Simulation Methods and Validation Criteria for Modeling Cardiac Ventricular Electrophysiology.
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ABSTRACT:
SUBMITTER: Krishnamoorthi S
PROVIDER: S-EPMC4262432 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chaste is an open-source C++ library for computational biology that has well-developed cardiac electrophysiology tissue simulation support. In this paper, we introduce the features available for performing cardiac electrophysiology action potential simulations using a wide range of models from the Physiome repository. The mathematics of the models are described in CellML, with units for all quantities. The primary idea is that the model is defined in one place (the CellML file), and all model code is auto-generated at compile or run time; it never has to be manually edited. We use ontological annotation to identify model variables describing certain biological quantities (membrane voltage, capacitance, etc.) to allow us to import any relevant CellML models into the Chaste framework in consistent units and to interact with them via consistent interfaces. This approach provides a great deal of flexibility for analysing different models of the same system. Chaste provides a wide choice of numerical methods for solving the ordinary differential equations that describe the models. Fixed-timestep explicit and implicit solvers are provided, as discussed in previous work. Here we introduce the Rush-Larsen and Generalized Rush-Larsen integration techniques, made available via symbolic manipulation of the model equations, which are automatically rearranged into the forms required by these approaches. We have also integrated the CVODE solvers, a 'gold standard' for stiff systems, and we have developed support for symbolic computation of the Jacobian matrix, yielding further increases in the performance and accuracy of CVODE. We discuss some of the technical details of this work and compare the performance of the available numerical methods. Finally, we discuss how this is generalized in our functional curation framework, which uses a domain-specific language for defining complex experiments as a basis for comparison of model behavior.
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Project description:Cellular electrophysiology experiments, important for understanding cardiac arrhythmia mechanisms, are usually performed with channels expressed in non myocytes, or with non-human myocytes. Differences between cell types and species affect results. Thus, an accurate model for the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is needed. Such a model requires extensive experimental data, but essential elements have been unavailable. Here, we develop a human ventricular AP model using new undiseased human ventricular data: Ca(2+) versus voltage dependent inactivation of L-type Ca(2+) current (I(CaL)); kinetics for the transient outward, rapid delayed rectifier (I(Kr)), Na(+)/Ca(2+) exchange (I(NaCa)), and inward rectifier currents; AP recordings at all physiological cycle lengths; and rate dependence and restitution of AP duration (APD) with and without a variety of specific channel blockers. Simulated APs reproduced the experimental AP morphology, APD rate dependence, and restitution. Using undiseased human mRNA and protein data, models for different transmural cell types were developed. Experiments for rate dependence of Ca(2+) (including peak and decay) and intracellular sodium ([Na(+)](i)) in undiseased human myocytes were quantitatively reproduced by the model. Early afterdepolarizations were induced by I(Kr) block during slow pacing, and AP and Ca(2+) alternans appeared at rates >200 bpm, as observed in the nonfailing human ventricle. Ca(2+)/calmodulin-dependent protein kinase II (CaMK) modulated rate dependence of Ca(2+) cycling. I(NaCa) linked Ca(2+) alternation to AP alternans. CaMK suppression or SERCA upregulation eliminated alternans. Steady state APD rate dependence was caused primarily by changes in [Na(+)](i), via its modulation of the electrogenic Na(+)/K(+) ATPase current. At fast pacing rates, late Na(+) current and I(CaL) were also contributors. APD shortening during restitution was primarily dependent on reduced late Na(+) and I(CaL) currents due to inactivation at short diastolic intervals, with additional contribution from elevated I(Kr) due to incomplete deactivation.
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Project description:Recent developments in cardiac simulation have rendered the heart the most highly integrated example of a virtual organ. We are on the brink of a revolution in cardiac research, one in which computational modeling of proteins, cells, tissues, and the organ permit linking genomic and proteomic information to the integrated organ behavior, in the quest for a quantitative understanding of the functioning of the heart in health and disease. The goal of this review is to assess the existing state-of-the-art in whole-heart modeling and the plethora of its applications in cardiac research. General whole-heart modeling approaches are presented, and the applications of whole-heart models in cardiac electrophysiology and electromechanics research are reviewed. The article showcases the contributions that whole-heart modeling and simulation have made to our understanding of the functioning of the heart. A summary of the future developments envisioned for the field of cardiac simulation and modeling is also presented. Biophysically based computational modeling of the heart, applied to human heart physiology and the diagnosis and treatment of cardiac disease, has the potential to dramatically change 21st century cardiac research and the field of cardiology.
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Project description:The BeatBox simulation environment combines flexible script language user interface with the robust computational tools, in order to setup cardiac electrophysiology in-silico experiments without re-coding at low-level, so that cell excitation, tissue/anatomy models, stimulation protocols may be included into a BeatBox script, and simulation run either sequentially or in parallel (MPI) without re-compilation. BeatBox is a free software written in C language to be run on a Unix-based platform. It provides the whole spectrum of multi scale tissue modelling from 0-dimensional individual cell simulation, 1-dimensional fibre, 2-dimensional sheet and 3-dimensional slab of tissue, up to anatomically realistic whole heart simulations, with run time measurements including cardiac re-entry tip/filament tracing, ECG, local/global samples of any variables, etc. BeatBox solvers, cell, and tissue/anatomy models repositories are extended via robust and flexible interfaces, thus providing an open framework for new developments in the field. In this paper we give an overview of the BeatBox current state, together with a description of the main computational methods and MPI parallelisation approaches.
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Project description:Between-subject and within-subject variability is ubiquitous in biology and physiology, and understanding and dealing with this is one of the biggest challenges in medicine. At the same time, it is difficult to investigate this variability by experiments alone. A recent modelling and simulation approach, known as population of models (POM), allows this exploration to take place by building a mathematical model consisting of multiple parameter sets calibrated against experimental data. However, finding such sets within a high-dimensional parameter space of complex electrophysiological models is computationally challenging. By placing the POM approach within a statistical framework, we develop a novel and efficient algorithm based on sequential Monte Carlo (SMC). We compare the SMC approach with Latin hypercube sampling (LHS), a method commonly adopted in the literature for obtaining the POM, in terms of efficiency and output variability in the presence of a drug block through an in-depth investigation via the Beeler-Reuter cardiac electrophysiological model. We show improved efficiency for SMC that produces similar responses to LHS when making out-of-sample predictions in the presence of a simulated drug block. Finally, we show the performance of our approach on a complex atrial electrophysiological model, namely the Courtemanche-Ramirez-Nattel model.
| S-EPMC5014056 | biostudies-literature
Project description:BACKGROUND:Case studies have suggested the efficacy of catheter-free, electrophysiology-guided noninvasive cardiac radioablation for ventricular tachycardia (VT) using stereotactic body radiation therapy, although prospective data are lacking. METHODS:We conducted a prospective phase I/II trial of noninvasive cardiac radioablation in adults with treatment-refractory episodes of VT or cardiomyopathy related to premature ventricular contractions (PVCs). Arrhythmogenic scar regions were targeted by combining noninvasive anatomic and electric cardiac imaging with a standard stereotactic body radiation therapy workflow followed by delivery of a single fraction of 25 Gy to the target. The primary safety end point was treatment-related serious adverse events in the first 90 days. The primary efficacy end point was any reduction in VT episodes (tracked by indwelling implantable cardioverter defibrillators) or any reduction in PVC burden (as measured by a 24-hour Holter monitor) comparing the 6 months before and after treatment (with a 6-week blanking window after treatment). Health-related quality of life was assessed using the Short Form-36 questionnaire. RESULTS:Nineteen patients were enrolled (17 for VT, 2 for PVC cardiomyopathy). Median noninvasive ablation time was 15.3 minutes (range, 5.4-32.3). In the first 90 days, 2/19 patients (10.5%) developed a treatment-related serious adverse event. The median number of VT episodes was reduced from 119 (range, 4-292) to 3 (range, 0-31; P<0.001). Reduction was observed for both implantable cardioverter defibrillator shocks and antitachycardia pacing. VT episodes or PVC burden were reduced in 17/18 evaluable patients (94%). The frequency of VT episodes or PVC burden was reduced by 75% in 89% of patients. Overall survival was 89% at 6 months and 72% at 12 months. Use of dual antiarrhythmic medications decreased from 59% to 12% ( P=0.008). Quality of life improved in 5 of 9 Short Form-36 domains at 6 months. CONCLUSIONS:Noninvasive electrophysiology-guided cardiac radioablation is associated with markedly reduced ventricular arrhythmia burden with modest short-term risks, reduction in antiarrhythmic drug use, and improvement in quality of life. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT02919618.
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Project description:Clinical and experimental studies involving human hearts can have certain limitations. Methods such as computer simulations can be an important alternative or supplemental tool. Physiological simulation at the tissue or organ level typically involves the handling of partial differential equations (PDEs). Boundary conditions and distributed parameters, such as those used in pharmacokinetics simulation, add to the complexity of the PDE solution. These factors can tailor PDE solutions and their corresponding program code to specific problems. Boundary condition and parameter changes in the customized code are usually prone to errors and time-consuming. We propose a general approach for handling PDEs and boundary conditions in computational models using a replacement scheme for discretization. This study is an extension of a program generator that we introduced in a previous publication. The program generator can generate code for multi-cell simulations of cardiac electrophysiology. Improvements to the system allow it to handle simultaneous equations in the biological function model as well as implicit PDE numerical schemes. The replacement scheme involves substituting all partial differential terms with numerical solution equations. Once the model and boundary equations are discretized with the numerical solution scheme, instances of the equations are generated to undergo dependency analysis. The result of the dependency analysis is then used to generate the program code. The resulting program code are in Java or C programming language. To validate the automatic handling of boundary conditions in the program code generator, we generated simulation code using the FHN, Luo-Rudy 1, and Hund-Rudy cell models and run cell-to-cell coupling and action potential propagation simulations. One of the simulations is based on a published experiment and simulation results are compared with the experimental data. We conclude that the proposed program code generator can be used to generate code for physiological simulations and provides a tool for studying cardiac electrophysiology.
| S-EPMC4565589 | biostudies-literature
Project description:The relative importance of regulatory versus structural evolution for the evolution of different biological systems is a subject of controversy. The primacy of regulatory evolution in the diversification of morphological traits has been promoted by many evolutionary developmental biologists. For physiological traits, however, the role of regulatory evolution has received less attention or has been considered to be relatively unimportant. To address this issue for electrophysiological systems, we examined the importance of regulatory and structural evolution in the evolution of the electrophysiological function of cardiac myocytes in mammals. In particular, two related phenomena were studied: the change in action potential morphology in small mammals and the scaling of action potential duration across mammalian phylogeny. In general, the functional properties of the ion channels involved in ventricular action potential repolarization were found to be relatively invariant. In contrast, there were large changes in the expression levels of multiple ion channel and transporter genes. For the Kv2.1 and Kv4.2 potassium channel genes, which are primary determinants of the action potential morphology in small mammals, the functional properties of the proximal promoter regions were found to vary in concordance with species-dependent differences in mRNA expression, suggesting that evolution of cis-regulatory elements is the primary determinant of this trait. Scaling of action potential duration was found to be a complex phenomenon, involving changes in the expression of a large number of channels and transporters. In this case, it is concluded that regulatory evolution is the predominant mechanism by which the scaling is achieved.
| S-EPMC2585018 | biostudies-literature
Project description:PurposeLeft ventricular non-compaction (LVNC) is characterized by a 2-layered myocardium composed of a noncompacted (NC) and a compacted (C) layer. The echocardiographic NC:C ratio is difficult to assess in many patients. The aim of the study was to assess the value of cardiac computed tomography (CCT) for the diagnosis of LVNC.MethodsIn this prospective controlled study, segmental analysis of transthoracic echocardiography (TTE) and prospective ECG-triggered CCT was performed in 17 patients with LVNC and 19 healthy controls. In TTE maximal NC and C thickness was measured at enddiastole and endsystole in the segment with most prominent trabeculation in short axis views. In CCT, maximal segmental NC and C thickness was measured during diastole, and NC:C ratio was determined. Spearman's correlation coefficient and receiver operating characteristic curves were calculated.ResultsThe median [IQR] radiation dose was 1.3[1.2-1.5]mSv. The CCT thickness of the C layer was significantly lower in patients with LVNC as compared to controls in the inferolateral, midventricular, lateral-, inferior-, and septal-apical segments. The CCT NC:C ratio differed significantly between LVNC and controls in the inferior-midventricular and all the apical segments. NC:C ratio correlated significantly between TTE and CCT at enddiastole (σ = 0.8) and endsystole (σ = 0.9). Using a CCT NC:C ratio ≥1.8, all LVNC patients could be identified.ConclusionLVNC can be diagnosed with ECG-triggered low-dose CCT and discriminated from normal individuals using a NC:C ratio of ≥1.8 in diastole. There is a very good correlation of NC:C ratio in TTE and CCT.
| S-EPMC7351212 | biostudies-literature