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Variability refers to differences in physiological function between individuals, which may translate into different disease susceptibility and treatment efficacy. Experiments in human cardiomyocytes face wide variability and restricted tissue access; under these conditions, computational models are a useful complementary tool. We conducted a computational and experimental investigation in cardiomyocytes isolated from samples of the right atrial appendage of patients undergoing cardiac surgery to evaluate the impact of variability in action potentials (APs) and subcellular ionic densities on Ca2+ transient dynamics. Results showed that 1) variability in APs and ionic densities is large, even within an apparently homogenous patient cohort, and translates into ±100% variation in ionic conductances; 2) experimentally calibrated populations of models with wide variations in ionic densities yield APs overlapping with those obtained experimentally, even if AP characteristics of the original generic model differed significantly from experimental APs; 3) model calibration with AP recordings restricts the variability in ionic densities affecting upstroke and resting potential, but redundancy in repolarization currents admits substantial variability in ionic densities; and 4) model populations constrained with experimental APs and ionic densities exhibit three Ca2+ transient phenotypes, differing in intracellular Ca2+ handling and Na+/Ca2+ membrane extrusion. These findings advance our understanding of the impact of variability in human atrial electrophysiology. [ABSTRACT FROM AUTHOR]

Diffusion in biological tissues is known to be hindered by the structural complexity of the underlying medium. In the heart, improved characterisation on how this complexity influences acquired diffusion weighted signals is key to advancing our interpretation of diffusion magnetic resonance imaging, as well as to propose novel biomarkers to further characterise myocardial microstructure. In this work, we propose stretched Mittag–Leffler signal decay models for the quantification of the anomalous decay observed in acquired diffusion weighted signals. Our results, analysed in ex vivo healthy, fixed rat ventricles, indicate that such a representation suffices to capture the anomalous signal decay observed in the myocardial syncytium. The subdiffusive order of signal decay is shown to encode independent information to that encapsulated by standard diffusion tensor metrics, and thus may provide additional information on tissue microstructure. Moreover, subdiffusion gradients are shown to be indicative of the total structural heterogeneity spanning the left ventricular wall, which includes progressive myolaminae branching and spatially varying densities of perimysial collagen, microvasculature and adipose tissue. The proposed approach may therefore have important implications for the characterisation of tissue microstructure, both in cardiac and other tissue types. [ABSTRACT FROM AUTHOR]

Space-fractional operators have been used with success in a variety of practical applications to describe transport processes in media characterised by spatial connectivity properties and high structural heterogeneity altering the classical laws of diffusion. This study provides a systematic investigation of the spatio-temporal effects of a space-fractional model in cardiac electrophysiology. We consider a simplified model of electrical pulse propagation through cardiac tissue, namely the monodomain formulation of the Beeler-Reuter cell model on insulated tissue fibres, and obtain a space-fractional modification of the model by using the spectral definition of the one-dimensional continuous fractional Laplacian. The spectral decomposition of the fractional operator allows us to develop an efficient numerical method for the space-fractional problem. Particular attention is paid to the role played by the fractional operator in determining the solution behaviour and to the identification of crucial differences between the non-fractional and the fractional cases. We find a positive linear dependence of the depolarization peak height and a power law decay of notch and dome peak amplitudes for decreasing orders of the fractional operator. Furthermore, we establish a quadratic relationship in conduction velocity, and quantify the increasingly wider action potential foot and more pronounced dispersion of action potential duration, as the fractional order is decreased. A discussion of the physiological interpretation of the presented findings is made. [ABSTRACT FROM AUTHOR]

Aims. Human action potentials in the Brugada syndrome have been characterized by delayed or even complete loss of dome formation, especially in the right ventricular epicardial layers. Such a repolarization pattern is believed to trigger phase-2 reentry (P2R); however, little is known about the conditions necessary for its initiation. This study aims to determine the specific mechanisms that facilitate P2R induction in Brugada-affected cardiac tissue in humans. Methods. Ionic models for Brugada syndrome in human epicardial cells were developed and used to study the induction of P2R in cables, sheets, and a threedimensional model of the right ventricular free wall. Results. In one-dimensional cables, P2R can be induced by adjoining lost-dome and delayed-dome regions, as mediated by tissue excitability and transmembrane voltage profiles, and reduced coupling facilitates its induction. In two and three dimensions, sustained reentry can arise when three regions (delayed-dome, lost-dome, and normal epicardium) are present. Conclusions. Not only does P2R induction by Brugada syndrome require regions of action potential with delayed-dome and lost-dome, but in order to generate a sustained reentry froma triggered wave back multiple factors are necessary, including heterogeneity in action potential distribution, tissue coupling, direction of stimulation, the shape of the late plateau, the duration of lost-dome action potentials, and recovery of tissue excitability, which is predominantly modulated by tissue coupling. [ABSTRACT FROM AUTHOR]

Fractional differential equations are becoming increasingly used as a powerful modelling approach for understanding the many aspects of nonlocality and spatial heterogeneity. However, the numerical approximation of these models is demanding and imposes a number of computational constraints. In this paper, we introduce Fourier spectral methods as an attractive and easy-to-code alternative for the integration of fractional-in-space reaction-diffusion equations described by the fractional Laplacian in bounded rectangular domains of $$\mathbb {R}^n$$ . The main advantages of the proposed schemes is that they yield a fully diagonal representation of the fractional operator, with increased accuracy and efficiency when compared to low-order counterparts, and a completely straightforward extension to two and three spatial dimensions. Our approach is illustrated by solving several problems of practical interest, including the fractional Allen-Cahn, FitzHugh-Nagumo and Gray-Scott models, together with an analysis of the properties of these systems in terms of the fractional power of the underlying Laplacian operator. [ABSTRACT FROM AUTHOR]

Aims: Human atrial electrophysiology exhibits high inter-subject variability in both sinus rhythm (SR) and chronic atrial fibrillation (cAF) patients. Variability is however rarely investigated in experimental and theoretical electrophysiological studies, thus hampering the understanding of its underlying causes but also its implications in explaining differences in the response to disease and treatment. In our study, we aim at investigating the ability of populations of human atrial cell models to capture the inter-subject variability in action potential (AP) recorded in 363 patients both under SR and cAF conditions. Methods and Results: Human AP recordings in atrial trabeculae (n = 469) from SR and cAF patients were used to calibrate populations of computational SR and cAF atrial AP models. Three populations of over 2000 sampled models were generated, based on three different human atrial AP models. Experimental calibration selected populations of AP models yielding AP with morphology and duration in range with experimental recordings. Populations using the three original models can mimic variability in experimental AP in both SR and cAF, with median conductance values in SR for most ionic currents deviating less than 30% from their original peak values. All cAF populations show similar variations in GK1, GKur and Gto, consistent with AF-related remodeling as reported in experiments. In all SR and cAF model populations, inter-subject variability in IK1 and INaK underlies variability in APD90, variability in IKur, ICaL and INaK modulates variability in APD50 and combined variability in Ito and IKur determines variability in APD20. The large variability in human atrial AP triangulation is mostly determined by IK1 and either INaK or INaCa depending on the model. Conclusion: Experimentally-calibrated human atrial AP models populations mimic AP variability in SR and cAF patient recordings, and identify potential ionic determinants of inter-subject variability in human atrial AP duration and morphology in SR versus cAF. [ABSTRACT FROM AUTHOR]

The sodium-potassium pump is widely recognized as the principal mechanism for active ion transport across the cellular membrane of cardiac tissue, being responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients, crucial for cardiac cell electrophysiology. Importantly, sodium-potassium pump activity is impaired in a number of major diseased conditions, including ischemia and heart failure. However, its subtle ways of action on cardiac electrophysiology, both directly through its electrogenic nature and indirectly via the regulation of cell homeostasis, make it hard to predict the electrophysiological consequences of reduced sodium-potassium pump activity in cardiac repolarization. In this review, we discuss how recent studies adopting the systems biology approach, through the integration of experimental and modeling methodologies, have identified the sodium-potassium pump as one of the most important ionic mechanisms in regulating key properties of cardiac repolarization and its rate dependence, from subcellular to whole organ levels. These include the role of the pump in the biphasic modulation of cellular repolarization and refractoriness, the rate control of intracellular sodium and calcium dynamics and therefore of the adaptation of repolarization to changes in heart rate, as well as its importance in regulating pro-arrhythmic substrates through modulation of dispersion of repolarization and restitution. Theoretical findings are consistent across a variety of cell types and species including human, and widely in agreement with experimental findings. The novel insights and hypotheses on the role of the pump in cardiac electrophysiology obtained through this integrative approach could eventually lead to novel therapeutic and diagnostic strategies. [ABSTRACT FROM AUTHOR]

Left-to-right ventricular (LV/RV) differences in repolarization have been implicated in lethal arrhythmias in animal models. Our goal is to quantify LV/RV differences in action potential duration (APD) and APD rate adaptation and their contribution to arrhythmogenic substrates in the in vivo human heart using combined in vivo and in silico studies. Electrograms were acquired from 10 LV and 10 RV endocardial sites in 15 patients with normal ventricles. APD and APD adaptation were measured during an increase in heart rate. Analysis of in vivo electrograms revealed longer APD in LV than RV (207.8±21.5 vs 196.7±20.1 ms; P<0.05), and slower APD adaptation in LV than RV (time constant ts = 47.0±14.3 vs 35.6±6.5 s; P<0.05). Following rate acceleration, LV/RV APD dispersion experienced an increase of up to 91% in 12 patients, showing a strong correlation (r2 = 0.90) with both initial dispersion and LV/RV difference in slow adaptation. Pro-arrhythmic implications of measured LV/RV functional differences were studied using in silico simulations. Results show that LV/RV APD and APD adaptation heterogeneities promote unidirectional block following rate acceleration, albeit being insufficient for establishment of reentry in normal hearts. However, in the presence of an ischemic region at the LV/RV junction, LV/RV heterogeneity in APD and APD rate adaptation promotes reentrant activity and its degeneration into fibrillatory activity. Our results suggest that LV/RV heterogeneities in APD adaptation cause a transient increase in APD dispersion in the human ventricles following rate acceleration, which promotes unidirectional block and wave-break at the LV/RV junction, and may potentiate the arrhythmogenic substrate, particularly in patients with ischemic heart disease. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) patients often present an enhanced arrhythmogenicity that can lead to lethal arrhythmias, especially during exercise. Recent studies have indicated an abnormal response of HCM cardiomyocytes to β-adrenergic receptor stimulation (β-ARS), with prolongation of their action potential rather than shortening. The mechanisms underlying this aberrant response to sympathetic stimulation and its possible proarrhythmic role remain unknown. The aims of this study are to investigate the key ionic mechanisms underlying the HCM abnormal response to β-ARS and the resultant repolarisation abnormalities using human-based experimental and computational methodologies. We integrated and calibrated the latest models of human ventricular electrophysiology and β-ARS using experimental measurements of human adult cardiomyocytes from control and HCM patients. Our major findings include: (1) the developed in silico models of β-ARS capture the behaviour observed in the experimental data, including the aberrant response of HCM cardiomyocytes to β-ARS; (2) the reduced increase of potassium currents under β-ARS was identified as the main mechanism of action potential prolongation in HCM, rather than a more sustained inward calcium current; (3) action potential duration differences between healthy and HCM cardiomyocytes were increased upon β-ARS, while endocardial to epicardial differences in HCM cardiomyocytes were reduced; (4) models presenting repolarisation abnormalities were characterised by downregulation of the rapid delayed rectifier potassium current and the sodium‑potassium pump, while inward currents were upregulated. In conclusion, our results identify causal relationships between the HCM phenotype and its arrhythmogenic response to β-ARS through the downregulation of potassium currents. [Display omitted] • New experimental data confirms an abnormal β-adrenergic response in HCM cells • β-adrenergic response in human HCM myocytes was studied with mathematical modelling • Downregulation of potassium currents under β-ARS in HCM caused APD prolongation • HCM remodelling and its interaction with β-ARS promotes arrhythmogenic response [ABSTRACT FROM AUTHOR]

In this paper, the continuous adjoint method to compute shape sensitivities in aerodynamic design with turbulence modeling is described and developed. The focus is on compressible flows described by the Reynolds-averaged Navier-Stokes equations and the classical Spalart-Allmaras model for turbulence. Turbulence modeling usually requires, in particular, computation of the distance to the surface. Here, this distance is incorporated to the system as a new variable, solving the Eikonal equation. The accuracy of the sensitivity derivatives obtained with the complete turbulent approach is assessed by comparison with finite difference computations and the classical continuous adjoint with frozen viscosity, showing substantial improvements in the convergence properties of the method and in the quality of the obtained gradients. The validity of the overall methodology is illustrated with several design examples, including the optimization of three-dimensional geometries in combination with advanced freeform techniques for mesh deformation. [ABSTRACT FROM AUTHOR]

β-adrenergic receptor stimulation (β-ARS) is a physiological mechanism that regulates cardiovascular function under stress conditions or physical exercise. Triggered during the so-called "fight-or-flight" response, the activation of the β-adrenergic receptors located on the cardiomyocyte membrane initiates a phosphorylation cascade of multiple ion channel targets that regulate both cellular excitability and recovery and of different proteins involved in intracellular calcium handling. As a result, β-ARS impacts both the electrophysiological and the mechanical response of the cardiomyocyte. β-ARS also plays a crucial role in several cardiac pathologies, greatly modifying cardiac output and potentially causing arrhythmogenic events. Mathematical patient-specific models are nowadays envisioned as an important tool for the personalised study of cardiac disease, the design of tailored treatments, or to inform risk assessment. Despite that, only a reduced number of computational studies of heart disease have incorporated β-ARS modelling. In this review, we describe the main existing multiscale frameworks to equip cellular models of cardiac electrophysiology with a β-ARS response. We also outline various applications of these multiscale frameworks in the study of cardiac pathology. We end with a discussion of the main current limitations and the future steps that need to be taken to adapt these models to a clinical environment and to incorporate them in organ-level simulations. [ABSTRACT FROM AUTHOR]

Abstract: Modeling the dynamics of wave propagation in human ventricular tissue and studying wave stability require models that reproduce realistic characteristics in tissue. We present a minimal ventricular (MV) human model that is designed to reproduce important tissue-level characteristics of epicardial, endocardial and midmyocardial cells, including action potential (AP) amplitudes and morphologies, upstroke velocities, steady-state action potential duration (APD) and conduction velocity (CV) restitution curves, minimum APD, and minimum diastolic interval. The model is then compared with three previously published human ventricular cell models, the Priebe and Beuckelmann (PB), the Ten Tusscher–Noble–Noble–Panfilov (TNNP), and the Iyer–Mazhari–Winslow (IMW). For the first time, the stability of reentrant waves for all four models is analyzed, and quantitative comparisons are made among the models in single cells and in tissue. The PB, TNNP, and IMW models exhibit quantitative differences in APD and CV rate adaptation, as well as completely different reentrant wave dynamics of quasi-breakup, stability, and breakup, respectively. All the models have dominant frequencies comparable to clinical values except for the IMW model, which has a large range of frequencies extending beyond the clinical range for both ventricular tachycardia (VT) and ventricular fibrillation (VF). The TNNP and IMW models possess a large degree of short-term memory and we show for the first time the existence of memory in CV restitution. The MV model also can be fitted to reproduce the dynamics of other models and is computationally more efficient: the times required to simulate the MV, TNNP, PB and IMW models follow the ratio 1:31:50:8084. [Copyright &y& Elsevier]

Abstract: One possible way to solve a partial differential equation in an irregular region Ω is the use of the so-called domain embedding methods, in where the domain of interest is embedded within a rectangle. In order to apply a Fourier spectral method on the rectangle, the inhomogeneous term f(x, y) has to be extended to a new function g(x, y) that is periodic and infinitely differentiable, and equal to f(x, y) everywhere within Ω. Some authors have given explicit methods to compute extensions with infinite order convergence for the cases in where the boundary of Ω, ∂Ω, can be defined as the zero isoline of a function ψ(x, y). For the cases in where this is not possible, we suggest a new method to build these extensions via convolution with Gaussian kernels. [Copyright &y& Elsevier]

In this paper, we propose a numerical method to approximate the solution of partial differential equations in irregular domains with no-flux boundary conditions. The idea is to embed the domain into a box and use a smoothing term to encode the boundary conditions into a modified equation that can be approached by standard spectral methods. The main features of this method are its capability to deal with domains of arbitrary shape and its easy implementation via fast Fourier transform routines. We discuss several examples of practical interest and test the results against standard numerical methods. [ABSTRACT FROM AUTHOR]

Aims Lethal arrhythmias in hypertrophic cardiomyopathy (HCM) are widely attributed to myocardial ischaemia and fibrosis. How these factors modulate arrhythmic risk remains largely unknown, especially as invasive mapping protocols are not routinely used in these patients. By leveraging multiscale digital twin technologies, we aim to investigate ischaemic mechanisms of increased arrhythmic risk in HCM. Methods and results Computational models of human HCM cardiomyocytes, tissue, and ventricles were used to simulate outcomes of Phase 1A acute myocardial ischaemia. Cellular response predictions were validated with patch-clamp studies of human HCM cardiomyocytes (n = 12 cells, N = 5 patients). Ventricular simulations were informed by typical distributions of subendocardial/transmural ischaemia as analysed in perfusion scans (N = 28 patients). S1-S2 pacing protocols were used to quantify arrhythmic risk for scenarios in which regions of septal obstructive hypertrophy were affected by (i) ischaemia, (ii) ischaemia and impaired repolarization, and (iii) ischaemia, impaired repolarization, and diffuse fibrosis. HCM cardiomyocytes exhibited enhanced action potential and abnormal effective refractory period shortening to ischaemic insults. Analysis of ∼75 000 re-entry induction cases revealed that the abnormal HCM cellular response enabled establishment of arrhythmia at milder ischaemia than otherwise possible in healthy myocardium, due to larger refractoriness gradients that promoted conduction block. Arrhythmias were more easily sustained in transmural than subendocardial ischaemia. Mechanisms of ischaemia–fibrosis interaction were strongly electrophysiology dependent. Fibrosis enabled asymmetric re-entry patterns and break-up into sustained ventricular tachycardia. Conclusion HCM ventricles exhibited an increased risk to non-sustained and sustained re-entry, largely dominated by an impaired cellular response and deleterious interactions with the diffuse fibrotic substrate. [ABSTRACT FROM AUTHOR]

This study aims at identifying risk-related patterns of left ventricular contraction dynamics via novel volume transient characterization. A multicenter cohort of AMI survivors (n = 1021) who underwent Cardiac Magnetic Resonance (CMR) after infarction was considered for the study. The clinical endpoint was the 12-month rate of major adverse cardiac events (MACE, n = 73), consisting of all-cause death, reinfarction, and new congestive heart failure. Cardiac function was characterized from CMR in 3 potential directions: by (1) volume temporal transients (i.e. contraction dynamics); (2) feature tracking strain analysis (i.e. bulk tissue peak contraction); and (3) 3D shape analysis (i.e. 3D contraction morphology). A fully automated pipeline was developed to extract conventional and novel artificial-intelligence-derived metrics of cardiac contraction, and their relationship with MACE was investigated. Any of the 3 proposed directions demonstrated its additional prognostic value on top of established CMR indexes, myocardial injury markers, basic characteristics, and cardiovascular risk factors (P < 0.001). The combination of these 3 directions of enhancement towards a final CMR risk model improved MACE prediction by 13% compared to clinical baseline (0.774 (0.771—0.777) vs. 0.683 (0.681—0.685) cross-validated AUC, P < 0.001). The study evidences the contribution of the novel contraction characterization, enabled by a fully automated pipeline, to post-infarction assessment. [ABSTRACT FROM AUTHOR]

Background and Purpose: Early identification of drug-induced cardiac adverse events is key in drug development. Human-based computer models are emerging as an effective approach, complementary to in vitro and animal models. Drug-induced shortening of the electromechanical window has been associated with increased risk of arrhythmias. This study investigates the potential of a cellular surrogate for the electromechanical window (EMw) for prediction of pro-arrhythmic cardiotoxicity, and its underlying ionic mechanisms, using human-based computer models.Experimental Approach: In silico drug trials for 40 reference compounds were performed, testing up to 100-fold the therapeutic concentrations (EFTPCmax ) and using a control population of human ventricular action potential (AP) models, optimised to capture pro-arrhythmic ionic profiles. EMw was calculated for each model in the population as the difference between AP and Ca2+ transient durations at 90%. Drug-induced changes in the EMw and occurrence of repolarisation abnormalities (RA) were quantified.Key Results: Drugs with clinical risk of Torsade de Pointes arrhythmias induced a concentration-dependent EMw shortening, while safe drugs lead to increase or small change in EMw. Risk predictions based on EMw shortening achieved 90% accuracy at 10× EFTPCmax , whereas RA-based predictions required 100× EFTPCmax to reach the same accuracy. As it is dependent on Ca2+ transient, the EMw was also more sensitive than AP prolongation in distinguishing between pure hERG blockers and multichannel compounds also blocking the calcium current.Conclusion and Implications: The EMw is an effective biomarker for in silico predictions of drug-induced clinical pro-arrhythmic risk, particularly for compounds with multichannel blocking action. [ABSTRACT FROM AUTHOR]

The best pharmacological treatment for each atrial fibrillation (AF) patient is unclear. We aim to exploit AF simulations in 800 virtual atria to identify key patient characteristics that guide the optimal selection of anti‐arrhythmic drugs. The virtual cohort considered variability in electrophysiology and low voltage areas (LVA) and was developed and validated against experimental and clinical data from ionic currents to ECG. AF sustained in 494 (62%) atria, with large inward rectifier K+ current (IK1) and Na+/K+ pump (INaK) densities (IK1 0.11 ± 0.03 vs. 0.07 ± 0.03 S mF–1; INaK 0.68 ± 0.15 vs. 0.38 ± 26 S mF–1; sustained vs. un‐sustained AF). In severely remodelled left atrium, with LVA extensions of more than 40% in the posterior wall, higher IK1 (median density 0.12 ± 0.02 S mF–1) was required for AF maintenance, and rotors localized in healthy right atrium. For lower LVA extensions, rotors could also anchor to LVA, in atria presenting short refractoriness (median L‐type Ca2+ current, ICaL, density 0.08 ± 0.03 S mF–1). This atrial refractoriness, modulated by ICaL and fast Na+ current (INa), determined pharmacological treatment success for both small and large LVA. Vernakalant was effective in atria presenting long refractoriness (median ICaL density 0.13 ± 0.05 S mF–1). For short refractoriness, atria with high INa (median density 8.92 ± 2.59 S mF–1) responded more favourably to amiodarone than flecainide, and the opposite was found in atria with low INa (median density 5.33 ± 1.41 S mF–1). In silico drug trials in 800 human atria identify inward currents as critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics. Key points: Atrial fibrillation (AF) maintenance is facilitated by small L‐type Ca2+ current (ICaL) and large inward rectifier K+ current (IK1) and Na+/K+ pump.In severely remodelled left atrium, with low voltage areas (LVA) covering more than 40% of the posterior wall, sustained AF requires higher IK1 and rotors localize in healthy right atrium. For lower LVA extensions, rotors can also anchor to LVA, if the atria present short refractoriness (low ICaL)Vernakalant is effective in atria presenting long refractoriness (high ICaL). For short refractoriness, atria with fast Na+ current (INa) up‐regulation respond more favourably to amiodarone than flecainide, and the opposite is found in atria with low INa.The inward currents (ICaL and INa) are critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics. [ABSTRACT FROM AUTHOR]

Input-output (I/O) optimization at the low-level design of data layout on disk drastically impacts the efficiency of high performance computing (HPC) applications. However, such a low-level optimization is in general challenging, especially when using popular scientific file formats designed with an emphasis on portability and flexibility. To reconcile these two aspects, we present a novel low-level data layout for HPC applications, fully independent of the number of dimensions in the dataset. The new data layout improves reading and writing efficiency in large HPC applications using many processors, and in particular during parallel post-processing. Furthermore, its combination with a cached write mode, in order to aggregate multiple writes into larger ones, substantially decreased the writing times of the proposed strategy. When applied to our simulation framework for the forward calculation of the human electrocardiogram, the combined strategy resulted in drastic improvements in I/O performance, of up to 40% in writing and 93–98% in reading for post-processing tasks. Given the generality of the proposed strategies and scientific file formats used, our results may represent significant improvements in I/O performance of HPC applications across multiple disciplines, reducing execution and post-processing times and leading to a more efficient use of HPC resource envelopes. [ABSTRACT FROM AUTHOR]

Variability refers to differences in physiological function between individuals, which may translate into different disease susceptibility and treatment efficacy. Experiments in human cardiomyocytes face wide variability and restricted tissue access; under these conditions, computational models are a useful complementary tool. We conducted a computational and experimental investigation in cardiomyocytes isolated from samples of the right atrial appendage of patients undergoing cardiac surgery to evaluate the impact of variability in action potentials (APs) and subcellular ionic densities on Ca2+ transient dynamics. Results showed that 1) variability in APs and ionic densities is large, even within an apparently homogenous patient cohort, and translates into -100% variation in ionic conductances; 2) experimentally calibrated populations of models with wide variations in ionic densities yield APs overlapping with those obtained experimentally, even if AP characteristics of the original generic model differed significantly from experimental APs; 3) model calibration with AP recordings restricts the variability in ionic densities affecting upstroke and resting potential, but redundancy in repolarization currents admits substantial variability in ionic densities; and 4) model populations constrained with experimental APs and ionic densities exhibit three Ca2+ transient phenotypes, differing in intracellular Ca2+ handling and Na+/Ca2+ membrane extrusion. These findings advance our understanding of the impact of variability in human atrial electrophysiology. NEW & NOTEWORTHY Variability in human atrial electrophysiology is investigated by integrating for the first time cellular-level and ion channel recordings in computational electrophysiological models. Ion channel calibration restricts current densities but not cellular phenotypic variability. Reduced Na+/Ca2+ exchanger is identified as a primary mechanism underlying diastolic Ca2+ fluctuations in human atrial myocytes. [ABSTRACT FROM AUTHOR]

Cardiomyopathies have unresolved genotype–phenotype relationships and lack disease-specific treatments. Here we provide a framework to identify genotype-specific pathomechanisms and therapeutic targets to accelerate the development of precision medicine. We use human cardiac electromechanical in-silico modelling and simulation which we validate with experimental hiPSC-CM data and modelling in combination with clinical biomarkers. We select hypertrophic cardiomyopathy as a challenge for this approach and study genetic variations that mutate proteins of the thick (MYH7R403Q/+) and thin filaments (TNNT2R92Q/+, TNNI3R21C/+) of the cardiac sarcomere. Using in-silico techniques we show that the destabilisation of myosin super relaxation observed in hiPSC-CMs drives disease in virtual cells and ventricles carrying the MYH7R403Q/+ variant, and that secondary effects on thin filament activation are necessary to precipitate slowed relaxation of the cell and diastolic insufficiency in the chamber. In-silico modelling shows that Mavacamten corrects the MYH7R403Q/+ phenotype in agreement with hiPSC-CM experiments. Our in-silico model predicts that the thin filament variants TNNT2R92Q/+ and TNNI3R21C/+ display altered calcium regulation as central pathomechanism, for which Mavacamten provides incomplete salvage, which we have corroborated in TNNT2R92Q/+ and TNNI3R21C/+ hiPSC-CMs. We define the ideal characteristics of a novel thin filament-targeting compound and show its efficacy in-silico. We demonstrate that hybrid human-based hiPSC-CM and in-silico studies accelerate pathomechanism discovery and classification testing, improving clinical interpretation of genetic variants, and directing rational therapeutic targeting and design. [ABSTRACT FROM AUTHOR]

• Novel pipeline for generating cardiac digital twins, including a Purkinje network from clinical CMR and ECG recordings capable of simulating patient-specific QRS morphological phenotypes. • Novel human-based Purkinje network generation method to constrain the cardiac digital twins to physiological activation sequences. • Novel strategy to personalise to ECG R wave progression and QRS morphology. • Novel strategy to translate reduced-order Eikonal models to equivalent biophysically-detailed monodomain simulations. • Demonstrated generation of cardiac digital twins for control subjects and disease patients with abnormal QRS complexes. • The statistical methods presented in this work enable representing electrophysiological uncertainty in cohorts of digital twins for in silico trials. Cardiac in silico clinical trials can virtually assess the safety and efficacy of therapies using human-based modelling and simulation. These technologies can provide mechanistic explanations for clinically observed pathological behaviour. Designing virtual cohorts for in silico trials requires exploiting clinical data to capture the physiological variability in the human population. The clinical characterisation of ventricular activation and the Purkinje network is challenging, especially non-invasively. Our study aims to present a novel digital twinning pipeline that can efficiently generate and integrate Purkinje networks into human multiscale biventricular models based on subject-specific clinical 12-lead electrocardiogram and magnetic resonance recordings. Essential novel features of the pipeline are the human-based Purkinje network generation method, personalisation considering ECG R wave progression as well as QRS morphology, and translation from reduced-order Eikonal models to equivalent biophysically-detailed monodomain ones. We demonstrate ECG simulations in line with clinical data with clinical image-based multiscale models with Purkinje in four control subjects and two hypertrophic cardiomyopathy patients (simulated and clinical QRS complexes with Pearson's correlation coefficients > 0.7). Our methods also considered possible differences in the density of Purkinje myocardial junctions in the Eikonal-based inference as regional conduction velocities. These differences translated into regional coupling effects between Purkinje and myocardial models in the monodomain formulation. In summary, we demonstrate a digital twin pipeline enabling simulations yielding clinically consistent ECGs with clinical CMR image-based biventricular multiscale models, including personalised Purkinje in healthy and cardiac disease conditions. [Display omitted] [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is still orphan of a specific drug treatment. The erroneous consideration of HCM as a rare disease has hampered the design and conduct of large, randomized trials in the last 50 years, and most of the indications in the current guidelines are derived from small non-randomized studies, case series, or simply from the consensus of experts. Guideline-directed therapy of HCM includes non-selective drugs such as disopyramide, non-dihydropyridine calcium channel blockers, or β-adrenergic receptor blockers, mainly used in patients with symptomatic obstruction of the outflow tract. Following promising preclinical studies, several drugs acting on potential HCM-specific targets were tested in patients. Despite the huge efforts, none of these studies was able to change clinical practice for HCM patients, because tested drugs were proven to be scarcely effective or hardly tolerated in patients. However, novel compounds have been developed in recent years specifically for HCM, addressing myocardial hypercontractility and altered energetics in a direct manner, through allosteric inhibition of myosin. In this paper, we will critically review the use of different classes of drugs in HCM patients, starting from "old" established agents up to novel selective drugs that have been recently trialed in patients. [ABSTRACT FROM AUTHOR]

Personalized cardiac electrophysiology simulations have demonstrated great potential to study cardiac arrhythmias and help in therapy planning of radio-frequency ablation. Its application to analyze vulnerability to ventricular tachycardia and sudden cardiac death in infarcted patients has been recently explored. However, the detailed multi-scale biophysical simulations used in these studies are very demanding in terms of memory and computational resources, which prevents their clinical translation. In this work, we present a fast phenomenological system based on cellular automata (CA) to simulate personalized cardiac electrophysiology. The system is trained on biophysical simulations to reproduce cellular and tissue dynamics in healthy and pathological conditions, including action potential restitution, conduction velocity restitution and cell safety factor. We show that a full ventricular simulation can be performed in the order of seconds, emulate the results of a biophysical simulation and reproduce a patient's ventricular tachycardia in a model that includes a heterogeneous scar region. The system could be used to study the risk of arrhythmia in infarcted patients for a large number of scenarios. [ABSTRACT FROM AUTHOR]

Pharmacological treatment of atrial fibrillation (AF) exhibits limited efficacy. Further developments require a comprehensive characterization of ionic modulators of electrophysiology in human atria. Our aim is to systematically investigate the relative importance of ionic properties in modulating excitability, refractoriness, and rotor dynamics in human atria before and after AF-related electrical remodeling (AFER). Computer simulations of single cell and tissue atrial electrophysiology were conducted using two human atrial action potential (AP) models. Changes in AP, refractory period (RP), conduction velocity (CV), and rotor dynamics caused by alterations in key properties of all atrial ionic currents were characterized before and after AFER. Results show that the investigated human atrial electrophysiological properties are primarily modulated by maximal value of Na+/K+ pump current (GNaK) as well as conductances of inward rectifier potassium current (GK1) and fast inward sodium current (GNa). GNaK plays a fundamental role through both electrogenic and homeostatic modulation of AP duration (APD), APD restitution, RP, and reentrant dominant frequency (DF). GK1 controls DF through modulation of AP, APD restitution, RP, and CV. GNa is key in determining DF through alteration of CV and RP, particularly in AFER. Changes in ionic currents have qualitatively similar effects in control and AFER, but effects are smaller in AFER. The systematic analysis conducted in this study unravels the important role of the Na+/K+ pump current in determining human atrial electrophysiology. [ABSTRACT FROM AUTHOR]

Human-based computational modelling and simulation are powerful tools to accelerate the mechanistic understanding of cardiac patho-physiology, and to develop and evaluate therapeutic interventions. The aim of this study is to calibrate and evaluate human ventricular electro-mechanical models for investigations on the effect of the electro-mechanical coupling and pharmacological action on human ventricular electrophysiology, calcium dynamics, and active contraction. The most recent models of human ventricular electrophysiology, excitation-contraction coupling, and active contraction were integrated, and the coupled models were calibrated using human experimental data. Simulations were then conducted using the coupled models to quantify the effects of electro-mechanical coupling and drug exposure on electrophysiology and force generation in virtual human ventricular cardiomyocytes and tissue. The resulting calibrated human electro-mechanical models yielded active tension, action potential, and calcium transient metrics that are in agreement with experiments for endocardial, epicardial, and mid-myocardial human samples. Simulation results correctly predicted the inotropic response of different multichannel action reference compounds and demonstrated that the electro-mechanical coupling improves the robustness of repolarisation under drug exposure compared to electrophysiology-only models. They also generated additional evidence to explain the partial mismatch between in-silico and in-vitro experiments on drug-induced electrophysiology changes. The human calibrated and evaluated modelling and simulation framework constructed in this study opens new avenues for future investigations into the complex interplay between the electrical and mechanical cardiac substrates, its modulation by pharmacological action, and its translation to tissue and organ models of cardiac patho-physiology. [ABSTRACT FROM AUTHOR]

Introduction Hypertrophic cardiomyopathy (HCM) is a cause of sudden arrhythmic death, but the understanding of its pro-arrhythmic mechanisms and an effective pharmacological treatment are lacking. HCM electrophysiological remodelling includes both increased inward and reduced outward currents, but their role in promoting repolarisation abnormalities remains unknown. The goal of this study is to identify key ionic mechanisms driving repolarisation abnormalities in human HCM, and to evaluate anti-arrhythmic effects of single and multichannel inward current blocks. Methods Experimental ionic current, action potential (AP) and Ca 2 + -transient (CaT) recordings were used to construct populations of human non-diseased and HCM AP models (n = 9118), accounting for inter-subject variability. Simulations were conducted for several degrees of selective and combined inward current block. Results Simulated HCM cardiomyocytes exhibited prolonged AP and CaT, diastolic Ca 2 + overload and decreased CaT amplitude, in agreement with experiments. Repolarisation abnormalities in HCM models were consistently driven by L-type Ca 2 + current (I CaL ) re-activation, and I CaL block was the most effective intervention to normalise repolarisation and diastolic Ca 2 + , but compromised CaT amplitude. Late Na + current (I NaL ) block partially abolished repolarisation abnormalities, with small impact on CaT. Na + /Ca 2 + exchanger (I NCX ) block effectively restored repolarisation and CaT amplitude, but increased Ca 2 + overload. Multichannel block increased efficacy in normalising repolarisation, AP biomarkers and CaT amplitude compared to selective block. Conclusions Experimentally-calibrated populations of human AP models identify I CaL re-activation as the key mechanism for repolarisation abnormalities in HCM, and combined I NCX , I NaL and I CaL block as effective anti-arrhythmic therapies also able to partially reverse the HCM electrophysiological phenotype. [ABSTRACT FROM AUTHOR]

Physiological variability manifests itself via differences in physiological function between individuals of the same species, and has crucial implications in disease progression and treatment. Despite its importance, physiological variability has traditionally been ignored in experimental and computational investigations due to averaging over samples from multiple individuals. Recently, modelling frameworks have been devised for studying mechanisms underlying physiological variability in cardiac electrophysiology and pro-arrhythmic risk under a variety of conditions and for several animal species as well as human. One such methodology exploits populations of cardiac cell models constrained with experimental data, or experimentally-calibrated populations of models. In this review, we outline the considerations behind constructing an experimentally-calibrated population of models and review the studies that have employed this approach to investigate variability in cardiac electrophysiology in physiological and pathological conditions, as well as under drug action. We also describe the methodology and compare it with alternative approaches for studying variability in cardiac electrophysiology, including cell-specific modelling approaches, sensitivity-analysis based methods, and populations-of-models frameworks that do not consider the experimental calibration step. We conclude with an outlook for the future, predicting the potential of new methodologies for patient-specific modelling extending beyond the single virtual physiological human paradigm. [ABSTRACT FROM AUTHOR]

• Novel numerical method for capturing fine-scale heterogeneities using a coarse mesh. • Competitive homogenisation technique that functions naturally on irregular grids. • Error from Graph-based method is consistent with upscaling the homogeneous problem. • Performs well on some challenging problems of interest in Cardiac electrophysiology. Fibrosis, the excess of extracellular matrix, can affect, and even block, propagation of action potential in cardiac tissue. This can result in deleterious effects on heart function, but the nature and severity of these effects depend strongly on the localisation of fibrosis and its by-products in cardiac tissue, such as collagen scar formation. Computer simulation is an important means of understanding the complex effects of fibrosis on activation patterns in the heart, but concerns of computational cost place restrictions on the spatial resolution of these simulations. In this work, we present a novel numerical homogenisation technique that uses both Eikonal and graph approaches to allow fine-scale heterogeneities in conductivity to be incorporated into a coarser mesh. Homogenisation achieves this by deriving effective conductivity tensors so that a coarser mesh can then be used for numerical simulation. By taking a graph-based approach, our homogenisation technique functions naturally on irregular grids and does not rely upon any assumptions of periodicity, even implicitly. We present results of action potential propagation through fibrotic tissue in two dimensions that show the graph-based homogenisation technique is an accurate and effective way to capture fine-scale domain information on coarser meshes in the context of sharp-fronted travelling waves of activation. As test problems, we consider excitation propagation in tissue with diffuse fibrosis and through a tunnel-like structure designed to test homogenisation, interaction of an excitation wave with a scar region, and functional re-entry. [ABSTRACT FROM AUTHOR]