Key result
High-risk cardiomyopathic AF phenotype linked to ~4.5-fold higher risk of major cardiovascular events.
Why the study?
AF in adults aged <65 years is a heterogeneous condition with varying cardiovascular outcomes, prompting this effort to identify distinct clinical-echocardiographic phenotypes and evaluate their associations with adverse outcomes across European and Asian cohorts.
Do distinct clinical-echocardiographic phenotypes (Cardiometabolic-Early Remodelling and High-Risk Cardiomyopathic) predict a higher risk of composite adverse outcomes compared to the Low-Risk Normal Structure phenotype in young patients (<65 years) with atrial fibrillation?
Cohort (n=2,547)
Yes
Do distinct clinical-echocardiographic phenotypes (Cardiometabolic-Early Remodelling and High-Risk Cardiomyopathic) predict a higher risk of composite adverse outcomes compared to the Low-Risk Normal Structure phenotype in young patients (<65 years) with atrial fibrillation?
In patients under 65 with atrial fibrillation, integrating clinical and echocardiographic variables identifies three distinct phenotypes—low-risk normal structure, cardiometabolic-early remodelling, and high-risk cardiomyopathic—that strongly stratify the risk of major adverse cardiovascular events and mortality.
May refine risk stratification in young AF; hypothesis-generating and requires prospective validation before practice change.
Background Atrial fibrillation (AF) in younger adults is a highly heterogeneous condition, encompassing a broad clinical spectrum and associated with markedly different cardiovascular outcomes. Purpose We aimed to identify distinct clinical–echocardiographic phenotypes of AF in patients aged <65 years and to evaluate their associations with adverse outcomes across large European and Asian cohorts. Methods We analysed patients aged <65 years enrolled in the European (EORP-AF) and Asian (APHRS-AF) registries. Latent Class Analysis (LCA) integrating demographic, cardiovascular, and echocardiographic variables was performed to identify clinical phenotypes. The primary outcome was a composite of all-cause death, major adverse cardiovascular events (MACE), acute coronary syndrome (ACS), and thromboembolic events (TEE). Associations between phenotype membership and outcomes were assessed using Cox proportional-hazards models, with the low-risk class serving as the reference group. Results Among 2,547 patients, LCA identified three distinct phenotypes: Class 1 – Cardiometabolic–Early Remodelling (40%) included middle-aged, overweight patients (median age 60 years, BMI 27 kg/m²) with a high prevalence of hypertension (77%), dyslipidaemia (44%), and diabetes (19%), but largely preserved systolic function (LVEF 60%) and normal chamber dimensions. Class 2 – Low-Risk Normal Structure (28%) comprised the youngest participants (median age 52 years, 79% male) with minimal comorbidities (hypertension 5%, diabetes <1%), normal LV and LA size, and the lowest CHA₂DS₂-VASc and HAS-BLED scores; this phenotype was more common among Asian patients (53%). Class 3 – High-Risk Cardiomyopathic (32%) included predominantly European patients (80%) with advanced structural remodelling, enlarged LV and LA (LVEDD 56 mm; LA 48 mm), reduced systolic function (LVEF 45%), and frequent heart failure (70%) or coronary artery disease (33%), representing an overtly remodelled and high-risk phenotype. Compared with the Low-Risk Normal Structure, High-Risk Cardiomyopathic showed markedly higher risk for the composite outcome (HR 4.49, 95% CI 2.37–8.52), MACE (HR 3.76, 95% CI 1.90–7.44), all-cause death (HR 14.23, 95% CI 3.43–59.12), and ACS (HR 2.56, 95% CI 1.03–6.39). Cardiometabolic–Early Remodelling exhibited intermediate risk across all endpoints. Conclusions Three reproducible AF phenotypes emerged, spanning from idiopathic to cardiometabolic and cardiomyopathic forms associated with worsening outcomes. These findings emphasize the clinical heterogeneity of AF and the value of phenotype-driven risk stratification.
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Rigutini et al. (2026) conducted a cohort in Atrial fibrillation (n=2,547). High-Risk Cardiomyopathic phenotype (Class 3) vs. Low-Risk Normal Structure phenotype (Class 2) was evaluated on Composite of all-cause death, major adverse cardiovascular events (MACE), acute coronary syndrome (ACS), and thromboembolic events (TEE) (HR 4.49, 95% CI 2.37-8.52). High-Risk Cardiomyopathic AF phenotype had a markedly higher risk of death, MACE, ACS, or thromboembolism vs Low-Risk Normal Structure (HR 4.49; 95% CI 2.37-8.52).
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