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1.
PLoS Comput Biol ; 16(9): e1008086, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32966275

RESUMO

Clinical evidence suggests a link between fibrosis in the left atrium (LA) and atrial fibrillation (AF), the most common sustained arrhythmia. Image-derived fibrosis is increasingly used for patient stratification and therapy guidance. However, locations of re-entrant drivers (RDs) sustaining AF are unknown and therapy success rates remain suboptimal. This study used image-derived LA models to explore the dynamics of RD stabilization in fibrotic regions and generate maps of RD locations. LA models with patient-specific geometry and fibrosis distribution were derived from late gadolinium enhanced magnetic resonance imaging of 6 AF patients. In each model, RDs were initiated at multiple locations, and their trajectories were tracked and overlaid on the LA fibrosis distributions to identify the most likely regions where the RDs stabilized. The simulations showed that the RD dynamics were strongly influenced by the amount and spatial distribution of fibrosis. In patients with fibrosis burden greater than 25%, RDs anchored to specific locations near large fibrotic patches. In patients with fibrosis burden below 25%, RDs either moved near small fibrotic patches or anchored to anatomical features. The patient-specific maps of RD locations showed that areas that harboured the RDs were much smaller than the entire fibrotic areas, indicating potential targets for ablation therapy. Ablating the predicted locations and connecting them to the existing pulmonary vein ablation lesions was the most effective in-silico ablation strategy.


Assuntos
Fibrose , Átrios do Coração/patologia , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Modelos Biológicos
2.
Sci Rep ; 10(1): 15284, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943714

RESUMO

Acute myocardial ischaemia and reperfusion (I-R) are major causes of ventricular arrhythmias in patients with a history of coronary artery disease. Ursodeoxycholic acid (UDCA) has previously been shown to be antiarrhythmic in fetal hearts. This study was performed to investigate if UDCA protects against ischaemia-induced and reperfusion-induced arrhythmias in the adult myocardium, and compares the effect of acute (perfusion only) versus prolonged (2 weeks pre-treatment plus perfusion) UDCA administration. Langendorff-perfused adult Sprague-Dawley rat hearts were subjected to acute regional ischaemia by ligation of the left anterior descending artery (10 min), followed by reperfusion (2 min), and arrhythmia incidence quantified. Prolonged UDCA administration reduced the incidence of acute ischaemia-induced arrhythmias (p = 0.028), with a reduction in number of ventricular ectopic beats during the ischaemic phase compared with acute treatment (10 ± 3 vs 58 ± 15, p = 0.036). No antiarrhythmic effect was observed in the acute UDCA administration group. Neither acute nor prolonged UDCA treatment altered the incidence of reperfusion arrhythmias. The antiarrhythmic effect of UDCA may be partially mediated by an increase in cardiac wavelength, due to the attenuation of conduction velocity slowing (p = 0.03), and the preservation of Connexin43 phosphorylation during acute ischaemia (p = 0.0027). The potential antiarrhythmic effects of prolonged UDCA administration merit further investigation.

4.
Front Physiol ; 9: 1352, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349483

RESUMO

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.

5.
Med Image Anal ; 50: 36-53, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30208355

RESUMO

Structural changes to the wall of the left atrium are known to occur with conditions that predispose to Atrial fibrillation. Imaging studies have demonstrated that these changes may be detected non-invasively. An important indicator of this structural change is the wall's thickness. Present studies have commonly measured the wall thickness at few discrete locations. Dense measurements with computer algorithms may be possible on cardiac scans of Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). The task is challenging as the atrial wall is a thin tissue and the imaging resolution is a limiting factor. It is unclear how accurate algorithms may get and how they compare in this new emerging area. We approached this problem of comparability with the Segmentation of Left Atrial Wall for Thickness (SLAWT) challenge organised in conjunction with MICCAI 2016 conference. This manuscript presents the algorithms that had participated and evaluation strategies for comparing them on the challenge image database that is now open-source. The image database consisted of cardiac CT (n=10) and MRI (n=10) of healthy and diseased subjects. A total of 6 algorithms were evaluated with different metrics, with 3 algorithms in each modality. Segmentation of the wall with algorithms was found to be feasible in both modalities. There was generally a lack of accuracy in the algorithms and inter-rater differences showed that algorithms could do better. Benchmarks were determined and algorithms were ranked to allow future algorithms to be ranked alongside the state-of-the-art techniques presented in this work. A mean atlas was also constructed from both modalities to illustrate the variation in thickness within this small cohort.


Assuntos
Átrios do Coração/anatomia & histologia , Imagem por Ressonância Magnética , Tomografia Computadorizada por Raios X , Algoritmos , Fibrilação Atrial , Bioestatística , Bases de Dados Factuais , Humanos , Variações Dependentes do Observador
6.
Front Physiol ; 9: 1757, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30618785

RESUMO

Introduction: Atrial fibrillation (AF) is a widespread cardiac arrhythmia that commonly affects the left atrium (LA), causing it to quiver instead of contracting effectively. This behavior is triggered by abnormal electrical impulses at a specific site in the atrial wall. Catheter ablation (CA) treatment consists of isolating this driver site by burning the surrounding tissue to restore sinus rhythm (SR). However, evidence suggests that CA can concur to the formation of blood clots by promoting coagulation near the heat source and in regions with low flow velocity and blood stagnation. Methods: A patient-specific modeling workflow was created and applied to simulate thermal-fluid dynamics in two patients pre- and post-CA. Each model was personalized based on pre- and post-CA imaging datasets. The wall motion and anatomy were derived from SSFP Cine MRI data, while the trans-valvular flow was based on Doppler ultrasound data. The temperature distribution in the blood was modeled using a modified Pennes bioheat equation implemented in a finite-element based Navier-Stokes solver. Blood particles were also classified based on their residence time in the LA using a particle-tracking algorithm. Results: SR simulations showed multiple short-lived vortices with an average blood velocity of 0.2-0.22 m/s. In contrast, AF patients presented a slower vortex and stagnant flow in the LA appendage, with the average blood velocity reduced to 0.08-0.14 m/s. Restoration of SR also increased the blood kinetic energy and the viscous dissipation due to the presence of multiple vortices. Particle tracking showed a dramatic decrease in the percentage of blood remaining in the LA for longer than one cycle after CA (65.9 vs. 43.3% in patient A and 62.2 vs. 54.8% in patient B). Maximum temperatures of 76° and 58°C were observed when CA was performed near the appendage and in a pulmonary vein, respectively. Conclusion: This computational study presents novel models to elucidate relations between catheter temperature, patient-specific atrial anatomy and blood velocity, and predict how they change from SR to AF. The models can quantify blood flow in critical regions, including residence times and temperature distribution for different catheter positions, providing a basis for quantifying stroke risks.

7.
IEEE Trans Med Imaging ; 36(8): 1607-1614, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28422654

RESUMO

Knowledge of atrial wall thickness (AWT) has the potential to provide important information for patient stratification and the planning of interventions in atrial arrhythmias. To date, information about AWT has only been acquired in post-mortem or poor-contrast computed tomography (CT) studies, providing limited coverage and highly variable estimates of AWT. We present a novel contrast agent-free MRI sequence for imaging AWT and use it to create personalized AWT maps and a biatrial atlas. A novel black-blood phase-sensitive inversion recovery protocol was used to image ten volunteers and, as proof of concept, two atrial fibrillation patients. Both atria were manually segmented to create subject-specific AWT maps using an average of nearest neighbors approach. These were then registered non-linearly to generate an AWT atlas. AWT was 2.4 ± 0.7 and 2.7 ± 0.7 mm in the left and right atria, respectively, in good agreement with post-mortem and CT data, where available. AWT was 2.6 ± 0.7 mm in the left atrium of a patient without structural heart disease, similar to that of volunteers. In a patient with structural heart disease, the AWT was increased to 3.1 ± 1.3 mm. We successfully designed an MRI protocol to non-invasively measure AWT and create the first whole-atria AWT atlas. The atlas can be used as a reference to study alterations in thickness caused by atrial pathology. The protocol can be used to acquire personalized AWT maps in a clinical setting and assist in the treatment of atrial arrhythmias.


Assuntos
Átrios do Coração , Fibrilação Atrial , Sistema de Condução Cardíaco , Humanos , Imagem por Ressonância Magnética , Tomografia Computadorizada por Raios X
8.
Front Physiol ; 8: 68, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28261103

RESUMO

The left atrium (LA) can change in size and shape due to atrial fibrillation (AF)-induced remodeling. These alterations can be linked to poorer outcomes of AF ablation. In this study, we propose a novel comprehensive computational analysis of LA anatomy to identify what features of LA shape can optimally predict post-ablation AF recurrence. To this end, we construct smooth 3D geometrical models from the segmentation of the LA blood pool captured in pre-procedural MR images. We first apply this methodology to characterize the LA anatomy of 144 AF patients and build a statistical shape model that includes the most salient variations in shape across this cohort. We then perform a discriminant analysis to optimally distinguish between recurrent and non-recurrent patients. From this analysis, we propose a new shape metric called vertical asymmetry, which measures the imbalance of size along the anterior to posterior direction between the superior and inferior left atrial hemispheres. Vertical asymmetry was found, in combination with LA sphericity, to be the best predictor of post-ablation recurrence at both 12 and 24 months (area under the ROC curve: 0.71 and 0.68, respectively) outperforming other shape markers and any of their combinations. We also found that model-derived shape metrics, such as the anterior-posterior radius, were better predictors than equivalent metrics taken directly from MRI or echocardiography, suggesting that the proposed approach leads to a reduction of the impact of data artifacts and noise. This novel methodology contributes to an improved characterization of LA organ remodeling and the reported findings have the potential to improve patient selection and risk stratification for catheter ablations in AF.

9.
PLoS Comput Biol ; 12(12): e1005245, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27984585

RESUMO

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.


Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/fisiopatologia , Átrios do Coração/citologia , Átrios do Coração/efeitos dos fármacos , Modelos Cardiovasculares , Animais , Fenômenos Biomecânicos , Cães , Reprodutibilidade dos Testes , Análise de Célula Única
10.
Front Physiol ; 7: 474, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27826248

RESUMO

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.

11.
Annu Int Conf IEEE Eng Med Biol Soc ; 2016: 489-492, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28261003

RESUMO

Radiofrequency catheter ablation procedures are a first-line method of clinical treatment for atrial fibrillation. However, they suffer from suboptimal success rates and are also prone to potentially serious adverse effects. These limitations can be at least partially attributed to the inter- and intra- patient variations in atrial wall thickness, and could be mitigated by patient-specific approaches to the procedure. In this study, a modelling approach to optimising ablation procedures in subject-specific 3D atrial geometries was applied. The approach enabled the evaluation of optimal ablation times to create lesions for a given wall thickness measured from MRI. A nonliner relationship was revealed between the thickness and catheter contact time required for fully transmural lesions. Hence, our approach based on MRI reconstruction of the atrial wall combined with subject-specific modelling of ablation can provide useful information for improving clinical procedures.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter , Modelagem Computacional Específica para o Paciente , Fibrilação Atrial/diagnóstico por imagem , Ablação por Cateter/efeitos adversos , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Resultado do Tratamento
13.
Europace ; 16(3): 416-23, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24569896

RESUMO

AIMS: Atrial fibrillation (AF), the commonest cardiac arrhythmia, has been strongly linked with arrhythmogenic sources near the pulmonary veins (PVs), but underlying mechanisms are not fully understood. We aim to study the generation and sustenance of wave sources in a model of the PV tissue. METHODS AND RESULTS: A previously developed biophysically detailed three-dimensional canine atrial model is applied. Effects of AF-induced electrical remodelling are introduced based on published experimental data, as changes of ion channel currents (ICaL, IK1, Ito, and IKur), the action potential (AP) and cell-to-cell coupling levels. Pharmacological effects are introduced by blocking specific ion channel currents. A combination of electrical heterogeneity (AP tissue gradients of 5-12 ms) and anisotropy (conduction velocities of 0.75-1.25 and 0.21-0.31 m/s along and transverse to atrial fibres) can results in the generation of wave breaks in the PV region. However, a long wavelength (171 mm) prevents the wave breaks from developing into re-entry. Electrical remodelling leads to decreases in the AP duration, conduction velocity and wavelength (to 49 mm), such that re-entry becomes sustained. Pharmacological effects on the tissue heterogeneity and vulnerability (to wave breaks and re-entry) are quantified to show that drugs that increase the wavelength and stop re-entry (IK1 and IKur blockers) can also increase the heterogeneity (AP gradients of 26-27 ms) and the likelihood of wave breaks. CONCLUSION: Biophysical modelling reveals large conduction block areas near the PVs, which are due to discontinuous fibre arrangement enhanced by electrical heterogeneity. Vulnerability to re-entry in such areas can be modulated by pharmacological interventions.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/administração & dosagem , Relógios Biológicos/efeitos dos fármacos , Modelos Animais de Doenças , Sistema de Condução Cardíaco/fisiopatologia , Modelos Cardiovasculares , Veias Pulmonares/fisiopatologia , Animais , Simulação por Computador , Cães , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Veias Pulmonares/efeitos dos fármacos
14.
Artigo em Inglês | MEDLINE | ID: mdl-25570275

RESUMO

Complex fractionated atrial electrograms (CFAEs) are often used as a clinical marker for re-entrant drivers of atrial fibrillation. However, outcomes of clinical ablation procedures based on CFAEs are controversial and the mechanistic links between fractionation, re-entrant activity and the characteristics of the atrial substrate are not completely understood. We explore such links by simulating electrograms arising from both normal and re-entrant electrical activity in atrial tissue models. 2D and 3D tissue geometries with a range of conditions for intracellular coupling and myofiber orientation fields were studied. Electrograms were fractionated in the presence of complex atrial fiber fields and in 3D irregular geometries, due to far-field excitations. The complexity of the local electrical activity was not a strong determinant of the degree of fractionation. These results suggest that electrogram fractionation is more strongly linked to atrial substrate characteristics (including tissue geometry, fiber orientation and degree of intercelullar coupling) than to the electrical activation pattern sustaining atrial fibrillation.


Assuntos
Técnicas Eletrofisiológicas Cardíacas/métodos , Átrios do Coração/fisiopatologia , Simulação por Computador , Humanos , Processamento de Sinais Assistido por Computador
15.
J Physiol ; 591(17): 4249-72, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23732649

RESUMO

Chronic atrial fibrillation (AF) is associated with structural and electrical remodelling in the atria, which are associated with a high recurrence of AF. Through biophysically detailed computer modelling, this study investigated mechanisms by which AF-induced electrical remodelling promotes and perpetuates AF. A family of Courtemanche-Ramirez-Nattel variant models of human atrial cell action potentials (APs), taking into account of intrinsic atrial electrophysiological properties, was modified to incorporate various experimental data sets on AF-induced changes of major ionic channel currents (ICaL, IKur, Ito, IK1, IKs, INaCa) and on intracellular Ca(2+) handling. The single cell models for control and AF-remodelled conditions were incorporated into multicellular three-dimensional (3D) atrial tissue models. Effects of the AF-induced electrical remodelling were quantified as the changes of AP profile, AP duration (APD) and its dispersion across the atria, and the vulnerability of atrial tissue to the initiation of re-entry. The dynamic behaviour of re-entrant excitation waves in the 3D models was characterised. In our simulations, AF-induced electrical remodelling abbreviated atrial APD non-uniformly across the atria; this resulted in relatively short APDs co-existing with marked regional differences in the APD at junctions of the crista terminalis/pectinate muscle, pulmonary veins/left atrium. As a result, the measured tissue vulnerability to re-entry initiation at these tissue junctions was increased. The AF-induced electrical remodelling also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. Under the AF-remodelled condition, re-entrant scroll waves in the 3D model degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, realistic 3D atrial tissue models indicate that AF-induced electrical remodelling produces regionally heterogeneous and shortened APD; these respectively facilitate initiation and maintenance of re-entrant excitation waves.


Assuntos
Potenciais de Ação , Fibrilação Atrial/fisiopatologia , Remodelamento Atrial , Átrios do Coração/metabolismo , Modelos Cardiovasculares , Átrios do Coração/citologia , Humanos , Canais Iônicos/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia
16.
Interface Focus ; 3(2): 20120067, 2013 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-24427521

RESUMO

Sheep are often used as animal models for experimental studies into the underlying mechanisms of cardiac arrhythmias. Previous studies have shown that biophysically detailed computer models of the heart provide a powerful alternative to experimental animal models for underpinning such mechanisms. In this study, we have developed a family of mathematical models for the electrical action potentials of various sheep atrial cell types. The developed cell models were then incorporated into a three-dimensional anatomical model of the sheep atria, which was recently reconstructed and segmented based on anatomical features within different regions. This created a novel biophysically detailed computational model of the three-dimensional sheep atria. Using the model, we then investigated the mechanisms by which paroxysmal rapid focal activity in the pulmonary veins can transit to sustained atrial fibrillation. It was found that the anisotropic property of the atria arising from the fibre structure plays an important role in facilitating the development of fibrillatory atrial excitation waves, and the electrical heterogeneity plays an important role in its initiation.

17.
Interface Focus ; 3(2): 20120069, 2013 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-24427522

RESUMO

Mechanisms underlying the genesis of re-entrant substrate for the most common cardiac arrhythmia, atrial fibrillation (AF), are not well understood. In this study, we develop a multi-scale three-dimensional computational model that integrates cellular electrophysiology of the left atrium (LA) and pulmonary veins (PVs) with the respective tissue geometry and fibre orientation. The latter is reconstructed in unique detail from high-resolution (approx. 70 µm) contrast micro-computed tomography data. The model is used to explore the mechanisms of re-entry initiation and sustenance in the PV region, regarded as the primary source of high-frequency electrical activity in AF. Simulations of the three-dimensional model demonstrate that an initial break-down of normal electrical excitation wave-fronts can be caused by the electrical heterogeneity between the PVs and LA. High tissue anisotropy is then responsible for the slow conduction and generation of a re-entrant circuit near the PVs. Evidence of such circuits has been seen clinically in AF patients. Our computational study suggests that primarily the combination of electrical heterogeneity and conduction anisotropy between the PVs and LA tissues leads to the generation of a high-frequency (approx. 10 Hz) re-entrant source near the PV sleeves, thus providing new insights into the arrhythmogenic mechanisms of excitation waves underlying AF.

18.
IEEE Trans Med Imaging ; 32(1): 8-17, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22829390

RESUMO

Micro-computed tomography (micro-CT) has been widely used to generate high-resolution 3-D tissue images from small animals nondestructively, especially for mineralized skeletal tissues. However, its application to the analysis of soft cardiovascular tissues has been limited by poor inter-tissue contrast. Recent ex vivo studies have shown that contrast between muscular and connective tissue in micro-CT images can be enhanced by staining with iodine. In the present study, we apply this novel technique for imaging of cardiovascular structures in canine hearts. We optimize the method to obtain high-resolution X-ray micro-CT images of the canine atria and its distinctive regions-including the Bachmann's bundle, atrioventricular node, pulmonary arteries and veins-with clear inter-tissue contrast. The imaging results are used to reconstruct and segment the detailed 3-D geometry of the atria. Structure tensor analysis shows that the arrangement of atrial fibers can also be characterized using the enhanced micro-CT images, as iodine preferentially accumulates within the muscular fibers rather than in connective tissues. This novel technique can be particularly useful in nondestructive imaging of 3-D cardiac architectures from large animals and humans, due to the combination of relatively high speed ( ~ 1 h/per scan of the large canine heart) and high voxel resolution (36 µm) provided. In summary, contrast micro-CT facilitates fast and nondestructive imaging and segmenting of detailed 3-D cardiovascular geometries, as well as measuring fiber orientation, which are crucial in constructing biophysically detailed computational cardiac models.


Assuntos
Coração/anatomia & histologia , Coração/diagnóstico por imagem , Imageamento Tridimensional/métodos , Compostos de Iodo/química , Modelos Cardiovasculares , Microtomografia por Raio-X/métodos , Animais , Meios de Contraste/química , Vasos Coronários/anatomia & histologia , Vasos Coronários/diagnóstico por imagem , Cães , Feminino
19.
J Mol Cell Cardiol ; 53(2): 145-55, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22537893

RESUMO

Transmural gradients in myocyte action potential duration (APD) and Ca(2+)-handling proteins are argued to be important for both the normal functioning of the ventricle and arrhythmogenesis. In rabbit, the transmural gradient in APD (left ventricular wedge preparation) is minimal in the neonate. During postnatal development, APD increases both in the epicardium and the endocardium, but the prolongation is more substantial in the endocardium leading to a significant transmural gradient. We have investigated changes in the expression of ion channels and also Ca(2+)-handling proteins in the subepicardial and subendocardial layers of the left ventricular free wall in neonatal (2-7 days of age) and adult male (~6 months of age) New Zealand White rabbits using quantitative PCR and also, when possible, in situ hybridisation and immunohistochemistry. In the adult, there were significant and substantial transmural gradients in Ca(v)1.2, KChIP2, ERG, K(v)LQT1, K(ir)2.1, NCX1, SERCA2a and RyR2 at the mRNA and, in some cases, protein level-in every case the mRNA or protein was more abundant in the epicardium than the endocardium. Of the eight transmural gradients seen in the adult, only three were observed in the neonate and, in two of these cases, the gradients were smaller than those in the adult. However, in the neonate there were also transmural gradients not observed in the adult: in HCN4, Na(v)1.5, minK, K(ir)3.1 and Cx40 mRNAs - in every case the mRNA was more abundant in the endocardium than the epicardium. If the postnatal changes in ion channel mRNAs are used to predict changes in ionic conductances, mathematical modelling predicts the changes in APD observed experimentally. It is concluded that many of the well known transmural gradients in the ventricle develop postnatally.


Assuntos
Ventrículos do Coração/metabolismo , Animais , Animais Recém-Nascidos , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Endocárdio/metabolismo , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Imuno-Histoquímica , Hibridização In Situ , Canal de Potássio KCNQ1/genética , Canal de Potássio KCNQ1/metabolismo , Proteínas Interatuantes com Canais de Kv/genética , Proteínas Interatuantes com Canais de Kv/metabolismo , Masculino , Canal de Sódio Disparado por Voltagem NAV1.5 , Pericárdio/metabolismo , Reação em Cadeia da Polimerase , Ratos , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Canais de Sódio/genética , Canais de Sódio/metabolismo , Trocador de Sódio e Cálcio/genética , Trocador de Sódio e Cálcio/metabolismo
20.
Artigo em Inglês | MEDLINE | ID: mdl-23365867

RESUMO

Mechanisms underlying the genesis of re-entrant substrate for atrial fibrillation (AF) in the pulmonary veins (PVs) and left atrium (LA) are not well understood. We develop a biophysically detailed computational model for the PVs and surrounding LA tissue. The model integrates canine PV and LA single cell electrophysiology with the respective 3D tissue geometry and fiber orientation reconstructed from micro-CT data. The model simulations demonstrate that a combination of tissue anisotropy and electrical heterogeneity between the PVs and LA causes a break-down of normal electrical excitation wave-fronts. This leads to the generation of a high-frequency re-entrant source near the PV sleeves. Evidence of such sources have been seen clinically in AF patients. In summary, our modeling results provide new insights into the arrhythmogenic mechanisms of re-entrant excitation waves underlying AF.


Assuntos
Fibrilação Atrial/fisiopatologia , Simulação por Computador , Modelos Cardiovasculares , Veias Pulmonares/fisiopatologia , Animais , Fibrilação Atrial/patologia , Cães , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Humanos , Veias Pulmonares/patologia
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