Atrial fibrillation: Insights from animal models, computational modeling, and clinical studies

Figures

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  Fig. 1. Insights from Animal Models Reflecting Two Schools of Thought. (a) Multiple Wavelets: schematic of epicardial breakthroughs (star) resulting from fibrillation wave propagating from left to right in the endocardium. The wave propagates transmurally from endo to epicardium, activating the surrounding epicardium in different ways (II-IV). Isochrones are drawn at 5-ms intervals in cross-sectional view of the atrial wall (left). A 3D view illustrates the epicardium as a single syncytium of cells (middle) or with multiple narrow pathways resulting from longitudinal dissociation of muscle bundles (right) [Modified with permission from14]. (b) AF driver (“mother rotor”): schematic of reentry around an anatomical (I) and a functional obstacle (II), where the wavelength (black) is shorter than the path length, allowing for a fully excitable gap (white); the arrows pointing inwards represent centripetal forces towards a refractory center (II). Snapshot of a spiral wave (III). Near the core, CV (arrows), APD (illustrative examples shown for positions 1, 2, and 3), and wavelength (distance from wavefront to wave tail) are decreased. Phase singularity (∗) occurs where the wavefront and the…

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  Fig. 2. Mechanisms of AF maintenance: ectopic foci on PVs, rotors, and wavelets. Representation of AF maintenance near a PV by an ectopic focus on the vein (I), a rotor (II), or multiple wavelets (III). Representation of rotor maintenance in conjunction with other mechanisms: rotor formation as a result of wavebreaks near an ectopic focus (IV), intramural rotors resulting in endocardial or epicardial breakthroughs (V), and drifting rotors (trajectory illustrated in blue) causing multiple epicardial wavelets [From22]. While insight about how rotational activity sustains AF has been derived from animal studies, ectopic foci as drivers of AF were first recorded in human studies.

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  Fig. 3. Patient-specific atrial wall and fibrosis. (a) 3D anatomy of the LA reconstructed from LGE MRI scans (normal tissue in blue and fibrotic tissue in green). The atrium wall is rendered from segmentation of the epi and endocardial borders. Enhanced voxels above a certain threshold are marked as fibrotic tissue and projected on the surface of the atria [Modified with permission from35]. (b) Left atrial fibrosis on LGE MRI correlates with biopsy specimens from control patient without AF (Aa-Ac), AF patient with moderate fibrosis distribution (Ba-Bc), and AF patient with advanced amount of fibrosis (Ca-Cc). For each patient, the 3D LGE MRI rendering (top), the Masson trichrome staining (middle; collagen in blue and myocytes in red), and the subtraction images (bottom) are shown. Red box indicates biopsy location [Modified with permission from36].

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  Fig. 4. Whole-atria computational models integrate information from cell to tissue to organ level. At the cell level, the atrial EP is captured by the AP from fibrotic AF (green) and non-fibrotic AF cells (black) (top left). At the tissue level, atrial fiber architecture retrieved from DT MRI of explanted human atria (bottom left) dictates the preferential direction for wave propagation along the fibers on the endocardium (endo) and epicardium (epi). At the organ level, patient-specific atrial geometry and fibrosis distribution are reconstructed from LGE MRI and integrated into a personalized computational model (top right). AF inducibility can be simulated in the model. An activation map of an AF simulation (after virtual PVI) is shown (bottom right); black and gray are outside the 800 ms time range. Anatomical structures: left atrial appendage (LAA), left superior pulmonary vein (LSPV), left inferior pulmonary vein (LIPV), right superior pulmonary vein (RSPV), right inferior pulmonary vein (RIPV), superior vena cava (SVC), inferior vena cava (IVC), and right atrial appendage (RAA) [Modified with permission from45].

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  Fig. 5. Personalized Computational Modeling of the Atria for Ablation Guidance: The OPTIMA approach. (a) Patient-derived atrial geometry and fibrosis distribution on the left and right atria (left). Activation map after rapid pacing and virtual PVI ablation (middle). Certain areas were activated before (black) or after (gray) the 800 ms time range. Two reentries (pink arrows) were identified near the RAA. OPTIMA ablation strategy showing ablation targets (red circles) and lesion lines (red line) connecting the targets to a non-conductive boundary (right). Anatomical structures: left atrial appendage (LAA), left superior pulmonary vein (LSPV), left inferior pulmonary vein (LIPV), right superior pulmonary vein (RSPV), right inferior pulmonary vein (RIPV), superior vena cava (SVC), inferior vena cava (IVC), right atrial appendage (RAA), tricuspid valve (TCV), and mitral valve (MV). (b) Steps undertaken to identify OPTIMA ablation targets. An initial set of lesions is determined after analysis of the rapid pacing in the model. Virtual ablations are performed targeting the reentrant drivers and the rapid pacing protocol is repeated to determine whether new (emergent) reentries arise in the…