Atrial fibrillation (AF) -the most common arrhythmia -significantly increases the risk of stroke and heart failure. Although catheter ablation can restore normal heart rhythms, patients with persistent AF who develop atrial fibrosis often undergo multiple failed ablations and thus increased procedural risks. Here, we present personalized computational modelling for the reliable predetermination of ablation targets, which are then used to guide the ablation procedure in patients with persistent AF and atrial fibrosis. We first show that a computational model of the atria of patients identifies fibrotic tissue that if ablated will not sustain AF. We then integrated the target-ablation sites in a clinical-mapping system, and tested its feasibility in 10 patients with persistent AF. The computational prediction of ablation targets avoids lengthy electrical mapping Reprints and permissions information is available at www.nature.com/reprints.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, causing morbidity and mortality in millions worldwide. The atria of patients with persistent AF (PsAF) are characterized by the presence of extensive and distributed atrial fibrosis, which facilitates the formation of persistent reentrant drivers (RDs, i.e., spiral waves), which promote fibrillatory activity. Targeted catheter ablation of RD-harboring tissues has shown promise as a clinical treatment for PsAF, but the outcomes remain sub-par. Personalized computational modeling has been proposed as a means of non-invasively predicting optimal ablation targets in individual PsAF patients, but it remains unclear how RD localization dynamics are influenced by inter-patient variability in the spatial distribution of atrial fibrosis, action potential duration (APD), and conduction velocity (CV). Here, we conduct simulations in computational models of fibrotic atria derived from the clinical imaging of PsAF patients to characterize the sensitivity of RD locations to these three factors. We show that RDs consistently anchor to boundaries between fibrotic and non-fibrotic tissues, as delineated by late gadolinium-enhanced magnetic resonance imaging, but those changes in APD/CV can enhance or attenuate the likelihood that an RD will anchor to a specific site. These findings show that the level of uncertainty present in patient-specific atrial models reconstructed without any invasive measurements (i.e., incorporating each individual's unique distribution of fibrotic tissue from medical imaging alongside an average representation of AF-remodeled electrophysiology) is sufficiently high that a personalized ablation strategy based on targeting simulation-predicted RD trajectories alone may not produce the desired result.
Electrocardiographic mapping (ECGI) detects reentrant drivers (RDs) that perpetuate arrhythmia in persistent AF (PsAF). Patient-specific computational models derived from late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) identify all latent sites in the fibrotic substrate that could potentially sustain RDs, not just those manifested during mapped AF. The objective of this study was to compare RDs from simulations and ECGI (RDsim/RDECGI) and analyze implications for ablation. We considered 12 PsAF patients who underwent RDECGI ablation. For the same cohort, we simulated AF and identified RDsim sites in patient-specific models with geometry and fibrosis distribution from pre-ablation LGE-MRI. RDsim- and RDECGI-harboring regions were compared, and the extent of agreement between macroscopic locations of RDs identified by simulations and ECGI was assessed. Effects of ablating RDECGI/RDsim were analyzed. RDsim were predicted in 28 atrial regions (median [inter-quartile range (IQR)] = 3.0 [1.0; 3.0] per model). ECGI detected 42 RDECGI-harboring regions (4.0 [2.0; 5.0] per patient). The number of regions with RDsim and RDECGI per individual was not significantly correlated (R = 0.46, P = ns). The overall rate of regional agreement was fair (modified Cohen's κ0 statistic = 0.11), as expected, based on the different mechanistic underpinning of RDsim- and RDECGI. nineteen regions were found to harbor both RDsim and RDECGI, suggesting that a subset of clinically observed RDs was fibrosis-mediated. The most frequent source of differences (23/32 regions) between the two modalities was the presence of RDECGI perpetuated by mechanisms other than the fibrotic substrate. In 6/12 patients, there was at least one region where a latent RD was observed in simulations but was not manifested during clinical mapping. Ablation of fibrosis-mediated RDECGI (i.e., targets in regions that also harbored RDsim) trended toward a higher rate of positive response compared to ablation of other RDECGI targets (57 vs. 41%, P = ns). Our analysis suggests that RDs in human PsAF are at least partially fibrosis-mediated. Substrate-based ablation combining simulations with ECGI could improve outcomes.
Focal impulse and rotor mapping (FIRM) involves intracardiac detection and catheter ablation of re-entrant drivers (RDs), some of which may contribute to arrhythmia perpetuation in persistent atrial fibrillation (PsAF). Patient-specific computational models derived from late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) has the potential to non-invasively identify all areas of the fibrotic substrate where RDs could potentially be sustained, including locations where RDs may not manifest during mapped AF episodes. The objective of this study was to carry out multi-modal assessment of the arrhythmogenic propensity of the fibrotic substrate in PsAF patients by comparing locations of RD-harboring regions found in simulations and detected by FIRM (RDsim and RDFIRM) and analyze implications for ablation strategies predicated on targeting RDs. For 11 PsAF patients who underwent pre-procedure LGE-MRI and FIRM-guided ablation, we retrospectively simulated AF in individualized atrial models, with geometry and fibrosis distribution reconstructed from pre-ablation LGE-MRI scans, and identified RDsim sites. Regions harboring RDsim and RDFIRM were compared. RDsim were found in 38 atrial regions (median [inter-quartile range (IQR)] = 4 [3; 4] per model). RDFIRM were identified and subsequently ablated in 24 atrial regions (2 [1; 3] per patient), which was significantly fewer than the number of RDsim-harboring regions in corresponding models (p < 0.05). Computational modeling predicted RDsim in 20 of 24 (83%) atrial regions identified as RDFIRM-harboring during clinical mapping. In a large number of cases, we uncovered RDsim-harboring regions in which RDFIRM were never observed (18/22 regions that differed between the two modalities; 82%); we termed such cases “latent” RDsim sites. During follow-up (230 [180; 326] days), AF recurrence occurred in 7/11 (64%) individuals. Interestingly, latent RDsim sites were observed in all seven computational models corresponding to patients who experienced recurrent AF (2 [2; 2] per patient); in contrast, latent RDsim sites were only discovered in two of four patients who were free from AF during follow-up (0.5 [0; 1.5] per patient; p < 0.05 vs. patients with AF recurrence). We conclude that substrate-based ablation based on computational modeling could improve outcomes.
Direct remuscularization approaches to cell-based heart repair seek to restore ventricular contractility following myocardial infarction (MI) by introducing new cardiomyocytes (CMs) to replace lost or injured ones. However, despite promising improvements in cardiac function, high incidences of ventricular arrhythmias have been observed in animal models of MI injected with pluripotent stem cell-derived cardiomyocytes (PSC-CMs). The mechanisms of arrhythmogenesis remain unclear. Here, we present a comprehensive framework for computational modeling of direct remuscularization approaches to cell therapy. Our multiscale 3D whole-heart modeling framework integrates realistic representations of cell delivery and transdifferentiation therapy modalities as well as representation of spatial distributions of engrafted cells, enabling simulation of clinical therapy and the prediction of emergent electrophysiological behavior and arrhythmogenensis. We employ this framework to explore how varying parameters of cell delivery and transdifferentiation could result in three mechanisms of arrhythmogenesis: focal ectopy, heart block, and reentry.
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