Cutting-edge studies on atrial fibrillation, left bundle branch area pacing, and subcutaneous defibrillators
Year: 2026
Type: article
Abstract: For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on Arrhythmias starts with a State of the Art Review entitled ‘Atrial fibrillation: an underappreciated complication of diabetes’, by Lingli Cai from Shanghai JiaoTong University School of Medicine in China, and colleagues.1 The authors outline the intricate and close relationship between diabetes and atrial fibrillation (AF), addressing the epidemiology, pathogenesis, and management strategies built on the CARE-based approach in diabetic patients. Such consideration may facilitate timely prevention, early detection, and effective intervention, ultimately improving the health outcomes of patients with AF and diabetes. AF should be recognized as a complication of diabetes, with a prevalence of up to 25%. AF can develop in individuals with diabetes independent of hypertension, atherosclerotic cardiovascular disease, or heart failure. The pathogenesis linking diabetes to AF is multifactorial, involving atrial structural, electrical, electromechanical, and autonomic remodelling, as well as diabetes-related metabolic comorbidities. Given that the prevalence of diabetes (mainly type 2) is expected to increase further, the co-existent burden of AF on individuals, society, and healthcare systems will continue to increase. Thus, an integrated CARE-based management approach should be adopted to optimize care for diabetic patients across all stages of those at risk for AF and those with subclinical or clinical AF. This comprises ‘Comorbidity and risk factor management’, ‘Avoidance of stroke and thromboembolism’, ‘Reduction of symptoms by rate and rhythm control’, and ‘Evaluation and dynamic reassessment’. AF is characterized by a complex pathogenesis, is the most common sustained cardiac arrhythmia in humans, represents a substantial burden for patients, clinicians, and healthcare systems worldwide, and requires a careful management.2–12 In a Fast Track Clinical Research article entitled ‘Pulsed field vs radiofrequency ablation for paroxysmal atrial fibrillation: the BEAT PAROX-AF trial’, Pierre Jais from the University of Bordeaux in France, and colleagues compare single-procedure efficacy and safety of pulsed field ablation (PFA) vs radiofrequency ablation (RFA) in patients with drug-resistant paroxysmal AF.13 BEAT PAROX-AF is a European, multicentre, open-label, randomized, controlled, superiority trial conducted across nine European sites. Eligible patients (aged 18–80 years) with symptomatic, drug-resistant paroxysmal AF were randomized (1:1) to either PFA (pentaspline) or RFA following the CLOSE protocol (contact force sensing catheter and electro-anatomical mapping system). The primary endpoint was the single-procedure success rate after 12 months defined as the absence of recurrence ≥30 s atrial arrhythmia, cardioversion, class I/III antiarrhythmic drug resumption after a 2-month blanking period, or any repeat ablation. From December 2021 to January 2024, a total of 292 patients were randomized and 289 (median age 63 years, 58% male) were analysed. Single-procedure success at 12 months was 77% in the PFA group and 77% in the RFA group (P = .84). Procedure-related serious adverse events occurred in 3.4% of PFA vs 7.6% of RFA patients. No deaths, persistent phrenic palsy, or stroke occurred. In the RFA group, two patients had pulmonary vein stenosis >70% and 12 had stenosis >50%; there were also two tamponades, and one oesophageal bleed (Figure 1). Structured Graphical Abstract13 The authors conclude that this randomized trial performed in patients with paroxysmal AF does not demonstrate superior efficacy of single-shot PFA vs point-by-point RFA using the CLOSE protocol regarding single-procedure freedom from atrial arrhythmias, but fewer safety events being observed in this study with PFA. The manuscript is accompanied by an Editorial by Rajeev Pathak and Prashanthan Sanders from Canberra Heart Rhythm Centre in Australia, and the University of Adelaide and Royal Adelaide Hospital in Australia.14 The authors note that BEAT PAROX-AF is a landmark in comparative ablation, demonstrating that PFA matches optimized RFA in efficacy while offering shorter procedures and a reassuring safety profile. The absence of superiority underscores that procedural innovation alone cannot overcome the biological drivers of AF, constrained by comorbidities and atrial remodelling. The way forward lies in synergy: advanced ablation technologies combined with structured risk factor modification. PFA is now validated as a viable alternative to RFA for paroxysmal AF, with efficiency and safety trends likely to shape adoption and guideline integration. Ultimately, sustained success will require aligning technological advances such as PFA with structured risk factor management to ensure that procedural progress translates into durable patient benefit. Left bundle branch area pacing (LBBAP) promotes physiological synchronous activation of the left ventricle and may be particularly beneficial in patients with atrioventricular block (AVB), but its mortality benefit remains unclear. In a Clinical Research article entitled ‘Left bundle branch area pacing vs right ventricular pacing for atrioventricular block: the MELOS RELOADED study’, Marek Jastrzębski from Jagiellonian University in Kraków, Poland, and colleagues aim to compare long-term survival in AVB patients receiving either LBBAP or right ventricular pacing (RVP) and to analyse predictors of mortality during LBBAP.15 MELOS RELOADED, a multicentre European collaboration, was a registry-based study of pacemaker patients with AVB, left ventricular ejection fraction (LVEF) > 40%, and ventricular pacing >20%. The primary outcome was all-cause mortality based on national registries. A 1:1 propensity score matching was performed between the RVP and LBBAP groups. Kaplan–Meier curves and multivariable Cox proportional hazards models were used to estimate survival. In total, 3382 patients receiving LBBAP or RVP were matched. At 4-year follow-up, the Kaplan–Meier curve showed an absolute difference in survival of 11.8% in favour of LBBAP (P < .001). LBBAP was a robust predictor of reduced mortality, with a hazard ratio (HR) of 0.53 (P < .001). Within the LBBAP group, the following independent predictors of increased mortality were identified: lack of confirmed left bundle branch capture (HR 1.85, P < .001), lower percentage of ventricular pacing (HR 1.12), and age. The authors conclude that this is the first large study demonstrating the long-term survival benefit of LBBAP. This strengthens the use of LBBAP in AVB patients while awaiting the results of randomized trials. Confirmation of left bundle branch capture seems advisable to achieve optimal results with LBBAP. The manuscript is accompanied by an Editorial by Kenneth Ellenbogen and Pugazhendhi Vijayaraman from the VCU School of Medicine in Richmond, VA, USA, and the Geisinger Heart Institute in Wilkes Barre, PA, USA.16 The authors highlight that this important study sets the bar for ongoing prospective trials and argues strongly for changes in practice and changes in guidelines. Given that the mean ejection fraction in this study was 60%, it argues that at least for patients with a normal ejection fraction, spending an extra 5 min placing a conduction system lead in the interventricular septum is worth the time and effort, with better clinical outcomes. Implanters need to keep in mind that although follow-up in this study was for 4 years, the average pulse generator longevity is upwards of 10 years and it is likely that the mortality and heart failure curves would continue to separate. It is also important to recognize that this was an on-treatment analysis, and we should await the results of large, randomized clinical trials for a definitive answer. The risk of complications is similar for patients with RVP, although the set of complications is different, and implanters should be aware of the different sets of complications. The take-home lesson is that conduction system pacing can be accomplished in most patients with AVB and can result in improved clinical outcomes. We encourage implanting cardiologists to heed this message and strive to achieve conduction system capture, and congratulate the authors on a very important contribution. Genetic testing is playing a growing role in cardiovascular medidine.17–20 AF was not historically considered a genetic syndrome until case reports began emerging of patients and families with early-onset AF and genetic ‘overlap syndromes’. These patients presented initially with AF and later developed other serious cardiac manifestations such as heart failure, conduction disease, or sudden death due to rare genetic variants. In a Clinical Research article entitled ‘Genetic evaluation of early-onset atrial fibrillation: impact on patient management’, J. Lukas Laws from Vanderbilt University Medical Center in Nashville, TN, USA, and colleagues aim to define the results of genetic evaluation and its therapeutic impact for patients referred to a dedicated AF precision medicine clinic.21 Patients diagnosed with AF before age 60 were candidates for referral. In addition to standard evaluation with history, physical exam, and ECG, genetic evaluation included a three-generation pedigree, cardiac imaging, ambulatory monitoring, and clinical genetic testing with a cardiomyopathy/arrhythmia panel. Overall, 264 participants were referred: the median age was 47 years, 29% were female, and 89% were White. Median age at AF diagnosis was 39 years, and median time from AF diagnosis to evaluation was 3.7 years. A total of 242 patients underwent genetic testing, which identified a pathogenic or likely pathogenic variant in 20%. The strongest predictors of positive genetic testing were history of cardiomyopathy, infranodal conduction disease, and elevated T1 or late gadolinium enhancement on cardiac magnetic resonance imaging (all P < .05). The strongest predictors of negative genetic testing were obstructive sleep apnoea and a normal 12-lead ECG (both P < .04). Overall, genetic testing changed clinical management in 52% of patients with positive genetic testing, highlighted by seven new implantable cardioverter-defibrillator (ICD) placements and initiation of disease-modifying therapy in 16 patients (Figure 2). Genetic evaluation of patients with early onset atrial fibrillation in a dedicated precision medicine clinic demonstrated high yield of pathogenic variants and significant impact on clinical management. ECG: electrocardiogram, ICD: implantable cardiac-defibrillator, MRI: magnetic resonance imaging.21 The authors conclude that genetic testing is positive in 20% of patients with early-onset AF referred to a dedicated AF precision medicine clinic. Genetic testing results may change clinical management in genotype-positive patients. The manuscript is accompanied by an Editorial by Calum MacRae from MassGeneral Brigham Heart and Vascular Institute and Harvard Medical School in Boston, MA, USA.22 The author underscores that the clinical and genetic diagnosis and management of inherited conditions is often confounded by uncertainty of genotype piled on top of uncertainty of phenotype—the real cause of overlap. Transformative progress is unlikely without substantial scaling of genotyping combined with new lower cost and higher resolution phenotyping tools. Comprehensive genotyping is now available at low cost, but comprehensive phenotyping is not yet on the horizon. The traditional clinical physical exam is in decline, with high variability as general clinicians become deskilled, while specialist medicine has stuck with bespoke organ-based phenotyping. The use of artificial intelligence to extract additional information content from existing diagnostic tools will aid in defining currently ‘subclinical’ phenotypes. However, the discovery or design of novel mechanistically uniform computable phenotypes with the relevant attributes and the elucidation of their genetic or environmental mechanisms is unlikely to be based on post-hoc pattern recognition by individual investigators. Accelerated progress will require deep learning across many millions of patients in universally available passively collected data. Although use of the subcutaneous ICD (S-ICD) is increasing, evidence from industry-independent and unselected populations remains limited. In a Clinical Research article entitled ‘Long-term outcomes of subcutaneous implantable cardioverter defibrillators: the French nationwide HONEST study’, Fawzi Kerkouri from European Georges Pompidou Hospital in Paris, France, and colleagues try to fill the gap in the literature regarding long-term outcomes in large, unselected cohorts with minimal loss to follow-up.23 HONEST is an ongoing nationwide academic observational study enrolling 98% of patients implanted with an S-ICD across France (2012–2019). Five-year clinical endpoints were centrally adjudicated. Overall, 4924 patients were enrolled (mean age 50 years, 77% male, 63% for primary prevention). Peri-operative complications (within 30 days) occurred in 4.4%. At 5 years, cumulative incidence rates were 13.8% for inappropriate shocks, 10.8% for early battery depletion, 2.4% for infections, 1.5% for lead dysfunction, and 1.4% for chronic discomfort. Reoperation was required in 16.9%, need for cardiac pacing in 3.1%, and S-ICD extraction in 8.4%. Inappropriate shocks were independently associated with male sex (HR 1.29, P < .001), obesity (HR 1.35, P = .032), arrhythmogenic right ventricular cardiomyopathy (HR 1.7, P = .036), and the presence of a pacemaker (HR 2.2, P = .016). SMART Pass filtering significantly reduced inappropriate shocks (HR 0.67, P = .007). Among patients with inappropriate shocks, ∼1% developed induced ventricular fibrillation (one fatality), and 10% underwent device extraction. Ineffective shocks or undetected arrhythmias occurred in only 0.2%. Among 547 deaths (11.1%), 54% were cardiovascular, including 26 sudden deaths, and 8 were S-ICD/procedure-related, with none related to S-ICD extraction. The authors conclude that this nationwide study refines the long-term event profile of S-ICD therapy and may inform clinical practice and device selection. The manuscript is accompanied by an Editorial by Alireza Sepehri Shamloo and Nikolaos Dagres from the German Heart Institute Berlin, Germany.24 The authors note that the HONEST study represents an important piece of evidence in the evolution of subcutaneous defibrillation therapy, a nationwide, independent assessment confirming that subcutaneous defibrillation provides durable protection, low infection and extraction risk, and a declining burden of inappropriate shocks under modern programming. In 2025, the S-ICD is no longer a niche alternative. It is a reliable defibrillator modality for patients without need for pacing or resynchronization therapy—a system that has matured. The next advances will not come from re-entering veins but from integrating pacing when required, refining discrimination, and extending device longevity. Most importantly, we still need to define which patients derive benefit from ICD therapy, particularly for primary prevention of sudden cardiac death, in order to avoid unnecessary complications. The use of LBBAP for cardiac resynchronization therapy is emerging as an alternative pacing strategy to biventricular pacing (BiVP) in dyssynchronous heart failure (DHF). In a Translational Science article entitled ‘Left bundle branch vs biventricular pacing: mechanistic insights from a canine model’, Hao Huang from the Chinese Academy of Medical Sciences and Peking Union Medical College in China, and colleagues aim to explore the differences in treatment effects between the two pacing modalities using electrocardiographic, echocardiographic, and molecular measurements.25 Adult canines underwent left bundle branch ablation, then followed by either 6 weeks of atrial tachypacing (DHF group, n = 8) or 3 weeks of atrial tachypacing followed by another 3 weeks of BiVP (n = 8) or LBBAP (n = 8) tachypacing. Non-intervened canines constituted the control group (n = 7). Electrocardiographic, echocardiographic, and molecular features were compared between BiVP-treated and LBBAP-treated DHF canines. BiVP- and LBBAP-treated canines achieved equivalent reductions in QRS duration (P = .276). Both BiVP and LBBAP increased LVEF (9% and 10% respectively; P = .390), while LBBAP significantly outperformed BiVP in improving left ventricular global longitudinal strain (P = .019). Both BiVP and LBBAP reversed biomarkers of heart failure, while LBBAP more significantly modulated cytoskeleton proteins, transforming growth factor-β (TGF-β) signalling pathways, and SERCA2a expression. Moreover, LBBAP contributed to a more comprehensive improvement in myocardial energy metabolism compared with BiVP. The authors conclude that this study in a DHF animal model indicates that LBBAP results in electrocardiographic, echocardiographic, and molecular recovery at least as good as that during BiVP. The superiority of LBBAP is especially reflected in more pronounced normalization of the cardiac cytoskeleton, calcium handling, and energy metabolism. The manuscript is accompanied by an Editorial by Haran Burri and Brenda Kwak from the University of Geneva, Switzerland.26 The authors conclude that basic science is the foundation upon which therapeutic strategies are built. While correlative in nature, this study yields novel insights into the mechanisms underlying the beneficial effects of BiVP and LBBAP, which have been lacking until now. The results provide proof of the physiological of LBBAP at the molecular which to be those of BiVP capture of the left bundle is AF is a common complication after cardiac and is associated with outcomes. patients is for However, models have low and In a Translational Science article entitled calcium with clinical predictors of atrial from the University Medical Centre in and colleagues aim to integrating with clinical risk the risk of Clinical from patients cardiac without AF from two were analysed. 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Source: European Heart Journal
Author: Filippo Crea
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W7147596511