Numerical simulation of electrocardiograms for full cardiac cycles in healthy and pathological conditions

This work is dedicated to the simulation of full cycles of the electrical activity of the heart and the corresponding body surface potential. The model is based on a realistic torso and heart anatomy, including ventricles and atria. One of the specificities of our approach is to model the atria as a surface, which is the kind of data typically provided by medical imaging for thin volumes. The bidomain equations are considered in their usual formulation in the ventricles, and in a surface formulation on the atria. Two ionic models are used: the Courtemanche-Ramirez-Nattel model on the atria, and the "Minimal model for human Ventricular action potentials" (MV) by Bueno-Orovio, Cherry and Fenton in the ventricles. The heart is weakly coupled to the torso by a Robin boundary condition based on a resistor- capacitor transmission condition. Various ECGs are simulated in healthy and pathological conditions (left and right bundle branch blocks, Bachmann's bundle block, Wolff-Parkinson-White syndrome). To assess the numerical ECGs, we use several qualitative and quantitative criteria found in the medical literature. Our simulator can also be used to generate the signals measured by a vest of electrodes. This capability is illustrated at the end of the article

Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases

Aims The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them. Methods and Results We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analyzed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as “pathogenic” by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that 2 variants in KCNH2 and SCN5A, 4 variants in SCN10A, and 1 variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from “Uncertain significance” to “Likely pathogenic” in 6 probands. Conclusions Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD. Translational Perspective Whole-exome sequencing (WES) may be helpful in determining the causes of cardiac conduction system disease (CCSD), however, the identification of pathogenic variants remains a challenge. We performed WES of 23 probands diagnosed with early-onset CCSD, and identified 12 pathogenic or likely pathogenic variants in 11 of these probands (48%) according to the 2015 ACMG standards and guidelines. In this context, functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants, and SCN10A may be one of the major development factors in CCSD

Connexins and the atrioventricular node

The structure and functioning of the atrioventricular (AV) node has remained mysterious owing to its high degree of complexity. In this review article, we integrate advances in knowledge regarding connexin expression in the AV node. Complex patterning of 4 different connexin isoforms with single channel conductances ranging from ultralow to high explains the dual pathway electrophysiology of the AV node, the presence of 2 nodal extensions, longitudinal dissociation in the penetrating bundle, and, most importantly, how the AV node maintains slow conduction between the atria and the ventricles. It is shown that the complex patterning of connexins is the consequence of the embryonic development of the cardiac conduction system. Finally, it is argued that connexin dysregulation may be responsible for AV node dysfunction

The electrophysiology of the atrioventricular node in normal and failing rabbit hearts

Conduction abnormalities affect prognosis in chronic heart failure (CHF). Previous investigators have observed abnormal delay in atrioventricular (AV) conduction in a rabbit model of left ventricular dysfunction (LVD) due to apical myocardial infarction. In this model, AV conduction time increased with increasing pacing rates, suggesting the most likely site of delay is the AV node. The mechanisms by which this occurs are not fully understood. The purpose of this thesis was to confirm that the abnormal prolongation of AV conduction time originates at the AV node in a rabbit model of LVD due to apical myocardial infarction, and explore possible mechanisms underlying the observation. Using surface electrogram recording and standardised pacing techniques in an isolated AV node tissue preparation I confirmed that there is abnormal prolongation of AV nodal conduction in this rabbit model of LVD, as evidenced by prolongation of atrio-hisian (AH) interval and Wenckebach cycle length (WCL) in LVD compared to control. Furthermore, using optical mapping of electrical activation using voltage sensitive dye I observed that the prolongation of the AH interval is predominantly a consequence of conduction delay between the inputs of the AV node and the compact nodal region. Neuro-hormonal derangement in chronic heart failure has a central role in the pathogenesis of the disease, with evidence of downregulation of beta ()-adrenoceptors in the left ventricular myocardium. I therefore explored the possibility of β-adrenoceptor downregulation in the AV node as a mechanism underlying the abnormal AH interval prolongation in LVD. There was no evidence of β-adrenoceptor downregulation in the AV node in LVD compared to control to account for the observed abnormal conduction delay. Adenosine is known to have profound effects on AV nodal conduction and the possibility of tonic excess of adenosine in LVD was explored as a possible mechanism for the prolonged conduction delay. Using an exogenously applied adenosine A1 receptor antagonist there was no evidence of excess endogenous adenosine in LVD compared to control. There was, however, an increase in the sensitivity of the LVD samples compared to control to exogenous adenosine, with a significant increase in AH interval and WCL with increasing concentrations. This thesis also investigates the effect of acidosis on AV nodal conduction. There was significant prolongation of the spontaneous sinus cycle length, AH interval and WCL, as well as the AV nodal functional and effective refractory periods, proportional to the degree of acidosis. These effects were reversible with return to normal pH. Optical mapping studies showed that the spatiotemporal pattern of AV nodal delay during acidosis was similar to that observed in LVD, with the predominant delay in conduction between the AV nodal inputs and the compact AV node. In summary this thesis has confirmed that even in the absence of a direct ischaemic insult to the AV junction, conduction abnormalities in the AV node may still occur as a pathophysiological response to a myocardial infarction resulting in LVD. The mechanisms underlying this response are likely to be complex and multiple, and are not yet clear. Establishing the electrophysiological basis and the effects of neuro-hormonal modulators of atrioventricular nodal function may lead to development of targeted therapeutic strategies to improve overall survival and improve symptom control for patients with CHF

HD Physiology Project-Japanese efforts to promote multilevel integrative systems biology and physiome research.

The HD Physiology Project is a Japanese research consortium that aimed to develop methods and a computational platform in which physiological and pathological information can be described in high-level definitions across multiple scales of time and size. During the 5 years of this project, an appropriate software platform for multilevel functional simulation was developed and a whole-heart model including pharmacokinetics for the assessment of the proarrhythmic risk of drugs was developed. In this article, we outline the description and scientific strategy of this project and present the achievements and influence on multilevel integrative systems biology and physiome research

Modelling and robust estimation of AV node function during AF

Objective: The purpose of the present thesis is to enrich the robustness of a statistical atrioventricular (AV) node model during atrial Fibrillation (AF). The model takes into account electrophysiological properties as the two pathways, their refractory periods and concealed conduction; these pathways are located between sinoatrial (SA) and AV node. It is highly desirable understanding of the AV node function, in order to achieve optimal arrhythmia management for those patients affected by AF, which is the most common arrhythmia. Methods: The simulation has been improved by introducing a new parameter that represents the probability of an impulse choosing either one of the two pathways. Exploration data has been conducted keeping fixed a set of parameters while varying one of them. Results: The model concerns a relationship between the probability of an atrial impulse passing through (output parameter, a) and choosing (input parameter, g) either one of two pathway. To test its accuracy and precision mean absolute error (MAE) and root mean square error (RMSE) have been calculated for different g, obtaining, MAE = 3:8_8:2023_1

Model-based Analysis of Temporal Patterns in Atrioventricular Node Conduction During Atrial Fibrillation

The lifetime risk of developing atrial fibrillation (AF) is estimated to be between 1in 3 to 1 in 4 individuals, making it the most common arrhythmia in the world.For persistent AF, rate control drugs with the purpose to affect the conduction properties of the atrioventricular (AV) node are the most common treatment. The drug of choice varies between β-blockers and calcium channel blockers, often chosen empirically. This can lead to long periods of time before sufficient treatment is found. However, due to the physiological differences between the drug types, it could be possible to predict the effect of the drugs and thus assist in treatment selection. The main focus of this thesis is therefore to assess drug-dependent differences in the AV node, using non-invasive measurements. This thesis comprises an introduction to the subject as well as two papers. The first paper proposes a framework for assessing the conduction properties of the AV node non-invasively using a mathematical model of the AV node in combination with a genetic algorithm.The second paper is a continuation of the work in paper I, where the proposed workflow was adapted to assess the drug-dependent effect on the AV node of four different rate control drugs during a period of 24 hours.The methods presented in this thesis have made it possible to assess both the refractory period and the conduction delay in the AV node in a robust way using ECG, and by doing so found population-related differences in AV node conduction properties between drug types

Numerical Simulations of Dynamics Behaviour of the Action Potential of the Human Heart\u27s Conduction System

A proposed model consisting of two coupled van der Pol models is considered as a description of the heart action potential. A system of ordinary differential equations is used to recreate pathological behaviour in the conducting system of the heart such as Wolff-Parkinson-White (WPW) syndrome and the most common tachycardia: atrioventricular nodal reentrant tachycardia (AVNRT). Part of the population has abnormal accessory pathways: fast and slow. These pathways in the atrioventricular node (AV node) are anatomical and functional excipients of supraventricular tachycardia. However, the appearance of two pathways in the AV node may be an excipient of arrhythmia—the WPW syndrome. The difference in the conduction time between these pathways is the most important factor. This is the reason to introduce three types of couplings and delay to our system in order to reproduce different types of the AVNRT. In our research, the result of introducing the feedback loops and couplings entails the creation of waves which can correspond to the re-entry waves which occur in the AVNRT. Our main aim is to study solutions of the equations of the system and to take into consideration the influence of feedback and delays which occur in the pathological modes. The proposed models made it possible to reproduce the most important physiological properties of the discussed pathologies. Since the model is phenomenological, the results are accurate as far as a simple model can describe the potential found in one of the more complex oscillators found in biology

Model for educational simulation of the neonatal electrocardiogram

Tese de mestrado. Engenharia Biomédica. Faculdade de Engenharia. Universidade do Porto. 200