Early-onset atrial fibrillation without structural heart disease: lifestyle and hereditary risk factors

Authors, Journal, Affiliations, Type, DOI

• Robin Richard Vitton, Karine Nguyen, Frédéric Franceschi, Laurent Fauchier, Jerome Hourdain, Linda Koutbi, Lilith Tovmassian, Marie Wilkin, Cedric Biermé, Elsa Schemoul, Caroline Brunet, Noemie Resseguier, Victor Klein, Eloi Marijon, Jean-Claude Deharo, Baptiste Maille
• European Heart Journal (2026), Rapid Communications — Arrhythmias
• Timone University Hospital, Marseille; University Hospital of Tours; HEGP Paris, France
• Type: Prospective observational cohort study
• DOI: https://doi.org/10.1093/eurheartj/ehag205

Overview

This is the largest prospective cohort study of AF determinants specifically in patients under age 40 without structural heart disease (SHD), enrolling 122 consecutive patients (mean age 31.2 years; 83% male) from two French academic centers between 2016–2022, with median follow-up of 52 months. Almost all patients (89%) had at least one lifestyle risk factor, with obesity/overweight (30%), intensive sport (27%), and excessive alcohol (22%) being most prevalent; one in four had hereditary predisposition. Genetic testing (accepted by 57%) yielded pathogenic/likely pathogenic variants in 11.6%, predominantly in cardiomyopathy genes (TTN, LMNA, PKP2, TNNI3). Catheter ablation was effective (86% success at one year, 93% after two procedures), but stroke occurred in 4.1% of patients — all with CHA₂DS₂-VA = 0 and none anticoagulated — highlighting an unresolved risk stratification gap in this population.

Keywords

Atrial fibrillation, Young atrial fibrillation, Genetic testing, Lifestyle risk factors

Key Takeaways

Introduction

• AF before age 40 is rare, particularly without SHD, and is insufficiently described
• In older adults, AF is driven by age-related remodeling and cardiovascular risk factors; determinants of young-onset AF are less defined
• Many young patients develop AF despite normal hearts and no acute triggers — raising questions about lifestyle, familial, and genetic contributions
• Prognostic data in this specific phenotype are scarce; most existing studies are retrospective and merge all-age-onset AF without distinguishing SHD status

Methods

• Prospective recruitment 2016–2022 at two French academic hospitals
• Inclusion: first documented AF episode before age 40, prior to or at inclusion, in absence of SHD
• SHD exclusion criteria: normal LVEF, no significant valvular/congenital/acquired cardiomyopathy, no pulmonary hypertension, no cardiac surgery/MI/myocarditis/pericardial disease, no HTN/DM/thyroid disease/chronic lung disease, no known channelopathy
• Acute medical AF (post-operative, sepsis-related, endocrine) excluded
• Lifestyle risk factors assessed by standardized clinician-administered interview per guideline definitions:
  • Overweight: BMI >27 kg/m²
  • Intensive sport: >6 h/week (current or former)
  • Excessive alcohol: binge (≥5 drinks/occasion) or chronic (≥10 drinks/week)
  • Also: sedentary behaviour, obstructive sleep apnoea, psychiatric disorders, recreational drug use
• Familial AF: AF in ≥1 first-degree relative < age 60
• Other familial CVD: congenital HD, cardiomyopathy, channelopathy, stroke, SCD, or MI in a first-degree relative <60 years
• Cardiac work-up: 12-lead ECG, transthoracic echo, CMR when available (49%)
• Genetic testing: systematically offered via cardiomyopathy/channelopathy panels; ACMG variant classification
• Follow-up: at least annual

Results — Lifestyle and Hereditary Risk Factors

• 122 patients; mean age 31.2 ± 6.2 years; 83% male; median follow-up 52 months (IQR 21–104)
• ≥1 lifestyle risk factor in 109 patients (89%): 23% had 1, 31% had 2, 35% had ≥3
• Modifiable lifestyle risk factor present in 90 patients (74%)
• Most frequent lifestyle risk factors:
  • Overweight/obesity: 36 (30%)
  • Intensive sport activity: 33 (27%)
  • Excessive alcohol: 27 (22%)
  • Recreational drug use: 13 (11%)
• Self-reported AF triggers in 64 (48%): psychological stress (20%), exercise (11%), alcohol (11%)
• Hereditary predisposition in 31 (25%): familial AF in 19 (16%), family history of CVD in 12 (10%)
• LA volume: mean 27 ± 7.8 mL/m²; LA enlargement in only 18 (15%)
• CMR (49%): consistently normal ventricular volumes without scar or fibrosis

Results — Genetic Testing

• 69 patients (57%) accepted genetic testing
• P/LP variants: 8 patients (11.6%)
• VUS: 27 patients (39.1%)
• Among the 8 familial AF patients who were tested: all carried variants (3 P/LP, 5 VUS); segregation analysis performed for VUS cases where relevant
• P/LP variants predominantly in cardiomyopathy genes (74%):
  • TTN: 4 variants
  • LMNA: 2 variants
  • PKP2: 2 variants
  • TNNI3: 1 variant

Results — Clinical Outcomes

• Paroxysmal AF at presentation: 104 (85%)
• TICM at diagnosis: 10 (8%)
• Single AF episode during entire follow-up: 14 (11%)
• Catheter ablation performed in 77 (63%): equally split cryoballoon/radiofrequency
  • First-line ablation: 17 (14%)
  • After antiarrhythmic drug failure: 60 (49%)
  • 1-year success after first procedure: 86%
  • Success after two procedures: 93%
• Progression to persistent AF: 7 (6%); no patient developed permanent AF
• Stroke: 5 patients (4.1%) — 4 at initial AF presentation, 1 during follow-up
  • All five had CHA₂DS₂-VA = 0 and were not anticoagulated at the time of stroke
• Other adverse events: 3 TICM recurrences, 1 resuscitated ventricular fibrillation, 1 sudden death (likely drug overdose)

Discussion

• Despite limited sample size and observational design, this represents the largest prospective description of AF determinants in patients <40 without SHD
• Most participants exhibited AF determinants typical of older populations (male sex, modifiable lifestyle factors)
• Comprehensive risk factor modification is particularly relevant in this young population
• No significant differences between tested and non-tested participants (voluntary testing design)
• Hereditary predisposition in 1 in 4 patients; pathogenic variants frequent especially in familial cases — supports genetic testing in selected young patients, particularly with positive family history, even without overt SHD
• Despite absence of SHD, major comorbidities, and very low baseline thromboembolic risk (93% CHA₂DS₂-VA = 0), clinically relevant outcomes occurred
• Findings highlight need for dedicated long-term follow-up registries

Limitations of the document

• Small sample size (n=122); wide CIs for outcome event rates
• Single-country, two-centre academic study; may not be generalizable
• Observational, non-randomised design
• Self-reported lifestyle information may introduce recall bias
• Genetic testing acceptance only 57%; selection bias cannot be excluded despite no detected demographic difference between tested/untested groups
• Voluntary genetic testing limits interpretation of true population yield
• CMR not performed in all patients (only 49%)
• Moderate median follow-up (52 months); late cardiomyopathy emergence may be missed

Key Concepts Mentioned

• concepts/Early-Onset-Atrial-Fibrillation — specific phenotype studied
• concepts/Genetic-Testing-in-AF — systematic testing with ACMG classification
• concepts/Catheter-Ablation-AF — 86–93% success rate reported
• concepts/CHA2DS2-VA — score = 0 in 93% yet stroke occurred in 4.1%

Key Entities Mentioned

• entities/Atrial-Fibrillation — central topic
• entities/TTN — most common P/LP gene (4 variants); in <40 AF without SHD
• entities/LMNA — 2 P/LP variants; young AF (<40) without structural disease
• entities/PKP2 — 2 P/LP variants; AF without overt ARVC/structural disease

Wiki Pages Updated

• wiki/sources/eoaf-riskfactor-ehj-2026.md (created)
• wiki/concepts/Early-Onset-Atrial-Fibrillation.md (updated)
• wiki/concepts/Genetic-Testing-in-AF.md (updated)
• wiki/entities/Atrial-Fibrillation.md (updated)
• wiki/entities/LMNA.md (updated)
• wiki/entities/TTN.md (updated)
• wiki/entities/PKP2.md (updated)
• wiki/wikiindex.md (updated)
• log.md (updated)