Atrial cardiomyopathy as a multidomain disease: longitudinal evidence for autonomic remodelling

AIMS: Atrial cardiomyopathy (AtCM) is increasingly recognized as a substrate for atrial fibrillation (AF), yet its operationalization remains limited and largely marker-driven. Whether autonomic remodelling represents a longitudinally evolving domain within a multidomain framework of AtCM remains unclear. OBJECTIVES: To determine whether autonomic remodelling, assessed through static and longitudinal heart rate variability (HRV) abnormalities, defines a distinct domain of AtCM and contributes to atrial disease burden and clinical risk. METHODS AND RESULTS: We studied 670 individuals aged 65 years without prior AF or major cardiovascular disease from the prospective PROOF cohort with 24-h Holter ECGs at baseline and 5 years. Heart rate variability metrics, premature atrial contraction (PAC) burden, and left atrial (LA) size were assessed. Incident AF and cardiovascular outcomes were adjudicated over a median follow-up of 12.1 years. Seventy-two participants (10.7%) developed AF. Static HRV abnormalities and adverse 5-year HRV trajectories were independently associated with subsequent AF. Autonomic abnormalities showed limited concordance with PAC burden and LA enlargement, supporting their role as a distinct AtCM domain. Increasing involvement of remodelling domains was associated with higher risks of AF and cardiovascular outcomes. Participants with ≥2 domains exhibited higher risks of AF (HR 2.43; 95% CI 1.72-3.45), major adverse cardiovascular events (HR 1.42), and all-cause mortality (HR 1.35). CONCLUSION: Atrial cardiomyopathy is a cumulative, multidomain disease process in which structural, electrical, and autonomic abnormalities define atrial disease burden. Longitudinal autonomic remodelling constitutes an independent and evolving axis within this framework, shifting the focus from isolated arrhythmia detection towards progressive characterization of atrial substrate.