Circulation. Arrhythmia and electrophysiology, 2016
Heart block is associated with pulmonary hypertension, and the aim of the study was to test the h... more Heart block is associated with pulmonary hypertension, and the aim of the study was to test the hypothesis that the heart block is the result of a change in the ion channel transcriptome of the atrioventricular (AV) node. The most commonly used animal model of pulmonary hypertension, the monocrotaline-injected rat, was used. The functional consequences of monocrotaline injection were determined by echocardiography, ECG recording, and electrophysiological experiments on the Langendorff-perfused heart and isolated AV node. The ion channel transcriptome was measured by quantitative PCR, and biophysically detailed computer modeling was used to explore the changes observed. After monocrotaline injection, echocardiography revealed the pattern of pulmonary artery blood flow characteristic of pulmonary hypertension and right-sided hypertrophy and failure; the Langendorff-perfused heart and isolated AV node revealed dysfunction of the AV node (eg, 50% incidence of heart block in isolated AV ...
ABSTRACT Mechanisms underlying the upright T wave in mammalian hearts are controversial; whilst i... more ABSTRACT Mechanisms underlying the upright T wave in mammalian hearts are controversial; whilst it is generally agreed that the dispersion of action potential duration (APD) throughout the ventricles lies behind the genesis of the positive T wave, the precise mechanism is still subject to debate. The variation in APD throughout the heart is owing to the heterogeneous distribution of ion channels and varying kinetics. This heterogeneity can broadly be split into three groups: transmural (TM) heterogeneity, apico-basal (AB) heterogeneity and interventricular (IV) heterogeneity (i.e. between left and right ventricles). The aim of this study was to use a biophysically detailed computer model to investigate possible contributions of TM, AB and IV heterogeneities to the positive T-wave. A family of single cell computational models was developed for rabbit ventricular myocytes in a previous study. The kinetics and conductances of the Hodgkin-Huxley equations were modified to create four distinct cell types; Purkinje fibre (PF) and endocardial, midcardial and epicardial cells of the left ventricle (LV), accounting for the transmural heterogeneity of the heart. In the present study, the LV single cell rabbit models were modified based on experimental data (Convery et al., 1998; Suto et al., 2005, 2007) to create a set of RV single cell models. Furthermore, ICa,L, IKr and IKs current densities were varied linearly to account for observed differences between apex and base (Cheng et al., 1999; Sims et al., 2008). The single cell models were incorporated into an anatomical model of the ventricles generated by a DT-MRI scan. The monodomain model was used to provide electrotonic coupling between cells, with the diffusion tensor being constructed from DT-MRI data and known conduction velocities. In simulations, the ventricles were activated by stimulating the top end of the PF network with a basic cycle length of 330 ms. The effects of each type of heterogeneity were assessed using five different configurations: 1) completely heterogeneous, 2) completely homogeneous, 3) only AB heterogeneity present, 4) only TM heterogeneity present, 5) AB and TM heterogeneity present. A limb II pseudo-ECG was calculated for each configuration, and the ECG characteristics were compared. In addition, a cross-section from the LV free wall was stimulated from the endocardial surface to simulate a ventricular wedge preparation. Our simulation data suggested that while the TM heterogeneity is sufficient to produce an upright T-wave in the ventricular wedge preparation, it is necessary to have both TM and AB heterogeneity present in order to produce a fully upright T-wave in the whole heart setting. In conclusion, this study provides mechanistic insights towards understanding the ionic basis underlying the positive T-wave in the ECG.
Recent studies introduced intensity based structure tensor analysis to extract the myocardium str... more Recent studies introduced intensity based structure tensor analysis to extract the myocardium structure from micro X-ray computed tomography (micro-CT) images. The implementation of this method is empirical and encounters difficulties in validating the results. In this study, we performed series of tests using structure tensor analysis on synthetic tissue wedges with predefined fibre orientations, optimised the parameters of the method and applied it to the micro-CT images of a rabbit ventricular tissue. The accuracy of the method with several derivative filters and various parameters was investigated by quantifying the error in estimation in inclination angles. A measure of coherence was implemented to assess the coherence and reliability of the extracted orientations. We introduced Gaussian noise to investigate the robustness of this method. Our results suggest that the derivative of Gaussian and optimised Sobel derivative filter have better and balanced performances with overall mean error around 4. The scale parameters play an important role in securing the accuracy. The algorithm is resistant to Gaussian noise. Using this method the myofibre orientation was successfully extracted from the ventricular tissue wedge images of the rabbit heart.
Atrial fibrillation (AF) is the world's most common cardiac arrhythmia. Due to the complexity of ... more Atrial fibrillation (AF) is the world's most common cardiac arrhythmia. Due to the complexity of the heart and highly irregular electrical activity during AF it is a grand challenge to underpin the mechanisms underlying the initiation and maintenance of AF. Complimentary to experimental physiology, biophysically detailed models of the heart provide a powerful platform for investigating the substrates that prompt and perpetuate AF. In the last decade, there has been significant progress in the development of atrial models at the cellular, tissue and whole organ levels. This article presents a review of recent advances in modelling of the human atria and their application to understanding AF.
Electrical wave-front propagation in the atria is determined largely by local fiber orientation. ... more Electrical wave-front propagation in the atria is determined largely by local fiber orientation. Recent study suggests that atrial fibrillation (AF) progresses with enhanced anisotropy. In this work, a 3D rabbit atrial anatomical model at 20×20×20 μm 3 resolution with realistic fiber orientation was constructed based on the novel contrast-enhanced micro-CT imaging. The FentonKarma cellular activation model was adapted to reproduce rabbit atrial action potential period of 80 ms. Diffusivities were estimated for longitudinal and transverse directions of the fiber orientation respectively. Pacing was conducted in the 3D anisotropic atrial model with a reducing S2 interval to facilitate initiation of atrial arrhythmia. Multiple simulations were conducted with varying values of diffusion anisotropy and stimulus locations to evaluate the role of anisotropy in initiating AF. Under physiological anisotropy conditions, a rapid right atrial activation was followed by the left atrial activatio...
The atrioventricular (AV) node is a specialised region of the cardiac conduction system, allowing... more The atrioventricular (AV) node is a specialised region of the cardiac conduction system, allowing electrical excitation to propagate from the atria to the ventricles. AV block occurs when the AV node prevents electrical excitation waves reaching the ventricles, ultimately leading to a decrease in cardiac output. HCN4 and SCN5A defects have been associated with AV block, but the mechanisms underlying impaired AV node conduction remain incompletely understood. In this study we constructed a one-dimensional model for the mouse whole heart featuring detailed single cell models for sino-atrial node, atrium, ventricle and the AV node. The functional effects of HCN4 knockout and the D1595N (SCN5A) mutation were simulated by modifying ion channel properties of I f and I Na respectively. Complete block of I f in the model caused bradycardia; however, propagation was unaltered with no change in conduction velocity, suggesting the AV block caused by HCN4 knockout is not a result of reduced I f density. The D1595N mutation reduced conduction velocity throughout the model, leading to an increased PR interval (63ms vs. 43ms in control) indicative of 1 st degree AV node block. The AV node exhibited reduced excitability which led to 2:1 block at a faster pacing rate.
X-ray computed tomography (XCT) has been shown to be an effective imaging technique for a variety... more X-ray computed tomography (XCT) has been shown to be an effective imaging technique for a variety of materials. Due to the relatively low differential attenuation of X-rays in biological tissue, a high density contrast agent is often required to obtain optimal contrast. The contrast agent, iodine potassium iodide (I 2 KI), has been used in several biological studies to augment the use of XCT scanning. Recently I 2 KI was used in XCT scans of animal hearts to study cardiac structure and to generate 3D anatomical computer models. However, to date there has been no thorough study into the optimal use of I 2 KI as a contrast agent in cardiac muscle with respect to the staining times required, which has been shown to impact significantly upon the quality of results. In this study we address this issue by systematically scanning samples at various stages of the staining process. To achieve this, mouse hearts were stained for up to 58 hours and scanned at regular intervals of 6-7 hours throughout this process. Optimal staining was found to depend upon the thickness of the tissue; a simple empirical exponential relationship was derived to allow calculation of the required staining time for cardiac samples of an arbitrary size.
Circulation. Arrhythmia and electrophysiology, 2016
Catheter ablation (CA) of ventricular tachycardia (VT) in patients with nonischemic dilated cardi... more Catheter ablation (CA) of ventricular tachycardia (VT) in patients with nonischemic dilated cardiomyopathy can be challenging because of the complexity of underlying substrates. We sought to determine the long-term outcomes of endocardial and adjuvant epicardial CA in nonischemic dilated cardiomyopathy. We examined 282 consecutive patients (aged 59±15 years, 80% males) with nonischemic dilated cardiomyopathy who underwent CA. Ablation was guided by activation/entrainment mapping for tolerated VT and pacemapping/targeting of abnormal electrograms for unmappable VT. Adjuvant epicardial ablation was performed for recurrent VT or persistent inducibility after endocardial-only ablation. Epicardial ablation was performed in 90 (32%) patients. Before ablation, patients failed a median of 2 antiarrhythmic drugs), including amiodarone, in 166 (59%) patients. The median follow-up after the last procedure was 48 (19-67) months. Overall, VT-free survival was 69% at 60-month follow-up. Transplan...
The effect of phosphotungstic acid (PTA) and iodine solution (IKI) staining was investigated as a... more The effect of phosphotungstic acid (PTA) and iodine solution (IKI) staining was investigated as a method of enhancing contrast in the X-ray computed tomography of porcine anterior cruciate ligaments (ACL) and patellar tendons (PT). We show that PTA enhanced surface contrast, but was ineffective at penetrating samples, whereas IKI penetrated more effectively and enhanced contrast after 70 hours of staining. Contrast enhancement was compared when using laboratory and synchrotron based X-ray sources. Using the laboratory source, PT fascicles were tracked and their alignment was measured. Individual ACL fascicles could not be identified, but identifiable features were evident that were tracked. Higher resolution scans of fascicle bundles from the PT and ACL were obtained using synchrotron imaging techniques. These scans exhibited greater contrast between the fascicles and matrix in the PT sample, facilitating the identification of the fascicle edges; however, it was still not possible t...
Circulation. Arrhythmia and electrophysiology, 2016
Heart block is associated with pulmonary hypertension, and the aim of the study was to test the h... more Heart block is associated with pulmonary hypertension, and the aim of the study was to test the hypothesis that the heart block is the result of a change in the ion channel transcriptome of the atrioventricular (AV) node. The most commonly used animal model of pulmonary hypertension, the monocrotaline-injected rat, was used. The functional consequences of monocrotaline injection were determined by echocardiography, ECG recording, and electrophysiological experiments on the Langendorff-perfused heart and isolated AV node. The ion channel transcriptome was measured by quantitative PCR, and biophysically detailed computer modeling was used to explore the changes observed. After monocrotaline injection, echocardiography revealed the pattern of pulmonary artery blood flow characteristic of pulmonary hypertension and right-sided hypertrophy and failure; the Langendorff-perfused heart and isolated AV node revealed dysfunction of the AV node (eg, 50% incidence of heart block in isolated AV ...
ABSTRACT Mechanisms underlying the upright T wave in mammalian hearts are controversial; whilst i... more ABSTRACT Mechanisms underlying the upright T wave in mammalian hearts are controversial; whilst it is generally agreed that the dispersion of action potential duration (APD) throughout the ventricles lies behind the genesis of the positive T wave, the precise mechanism is still subject to debate. The variation in APD throughout the heart is owing to the heterogeneous distribution of ion channels and varying kinetics. This heterogeneity can broadly be split into three groups: transmural (TM) heterogeneity, apico-basal (AB) heterogeneity and interventricular (IV) heterogeneity (i.e. between left and right ventricles). The aim of this study was to use a biophysically detailed computer model to investigate possible contributions of TM, AB and IV heterogeneities to the positive T-wave. A family of single cell computational models was developed for rabbit ventricular myocytes in a previous study. The kinetics and conductances of the Hodgkin-Huxley equations were modified to create four distinct cell types; Purkinje fibre (PF) and endocardial, midcardial and epicardial cells of the left ventricle (LV), accounting for the transmural heterogeneity of the heart. In the present study, the LV single cell rabbit models were modified based on experimental data (Convery et al., 1998; Suto et al., 2005, 2007) to create a set of RV single cell models. Furthermore, ICa,L, IKr and IKs current densities were varied linearly to account for observed differences between apex and base (Cheng et al., 1999; Sims et al., 2008). The single cell models were incorporated into an anatomical model of the ventricles generated by a DT-MRI scan. The monodomain model was used to provide electrotonic coupling between cells, with the diffusion tensor being constructed from DT-MRI data and known conduction velocities. In simulations, the ventricles were activated by stimulating the top end of the PF network with a basic cycle length of 330 ms. The effects of each type of heterogeneity were assessed using five different configurations: 1) completely heterogeneous, 2) completely homogeneous, 3) only AB heterogeneity present, 4) only TM heterogeneity present, 5) AB and TM heterogeneity present. A limb II pseudo-ECG was calculated for each configuration, and the ECG characteristics were compared. In addition, a cross-section from the LV free wall was stimulated from the endocardial surface to simulate a ventricular wedge preparation. Our simulation data suggested that while the TM heterogeneity is sufficient to produce an upright T-wave in the ventricular wedge preparation, it is necessary to have both TM and AB heterogeneity present in order to produce a fully upright T-wave in the whole heart setting. In conclusion, this study provides mechanistic insights towards understanding the ionic basis underlying the positive T-wave in the ECG.
Recent studies introduced intensity based structure tensor analysis to extract the myocardium str... more Recent studies introduced intensity based structure tensor analysis to extract the myocardium structure from micro X-ray computed tomography (micro-CT) images. The implementation of this method is empirical and encounters difficulties in validating the results. In this study, we performed series of tests using structure tensor analysis on synthetic tissue wedges with predefined fibre orientations, optimised the parameters of the method and applied it to the micro-CT images of a rabbit ventricular tissue. The accuracy of the method with several derivative filters and various parameters was investigated by quantifying the error in estimation in inclination angles. A measure of coherence was implemented to assess the coherence and reliability of the extracted orientations. We introduced Gaussian noise to investigate the robustness of this method. Our results suggest that the derivative of Gaussian and optimised Sobel derivative filter have better and balanced performances with overall mean error around 4. The scale parameters play an important role in securing the accuracy. The algorithm is resistant to Gaussian noise. Using this method the myofibre orientation was successfully extracted from the ventricular tissue wedge images of the rabbit heart.
Atrial fibrillation (AF) is the world's most common cardiac arrhythmia. Due to the complexity of ... more Atrial fibrillation (AF) is the world's most common cardiac arrhythmia. Due to the complexity of the heart and highly irregular electrical activity during AF it is a grand challenge to underpin the mechanisms underlying the initiation and maintenance of AF. Complimentary to experimental physiology, biophysically detailed models of the heart provide a powerful platform for investigating the substrates that prompt and perpetuate AF. In the last decade, there has been significant progress in the development of atrial models at the cellular, tissue and whole organ levels. This article presents a review of recent advances in modelling of the human atria and their application to understanding AF.
Electrical wave-front propagation in the atria is determined largely by local fiber orientation. ... more Electrical wave-front propagation in the atria is determined largely by local fiber orientation. Recent study suggests that atrial fibrillation (AF) progresses with enhanced anisotropy. In this work, a 3D rabbit atrial anatomical model at 20×20×20 μm 3 resolution with realistic fiber orientation was constructed based on the novel contrast-enhanced micro-CT imaging. The FentonKarma cellular activation model was adapted to reproduce rabbit atrial action potential period of 80 ms. Diffusivities were estimated for longitudinal and transverse directions of the fiber orientation respectively. Pacing was conducted in the 3D anisotropic atrial model with a reducing S2 interval to facilitate initiation of atrial arrhythmia. Multiple simulations were conducted with varying values of diffusion anisotropy and stimulus locations to evaluate the role of anisotropy in initiating AF. Under physiological anisotropy conditions, a rapid right atrial activation was followed by the left atrial activatio...
The atrioventricular (AV) node is a specialised region of the cardiac conduction system, allowing... more The atrioventricular (AV) node is a specialised region of the cardiac conduction system, allowing electrical excitation to propagate from the atria to the ventricles. AV block occurs when the AV node prevents electrical excitation waves reaching the ventricles, ultimately leading to a decrease in cardiac output. HCN4 and SCN5A defects have been associated with AV block, but the mechanisms underlying impaired AV node conduction remain incompletely understood. In this study we constructed a one-dimensional model for the mouse whole heart featuring detailed single cell models for sino-atrial node, atrium, ventricle and the AV node. The functional effects of HCN4 knockout and the D1595N (SCN5A) mutation were simulated by modifying ion channel properties of I f and I Na respectively. Complete block of I f in the model caused bradycardia; however, propagation was unaltered with no change in conduction velocity, suggesting the AV block caused by HCN4 knockout is not a result of reduced I f density. The D1595N mutation reduced conduction velocity throughout the model, leading to an increased PR interval (63ms vs. 43ms in control) indicative of 1 st degree AV node block. The AV node exhibited reduced excitability which led to 2:1 block at a faster pacing rate.
X-ray computed tomography (XCT) has been shown to be an effective imaging technique for a variety... more X-ray computed tomography (XCT) has been shown to be an effective imaging technique for a variety of materials. Due to the relatively low differential attenuation of X-rays in biological tissue, a high density contrast agent is often required to obtain optimal contrast. The contrast agent, iodine potassium iodide (I 2 KI), has been used in several biological studies to augment the use of XCT scanning. Recently I 2 KI was used in XCT scans of animal hearts to study cardiac structure and to generate 3D anatomical computer models. However, to date there has been no thorough study into the optimal use of I 2 KI as a contrast agent in cardiac muscle with respect to the staining times required, which has been shown to impact significantly upon the quality of results. In this study we address this issue by systematically scanning samples at various stages of the staining process. To achieve this, mouse hearts were stained for up to 58 hours and scanned at regular intervals of 6-7 hours throughout this process. Optimal staining was found to depend upon the thickness of the tissue; a simple empirical exponential relationship was derived to allow calculation of the required staining time for cardiac samples of an arbitrary size.
Circulation. Arrhythmia and electrophysiology, 2016
Catheter ablation (CA) of ventricular tachycardia (VT) in patients with nonischemic dilated cardi... more Catheter ablation (CA) of ventricular tachycardia (VT) in patients with nonischemic dilated cardiomyopathy can be challenging because of the complexity of underlying substrates. We sought to determine the long-term outcomes of endocardial and adjuvant epicardial CA in nonischemic dilated cardiomyopathy. We examined 282 consecutive patients (aged 59±15 years, 80% males) with nonischemic dilated cardiomyopathy who underwent CA. Ablation was guided by activation/entrainment mapping for tolerated VT and pacemapping/targeting of abnormal electrograms for unmappable VT. Adjuvant epicardial ablation was performed for recurrent VT or persistent inducibility after endocardial-only ablation. Epicardial ablation was performed in 90 (32%) patients. Before ablation, patients failed a median of 2 antiarrhythmic drugs), including amiodarone, in 166 (59%) patients. The median follow-up after the last procedure was 48 (19-67) months. Overall, VT-free survival was 69% at 60-month follow-up. Transplan...
The effect of phosphotungstic acid (PTA) and iodine solution (IKI) staining was investigated as a... more The effect of phosphotungstic acid (PTA) and iodine solution (IKI) staining was investigated as a method of enhancing contrast in the X-ray computed tomography of porcine anterior cruciate ligaments (ACL) and patellar tendons (PT). We show that PTA enhanced surface contrast, but was ineffective at penetrating samples, whereas IKI penetrated more effectively and enhanced contrast after 70 hours of staining. Contrast enhancement was compared when using laboratory and synchrotron based X-ray sources. Using the laboratory source, PT fascicles were tracked and their alignment was measured. Individual ACL fascicles could not be identified, but identifiable features were evident that were tracked. Higher resolution scans of fascicle bundles from the PT and ACL were obtained using synchrotron imaging techniques. These scans exhibited greater contrast between the fascicles and matrix in the PT sample, facilitating the identification of the fascicle edges; however, it was still not possible t...
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