Slow Conduction in the Border Zones of Patchy Fibrosis Stabilizes the Drivers for Atrial Fibrillation: Insights from Multi-Scale Human Atrial Modeling.
ABSTRACT: Introduction: The genesis of atrial fibrillation (AF) and success of AF ablation therapy have been strongly linked with atrial fibrosis. Increasing evidence suggests that patient-specific distributions of fibrosis may determine the locations of electrical drivers (rotors) sustaining AF, but the underlying mechanisms are incompletely understood. This study aims to elucidate a missing mechanistic link between patient-specific fibrosis distributions and AF drivers. Methods: 3D atrial models integrated human atrial geometry, rule-based fiber orientation, region-specific electrophysiology, and AF-induced ionic remodeling. A novel detailed model for an atrial fibroblast was developed, and effects of myocyte-fibroblast (M-F) coupling were explored at single-cell, 1D tissue and 3D atria levels. Left atrial LGE MRI datasets from 3 chronic AF patients were segmented to provide the patient-specific distributions of fibrosis. The data was non-linearly registered and mapped to the 3D atria model. Six distinctive fibrosis levels (0-healthy tissue, 5-dense fibrosis) were identified based on LGE MRI intensity and modeled as progressively increasing M-F coupling and decreasing atrial tissue coupling. Uniform 3D atrial model with diffuse (level 2) fibrosis was considered for comparison. Results: In single cells and tissue, the largest effect of atrial M-F coupling was on the myocyte resting membrane potential, leading to partial inactivation of sodium current and reduction of conduction velocity (CV). In the 3D atria, further to the M-F coupling, effects of fibrosis on tissue coupling greatly reduce atrial CV. AF was initiated by fast pacing in each 3D model with either uniform or patient-specific fibrosis. High variation in fibrosis distributions between the models resulted in varying complexity of AF, with several drivers emerging. In the diffuse fibrosis models, waves randomly meandered through the atria, whereas in each the patient-specific models, rotors stabilized in fibrotic regions. The rotors propagated slowly around the border zones of patchy fibrosis (levels 3-4), failing to spread into inner areas of dense fibrosis. Conclusion: Rotors stabilize in the border zones of patchy fibrosis in 3D atria, where slow conduction enable the development of circuits within relatively small regions. Our results can provide a mechanistic explanation for the clinical efficacy of ablation around fibrotic regions.
Project description:Structural remodeling of human atria plays a key role in sustaining atrial fibrillation (AF), but insufficient quantitative analysis of human atrial structure impedes the treatment of AF. We aimed to develop a novel 3-dimensional (3D) structural and computational simulation analysis tool that could reveal the structural contributors to human reentrant AF drivers.High-resolution panoramic epicardial optical mapping of the coronary-perfused explanted intact human atria (63-year-old woman, chronic hypertension, heart weight 608 g) was conducted during sinus rhythm and sustained AF maintained by spatially stable reentrant AF drivers in the left and right atrium. The whole atria (107×61×85 mm3) were then imaged with contrast-enhancement MRI (9.4 T, 180×180×360-?m3 resolution). The entire 3D human atria were analyzed for wall thickness (0.4-11.7 mm), myofiber orientations, and transmural fibrosis (36.9% subendocardium; 14.2% midwall; 3.4% subepicardium). The 3D computational analysis revealed that a specific combination of wall thickness and fibrosis ranges were primarily present in the optically defined AF driver regions versus nondriver tissue. Finally, a 3D human heart-specific atrial computer model was developed by integrating 3D structural and functional mapping data to test AF induction, maintenance, and ablation strategies. This 3D model reproduced the optically defined reentrant AF drivers, which were uninducible when fibrosis and myofiber anisotropy were removed from the model.Our novel 3D computational high-resolution framework may be used to quantitatively analyze structural substrates, such as wall thickness, myofiber orientation, and fibrosis, underlying localized AF drivers, and aid the development of new patient-specific treatments.
Project description:<h4>Background</h4> Atrial fibrillation (AF) is associated with profound structural and functional changes in the atria. In the present study, we investigated the association between left atrial (LA) phasic function and the extent of LA fibrosis using advanced cardiovascular magnetic resonance (CMR) imaging techniques, including 3-dimensional (3D) late gadolinium enhancement (LGE) and feature tracking. <h4>Methods</h4> Patients with paroxysmal and persistent AF (n = 105) underwent CMR in sinus rhythm. LA global reservoir strain, conduit strain and contractile strain were derived from cine CMR images using CMR feature tracking. The extent of LA fibrosis was assessed from 3D LGE images. Healthy subjects underwent CMR and served as controls (n = 19). <h4>Results</h4> Significantly lower LA reservoir strain, conduit strain and contractile strain were found in AF patients, as compared to healthy controls (− 15.9 ± 3.8% vs. − 21.1 ± 3.6% P < 0.001, − 8.7 ± 2.7% vs. − 12.6 ± 2.5% P < 0.001 and − 7.2 ± 2.3% vs. − 8.6 ± 2.2% P = 0.02, respectively). Patients with a high degree of LA fibrosis (dichotomized by the median value) had lower reservoir strain and conduit strain compared to patients with a low degree of LA fibrosis (− 15.0 ± 3.9% vs. − 16.9 ± 3.3%, P = 0.02 and − 7.9 ± 2.7% vs. − 9.5 ± 2.6%, P = 0.01, respectively). In contrast, no difference was found for LA contractile strain (− 7.1 ± 2.4% vs. − 7.4 ± 2.3%, P = 0.55). <h4>Conclusions</h4> Impaired LA reservoir and conduit strain are present in AF patients with extensive atrial fibrosis. Future studies are needed to examine the biologic nature of this association and possible therapeutic implications. <h4>Supplementary Information</h4> The online version contains supplementary material available at 10.1186/s12968-021-00820-6.
Project description:Anti-arrhythmic drug therapy is a frontline treatment for atrial fibrillation (AF), but its success rates are highly variable. This is due to incomplete understanding of the mechanisms of action of specific drugs on the atrial substrate at different stages of AF progression. We aimed to elucidate the role of cellular, tissue and organ level atrial heterogeneities in the generation of a re-entrant substrate during AF progression, and their modulation by the acute action of selected anti-arrhythmic drugs. To explore the complex cell-to-organ mechanisms, a detailed biophysical models of the entire 3D canine atria was developed. The model incorporated atrial geometry and fibre orientation from high-resolution micro-computed tomography, region-specific atrial cell electrophysiology and the effects of progressive AF-induced remodelling. The actions of multi-channel class III anti-arrhythmic agents vernakalant and amiodarone were introduced in the model by inhibiting appropriate ionic channel currents according to experimentally reported concentration-response relationships. AF was initiated by applied ectopic pacing in the pulmonary veins, which led to the generation of localized sustained re-entrant waves (rotors), followed by progressive wave breakdown and rotor multiplication in both atria. The simulated AF scenarios were in agreement with observations in canine models and patients. The 3D atrial simulations revealed that a re-entrant substrate was typically provided by tissue regions of high heterogeneity of action potential duration (APD). Amiodarone increased atrial APD and reduced APD heterogeneity and was more effective in terminating AF than vernakalant, which increased both APD and APD dispersion. In summary, the initiation and sustenance of rotors in AF is linked to atrial APD heterogeneity and APD reduction due to progressive remodelling. Our results suggest that anti-arrhythmic strategies that increase atrial APD without increasing its dispersion are effective in terminating AF.
Project description:AIMS:Inadequate modification of the atrial fibrotic substrate necessary to sustain re-entrant drivers (RDs) may explain atrial fibrillation (AF) recurrence following failed pulmonary vein isolation (PVI). Personalized computational models of the fibrotic atrial substrate derived from late gadolinium enhanced (LGE)-magnetic resonance imaging (MRI) can be used to non-invasively determine the presence of RDs. The objective of this study is to assess the changes of the arrhythmogenic propensity of the fibrotic substrate after PVI. METHODS AND RESULTS:Pre- and post-ablation individualized left atrial models were constructed from 12 AF patients who underwent pre- and post-PVI LGE-MRI, in six of whom PVI failed. Pre-ablation AF sustained by RDs was induced in 10 models. RDs in the post-ablation models were classified as either preserved or emergent. Pre-ablation models derived from patients for whom the procedure failed exhibited a higher number of RDs and larger areas defined as promoting RD formation when compared with atrial models from patients who had successful ablation, 2.6?±?0.9 vs. 1.8?±?0.2 and 18.9?±?1.6% vs. 13.8?±?1.5%, respectively. In cases of successful ablation, PVI eliminated completely the RDs sustaining AF. Preserved RDs unaffected by ablation were documented only in post-ablation models of patients who experienced recurrent AF (2/5 models); all of these models had also one or more emergent RDs at locations distinct from those of pre-ablation RDs. Emergent RDs occurred in regions that had the same characteristics of the fibrosis spatial distribution (entropy and density) as regions that harboured RDs in pre-ablation models. CONCLUSION:Recurrent AF after PVI in the fibrotic atria may be attributable to both preserved RDs that sustain AF pre- and post-ablation, and the emergence of new RDs following ablation. The same levels of fibrosis entropy and density underlie the pro-RD propensity in both pre- and post-ablation substrates.
Project description:Current clinical guidelines establish Pulmonary Vein (PV) isolation as the indicated treatment for Atrial Fibrillation (AF). However, AF can also be triggered or sustained due to atrial drivers located elsewhere in the atria. We designed a new simulation workflow based on personalized computer simulations to characterize AF complexity of patients undergoing PV ablation, validated with non-invasive electrocardiographic imaging and evaluated at one year after ablation. We included 30 patients using atrial anatomies segmented from MRI and simulated an automata model for the electrical modelling, consisting of three states (resting, excited and refractory). In total, 100 different scenarios were simulated per anatomy varying rotor number and location. The 3 states were calibrated with Koivumaki action potential, entropy maps were obtained from the electrograms and compared with ECGi for each patient to analyze PV isolation outcome. The completion of the workflow indicated that successful AF ablation occurred in patients with rotors mainly located at the PV antrum, while unsuccessful procedures presented greater number of driving sites outside the PV area. The number of rotors attached to the PV was significantly higher in patients with favorable long-term ablation outcome (1-year freedom from AF: 1.61 ± 0.21 vs. AF recurrence: 1.40 ± 0.20; <i>p</i>-value = 0.018). The presented workflow could improve patient stratification for PV ablation by screening the complexity of the atria.
Project description:Anatomically based procedures to ablate atrial fibrillation (AF) are often successful in terminating paroxysmal AF. However, the ability to terminate persistent AF remains disappointing. New mechanistic approaches use multiple-electrode basket catheter mapping to localize and target AF drivers in the form of rotors but significant concerns remain about their accuracy. We aimed to evaluate how electrode-endocardium distance, far-field sources and inter-electrode distance affect the accuracy of localizing rotors. Sustained rotor activation of the atria was simulated numerically and mapped using a virtual basket catheter with varying electrode densities placed at different positions within the atrial cavity. Unipolar electrograms were calculated on the entire endocardial surface and at each of the electrodes. Rotors were tracked on the interpolated basket phase maps and compared with the respective atrial voltage and endocardial phase maps, which served as references. Rotor detection by the basket maps varied between 35-94% of the simulation time, depending on the basket's position and the electrode-to-endocardial wall distance. However, two different types of phantom rotors appeared also on the basket maps. The first type was due to the far-field sources and the second type was due to interpolation between the electrodes; increasing electrode density decreased the incidence of the second but not the first type of phantom rotors. In the simulations study, basket catheter-based phase mapping detected rotors even when the basket was not in full contact with the endocardial wall, but always generated a number of phantom rotors in the presence of only a single real rotor, which would be the desired ablation target. Phantom rotors may mislead and contribute to failure in AF ablation procedures.
Project description:Recent studies strongly suggest that the majority of atrial fibrillation (AF) patients with diagnosed or subclinical cardiac diseases have established or even pre-existing fibrotic structural remodeling, which may lead to conduction abnormalities and reentrant activity that sustain AF. As conventional treatments fail to treat AF in far too many cases, an urgent need exists to identify specific structural arrhythmogenic fibrosis patterns, which may maintain AF, in order to identify effective ablation targets for AF treatment. However, the existing challenge is to define what exact structural remodeling within the complex 3D human atrial wall is arrhythmogenic, as well as linking arrhythmogenic fibrosis to an underlying mechanism of AF maintenance in the clinical setting. This review is focused on the role of 3D fibrosis architecture in the mechanisms of AF maintenance revealed by submillimeter, high-resolution ex-vivo imaging modalities directly of human atria, as well as from in-silico 3D computational techniques that can be able to overcome in-vivo clinical limitations. The systematic integration of functional and structural imaging ex-vivo may inform the necessary integration of electrode and structural mapping in-vivo. A holistic view of AF driver mechanisms may begin to identify the defining characteristics or "fingerprints" of reentrant AF drivers, such as 3D fibrotic architecture, in order to design optimal patient-specific ablation strategies.
Project description:Ablation is an effective therapy in patients with atrial fibrillation (AF) in which an electrical driver can be identified.The aim of this study was to present and discuss a novel and strictly noninvasive approach to map and identify atrial regions responsible for AF perpetuation.Surface potential recordings of 14 patients with AF were recorded using a 67-lead recording system. Singularity points (SPs) were identified in surface phase maps after band-pass filtering at the highest dominant frequency (HDF). Mathematical models of combined atria and torso were constructed and used to investigate the ability of surface phase maps to estimate rotor activity in the atrial wall.The simulations show that surface SPs originate at atrial SPs, but not all atrial SPs are reflected at the surface. Stable SPs were found in AF signals during 8.3% ± 5.7% vs. 73.1% ± 16.8% of the time in unfiltered vs. HDF-filtered patient data, respectively (P < .01). The average duration of each rotational pattern was also lower in unfiltered than in HDF-filtered AF signals (160 ± 43 ms vs. 342 ± 138 ms; P < .01), resulting in 2.8 ± 0.7 rotations per rotor. Band-pass filtering reduced the apparent meandering of surface HDF rotors by reducing the effect of the atrial electrical activity occurring at different frequencies. Torso surface SPs representing HDF rotors during AF were reflected at specific areas corresponding to the fastest atrial location.Phase analysis of surface potential signals after HDF filtering during AF shows reentrant drivers localized to either the left atrium or the right atrium, helping in localizing ablation targets.
Project description:<h4>Background</h4>Although rotors have been considered among the drivers of atrial fibrillation (AF), the rotor definition is inconsistent. We evaluated the nature of rotors in 2D and 3D in- silico models of persistent AF (PeAF) by analyzing phase singularity (PS), dominant frequency (DF), Shannon entropy (ShEn), and complex fractionated atrial electrogram cycle length (CFAE-CL) and their ablation.<h4>Methods</h4>Mother rotor was spatiotemporally defined as stationary reentries with a meandering tip remaining within half the wavelength and lasting longer than 5 s. We generated 2D- and 3D-maps of the PS, DF, ShEn, and CFAE-CL during AF. The spatial correlations and ablation outcomes targeting each parameter were analyzed.<h4>Results</h4>1. In the 2D PeAF model, we observed a mother rotor that matched relatively well with DF (>9 Hz, 71.0%, p<0.001), ShEn (upper 2.5%, 33.2%, p<0.001), and CFAE-CL (lower 2.5%, 23.7%, p<0.001). 2. The 3D-PeAF model also showed mother rotors that had spatial correlations with DF (>5.5 Hz, 39.7%, p<0.001), ShEn (upper 8.5%, 15.1%, p <0.001), and CFAE (lower 8.5%, 8.0%, p = 0.002). 3. In both the 2D and 3D models, virtual ablation targeting the upper 5% of the DF terminated AF within 20 s, but not the ablations based on long-lasting PS, high ShEn area, or lower CFAE-CL area.<h4>Conclusion</h4>Mother rotors were observed in both 2D and 3D human AF models. Rotor locations were well represented by DF, and their virtual ablation altered wave dynamics and terminated AF.