Computational Simulation of an Electrophysiological Human Heart Failure Model with an Early AfterDepolarization Arrhythmia Application

The main purpose of this dissertation is to develop a population-based cellular model of remodeled electrophysiological properties in a single cell of a human ventricle under heart failure conditions. The developed model is used to study ventricular arrhythmia (VA) applications under heart failure (HF) conditions, such as inducing early afterdepolarizations (EADs) in single cells and initiating spiral waves in tissue. Early afterdepolarizations as well as reentrant waves are an important cause of ventricular arrhythmias in heart failure. However, the underlying transmural distribution of alterations in currents is unknown. Therefore, it is important to study the impact of remodeled transmural currents on inducibility of early afterdepolarization in heart failure across population-level variability. We seek to develop a populationbased transmural heart failure electrophysiological model and assess the relative contribution of each ionic current in early afterdepolarization development during HF. We developed an electrophysiological model that incorporates HF-induced remodeling of related currents, pumps and exchangers as documented in the literature, by modifying a recently published model of human ventricular cell electrophysiology, namely the O\u27Hara, Virag, Varro, and Rudy (OVVR) model. To do so, we broke down our work into the following categories: First, we analyzed healthy human models where we implemented six cellular models under normal conditions in tissue to validate the behavior of these models. Second, we developed and analyzed a human heart failure model, where we developed a general HF model in an isolated myocyte and characterized the difference between normal and HF electrophysiological properties in a single myocyte (0D). The analysis included action potential (AP) properties, sodium concentration and calcium dynamics. We used steady-state and S1-S2 protocols to assess the dynamics of the developed HF model. In addition, we built a more human-specific HF model and introduced population-based remodeling variability on the developed human-specific HF model for three cell types as observed experimentally. Then, the developed HF models were extended to include the analysis of a one-dimensional cable (1D) where we measured the conduction velocity (CV) under HF conditions and compared it with the normal case. Since arrhythmia can be caused by abnormal formation and/or propagation of the excitation wave, it is important to investigate the behavior of our developed models under this scenario. Therefore, we induced arrhythmia in a two-dimensional (2D) tissue by initiating spiral waves using a cross-field stimulation protocol. Then, we measured the vulnerability window, stability of reentrant waves, spiral tip trajectory, duration of induced arrhythmias, dominant action potential duration (APD) and rotation period in the myocytes that constituted the tissue during reentry. Third, we assessed the inducibility of EAD for the general HF model as well as the human-specific HF model across population-level remodeling variability for all types of human ventricular cells. Our thesis should help to elucidate the roles of alterations in electrophysiology on ventricular arrhythmia properties during HF

Calibration of ionic and cellular cardiac electrophysiology models

© 2020 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc. Cardiac electrophysiology models are among the most mature and well-studied mathematical models of biological systems. This maturity is bringing new challenges as models are being used increasingly to make quantitative rather than qualitative predictions. As such, calibrating the parameters within ion current and action potential (AP) models to experimental data sets is a crucial step in constructing a predictive model. This review highlights some of the fundamental concepts in cardiac model calibration and is intended to be readily understood by computational and mathematical modelers working in other fields of biology. We discuss the classic and latest approaches to calibration in the electrophysiology field, at both the ion channel and cellular AP scales. We end with a discussion of the many challenges that work to date has raised and the need for reproducible descriptions of the calibration process to enable models to be recalibrated to new data sets and built upon for new studies. This article is categorized under: Analytical and Computational Methods > Computational Methods Physiology > Mammalian Physiology in Health and Disease Models of Systems Properties and Processes > Cellular Models

Lessons Learned from Multi-scale Modeling of the Failing Heart

[EN] Heart failure constitutes a major public health problem worldwide. Affected patients experience a number of changes in the electrical function of the heart that predispose to potentially lethal cardiac arrhythmias. Due to the multitude of electrophysiological changes that may occur during heart failure, the scientific literature is complex and sometimes ambiguous, perhaps because these findings are highly dependent on the etiology, the stage of heart failure, and the experimental model used to study these changes. Nevertheless, a number of common features of failing hearts have been documented. Prolongation of the action potential (AP) involving ion channel remodeling and alterations in calcium handling have been established as the hallmark characteristics of myocytes isolated from failing hearts. Intercellular uncoupling and fibrosis are identified as major arrhythmogenic factors. Multi-scale computational simulations are a powerful tool that complements experimental and clinical research. The development of biophysically detailed computer models of single myocytes and cardiac tissues has contributed greatly to our understanding of processes underlying excitation and repolarization in the heart. The electrical, structural, and metabolic remodeling that arises in cardiac tissues during heart failure has been addressed from different computational perspectives to further understand the arrhythmogenic substrate. This review summarizes the contributions from computational modeling and simulation to predict the underlying mechanisms of heart failure phenotypes and their implications for arrhythmogenesis, ranging from the cellular level to whole-heart simulations. The main aspects of heart failure are presented in several related sections. An overview of the main electrophysiological and structural changes that have been observed experimentally in failing hearts is followed by the description and discussion of the simulation work in this field at the cellular level, and then in 2D and 3D cardiac structures. The implications for arrhythmogenesis in heart failure are also discussed including therapeutic measures, such as drug effects and cardiac resynchronization therapy. Finally, the future challenges in heart failure modeling and simulation will be discussed.This work was partially supported by (i) the "VI Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica" from the Ministerio de Economia y Competitividad of Spain and the European Commission (European Regional Development Funds ERDF-FEDER) (grant number TIN2012-37546-C03-01), and by (ii) Programa Prometeo de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana (grant number PROMETEO/2012/030).Gómez García, JF.; Cardona-Urrego, KE.; Trénor Gomis, BA. (2015). Lessons Learned from Multi-scale Modeling of the Failing Heart. Journal of Molecular and Cellular Cardiology. 89:146-159. https://doi.org/10.1016/j.yjmcc.2015.10.016S1461598

Electrophysiological and Structural Remodeling in Heart Failure Modulate Arrhythmogenesis. 1D Simulation Study

Background: Heart failure is a final common pathway or descriptor for various cardiac pathologies. It is associated with sudden cardiac death, which is frequently caused by ventricular arrhythmias. Electrophysiological remodeling, intercellular uncoupling, fibrosis and autonomic imbalance have been identified as major arrhythmogenic factors in heart failure etiology and progression. Objective: In this study we investigate in silico the role of electrophysiological and structural heart failure remodeling on the modulation of key elements of the arrhythmogenic substrate, i.e., electrophysiological gradients and abnormal impulse propagation. Methods: Two different mathematical models of the human ventricular action potential were used to formulate models of the failing ventricular myocyte. This provided the basis for simulations of the electrical activity within a transmural ventricular strand. Our main goal was to elucidate the roles of electrophysiological and structural remodeling in setting the stage for malignant life-threatening arrhythmias. Results: Simulation results illustrate how the presence of M cells and heterogeneous electrophysiological remodeling in the human failing ventricle modulate the dispersion of action potential duration and repolarization time. Specifically, selective heterogeneous remodeling of expression levels for the Na+ /Ca2+ exchanger and SERCA pump decrease these heterogeneities. In contrast, fibroblast proliferation and cellular uncoupling both strongly increase repolarization heterogeneities. Conduction velocity and the safety factor for conduction are also reduced by the progressive structural remodeling during heart failure. Conclusion: An extensive literature now establishes that in human ventricle, as heart failure progresses, gradients for repolarization are changed significantly by protein specific electrophysiological remodeling (either homogeneous or heterogeneous). Our simulations illustrate and provide new insights into this. Furthermore, enhanced fibrosis in failing hearts, as well as reduced intercellular coupling, combine to increase electrophysiological gradients and reduce electrical propagation. In combination these changes set the stage for arrhythmias.This work was partially supported by (i) the "VI Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica" from the Ministerio de Economia y Competitividad of Spain (grant number TIN2012-37546-C03-01) and the European Commission (European Regional Development Funds - ERDF - FEDER), (ii) the Direccion General de Politica Cientifica de la Generalitat Valenciana (grant number GV/2013/119), and (iii) Programa Prometeo (PROMETEO/2012/030) de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Gómez García, JF.; Cardona, K.; Romero Pérez, L.; Ferrero De Loma-Osorio, JM.; Trénor Gomis, BA. (2014). Electrophysiological and Structural Remodeling in Heart Failure Modulate Arrhythmogenesis. 1D Simulation Study. PLoS ONE. 9(9). https://doi.org/10.1371/journal.pone.0106602S9

Changes in Intracellular Na+ following Enhancement of Late Na+ Current in Virtual Human Ventricular Myocytes

The slowly inactivating or late Na+ current, INa-L, can contribute to the initiation of both atrial and ventricular rhythm disturbances in the human heart. However, the cellular and molecular mechanisms that underlie these pro-arrhythmic influences are not fully understood. At present, the major working hypothesis is that the Na+ influx corresponding to I(Na-L)significantly increases intracellular Na+, [Na]; and the resulting reduction in the electrochemical driving force for Na+ reduces and (may reverse) Na+/Ca2+ exchange. These changes increase intracellular Ca2+, [Ca2+]; which may further enhance I(Na-L)due to calmodulindependent phosphorylation of the Na+ channels. This paper is based on mathematical simulations using the O'Hara et al (2011) model of baseline or healthy human ventricular action potential waveforms(s) and its [Ca2(+)]; homeostasis mechanisms. Somewhat surprisingly, our results reveal only very small changes (<= 1.5 mM) in [Na] even when INa-L is increased 5-fold and steady-state stimulation rate is approximately 2 times the normal human heart rate (i.e. 2 Hz). Previous work done using well-established models of the rabbit and human ventricular action potential in heart failure settings also reported little or no change in [Na] when I(Na-L)was increased. Based on our simulations, the major short-term effect of markedly augmenting I(Na-L)is a significant prolongation of the action potential and an associated increase in the likelihood of reactivation of the L-type Ca2+ current, Ica-L. Furthermore, this action potential prolongation does not contribute to [Na]; increase.This work was supported by (i) the "VI Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica" from the Ministerio de Economia y Competitividad of Spain (grant number TIN2012-37546-C03-01) and the European Commission (European Regional Development Funds-ERDF-FEDER), (ii) by the Direccion General de Politica Cientifica de la Generalitat Valenciana (grant number GV/2013/119), and by (iii), Programa Prometeo (PROMETEO/2016/088) de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.K Cardona; Trénor Gomis, BA.; W Giles (2016). Changes in Intracellular Na+ following Enhancement of Late Na+ Current in Virtual Human Ventricular Myocytes. PLoS ONE. 11(11). https://doi.org/10.1371/journal.pone.0167060S111

Waste management by restaurant operators in Petaling Jaya / Nasr Eldin Abdallah Elshrif Ebrahiem

There are number of factors contribute to municipal waste generation growth rate globally and locally factors are represented by increasing population levels, development, rapid urbanization and the rise in community living standards. Malaysia municipal waste is growing rapidly due to influence by these factors. This makes improving waste management practice highly demanded in every sector producing this waste. Restaurants have credible share in municipal waste as one of major waste source globally and in Malaysia as well, therefore this increase the necessity of study waste management practice among restaurants. This study aims to investigate waste management practice among restaurants in Petaling Jaya city with reference to the compliance, awareness on waste management, and incorporating these findings on waste management practice. The study was done using two approaches; the first approach way a survey to study the compliance of the restaurants to the Local Government Act (LGA) 1976 and that was done by researcher walkthrough investigation. The second approach was done by questionnaire through personal interview by the researcher. SS2 district has been suggested by Petaling Jaya city council for being the most complied area. Perception and waste management practice were assessed by e-checklists prepared according to Green Restaurant Checklist prepared by Burbank Green Alliance, January 2009 and Supplemental Checklist for Restaurants and Food Service prepared by Green Business Program, February 23 2010. Perception and waste management practice were done based on interview by modifying the checklists into questionnaire. The data of this study has been analyzed manually by analyzing the closed-ended questions and answers and then find out the total result from different parts in the study. Compliance study is to assess commitment of restaurants operators to the Local Government Act 1976. , which find 93% compliance among the surveyed restaurants. Perception study on waste management is to find out level of understanding by restaurants operators on waste management iv aspects. The total result of perception study on waste management was 21%. Waste management practice is converting perception of restaurants operators on good waste management performance. The total result of waste management practice performance was 66%. Therefore, the result of waste management practice comes as effort of empowering the Act which gives restaurant operators high compliance