Use of Atrial Fibrillation Electrograms and T1/T2 Magnetic Resonance Imaging to Define the Progressive Nature of Molecular and Structural Remodeling: A New Paradigm Underlying the Emergence of Persistent Atrial Fibrillation.

BACKGROUND: The temporal progression states of the molecular and structural substrate in atrial fibrillation (AF) are not well understood. We hypothesized that these can be detected by AF electrograms and magnetic resonance imaging parametric mapping. METHODS AND RESULTS: AF was induced in 43 dogs (25-35 kg, ≥1 year) by rapid atrial pacing (RAP) (3-33 weeks, 600 beats/min), and 4 controls were used. We performed high-resolution epicardial mapping (UnEmap, 6 atrial regions, both atria, 130 electrodes, distance 2.5 mm) and analyzed electrogram cycle length, dominant frequency, organization index, and peak-to-peak bipolar voltage. Implantable telemetry recordings were used to quantify parasympathetic nerve activity over RAP time. Magnetic resonance imaging native T1, postcontrast T1, T2 mapping, and extracellular volume fraction were assessed (1.5T, Siemens) at baseline and AF. In explanted atrial tissue, DNA oxidative damage (8-hydroxy-2'-deoxyguanosine staining) and percentage of fibrofatty tissue were quantified. Cycle length and organization index decreased (R=0.5, P<0.05; and R=0.5, P<0.05; respectively), and dominant frequency increased (R=0.3, P n.s.) until 80 days of RAP but not thereafter. In contrast, voltage continued to decrease throughout the duration of RAP (R=0.6, P<0.05). Parasympathetic nerve activity increased following RAP and plateaued at 80 days. Magnetic resonance imaging native T1 and T2 times increased with RAP days (R=0.5, P<0.05; R=0.6, P<0.05) in the posterior left atrium throughout RAP. Increased RAP days correlated with increasing 8-hydroxy-2'-deoxyguanosine levels and with fibrosis percentage (R=0.5, P<0.05 for both). CONCLUSIONS: A combination of AF electrogram characteristics and T1/T2 magnetic resonance imaging can detect early-stage AF remodeling (autonomic remodeling, oxidative stress) and advanced AF remodeling due to oxidative stress and fibrosis.

Comprehensive evaluation of electrophysiological and 3D structural features of human atrial myocardium with insights on atrial fibrillation maintenance mechanisms.

Atrial fibrillation (AF) occurrence and maintenance is associated with progressive remodeling of electrophysiological (repolarization and conduction) and 3D structural (fibrosis, fiber orientations, and wall thickness) features of the human atria. Significant diversity in AF etiology leads to heterogeneous arrhythmogenic electrophysiological and structural substrates within the 3D structure of the human atria. Since current clinical methods have yet to fully resolve the patient-specific arrhythmogenic substrates, mechanism-based AF treatments remain underdeveloped. Here, we review current knowledge from in-vivo, ex-vivo, and in-vitro human heart studies, and discuss how these studies may provide new insights on the synergy of atrial electrophysiological and 3D structural features in AF maintenance. In-vitro studies on surgically acquired human atrial samples provide a great opportunity to study a wide spectrum of AF pathology, including functional changes in single-cell action potentials, ion channels, and gene/protein expression. However, limited size of the samples prevents evaluation of heterogeneous AF substrates and reentrant mechanisms. In contrast, coronary-perfused ex-vivo human hearts can be studied with state-of-the-art functional and structural technologies, such as high-resolution near-infrared optical mapping and contrast-enhanced MRI. These imaging modalities can resolve atrial arrhythmogenic substrates and their role in reentrant mechanisms maintaining AF and validate clinical approaches. Nonetheless, longitudinal studies are not feasible in explanted human hearts. As no approach is perfect, we suggest that combining the strengths of direct human atrial studies with high fidelity approaches available in the laboratory and in realistic patient-specific computer models would elucidate deeper knowledge of AF mechanisms. We propose that a comprehensive translational pipeline from ex-vivo human heart studies to longitudinal clinically relevant AF animal studies and finally to clinical trials is necessary to identify patient-specific arrhythmogenic substrates and develop novel AF treatments.