Atrial Cardiomyopathy in Atrial Fibrillation: A Multimodal Diagnostic Framework

Abstract

Atrial fibrillation (AF) is increasingly recognized as the clinical manifestation of an underlying atrial disease process rather than a purely electrical disorder. This evolving paradigm has given rise to the concept of atrial cardiomyopathy (AtCM), encompassing structural, electrical, contractile, and molecular remodeling of the atrial myocardium that contributes to AF initiation, maintenance, and progression. Although consensus definitions of AtCM now exist, its integration into clinical practice remains limited, with AF management still largely guided by arrhythmic patterns rather than substrate characterization. This review synthesizes current diagnostic strategies for AtCM within the context of AF, emphasizing a multimodal approach. We outline advances in cardiac imaging-including echocardiography, cardiac magnetic resonance, and computed tomography-for detailed assessment of atrial morphology, function, and fibrosis. Electroanatomic mapping is discussed as a key invasive tool for substrate localization, while electrocardiographic indices such as P-wave morphology and dispersion serve as accessible surrogates of electrical remodeling. In parallel, we examine the role of circulating biomarkers and emerging genomic, transcriptomic, and epigenomic markers in refining disease phenotyping. Despite promising progress, significant challenges remain. Standardization of imaging protocols, validation of biomarker thresholds, and integration of artificial intelligence tools are needed to enhance clinical utility. A diagnostic framework informed by atrial substrate assessment may support more tailored therapeutic decision-making in AF. Future research should prioritize the harmonization of diagnostic criteria and explore how substrate profiling in AF may refine risk stratification and improve clinical outcomes.

Keywords: atrial cardiomyopathy; atrial fibrillation; atrial substrate; biomarkers; cardiac imaging; electroanatomic mapping; electrocardiography.

Figure 1

Integrated multimodal diagnostic framework for atrial cardiomyopathy in atrial fibrillation. This schematic illustrates a comprehensive approach to diagnosing atrial cardiomyopathy (AtCM) in the context of atrial fibrillation (AF), emphasizing the convergence of structural, electrical, functional, and molecular assessments. Central to the diagram is AtCM, surrounded by six key diagnostic domains: (1) imaging modalities (echocardiography, cardiac magnetic resonance, and computed tomography) provide detailed assessment of atrial size, function, fibrosis, and wall deformation; (2) electroanatomic mapping offers invasive evaluation of low-voltage areas, conduction velocity, and electrogram complexity; (3) ECG phenotyping captures electrical remodeling through P-wave indices, interatrial block, and f-wave morphology; (4) circulating biomarkers reflect hemodynamic stress, inflammation, and fibrosis; (5) omics-based markers—including genomic, transcriptomic, and epigenetic alterations—offer molecular insight into atrial remodeling; and (6) artificial intelligence tools enhance diagnostic precision through advanced ECG interpretation and substrate quantification. Together, these modalities contribute to a substrate-guided framework for risk stratification, therapy selection, and progression monitoring in AF. Abbreviations: TTE—transthoracic echocardiography; 3D—three-dimensional; CMR—cardiac magnetic resonance; LGE—late gadolinium enhancement; LA—left atrium; CCT—cardiac computed tomography; EAT—epicardial adipose tissue; LVA—low-voltage area; ECG—electrocardiogram; IAB—interatrial block; PTFV1—P-wave terminal force in lead V1; APWD—amplified P-wave duration; AI—artificial intelligence; AF—atrial fibrillation; NT-proBNP—N-terminal pro–B-type natriuretic peptide; GDF-15—growth differentiation factor-15; BMP10—bone morphogenetic protein 10; TIMP-1—tissue inhibitor of metalloproteinase-1; sST2—soluble suppression of tumorigenicity-2; CRP—C-reactive protein; vWF—von Willebrand factor; MYL4—myosin light chain 4; NPPA—natriuretic peptide A; SCN5A—sodium voltage-gated channel alpha subunit 5; NTM—neurotrimin; COLQ—collagen-like tail subunit of asymmetric acetylcholinesterase; CpG—cytosine–phosphate–guanine.