Quantitative assessment of transmural fibrosis profile in the human atrium: evidence for a three-dimensional arrhythmic substrate by slice-to-slice histology.

AIMS: Intramural fibrosis represents a crucial factor in the formation of a three-dimensional (3D) substrate for atrial fibrillation (AF). However, the transmural distribution of fibrosis and its relationship with atrial overload remain largely unknown. The aim of this study is to quantify the transmural profile of atrial fibrosis in patients with different degrees of atrial dilatation and arrhythmic profiles by a high-resolution 3D histology method. METHODS AND RESULTS: Serial microtome-cut tissue slices, sampling the entire atrial wall thickness at 5 µm spatial resolution, were obtained from right atrial appendage specimens in 23 cardiac surgery patients. Atrial slices were picrosirius red stained, imaged by polarized light microscopy, and analysed by a custom-made segmentation algorithm. In all patients, the intramural fibrosis content displayed a progressive decrease alongside tissue depth, passing from 68.6 ± 11.6% in the subepicardium to 10-13% in the subendocardium. Distinct transmural fibrotic profiles were observed in patients with atrial dilatation with respect to control patients, where the first showed a slower decrease of fibrosis along tissue depth (exponential decay constant: 171.2 ± 54.5 vs. 80.9 ± 24.4 µm, P < 0.005). Similar slow fibrotic profiles were observed in patients with AF (142.8 ± 41.7 µm). Subepicardial and midwall levels of fibrosis correlated with the degree of atrial dilatation (ρ = 0.72, P < 0.001), while no correlation was found in subendocardial layers. CONCLUSIONS: Quantification of fibrosis transmural profile at high resolution is feasible by slice-to-slice histology. Deeper penetration of fibrosis in subepicardial and midwall layers in dilated atria may concur to the formation of a 3D arrhythmic substrate.

Quantitative MRI T2 Mapping is Able to Assess Tissue Quality After Reparative and Regenerative Treatments of Osteochondral Lesions of the Talus.

BACKGROUND: Quantitative MRI has potential for tissue characterization after reparative and regenerative surgical treatment of osteochondral lesions of the talus (OCLTs). However available data is inconclusive and quantitative sequences can be difficult to implement in real-time clinical application. PURPOSE: To assess the potential of T2 mapping in discriminating articular tissue characteristics after reparative and regenerative surgery of OCLTs in real-world clinical settings. STUDY TYPE: Observational and prospective cohort study. POPULATION: 15 OCLT patients who had received either reparative treatment with arthroscopic microfracture surgery (MFS) for a grade I lesion or regenerative treatment with bone marrow derived cell transplantation (BMDCT) for a grade II lesion. FIELD STRENGTH/SEQUENCE: 1.5 T, proton density weighted TSE, T2-weighted true fast imaging with steady-state-free precession and multi-echo T2 mapping sequences. ASSESSMENT: Patients were evaluated at a minimum postoperative follow-up of 24 months. T2 maps of the ankle were generated and the distribution of T2 values was analyzed in manually identified volumes of interest (VOIs) for both treated lesions (TX) and healthy cartilage (CTRL). The amount of fibrocartilage, hyaline-like and remodeling tissue in TX VOIs was obtained, based on T2 thresholds from CTRL VOIs. STATISTICAL TESTS: Fisher's exact test for categorical data, nonparametric Mann-Whitney U test for continuous data. The statistical significance level was P < 0.05. RESULTS: From CTRL VOI analysis, T2 < 25 msec, 25 msec ≤ T2 ≤ 45 msec, and T2 > 45 msec were considered as representative for fibrocartilage, hyaline-like and remodeling tissue, respectively. Tissue composition of the two treatment groups was different, with significantly more fibrocartilage (+28%) and less hyaline-like tissue (-15%) in MFS than in BMDCT treated lesions. No difference in healthy tissue composition was found between the two groups (P = 0.75). DATA CONCLUSIONS: T2 mapping of surgically treated OCLTs can provide quantitative information about the type and amount of newly formed tissue at the lesion site, thereby facilitating surgical follow-up in a real-word clinical setting. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

Electroanatomic mapping and late gadolinium enhancement MRI in a genetic model of arrhythmogenic atrial cardiomyopathy.

INTRODUCTION: Although atrial arrhythmias may have genetic causes, very few data are available on evaluation of the arrhythmic substrate in genetic atrial diseases in humans. In this study, we evaluate the nature and evolution of the atrial arrhythmic substrate in a genetic atrial cardiomyopathy. METHODS AND RESULTS: Repeated electroanatomic mapping and tomographic evaluations were used to investigate the evolving arrhythmic substrate in 5 patients with isolated arrhythmogenic atrial cardiomyopathy, caused by Natriuretic Peptide Precursor A (NPPA) gene mutation. Atrial fibrosis was assessed using late gadolinium enhancement magnetic resonance imaging (LGE-MRI). The substrate of atrial tachycardia (AT) and atrial fibrillation (AF) was biatrial dilatation with patchy areas of low voltage and atrial wall scarring (in the right atrium: 68.5% ± 6.0% and 22.2% ± 10.2%, respectively). The evolution of the arrhythmic patterns to sinus node disease with atrial standstill (AS) was associated with giant atria with extensive low voltage and atrial scarring areas (in the right atrium: 99.5% ± 0.7% and 57.5% ± 33.2%, respectively). LGE-MRI-proven biatrial fibrosis (Utah stage IV) was associated with AS. Atrial conduction was slow and heterogeneous, with lines of conduction blocks. The progressive extension and spatial distribution of the scarring/fibrosis were strictly associated with the different types of arrhythmias. CONCLUSION: The evolution of the amount and distribution of atrial scarring/fibrosis constitutes the structural substrate for the different types of atrial arrhythmias in a pure genetic model of arrhythmogenic atrial cardiomyopathy.

Systematic in-silico evaluation of fibrosis effects on re-entrant wave dynamics in atrial tissue.

Despite the key role of fibrosis in atrial fibrillation (AF), the effects of different spatial distributions and textures of fibrosis on wave propagation mechanisms in AF are not fully understood. To clarify these aspects, we performed a systematic computational study to assess fibrosis effects on the characteristics and stability of re-entrant waves in electrically-remodelled atrial tissues. A stochastic algorithm, which generated fibrotic distributions with controlled overall amount, average size, and orientation of fibrosis elements, was implemented on a monolayer spheric atrial model. 245 simulations were run at changing fibrosis parameters. The emerging propagation patterns were quantified in terms of rate, regularity, and coupling by frequency-domain analysis of correspondent synthetic bipolar electrograms. At the increase of fibrosis amount, the rate of reentrant waves significantly decreased and higher levels of regularity and coupling were observed (p < 0.0001). Higher spatial variability and pattern stochasticity over repetitions was observed for larger amount of fibrosis, especially in the presence of patchy and compact fibrosis. Overall, propagation slowing and organization led to higher stability of re-entrant waves. These results strengthen the evidence that the amount and spatial distribution of fibrosis concur in dictating re-entry dynamics in remodeled tissue and represent key factors in AF maintenance.

A Simple Method to Quantify Outward Leakage of Medical Face Masks and Barrier Face Coverings: Implication for the Overall Filtration Efficiency.

Face masking proved essential to reduce transmission of COVID-19 and other respiratory infections in indoor environments, but standards and literature do not provide simple quantitative methods for quantifying air leakage at the face seal. This study reports an original method to quantify outward leakage and how wearing style impacts on leaks and filtration efficiency. The amount of air leakage was evaluated on four medical masks and four barrier face coverings, exploiting a theoretical model and an instrumented dummy head in a range of airflows between 30 and 160 L/min. The fraction of air leaking at the face seal of the medical masks and barrier face coverings ranged from 43% to 95% of exhaled air at 30 L/min and reduced to 10-85% at 160 L/min. Filter breathability was the main driver affecting both leak fraction and total filtration efficiency that varied from 5% to 53% and from 15% to 84% at 30 and 160 L/min, respectively. Minor changes were related to wearing style, supporting indications on the correct mask use. The fraction of air leaking from medical masks and barrier face coverings during exhalation is relevant and varies according to design and wearing style. The use of highly breathable filter materials reduces air leaks and improve total filtration efficiency.

Accuracy and Technical Predictability of Computer Guided Bone Harvesting from the Mandible: A Cone-Beam CT Analysis in 22 Consecutive Patients.

This study assesses the accuracy and technical predictability of a computer-guided procedure for harvesting bone from the external oblique ridge using a patient-specific cutting guide. Twenty-two patients needing bone augmentation for implant placement were subjected to mandibular osteotomy employing a case-specific stereolithographic surgical guide generated through computer aided design. Differences between planned and real cut planes were measured comparing pre- and post-operative Cone Beam Computed Tomography images of the donor site according to six validated angular and displacement indexes. Accuracy and technical predictability were assessed for 119 osteotomy planes over the study population. Three different guide fitting approaches were compared. An average root-mean-square discrepancy of 0.52 (0.30-0.97) mm was detected. The accuracy of apical and medial planes was higher than the mesial and distal planes due to occasional antero-posterior guide shift. Fitting the guide with an extra reference point on the closest tooth performed better than using only the bone surface, with two indexes significantly lower and less disperse. The study showed that the surgical plan was actualized with a 1 mm safety margin, allowing effective nerve preservation and reducing technical variability. When possible, surgical guide design should allow fitting on the closest tooth based on both radiological and/or intra-oral scan data.

A Divergence-Based Approach for the Identification of Atrial Fibrillation Focal Drivers From Multipolar Mapping: A Computational Study.

The expanding role of catheter ablation of atrial fibrillation (AF) has stimulated the development of novel mapping strategies to guide the procedure. We introduce a novel approach to characterize wave propagation and identify AF focal drivers from multipolar mapping data. The method reconstructs continuous activation patterns in the mapping area by a radial basis function (RBF) interpolation of multisite activation time series. Velocity vector fields are analytically determined, and the vector field divergence is used as a marker of focal drivers. The method was validated in a tissue patch cellular automaton model and in an anatomically realistic left atrial (LA) model with Courtemanche-Ramirez-Nattel ionic dynamics. Divergence analysis was effective in identifying focal drivers in a complex simulated AF pattern. Localization was reliable even with consistent reduction (47%) in the number of mapping points and in the presence of activation time misdetections (noise <10% of the cycle length). Proof-of-concept application of the method to human AF mapping data showed that divergence analysis consistently detected focal activation in the pulmonary veins and LA appendage area. These results suggest the potential of divergence analysis in combination with multipolar mapping to identify AF critical sites. Further studies on large clinical datasets may help to assess the clinical feasibility and benefit of divergence analysis for the optimization of ablation treatment.

A patient-specific mass-spring model for biomechanical simulation of aortic root tissue during transcatheter aortic valve implantation.

The success of transcatheter aortic valve implantation (TAVI) is highly dependent on the prediction of the interaction between the prosthesis and the aortic root anatomy. The simulation of the surgical procedure may be useful to guide artificial valve selection and delivery, nevertheless the introduction of simulation models into the clinical workflow is often hindered by model complexity and computational burden. To address this point, we introduced a patient-specific mass-spring model (MSM) with viscous damping, as a good trade-off between simulation accuracy and time-efficiency. The anatomical model consisted of a hexahedral mesh, segmented from pre-procedural patient-specific cardiac computer tomographic (CT) images of the aortic root, including valve leaflets and attached calcifications. Nodal forces were represented by linear-elastic springs acting on edges and angles. A fast integration approach based on the modulation of nodal masses was also tested. The model was validated on seven patients, comparing simulation results with post-procedural CT images with respect to calcification and aortic wall position. The validation showed that the MSM was able to predict calcification displacement with an average accuracy of 1.72 mm and 1.54 mm for the normal and fast integration approaches, respectively. Wall displacement root mean squared error after valve expansion was about 1 mm for both approaches, showing an improved matching with respect to the pre-procedural configuration. In terms of computational burden, the fast integration approach allowed a consistent reduction of the computational times, which decreased from 36 h to 21.8 min per 100 K hexahedra. Our findings suggest that the proposed linear-elastic MSM model may provide good accuracy and reduced computational times for TAVI simulations, fostering its inclusion in clinical routines.

Assessing the accuracy of computer-planned osteotomy guided by stereolithographic template: A methodological framework applied to the mandibular bone harvesting.

Intraoral autologous bone grafting represents a preferential choice for alveolar reconstruction prior to dental implant placement. Bone block harvesting guided by a computer-planned lithographic template is a novel and promising technique for optimizing the volume of harvested material, while controlling the osteotomy 3D position with respect to delicate anatomical structures. We provide a quantitative framework to non-invasively estimate the accuracy of this technique. In the proposed framework, the planned osteotomy geometry was compared to the real outcome of the procedure, obtained by segmentation of post-procedural cone beam computed tomography data. The comparison required the rigid registration between pre and post-procedural mandibular models, which was automatically accomplished by minimizing the sum of squared distances via a stochastic multi-trial iterative closest point algorithm. Bone harvesting accuracy was quantified by calculating a set of angular and displacement errors between the planned and real planes which characterized the excision block. The application of the framework to four cases showed its capability to quantify the tolerance associated with computer-guided bone harvesting techniques with submillimetric accuracy (<0.4 mm), within the limits of native image resolution. The validation methodology proved suitable for defining the safety margins of osteotomy surgical planning.

Isolation of the left atrial surface from cardiac multi-detector CT images based on marker controlled watershed segmentation.

The delineation of left atrium (LA) and pulmonary veins (PVs) anatomy from high resolution images holds importance for atrial fibrillation (AF) investigation and treatment. In this study, a semiautomatic segmentation procedure for LA and PVs inner surface from contrast enhanced CT data was developed. The procedure consists of a three dimensional marker controlled watershed segmentation applied to the external morphological gradient, followed by variable threshold surface extraction from the original intensity image. A preliminary anisotropic non-linear filtering was implemented to improve the S/N ratio of CT images. The performance of segmentation was evaluated on cardiac CT scans of 12 AF patients both qualitatively and quantitatively. The qualitative evaluation by expert radiologist assessed the segmentation as overall successful in all patients and capable of extracting both the LA body and the connected vascular trees. The quantitative validation, by computing discrepancy measures with respect to a manually segmented gold standard, indicated an average of about 90% of voxels correctly classified and an average border mismatch lower than 1.5 voxels (1.2 mm). The accurate extraction of the inner LA-PVs walls provided by this method, along with the minimal required human intervention, should facilitate the use of anatomical atrial models for the non-pharmacological treatment of AF.

A stochastic approach for automatic registration and fusion of left atrial electroanatomic maps with 3D CT anatomical images.

The integration of electroanatomic maps with highly resolved computed tomography cardiac images plays an important role in the successful planning of the ablation procedure of arrhythmias. In this paper, we present and validate a fully-automated strategy for the registration and fusion of sparse, atrial endocardial electroanatomic maps (CARTO maps) with detailed left atrial (LA) anatomical reconstructions segmented from a pre-procedural MDCT scan. Registration is accomplished by a parameterized geometric transformation of the CARTO points and by a stochastic search of the best parameter set which minimizes the misalignment between transformed CARTO points and the LA surface. The subsequent fusion of electrophysiological information on the registered CT atrium is obtained through radial basis function interpolation. The algorithm is validated by simulation and by real data from 14 patients referred to CT imaging prior to the ablation procedure. Results are presented, which show the validity of the algorithmic scheme as well as the accuracy and reproducibility of the integration process. The obtained results encourage the application of the integration method in post-intervention ablation assessment and basic AF research and suggest the development for real-time applications in catheter guiding during ablation intervention.

A Multi-Variate Predictability Framework to Assess Invasive Cardiac Activity and Interactions During Atrial Fibrillation.

OBJECTIVE: This study introduces a predictability framework based on the concept of Granger causality (GC), in order to analyze the activity and interactions between different intracardiac sites during atrial fibrillation (AF). METHODS: GC-based interactions were studied using a three-electrode analysis scheme with multi-variate autoregressive models of the involved preprocessed intracardiac signals. The method was evaluated in different scenarios covering simulations of complex atrial activity as well as endocardial signals acquired from patients. RESULTS: The results illustrate the ability of the method to determine atrial rhythm complexity and to track and map propagation during AF. CONCLUSION: The proposed framework provides information on the underlying activation and regularity, does not require activation detection or postprocessing algorithms and is applicable for the analysis of any multielectrode catheter. SIGNIFICANCE: The proposed framework can potentially help to guide catheter ablation interventions of AF.

Atrial fibrillation and NPPA gene p.S64R mutation: are cardiologists helpless spectators of healthy mutation carriers?

AIMS: Heterozygous p.(Ser64Arg) mutation in the natriuretic peptide precursor A gene has been associated with atrial fibrillation in the presence of common single nucleotide polymorphisms (rs10033464 and rs2200733; 4q25) that would act as modifiers. METHODS: We screened natriuretic peptide precursor A gene in 583 individuals and identified three unrelated carriers of the p.(Ser64Arg) mutation (0.5%). RESULTS: Only one of the three mutation carriers had episodes of atrial fibrillation. Cascade screening of the three families identified seven additional mutation carriers, none showing atrial fibrillation. The patients with atrial fibrillation also carried the rs2200733, which was however found in four additional nonatrial fibrillation family members and carriers of the p.(Ser64Arg). The prevalence of atrial fibrillation in p.(Ser64Arg) carriers was 10% and in those combining the mutation with the risk single nucleotide polymorphisms was 20%. In the unique mutated patient with atrial fibrillation, the arrhythmias was refractory to both pharmacological and ablation treatment, during 16 years of follow-up; his electrophysiological phenotype was characterized by short atrial cycle lengths with a median value of 131 ms that suggests shortening of atrial action potential. CONCLUSION: The prevalence of p.(Ser64Arg) mutation is low in the general population as is the prevalence of atrial fibrillation in mutation carriers (1/10). Atrial fibrillation in the affected mutated patient was lone at onset and progressively evolved with peculiar electrophysiological patterns.

A spectral approach for the quantitative description of cardiac collagen network from nonlinear optical imaging.

The assessment of collagen structure in cardiac pathology, such as atrial fibrillation (AF), is essential for a complete understanding of the disease. This paper introduces a novel methodology for the quantitative description of collagen network properties, based on the combination of nonlinear optical microscopy with a spectral approach of image processing and analysis. Second-harmonic generation (SHG) microscopy was applied to atrial tissue samples from cardiac surgery patients, providing label-free, selective visualization of the collagen structure. The spectral analysis framework, based on 2D-FFT, was applied to the SHG images, yielding a multiparametric description of collagen fiber orientation (angle and anisotropy indexes) and texture scale (dominant wavelength and peak dispersion indexes). The proof-of-concept application of the methodology showed the capability of our approach to detect and quantify differences in the structural properties of the collagen network in AF versus sinus rhythm patients. These results suggest the potential of our approach in the assessment of collagen properties in cardiac pathologies related to a fibrotic structural component.

The logical operator map identifies novel candidate markers for critical sites in patients with atrial fibrillation.

The identification of suitable markers for critical patterns during atrial fibrillation (AF) may be crucial to guide an effective ablation treatment. Single parameter maps, based on dominant frequency and complex fractionated electrograms, have been proposed as a tool for electrogram-guided ablation, however the specificity of these markers is debated. Experimental studies suggest that AF critical patterns may be identified on the basis of specific rate and organization features, where rapid organized and rapid fragmented activities characterize respectively localized sources and critical substrates. In this paper we introduce the logical operator map, a novel mapping tool for a point-by-point identification and localization of AF critical sites. Based on advanced signal and image processing techniques, the approach combines in a single map electrogram-derived rate and organization features with tomographic anatomical detail. The construction of the anatomically-detailed logical operator map is based on the time-domain estimation of atrial rate and organization in terms of cycle length and wave-similarity, the logical combination of these indexes to obtain suitable markers of critical sites, and the multimodal integration of electrophysiological and anatomical information by segmentation and registration techniques. Logical operator maps were constructed in 14 patients with persistent AF, showing the capability of the combined rate and organization markers to identify with high selectivity the subset of electrograms associated with localized sources and critical substrates. The precise anatomical localization of these critical sites revealed the confinement of rapid organized sources in the left atrium with organization and rate gradients towards the surrounding tissue, and the presence of rapid fragmented electrograms in proximity of the sources. By merging in a single map the most relevant electrophysiological and anatomical features of the AF process, the logical operator map may have significant clinical impact as a direct, comprehensive tool to understand arrhythmia mechanisms in the single patient and guide more conservative, step-wise ablation.

A fully adaptive multiresolution algorithm for atrial arrhythmia simulation on anatomically realistic unstructured meshes.

Biophysically detailed and anatomically realistic atrial models are emerging as a valuable tool in the study of atrial arrhythmias, nevertheless clinical use of these models would be favored by a reduction of computational times. This paper introduces a novel adaptive mesh algorithm, based on multiresolution representation (MR), for the efficient integration of cardiac ordinary differential equation (ODE)-partial differential equation (PDE) systems on unstructured triangle meshes. The algorithm applies a dynamically adapted node-centered finite volume method (FVM) scheme for integration of diffusion. The method accuracy and efficiency were evaluated by simulating propagation scenarios of increasing complexity levels (pacing, stable spirals, atrial fibrillation) on tomography-derived three-dimensional monolayer atrial models, based on a monodomain reaction-diffusion formulation coupled with the Courtemanche atrial ionic model. All simulated propagation patterns were accurately reproduced with substantially reduced computational times (10%-30% of the full-resolution simulation time). The proposed algorithm, combining the MR computational efficiency with the geometrical flexibility of unstructured meshes, may favor the development of patient-specific multiscale models of atrial arrhythmias and their application in the clinical setting.

Anatomic localization of rapid repetitive sources in persistent atrial fibrillation: fusion of biatrial CT images with wave similarity/cycle length maps.

OBJECTIVES: The aim of this study was to investigate the anatomic distribution of critical sources in patients with atrial fibrillation (AF) by fusion of biatrial computed tomography (CT) images with cycle length (CL) and wave similarity (WS) maps. BACKGROUND: Experimental and clinical studies show that atrial fibrillation (AF) may originate from rapid and repetitive (RR) sources of activation. Localization of RR sources may be crucial for an effective ablation treatment. Atrial electrograms showing rapid and repetitive activations can be identified by combining WS and CL analysis. METHODS: Patients with persistent AF underwent biatrial electroanatomic mapping and pre-procedural CT cardiac imaging. WS and CL maps were constructed in 17 patients by calculating the degree of repetitiveness of activation waveforms (similarity index [S]) and the cycle length at each atrial site. WS/CL maps were then integrated with biatrial 3-dimensional CT reconstructions by a stochastic approach. RESULTS: Repetitive sources of activation (S ≥ 0.5) were present in most patients with persistent AF (94%) and were mainly located at the pulmonary veins (82% of patients), at the superior caval vein (41%), on the anterior wall of the right atrium (23%), and at the left atrial appendage (23%). Potential driver sources showing both rapid and repetitive activations (CL = 140.7 ± 25.1 ms, S = 0.65 ± 0.15) were present only in a subset of patients (65%) and were confined to the pulmonary vein region (47% of patients) and left atrial appendage (12%). Differently, the repetitive activity of the superior caval vein was characterized by a slow activation rate (CL = 184.7 ± 14.6 ms). CONCLUSIONS: The identification and localization of RR sources is feasible by fusion of biatrial anatomic images with WS/CL maps. Potential driver sources are present only in a subset of patients with persistent AF and are mainly located in the pulmonary vein region.

A novel approach to propagation pattern analysis in intracardiac atrial fibrillation signals.

The purpose of this study is to investigate propagation patterns in intracardiac signals recorded during atrial fibrillation (AF) using an approach based on partial directed coherence (PDC), which evaluates directional coupling between multiple signals in the frequency domain. The PDC is evaluated at the dominant frequency of AF signals and tested for significance using a surrogate data procedure specifically designed to assess causality. For significantly coupled sites, the approach allows also to estimate the delay in propagation. The methods potential is illustrated with two simulation scenarios based on a detailed ionic model of the human atrial myocyte as well as with real data recordings, selected to present typical propagation mechanisms and recording situations in atrial tachyarrhythmias. In both simulation scenarios the significant PDCs correctly reflect the direction of coupling and thus the propagation between all recording sites. In the real data recordings, clear propagation patterns are identified which agree with previous clinical observations. Thus, the results illustrate the ability of the novel approach to identify propagation patterns from intracardiac signals during AF, which can provide important information about the underlying AF mechanisms, potentially improving the planning and outcome of arrhythmia ablation.