.8%) were in women, median age 76 years. Age‐standardized attendance rates were higher in women (77 versus 57 per 100 000 person‐years; incidence rate ratio, 1.35 [95% CI, 1.33–1.38]), especially in metropolitan areas and adults aged ≥70 years. Women had lower odds of prehospital treatment (56% versus 62%; adjusted odds ratio [aOR], 0.85 [95% CI, 0.79–0.92]) and mobile intensive care paramedic attendance (aOR, 0.85 [95% CI, 0.78–0.93]). Presentation‐conditioned aspirin and appropriate analgesia did not differ by sex. Women had fewer cardioversions (aOR, 0.79 [95% CI, 0.70–0.89]) but similar ablation rates (aOR, 0.95 [95% CI, 0.83–1.10]), higher 30‐day and 6‐month EMS reattendance (adjusted hazard ratios [aHRs], 1.29 and 1.35), and lower 30‐day and long‐term mortality (aHRs, 0.83 and 0.71). Conclusions: Women attended by EMS for atrial fibrillation had lower global prehospital treatment, higher reattendance, and lower mortality than men, supporting standardized prehospital pathways and rapid‐access follow‐up.

Background: Acute ischaemic stroke patients with atrial fibrillation (AF) are at high risk of suffering a recurrent stroke or other cardiovascular complications. It is uncertain whether early rhythm-control therapy is effective and safe in preventing recurrent strokes and cardiovascular complications in these patients. Study design: Early treatment of Atrial fibrillation for Stroke prevention Trial in acute STROKE (EAST-STROKE) is an international investigator-initiated, prospective, randomised, open, blinded endpoint assessment (PROBE) interventional multi-centre trial. Patients with acute ischaemic stroke and AF will be randomised within 4 weeks of stroke (1:1) to receive either early rhythm control and usual care or usual care alone. Usual care includes oral anticoagulation, rate control and treatment of cardiovascular conditions. Early rhythm control additionally comprises treatment with antiarrhythmic drugs, AF ablation or cardioversion. A minimum of 1746 participants will be randomised to observe 351 events. The adaptive design includes one interim analysis with sample size re-estimation after 50% of events. Study endpoints: The primary outcome is a composite of first recurrent ischaemic stroke, haemorrhagic stroke, unclassified stroke, cardiovascular death or hospitalisation due to worsening of heart failure or due to acute coronary syndrome, analysed as time to the first occurrence. Secondary outcomes include individual components of the primary outcome, functional status and patient-reported outcome measures. Safety outcomes comprise all-cause mortality and adverse events. Patients will be followed-up until the end of the trial with a minimum follow-up period of 24 months and an expected mean follow-up period of 42 months. Summary: EAST-STROKE will determine whether early rhythm-control therapy in addition to usual care is effective and safe in patients with acute ischaemic stroke and AF. Trial registration: ClinicalTrials.gov Identifier: NCT05293080; EUCT-No.: 2025-521260-35-00.

Aims: A dual-energy ablation system was developed to optimize targeted energy delivery via a flexible-tip, contact-force sensing catheter with electroanatomic mapping integration. This is the first report of long-term safety and effectiveness results of this system for ablation of paroxysmal atrial fibrillation (PAF). Methods and results: The FOCALFLEX study is a prospective, multicentre study. Patients with PAF were enrolled between August 2024 and January 2025, with 144 patients (62.0 ± 10.0 years, 62.6% male) undergoing ablation with the TactiFlex PFA System at 21 sites worldwide. Primary safety and effectiveness endpoints were the rate of pre-defined serious adverse events within 7 days and the 6-month freedom from documented AF/AFL/AT episodes >30 s after a 90-day blanking period. Pulmonary vein isolation (PVI) was performed in each case with pulsed field required for posterior left atrium (LA) ablation and radiofrequency (RF) for cavotricuspid isthmus or near coronary arteries. Non-PV targets and modality were at physician’s discretion. Acute effectiveness was confirmed via entrance block and post-ablation LA voltage map after a 20-min waiting period and was achieved in 99.6% (566/568) of treated PVs with 95.5 ± 37.1 pulsed field ablation (PFA) applications/patients. Procedure, fluoroscopy, LA dwell, and PV ablation times were 112.2 ± 29.5, 7.6 ± 5.7, 81.1 ± 19.7, and 47.4 ± 16.4 min, respectively. There were two (1.4%) primary safety events. At 6 months, 81.0% of subjects were free from documented arrhythmia recurrence and the protocol-defined primary effectiveness rate was 79.6%. There was one repeat ablation (0.7%) after the blanking period through 6 months. Conclusion: The FOCALFLEX study results demonstrate safety and effectiveness of a novel dual-mode RF/PFA system through 6 months of follow-up to treat symptomatic, recurrent PAF. Clinical trial registration: ClinicalTrials.gov Identifier: NCT06271967