A detailed mathematical model of the human atrial cardiomyocyte: integration of electrophysiology and cardiomechanics.

Mechano-electric regulations (MER) play an important role in the maintenance of cardiac performance. Mechano-calcium and mechano-electric feedback (MCF and MEF) pathways adjust the cardiomyocyte contractile force according to mechanical perturbations and affects electro-mechanical coupling. MER integrates all these regulations in one unit resulting in a complex phenomenon. Computational modelling is a useful tool to accelerate the mechanistic understanding of complex experimental phenomena. We have developed a novel model that integrates the MER loop for human atrial cardiomyocytes with proper consideration of feedforward and feedback pathways. The model couples a modified version of the action potential (AP) Koivumäki model with the contraction model by Quarteroni group. The model simulates iso-sarcometric and isometric twitches and the feedback effects on AP and Ca2+ -handling. The model showed a biphasic response of Ca2+ transient (CaT) peak to increasing pacing rates and highlights the possible mechanisms involved. The model has shown a shift of the threshold for AP and CaT alternans from 4.6 to 4 Hz under post-operative atrial fibrillation, induced by depressed SERCA activity. The alternans incidence was dependent on a chain of mechanisms including RyRs availability time, MCF coupling, CaMKII phosphorylation, and the stretch levels. As a result, the model predicted a 10% slowdown of conduction velocity for a 20% stretch, suggesting a role of stretch in creation of substrate formation for atrial fibrillation. Overall, we conclude that the developed model provides a physiological CaT followed by a physiological twitch. This model can open pathways for the future studies of human atrial electromechanics. KEY POINTS: With the availability of human atrial cellular data, interest in atrial-specific model integration has been enhanced. We have developed a detailed mathematical model of human atrial cardiomyocytes including the mechano-electric regulatory loop. The model has gone through calibration and evaluation phases against a wide collection of available human in-vitro data. The usefulness of the model for analysing clinical problems has been preliminaryly tested by simulating the increased incidence of Ca2+ transient and action potential alternans at high rates in post-operative atrial fibrillation condition. The model determines the possible role of mechano-electric feedback in alternans incidence, which can increase vulnerability to atrial arrhythmias by varying stretch levels. We found that our physiologically accurate description of Ca2+ handling can reproduce many experimental phenomena and can help to gain insights into the underlying pathophysiological mechanisms.

A Proof of Concept for Computational Fluid Dynamic Analysis of the Left Atrium in Atrial Fibrillation on a Patient-Specific Basis.

Atrial fibrillation (AF) is associated with a fivefold increase in the risk of cerebrovascular events, being responsible of 15-18% of all strokes. The morphological and functional remodeling of the left atrium (LA) caused by AF favors blood stasis and, consequently, stroke risk. In this context, several clinical studies suggest that the stroke risk stratification could be improved by using hemodynamic information on the LA and the left atrial appendage (LAA). The goal of this study was to develop a personalized computational fluid dynamics (CFD) model of the LA which could clarify the hemodynamic implications of AF on a patient-specific basis. In this paper, we present the developed model and its application to two AF patients as a preliminary advancement toward an optimized stroke risk stratification pipeline.

A Review of the Imaging Techniques for Measuring Kidney and Cyst Volume in Establishing Autosomal Dominant Polycystic Kidney Disease Progression.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the commonest inherited renal disorder; it is defined by progressive renal cyst formation and subsequent renal enlargement that leads to end-stage renal disease. Until recently, only symptomatic treatments for ADPKD existed. However, therapies that address the underlying pathophysiology of ADPKD are now available and accurate identification of the rate of disease progression is essential. SUMMARY: Published data on the different imaging modalities for measuring kidney and cyst volumes in ADPKD are reviewed. The advantages and drawbacks of the different techniques for calculating kidney volume from renal imaging are also examined, including the use of manual planimetry, stereology, and the ellipsoid equation, as well as the prospect of semi- and fully automatic techniques. The translation of these approaches into clinical practice and their role in informing treatment decisions is discussed. Key Messages: These new therapies require the accurate monitoring of disease progression, which along with diagnosis and prognosis, relies on the effective use of renal imaging techniques. There is growing support for the use of total kidney volume as a measure of cyst burden and as a prognostic predictor of renal function in ADPKD, showing promise as a marker of disease progression.

Heart-Brain Interactions in the MR Environment: Characterization of the Ballistocardiogram in EEG Signals Collected During Simultaneous fMRI.

The ballistocardiographic (BCG) artifact is linked to cardiac activity and occurs in electroencephalographic (EEG) recordings acquired inside the magnetic resonance (MR) environment. Its variability in terms of amplitude, waveform shape and spatial distribution over subject's scalp makes its attenuation a challenging task. In this study, we aimed to provide a detailed characterization of the BCG properties, including its temporal dependency on cardiac events and its spatio-temporal dynamics. To this end, we used high-density EEG data acquired during simultaneous functional MR imaging in six healthy volunteers. First, we investigated the relationship between cardiac activity and BCG occurrences in the EEG recordings. We observed large variability in the delay between ECG and subsequent BCG events (ECG-BCG delay) across subjects and non-negligible epoch-by-epoch variations at the single subject level. The inspection of spatial-temporal variations revealed a prominent non-stationarity of the BCG signal. We identified five main BCG waves, which were common across subjects. Principal component analysis revealed two spatially distinct patterns to explain most of the variance (85% in total). These components are possibly related to head rotation and pulse-driven scalp expansion, respectively. Our results may inspire the development of novel, more effective methods for the removal of the BCG, capable of isolating and attenuating artifact occurrences while preserving true neuronal activity.

Comparison of Total Kidney Volume Quantification Methods in Autosomal Dominant Polycystic Disease for a Comprehensive Disease Assessment.

BACKGROUND: In recent times, the scientific community has been showing increasing interest in the treatments aimed at slowing the progression of the autosomal dominant polycystic kidney disease (ADPKD). Therefore, in this paper, we test and evaluate the performance of several available methods for total kidney volume (TKV) computation in ADPKD patients - from echography to MRI - in order to optimize patient classification. METHODS: Two methods based on geometric assumptions (mid-slice [MS], ellipsoid [EL]) and a third one on true contour detection were tested on 40 ADPKD patients at different disease stage using MRI. The EL method was also tested using ultrasound images in a subset of 14 patients. Their performance was compared against TKVs derived from reference manual segmentation of MR images. Patient clinical classification was also performed based on computed volumes. RESULTS: Kidney volumes derived from echography significantly underestimated reference volumes. Geometric-based methods applied to MR images had similar acceptable results. The highly automated method showed better performance. Volume assessment was accurate and reproducible. Importantly, classification resulted in 79, 13, 10, and 2.5% of misclassification using kidney volumes obtained from echo and MRI applying the EL, the MS and the highly automated method respectively. CONCLUSION: Considering the fact that the image-based technique is the only approach providing a 3D patient-specific kidney model and allowing further analysis including cyst volume computation and monitoring disease progression, we suggest that geometric assumption (e.g., EL method) should be avoided. The contour-detection approach should be used for a reproducible and precise morphologic classification of the renal volume of ADPKD patients.

Patient-specific left atrium contraction quantification associated with atrial fibrillation: A region-based approach.

BACKGROUND AND OBJECTIVES: Atrial fibrillation (AF) is a widespread cardiac arrhythmia that significantly impacts heart function. AF disrupts atrial mechanical contraction, leading to irregular, uncoordinated, and slow blood flow inside the atria which favors the formation of clots, primarily within the left atrium (LA). A standardized region-based analysis of the LA is missing, and there is not even any consensus about how to define the LA regions. In this study we propose an automatic approach for regionalizing the LA into segments to provide a comprehensive 3D region-based LA contraction assessment. LA global and regional contraction were quantified in control subjects and in AF patients to describe mechanical abnormalities associated with AF. METHODS: The proposed automatic approach for LA regionalization was tested in thirteen control subjects and seventeen AF patients. After dividing LA into standard regions, we evaluated the global and regional mechanical function by measuring LA contraction parameters, such as regional volume, global and regional strains, regional wall motion and regional shortening fraction. RESULTS: LA regionalization was successful in all study subjects. In the AF group compared with control subjects, results showed: a global impairment of LA contraction which appeared more pronounced along radial and circumferential direction; a regional impairment of radial strain which was more pronounced in septal, inferior, and lateral regions suggesting a greater reduction in mechanical efficiency in these regions in comparison to the posterior and anterior ones. CONCLUSION: An automatic approach for LA regionalization was proposed. The regionalization method was proved to be robust with several LA anatomical variations and able to characterize contraction changes associated with AF.

Preliminary findings on left atrial appendage occlusion simulations applying different endocardial devices.

Atrial fibrillation (AF) is one of the most investigated arrhythmias since it is associated with a five-fold increase in the risk of strokes. Left atrium dilation and unbalanced and irregular contraction caused by AF favour blood stasis and, consequently, stroke risk. The left atrial appendage (LAA) is the site of the highest clots formation, increasing the incidence of stroke in AF population. For many years oral anticoagulation therapy has been the most used AF treatment option available to decrease stroke risk. Unfortunately, several contraindications including bleeding risk increase, interference with other drugs and with multiorgan functioning, might outweigh its remarkable benefits on thromboembolic events. For these reasons, in recent years, other approaches have been designed, including LAA percutaneous closure. Unfortunately, nowadays, LAA occlusion (LAAO) is restricted to small subgroups of patients and require a certain level of expertise and training to successfully complete the procedure without complications. The most critical clinical problems associated with LAAO are represented by peri-device leaks and device related thrombus (DRT). The anatomical variability of the LAA plays a key role in the choice of the correct LAA occlusion device and in its correct positioning with respect to the LAA ostium during the implant. In this scenario, computational fluid dynamics (CFD) simulations could have a crucial role in improving LAAO intervention. The aim of this study was to simulate the fluid dynamics effects of LAAO in AF patients to predict hemodynamic changes due to the occlusion. LAAO was simulated by applying two different types of closure devices based on the plug and the pacifier principles on 3D LA anatomical models derived from real clinical data in five AF patients. CFD simulations were performed on the left atrium model before and after the LAAO intervention with each device. Blood velocity, particle washout and endothelial damage were computed to quantify flow pattern changes after the occlusion in relation to the thrombogenic risk. Our preliminary results confirmed an improved blood washout after the simulated implants and the capability of foreseeing thrombogenic risk based on endothelial damage and maximum blood velocities in different scenarios. This tool may help to identify effective device configurations in limiting stroke risk for patient-specific LA morphologies.

Myocardial perfusion: near-automated evaluation from contrast-enhanced MR images obtained at rest and during vasodilator stress.

PURPOSE: To develop and validate a technique for near-automated definition of myocardial regions of interest suitable for perfusion evaluation during vasodilator stress cardiac magnetic resonance (MR) imaging. MATERIALS AND METHODS: The institutional review board approved the study protocol, and all patients provided informed consent. Image noise density distribution was used as a basis for endocardial and epicardial border detection combined with nonrigid registration. This method was tested in 42 patients undergoing contrast material-enhanced cardiac MR imaging (at 1.5 T) at rest and during vasodilator (adenosine or regadenoson) stress, including 15 subjects with normal myocardial perfusion and 27 patients referred for coronary angiography. Contrast enhancement-time curves were near-automatically generated and were used to calculate perfusion indexes. The results were compared with results of conventional manual analysis, using quantitative coronary angiography results as a reference for stenosis greater than 50%. Statistical analyses included the Student t test, linear regression, Bland-Altman analysis, and κ statistics. RESULTS: Analysis of one sequence required less than 1 minute and resulted in high-quality contrast enhancement curves both at rest and stress (mean signal-to-noise ratios, 17±7 [standard deviation] and 22±8, respectively), showing expected patterns of first-pass perfusion. Perfusion indexes accurately depicted stress-induced hyperemia (increased upslope, from 6.7 sec(-1)±2.3 to 15.6 sec(-1)±5.9; P<.0001). Measured segmental pixel intensities correlated highly with results of manual analysis (r=0.95). The derived perfusion indexes also correlated highly with (r up to 0.94) and showed the same diagnostic accuracy as manual analysis (area under the receiver operating characteristic curve, up to 0.72 vs 0.73). CONCLUSION: Despite the dynamic nature of contrast-enhanced image sequences and respiratory motion, fast near-automated detection of myocardial segments and accurate quantification of tissue contrast is feasible at rest and during vasodilator stress. This technique, shown to be as accurate as conventional manual analysis, allows detection of stress-induced perfusion abnormalities.

Indocyanine green fluorescence angiography after full-thickness bowel resection for rectosigmoid endometriosis: A multicentric experience with quantitative analysis.

OBJECTIVE: To evaluate effectiveness and reproducibility of qualitative and quantitative near-infrared indocyanine green (NIR-ICG) analyses as a tool for anastomotic perfusion assessment after full-thickness bowel resection for rectosigmoid endometriosis (RSE). METHODS: Symptomatic women with RSE undergoing minimally invasive full-thickness surgical excision of RSE and NIR-ICG evaluation from November 2019 to July 2020 were included. Study outcomes were the accuracy of qualitative and quantitative NIR-ICG analyses in predicting bowel fistula and their reproducibility. NIR-ICG predictive accuracy was assessed by calculating sensitivity, specificity, and area under the curve on receiver operating characteristic curves with 95% confidence intervals (CI). NIR-ICG reproducibility was assessed through Cohen's k coefficient to determine interoperator agreement between two observers. RESULTS: Of 33 patients, 2 (6%) developed bowel fistula. In predicting bowel fistula, qualitative and quantitative NIR-ICG evaluations showed sensitivity of 100% and 100%, specificity of 71% and 93%, and area under the curve of 0.86 (95% CI 0.67-1.00) and 0.96 (95% CI 0-1.00), respectively. Regarding interoperator agreement rate, it was reported as excellent for the qualitative analysis and very good for the quantitative analysis. CONCLUSION: Qualitative and quantitative NIR-ICG evaluations might be effective and reproducible tools for anastomotic perfusion assessment after discoid or segmental resection for RSE. Quantitative evaluation might be even more effective than qualitative evaluation in predicting bowel fistula.

Assessment of kidney volume in polycystic kidney disease using magnetic resonance imaging without contrast medium.

BACKGROUND/AIMS: Total renal volume (TRV) is an important index to evaluate the progression of autosomal-dominant polycystic kidney disease (ADPKD). TRV has been assessed by manually tracing renal contours from CT or MR scans, often employing contrast medium (CM). We developed a fast and nearly automated technique based on the analysis of MR images acquired without CM injection for TRV quantification. METHODS: 30 ADPKD patients underwent MRI. After the selection of one point inside each kidney for the entire volume, the automatic extraction of kidney contours was performed on each acquired slice; the segmentation procedure was based on region growing and on the application of morphological operators and curvature-based motion. The area inside each contour was calculated and TRV was derived. Volume measurements were validated by comparison with measurements obtained by stereology. RESULTS: TRV estimated in patients was 768 ± 545 ml (range 161-3,111 ml). The automatic measurements were in excellent correlation with the manual ones (r = 0.99, y = x - 0.7), with a small bias and narrow limits of agreement in both absolute (-5 ± 37 ml) and percentage (-0.6 ± 9.6%) terms. CONCLUSION: This preliminary study showed the feasibility of a fast and nearly automated method for determining TRV; importantly it does not require the use of potentially nephrotoxic CM.

Quantification of mitral annulus dynamic morphology in patients with mitral valve prolapse undergoing repair and annuloplasty during a 6-month follow-up.

AIMS: Mitral valve (MV) repair is the preferred treatment for mitral regurgitation associated with organic MV prolapse (MVP). Our goals were to describe by transthoracic real-time 3D echocardiography (RT3D TTE) the pre-operative changes in mitral annulus (MA) dynamic morphology related to MVP, compared with a normal population, and to evaluate the differential long-term effects induced by annuloplasty, using either an incomplete flexible band or a complete semi-rigid ring. METHODS AND RESULTS: Forty-four patients (62 ± 11 years) with organic MVP and ejection fraction >55% were studied by RT3D TTE the day before MV repair, and 3 and 6 months after (23 patients received a complete rigid ring-CAR, 21 an incomplete flexible band-COS). An age-matched group of 20 normal subjects (57 ± 9 years) was studied as control. After initialization, the MA was tracked frame-by-frame in 3D, and several parameters computed. Differences in MVP vs. controls, vs. pre-surgery, and between rings were tested (P < 0.05). MVP showed enlarged MA resulting in greater area and height during the cardiac cycle, with reduced planarity compared with controls. Annuloplasty resulted in reduced MA area in both CAR and COS, with minimal area change, and planar shape (more evident in CAR than COS). CONCLUSION: The main factor affecting MA function after annuloplasty appears to be the undersizing of the MA dimensions, and not the choice of the ring. This methodology could represent the basis for further evaluation of implanted rings, to provide the surgeon with additional information to be used in the pre-surgical planning and ring selection.

Computational Analysis of Mapping Catheter Geometry and Contact Quality Effects on Rotor Detection in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and catheter mapping has been proved to be an effective approach for detecting AF drivers to be targeted by ablation. Among drivers, the so-called rotors have gained the most attention: their identification and spatial location could help to understand which patient-specific mechanisms are acting, and thus to guide the ablation execution. Since rotor detection by multi-electrode catheters may be influenced by several structural parameters including inter-electrode spacing, catheter coverage, and endocardium-catheter distance, in this study we proposed a tool for testing the ability of different catheter shapes to detect rotors in different conditions. An approach based on the solution of the monodomain equations coupled with a modified Courtemanche ionic atrial model, that considers an electrical remodeling, was applied to simulate spiral wave dynamics on a 2D model for 7.75 s. The developed framework allowed the acquisition of unipolar signals at 2 KHz. Two high-density multipolar catheters were simulated (Advisor™ HD Grid and PentaRay®) and placed in a 2D region in which the simulated spiral wave persists longer. The configuration of the catheters was then modified by changing the number of electrodes, inter-electrodes distance, position, and atrial-wall distance for assessing how they would affect the rotor detection. In contact with the wall and at 1 mm distance from it, all the configurations detected the rotor correctly, irrespective of geometry, coverage, and inter-electrode distance. In the HDGrid-like geometry, the increase of the inter-electrode distance from 3 to 6 mm caused rotor detection failure at 2 mm distance from the LA wall. In the PentaRay-like configuration, regardless of inter-electrode distance, rotor detection failed at 3 mm endocardium-catheter distance. The asymmetry of this catheter resulted in rotation-dependent rotor detection. To conclude, the computational framework we developed is based on realistic catheter shapes designed with parameter configurations which resemble clinical settings. Results showed it is well suited to investigate how mapping catheter geometry and location affect AF driver detection, therefore it is a reliable tool to design and test new mapping catheters.

Impedance mapping with constant contact force on 3D electroanatomic map to characterize tissues at pulmonary veno-atrial junction.

PURPOSE: Generator impedance (Im) mapping with constant contact force (CF) by tip catheter at PV isolation (PVI) was assessed for a proposal of tissue characterization at PV-LA junction (PV-LAJ). METHODS: In this observational, prospective, single-center study, Im mapping at constant CF = 10 g (± 2 g) was performed before PVI at PV-LAJ. PV in-vein, PV ostium (PVos), and antrum (PVan) contours were manually traced based on the 3D electroanatomic map (3DEAM) integrating intracardiac echocardiography and computerized tomography. PVan contour-methods based on Im mapping was defined on 3DEAM as the atrial-like Im contour closest to PVos, and its distance from anatomical PVan contour > 5 mm was assumed as the non-concordance marker between contour and methods. RESULTS: Sixty-two patients (62 ± 9 years; 43 males) were enrolled, and 244 PV-LAJ were assessed. From in-vein PV to LA and, less prominently, from PVos to PVan and LA, Im showed a unidirectional decrease with highly variable individual-specific distribution and values. PVan non-concordance was found in 59/665 segments (8.8%), 18% of PV-LAJs, and 53% of pts; it prevailed in superior PV-LAJ and measured on average 7.2 ± 1.1 mm. Im decrease patterns and non-concordance were not associated with any clinical or anatomical feature, including PV dimensions and shape. CONCLUSIONS: Im mapping of LA-PVJ at constant CF added to 3DEAM may consistently track the tissue transition from PV to LA. PVan identified by Im was often located more toward LA than the 3D anatomical PVan, particularly in LSPV, suggesting the potential advantage of avoiding ablation of venous-like tissue. Im mapping can deserve further investigation for target characterization at LA-PVJ.

A global benchmark of algorithms for segmenting the left atrium from late gadolinium-enhanced cardiac magnetic resonance imaging.

Segmentation of medical images, particularly late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) used for visualizing diseased atrial structures, is a crucial first step for ablation treatment of atrial fibrillation. However, direct segmentation of LGE-MRIs is challenging due to the varying intensities caused by contrast agents. Since most clinical studies have relied on manual, labor-intensive approaches, automatic methods are of high interest, particularly optimized machine learning approaches. To address this, we organized the 2018 Left Atrium Segmentation Challenge using 154 3D LGE-MRIs, currently the world's largest atrial LGE-MRI dataset, and associated labels of the left atrium segmented by three medical experts, ultimately attracting the participation of 27 international teams. In this paper, extensive analysis of the submitted algorithms using technical and biological metrics was performed by undergoing subgroup analysis and conducting hyper-parameter analysis, offering an overall picture of the major design choices of convolutional neural networks (CNNs) and practical considerations for achieving state-of-the-art left atrium segmentation. Results show that the top method achieved a Dice score of 93.2% and a mean surface to surface distance of 0.7 mm, significantly outperforming prior state-of-the-art. Particularly, our analysis demonstrated that double sequentially used CNNs, in which a first CNN is used for automatic region-of-interest localization and a subsequent CNN is used for refined regional segmentation, achieved superior results than traditional methods and machine learning approaches containing single CNNs. This large-scale benchmarking study makes a significant step towards much-improved segmentation methods for atrial LGE-MRIs, and will serve as an important benchmark for evaluating and comparing the future works in the field. Furthermore, the findings from this study can potentially be extended to other imaging datasets and modalities, having an impact on the wider medical imaging community.

Volumetric quantification of myocardial perfusion using analysis of multi-detector computed tomography 3D datasets: comparison with nuclear perfusion imaging.

BACKGROUND: Although the ability of multi-detector computed tomography (MDCT) to detect perfusion abnormalities associated with acute and chronic myocardial infarction (MI) has been demonstrated, this methodology is based on visual interpretation of selected 2D slices. OBJECTIVES: We sought to develop a new technique for quantitative volumetric analysis of myocardial perfusion from 3D datasets and test it against resting nuclear myocardial perfusion imaging (NMPI) reference. METHODS: We studied 44 patients undergoing CTCA: a control group of 15 patients and a study group of 29 patients. MDCT datasets acquired for CTCA were analyzed using custom software designed to: (1) generate bull's eye display of myocardial perfusion and (2) calculate a quantitative index of extent and severity of perfusion abnormality, Q(H), for 16 volumetric myocardial segments. Visual interpretation of MDCT-derived bull's eyes was compared with rest NMPI scores using kappa statistics of agreement on a coronary territory and patient basis. Quantitative MDCT perfusion data were correlated with rest NMPI summed scores and used for objective detection of perfusion defects. RESULTS: Visual analysis of MDCT-derived bull's eyes accurately detected perfusion defects in agreement with NMPI (kappa = 0.70 by territory; 0.79 by patient). Quantitative data were in good agreement with NMPI, as reflected by: (1) correlation of 0.87 (territory) and 0.84 (patient) between summed Q(H) and NMPI scores, (2) area under ROC curve 0.87 with sensitivity of 0.79-0.92, specificity 0.83-0.91, and accuracy 0.83-0.89 for objective detection of abnormalities. CONCLUSIONS: Our new technique for volumetric analysis of 3D MDCT images allows accurate objective detection of perfusion defects. This perfusion information can be obtained without additional radiation or contrast load, and may aid in elucidating the significance of coronary lesions.

A fully automated left atrium segmentation approach from late gadolinium enhanced magnetic resonance imaging based on a convolutional neural network.

BACKGROUND: Several studies suggest that the evaluation of left atrial (LA) fibrosis is a relevant information for the assessment of the appropriate strategy in catheter ablation in atrial fibrillation (AF). Late gadolinium enhanced (LGE) cardiac magnetic resonance imaging (MRI) is a non-invasive technique, which might be employed for the non-invasive quantification of LA myocardial fibrotic tissue in patients with AF. Nowadays, the analysis of LGE MRI relies on manual tracing of LA boundaries and this procedure is time-consuming and prone to high inter-observer variability given the different degrees of observers' experience, LA wall thickness and data resolution. Therefore, an automated segmentation approach of the atrial cavity for the quantification of scar tissue would be highly desirable. METHODS: This study focuses on the design of a fully automated LGE MRI segmentation pipeline which includes a convolutional neural network (CNN) based on the successful architecture U-Net. The CNN was trained, validated and tested end-to-end with the data available from the Statistical Atlases and Computational Modelling of the Heart 2018 Atrial Segmentation Challenge (100 cardiac data). Two different approaches were tested: using both stacks of 2-D axial slices and using 3-D data (with the appropriate changes in the baseline architecture). In the latter approach, thanks to the 3-D convolution operator, all the information underlying 3-D data can be exploited. Once the training was completed using 80 cardiac data, a post-processing step was applied on 20 predicted segmentations belonging to the test set. RESULTS: By applying the 2-D and 3-D approaches, average Dice coefficient and mean Hausdorff distances were 0.896, 0.914, and 8.98 mm, 8.34 mm, respectively. Volumes of the anatomical LA meshes from the automated analysis were highly correlated with the volumes from ground truth [2-D: r=0.978, y=0.94x+0.07, bias=3.5 ml (5.6%), SD=5.3 mL (8.5%); 3-D: r=0.982, y=0.92x+2.9, bias=2.1 mL (3.5%), SD=5.2 mL (8.4%)]. CONCLUSIONS: These results suggest the proposed approach is feasible and provides accurate results. Despite the increase of the number of trainable parameters, the proposed 3-D CNN learns better features leading to higher performance, feasible for a real clinical application.

Mechanisms of beta-adrenergic modulation of I(Ks) in the guinea-pig ventricle: insights from experimental and model-based analysis.

Detailed understanding of I(Ks) gating complexity may provide clues regarding the mechanisms of repolarization instability and the resulting arrhythmias. We developed and tested a kinetic model to interpret physiologically relevant I(Ks) properties, including pause-dependence and modulation by beta-adrenergic receptors (beta-AR). I(Ks) gating was evaluated in guinea-pig ventricular myocytes at 36 degrees C in control and during beta-AR stimulation (0.1 micromol/L isoprenaline (ISO)). We tested voltage dependence of steady-state conductance (Gss), voltage dependence of activation and deactivation time constants (tau(act), tau(deact)), and pause-dependence of tau(act) during repetitive activations (tau(react)). The I(Ks) model was developed from the Silva and Rudy formulation. Parameters were optimized on control and ISO experimental data, respectively. ISO strongly increased Gss and its voltage dependence, changed the voltage dependence of tau(act) and tau(deact), and modified the pause-dependence of tau(react). A single set of model parameters reproduced all experimental data in control. Modification of only three transition rates led to a second set of parameters suitable to fit all ISO data. Channel unitary conductance and density were unchanged in the model, thus implying increased open probability as the mechanism of ISO-induced Gss enhancement. The new I(Ks) model was applied to analyze ISO effect on repolarization rate-dependence. I(Ks) kinetics and its beta-AR modulation were entirely reproduced by a single Markov chain of transitions (for each channel monomer). Model-based analysis suggests that complete opening of I(Ks) channels within a physiological range of potentials requires concomitant beta-AR stimulation. Transient redistribution of state occupancy, in addition to direct modulation of transition rates, may underlie beta-AR modulation of I(Ks) time dependence.

Theoretical investigation of action potential duration dependence on extracellular Ca2+ in human cardiomyocytes.

Reduction in [Ca2+]o prolongs the AP in ventricular cardiomyocytes and the QTc interval in patients. Although this phenomenon is relevant to arrhythmogenesis in the clinical setting, its mechanisms are counterintuitive and incompletely understood. To evaluate in silico the mechanisms of APD modulation by [Ca2+]o in human cardiomyocytes. We implemented the Ten Tusscher-Noble-Noble-Panfilov model of the human ventricular myocyte and modified the formulations of the rapidly and slowly activating delayed rectifier K+ currents (IKr and IKs) and L-type Ca2+ current (ICaL) to incorporate their known sensitivity to intra- or extracellular Ca2+. Simulations were run with the original and modified models at variable [Ca2+]o in the clinically relevant 1 to 3 mM range. The original model responds with APD shortening to decrease in [Ca2+]o, i.e. opposite to the experimental observations. Incorporation of Ca2+ dependency of K+ currents cannot reproduce the inverse relation between APD and [Ca2+]o. Only when ICaL inactivation process was modified, by enhancing its dependency on Ca2+, simulations predict APD prolongation at lower [Ca2+]o. Although Ca2+-dependent ICaL inactivation is the primary mechanism, secondary changes in electrogenic Ca2+ transport (by Na+/Ca2+ exchanger and plasmalemmal Ca2+-ATPase) contribute to the reversal of APD dependency on [Ca2+]o. This theoretical investigation points to Ca2+-dependent inactivation of ICaL as a mechanism primarily responsible for the dependency of APD on [Ca2+]o. The modifications implemented here make the model more suitable to analyze repolarization mechanisms when Ca2+ levels are altered.

Semi-automated analysis of dynamic changes in myocardial contrast from real-time three-dimensional echocardiographic images as a basis for volumetric quantification of myocardial perfusion.

AIMS: Despite the potential of real-time three-dimensional (3D) echocardiography (RT3DE) to assess myocardial perfusion, there is no quantification method available for perfusion analysis from RT3DE images. Such method would require 3D regions of interest (ROI) to be defined and adjusted frame-by-frame to compensate for cardiac translation and deformation. Our aims were to develop and test a technique for automated identification of 3D myocardial ROI suitable for translation-free quantification of myocardial videointensity over time, MVI(t), from contrast-enhanced RT3DE images. METHODS AND RESULTS: Twelve transthoracic RT3DE (Philips) data sets obtained in pigs during transition from no contrast to steady-state enhancement (Definity) were analysed using custom software. Analysis included: (i) semi-automated detection of left ventricular endo- and epicardial surfaces using level-set techniques in one frame to define a 3D myocardial ROI, (ii) rigid 3D registration to reduce translation and rotation, (iii) elastic 3D registration to compensate for deformation, and (iv) quantification of MVI(t) in the 3D ROI from the registered and non-registered data sets to assess the effectiveness of registration. For each MVI(t) curve we computed % variability during steady-state enhancement (100 x SD/mean) and goodness of fit (r2) to the indicator dilution equation MVI(t) = A[1-exp(-betat)]. Analysis of myocardial contrast throughout contrast inflow was feasible in all data sets. Three-dimensional registration improved MVI(t) curves in terms of both % variability (2.8 +/- 1.8 to 1.5 +/- 0.9%; P < 0.05) and goodness of fit (r2 from 0.79 +/- 0.2 to 0.90 +/- 0.1; P < 0.05). CONCLUSION: This is the first study to describe a new technique for semi-automated volumetric quantification of myocardial contrast from RT3DE images that includes registration and thus provides the basis for 3D measurement of myocardial perfusion.