Dataset Information

Three-dimensional Integrated Functional, Structural, and Computational Mapping to Define the Structural "Fingerprints" of Heart-Specific Atrial Fibrillation Drivers in Human Heart Ex Vivo.

ABSTRACT: 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-μm3 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.

SUBMITTER: Zhao J

PROVIDER: S-EPMC5586436 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Three-dimensional Integrated Functional, Structural, and Computational Mapping to Define the Structural "Fingerprints" of Heart-Specific Atrial Fibrillation Drivers in Human Heart Ex Vivo.

Zhao Jichao J Hansen Brian J BJ Wang Yufeng Y Csepe Thomas A TA Sul Lidiya V LV Tang Alan A Yuan Yiming Y Li Ning N Bratasz Anna A Powell Kimerly A KA Kilic Ahmet A Mohler Peter J PJ Janssen Paul M L PML Weiss Raul R Simonetti Orlando P OP Hummel John D JD Fedorov Vadim V VV

Journal of the American Heart Association 20170822 8

<h4>Background</h4>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.<h4>Methods and results</h4>High-resolution panoramic epicardial optical mapping of the coronary-perfused explanted ...[more]

PMID: 28862969

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Project description:BackgroundAlthough atrial fibrillation (AF), a common arrhythmia, frequently presents in patients with underlying valvular disease, its hemodynamic contributions are not fully understood. The present work aimed to computationally study how physical conditions imposed by pathologic valvular anatomy act on AF hemodynamics.MethodsWe simulated AF with different severity grades of left-sided valvular diseases and compared the cardiovascular effects that they exert during AF, compared to lone AF. The fluid dynamics model used here has been recently validated for lone AF and relies on a lumped parameterization of the four heart chambers, together with the systemic and pulmonary circulation. The AF modelling involves: (i) irregular, uncorrelated and faster heart rate; (ii) atrial contractility dysfunction. Three different grades of severity (mild, moderate, severe) were analyzed for each of the four valvulopathies (AS, aortic stenosis, MS, mitral stenosis, AR, aortic regurgitation, MR, mitral regurgitation), by varying-through the valve opening angle-the valve area.ResultsRegurgitation was hemodynamically more relevant than stenosis, as the latter led to inefficient cardiac flow, while the former introduced more drastic fluid dynamics variation. Moreover, mitral valvulopathies were more significant than aortic ones. In case of aortic valve diseases, proper mitral functioning damps out changes at atrial and pulmonary levels. In the case of mitral valvulopathy, the mitral valve lost its regulating capability, thus hemodynamic variations almost equally affected regions upstream and downstream of the valve. In particular, the present study revealed that both mitral and aortic regurgitation strongly affect hemodynamics, followed by mitral stenosis, while aortic stenosis has the least impact among the analyzed valvular diseases.DiscussionThe proposed approach can provide new mechanistic insights as to which valvular pathologies merit more aggressive treatment of AF. Present findings, if clinically confirmed, hold the potential to impact AF management (e.g., adoption of a rhythm control strategy) in specific valvular diseases.

Project description:Introduction: Catheter ablation (CA) is a common treatment for atrial fibrillation (AF), but the knowledge of optimal ablation sites, and hence clinical outcomes, are suboptimal. Increasing evidence suggest that ablation strategies based on patient-specific substrates information, such as distributions of fibrosis and atrial wall thickness (AWT), may be used to improve therapy. We hypothesized that competing influences of large AWT gradients and fibrotic patches on conductive properties of atrial tissue can determine locations of re-entrant drivers (RDs) sustaining AF. Methods: Two sets of models were used: (1) a simple model of 3D atrial tissue slab with a step change in AWT and a synthetic fibrosis patch, and (2) 3D models based on patient-specific right atrial (RA) and left atrial (LA) geometries. The latter were obtained from four healthy volunteers and two AF patients, respectively, using magnetic resonance imaging (MRI). A synthetic fibrotic patch was added in the RA and fibrosis distributions in the LA were obtained from gadolinium-enhanced MRI of the same patients. In all models, 3D geometry was combined with the Fenton-Karma atrial cell model to simulate RDs. Results: In the slab, RDs drifted toward, and then along the AWT step. However, with additional fibrosis, the RDs were localized in regions between the step and fibrosis. In the RA, RDs drifted toward and anchored to a large AWT gradient between the crista terminalis (CT) region and the surrounding atrial wall. Without such a gradient, RDs drifted toward the superior vena cava (SVC) or the tricuspid valve (TSV). With additional fibrosis, RDs initiated away from the CT anchored to the fibrotic patch, whereas RDs initiated close to the CT region remained localized between the two structures. In the LA, AWT was more uniform and RDs drifted toward the pulmonary veins (PVs). However, with additional fibrotic patches, RDs either anchored to them or multiplied. Conclusion: In the RA, RD locations are determined by both fibrosis and AWT gradients at the CT region. In the LA, they are determined by fibrosis due to the absence of large AWT gradients. These results elucidate mechanisms behind the stabilization of RDs sustaining AF and can help guide ablation therapy.

Project description:ObjectivesThis study sought to improve atrial fibrillation (AF) driver identification by integrating clinical multielectrode mapping with driver fingerprints defined by high-resolution ex vivo 3-dimensional (3D) functional and structural imaging.BackgroundClinical multielectrode mapping of AF drivers suffers from variable contact, signal processing, and structural complexity within the 3D human atrial wall, raising questions on the validity of such drivers.MethodsSustained AF was mapped in coronary-perfused explanted human hearts (n = 11) with transmural near-infrared optical mapping (∼0.3 mm2 resolution). Simultaneously, custom FIRMap catheters (∼9 × 9 mm2 resolution) mapped endocardial and epicardial surfaces, which were analyzed by Focal Impulse and Rotor Mapping activation and Rotational Activity Profile (Abbott Labs, Chicago, Illinois). Functional maps were integrated with contrast-enhanced cardiac magnetic resonance imaging (∼0.1 mm3 resolution) analysis of 3D fibrosis architecture.ResultsDuring sustained AF, near-infrared optical mapping identified 1 to 2 intramural, spatially stable re-entrant AF drivers per heart. Driver targeted ablation affecting 2.2 ± 1.1% of the atrial surface terminated and prevented AF. Driver regions had significantly higher phase singularity density and dominant frequency than neighboring nondriver regions. Focal Impulse and Rotor Mapping had 80% sensitivity to near-infrared optical mapping-defined driver locations (16 of 20), and matched 14 of 20 driver visualizations: 10 of 14 re-entries seen with Rotational Activity Profile; and 4 of 6 breakthrough/focal patterns. Focal Impulse and Rotor Mapping detected 1.1 ± 0.9 false-positive rotational activity profiles per recording, but these regions had lower intramural contrast-enhanced cardiac magnetic resonance imaging fibrosis than did driver regions (14.9 ± 7.9% vs. 23.2 ± 10.5%; p < 0.005).ConclusionsThe study revealed that both re-entrant and breakthrough/focal AF driver patterns visualized by surface-only clinical multielectrodes can represent projections of 3D intramural microanatomic re-entries. Integration of multielectrode mapping and 3D fibrosis analysis may enhance AF driver detection, thereby improving the efficacy of driver-targeted ablation.

Project description:BackgroundAtrial cardiomyopathy (atCM) is an emerging prognostic factor in cardiovascular disease. Fibrotic remodeling, cardiomyocyte hypertrophy, and capillary density are hallmarks of atCM. The contribution of etiological factors and atrial fibrillation (AF) to the development of differential atCM phenotypes has not been quantified. This study aimed to evaluate the association between histological features of atCM and the clinical phenotype.Methods and resultsWe examined left atrial (LA, n=95) and right atrial (RA, n=76) appendages from a European cohort of patients undergoing cardiac surgery. Quantification of histological atCM features was performed following wheat germ agglutinin/CD31/vimentin staining. The contributions of AF, heart failure, sex, and age to histological characteristics were determined with multiple linear regression models. Persistent AF was associated with increased endomysial fibrosis (LA: +1.13±0.47 μm, P=0.038; RA: +0.94±0.38 μm, P=0.041), whereas total extracellular matrix content was not. Men had larger cardiomyocytes (LA: +1.92±0.72 μm, P<0.001), while women had more endomysial fibrosis (LA: +0.99±0.56 μm, P=0.003). Patients with heart failure showed more endomysial fibrosis (LA: +1.85±0.48 μm, P<0.001) and extracellular matrix content (LA: +3.07±1.29%, P=0.016), and a higher capillary density (LA: +0.13±0.06, P=0.007) and size (LA: +0.46±0.22 μm, P=0.044). Fuzzy k-means clustering of histological features identified 2 subtypes of atCM: 1 characterized by enhanced endomysial fibrosis (LA: +3.17 μm, P<0.001; RA: +2.86 μm, P<0.001), extracellular matrix content (LA: +3.53%, P<0.001; RA: +6.40%, P<0.001) and fibroblast density (LA: +4.38%, P<0.001), and 1 characterized by cardiomyocyte hypertrophy (LA: +1.16 μm, P=0.008; RA: +2.58 μm, P<0.001). Patients with fibrotic atCM were more frequently female (LA: odds ratio [OR], 1.33, P=0.002; RA: OR, 1.54, P=0.004), with persistent AF (LA: OR, 1.22, P=0.036) or heart failure (LA: OR, 1.62, P<0.001). Hypertrophic features were more common in men (LA: OR=1.33, P=0.002; RA: OR, 1.54, P=0.004).ConclusionsFibrotic atCM is associated with female sex, persistent AF, and heart failure, while hypertrophic features are more common in men.

Project description:BackgroundThere is debate whether human atrial fibrillation is driven by focal drivers or multiwavelet reentry. We propose that the changing activation sequences surrounding a focal driver can at times self-sustain in the absence of that driver. Further, the relationship between focal drivers and surrounding chaotic activation is bidirectional; focal drivers can generate chaotic activation, which may affect the dynamics of focal drivers.Methods and resultsIn a propagation model, we generated tissues that support structural micro-reentry and moving functional reentrant circuits. We qualitatively assessed (1) the tissue's ability to support self-sustaining fibrillation after elimination of the focal driver, (2) the impact that structural-reentrant substrate has on the duration of fibrillation, the impact that micro-reentrant (3) frequency, (4) excitable gap, and (5) exposure to surrounding fibrillation have on micro-reentry in the setting of chaotic activation, and finally the likelihood fibrillation will end in structural reentry based on (6) the distance between and (7) the relative lengths of an ablated tissue's inner and outer boundaries. We found (1) focal drivers produced chaotic activation when waves encountered heterogeneous refractoriness; chaotic activation could then repeatedly initiate and terminate micro-reentry. Perpetuation of fibrillation following elimination of micro-reentry was predicted by tissue properties. (2) Duration of fibrillation was increased by the presence of a structural micro-reentrant substrate only when surrounding tissue had a low propensity to support self-sustaining chaotic activation. Likelihood of micro-reentry around the structural reentrant substrate increased as (3) the frequency of structural reentry increased relative to the frequency of fibrillation in the surrounding tissue, (4) the excitable gap of micro-reentry increased, and (5) the exposure of the structural circuit to the surrounding tissue decreased. Likelihood of organized tachycardia following termination of fibrillation increased with (6) decreasing distance and (7) disparity of size between focal obstacle and external boundary.ConclusionFocal drivers such as structural micro-reentry and the chaotic activation they produce are continuously interacting with one another. In order to accurately describe cardiac tissue's propensity to support fibrillation, the relative characteristics of both stationary and moving drivers must be taken into account.

Project description:BackgroundA reduced left atrial (LA) strain correlates with the presence of atrial fibrillation (AF). Conventional atrial strain analysis uses two-dimensional (2D) imaging, which is, however, limited by atrial foreshortening and an underestimation of through-plane motion. Retrospective gated computed tomography (RGCT) produces high-fidelity three-dimensional (3D) images of the cardiac anatomy throughout the cardiac cycle that can be used for estimating 3D mechanics. Its feasibility for LA strain measurement, however, is understudied.AimThe aim of this study is to develop and apply a novel workflow to estimate 3D LA motion and calculate the strain from RGCT imaging. The utility of global and regional strains to separate heart failure in patients with reduced ejection fraction (HFrEF) with and without AF is investigated.MethodsA cohort of 30 HFrEF patients with (n = 9) and without (n = 21) AF underwent RGCT prior to cardiac resynchronisation therapy. The temporal sparse free form deformation image registration method was optimised for LA feature tracking in RGCT images and used to estimate 3D LA endocardial motion. The area and fibre reservoir strains were calculated over the LA body. Universal atrial coordinates and a human atrial fibre atlas enabled the regional strain calculation and the fibre strain calculation along the local myofibre orientation, respectively.ResultsIt was found that global reservoir strains were significantly reduced in the HFrEF + AF group patients compared with the HFrEF-only group patients (area strain: 11.2 ± 4.8% vs. 25.3 ± 12.6%, P = 0.001; fibre strain: 4.5 ± 2.0% vs. 15.2 ± 8.8%, P = 0.001), with HFrEF + AF patients having a greater regional reservoir strain dyssynchrony. All regional reservoir strains were reduced in the HFrEF + AF patient group, in whom the inferior wall strains exhibited the most significant differences. The global reservoir fibre strain and LA volume + posterior wall reservoir fibre strain exceeded LA volume alone and 2D global longitudinal strain (GLS) for AF classification (area-under-the-curve: global reservoir fibre strain: 0.94 ± 0.02, LA volume + posterior wall reservoir fibre strain: 0.95 ± 0.02, LA volume: 0.89 ± 0.03, 2D GLS: 0.90 ± 0.03).ConclusionRGCT enables 3D LA motion estimation and strain calculation that outperforms 2D strain metrics and LA enlargement for AF classification. Differences in regional LA strain could reflect regional myocardial properties such as atrial fibrosis burden.

Dataset Information

Three-dimensional Integrated Functional, Structural, and Computational Mapping to Define the Structural "Fingerprints" of Heart-Specific Atrial Fibrillation Drivers in Human Heart Ex Vivo.

Publications

Three-dimensional Integrated Functional, Structural, and Computational Mapping to Define the Structural "Fingerprints" of Heart-Specific Atrial Fibrillation Drivers in Human Heart Ex Vivo.

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