Ruben Doste

Modelling and simulation are essential in biomedicine, and specifically in computational cardiology. Reliable, efficient and accurate solvers are critical. This study presents an open source, GPU-based cardiac electrophysiology solver for scalable digital twin multiscale simulations (M ono A lg 3D), incorporating conduction system calibration and performance optimization. The solver employs the monodomain equation coupled with the Purkinje network, solved via the finite volume method, featuring a GPU-based linear solver and concurrent simulation dispatch with MPI. We demonstrate a 10.94× speedup over a CPU-based solution and scalability by running 512 simulations on 128 compute nodes, completing all coarse-mesh simulations in less than 24 minutes and fine-mesh simulations in 303 minutes. We also demonstrate integration into a cardiac digital twin pipeline for personalisation based on clinical data. The proposed open source solver enhances computational efficiency and physiological fidelity, enabling large-scale, high-speed cardiac simulations. This work marks a significant step toward fast and scalable cardiac simulations on GPU architectures, with integration in a Digital Twin personalisation pipeline including the conduction system.

Background and Aim: Women are significantly under-represented in cardiovascular research and in the evaluation of treatment safety and efficacy, leading to poorer patient outcomes. Quantification and investigation of sex differences in human electromechanical function and underlying mechanisms is crucial. To address this, we present sex-specific human cellular and biventricular electromechanical models for mechanistic investigations into sex-differences in therapy evaluation through simulations. Methods: Protein genomic expression data from healthy human myocytes were used to calibrate sex-specific models of human cellular electrophysiology, subsequently integrated in biventricular electromechanical models with male and female anatomies. A validation, verification and uncertainty evaluation were implemented at the cellular and biventricular level, including validation using sex-specific datasets from randomised controlled trials for Dofetilide and Verapamil, with known sex-differences. Ionic mechanisms underlying sex-differences in drug response were mechanistically investigated. Results: Sex-specific electromechanical models recapitulate sex-differences from ionic currents to ECG biomarkers including QTc interval (Male: 312ms; Female: 339ms; 9% difference), T-wave amplitude (6-9% difference) and ST-steepness through electrophysiological changes alone. Sex-specific simulations demonstrate both ECG biomarkers and mechanical biomarkers (Female LVEF: 68%, Male LVEF: 50%) within healthy ranges in clinical data for male and female population in the UK Biobank (n= 806, 46% Male). ECGs sex-differences are primarily explained by ionic currents, whereas mechanical sex-differences are driven by anatomical differences, and secondarily through more robust calcium function in females. Under Dofetilide, simulations show exacerbated QT prolongation in women compared to men (54-78% increase in effect), and a T-wave amplitude decrease in males (up to 0.25 mV), consistent with clinical data. This is explained in simulations by lower repolarisation reserve in women (due to low potassium and high calcium currents) than men. Verapamil shows no effect on simulated QT in either sex, and divergent T-wave modulation (increased amplitude in females, decreased in males) consistent with clinical trial data. Simulations identify enhanced contractile reservoir in female compared to male, with lesser decreases to ejection fraction with calcium current block. Conclusion: Simulations using novel, sex-specific cellular and biventricular electromechanical models reveal the primary role of ionic currents sex-differences in ECG and drug response, whereas mechanical sex-differences are also underpinned by anatomical differences. Main Contributions: Development, calibration and validation of sex-specific human ventricular electromechanical, multiscale models. An analysis of clinical randomised trial data in the context of sex-specific effects of multi-channel blockers on the ECG by dosage, where previous analysis focused on pharmacokinetics. Consideration of both sex-specific electrophysiology and anatomy explains sex-specific differences on the impact of drugs on ECG and mechanics. Simulations demonstrate that the reduced repolarisation reserve in females increases the susceptibility to QTc prolongation via potassium channel block compared to males, and more robust calcium dynamics protect against t-wave amplitude reduction and the more severe contractility loss through L-type calcium inhibition observed in males.

Cardiac digital twins represent the required functional mechanisms of patient hearts to evaluate therapies and inform clinical decision-making virtually. A scalable generation of cardiac digital twins can enable virtual clinical trials on virtual cohorts to fast-track therapy development. Here, we present an open-source digital twinning framework for personalising electrophysiological function based on routinely acquired magnetic resonance imaging (MRI) data and the standard 12-lead electrocardiogram (ECG). We extended a Bayesian-based inference framework to infer electrical repolarisation characteristics. Fast simulations are conducted with a decoupled reaction-Eikonal model, including the Purkinje network and biophysically-detailed subcellular ionic current dynamics. Parameter uncertainty is represented by inferring a population of ventricular models rather than a single one, which means that parameter uncertainty can be propagated to virtual therapy evaluations. The framework is demonstrated in a healthy female subject, where our inferred reaction-Eikonal models reproduced the patient’s ECG with a Pearson’s correlation coefficient of 0.93. The methodologies for cardiac digital twinning presented here are a step towards personalised virtual therapy testing. The tools developed for this study are open-source, ensuring accessibility, inclusivity, and reproducibility, this is available on GitHub.

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. 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. 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.

Introduction: Hypertrophic cardiomyopathy (HCM) is a leading cause of lethal arrhythmias in the young. Although the arrhythmic substrate has been hypothesised to be amenable to late Na⁺ block with ranolazine, the specific mechanisms are not fully understood. Therefore, this study aimed to investigate the substrate mechanisms of safety and antiarrhythmic efficacy of ranolazine in HCM.Methods: Computational models of human tissue and ventricles were used to simulate the electrophysiological behaviour of diseased HCM myocardium for variable degrees of repolarisation impairment, validated against in vitro and clinical recordings. S1-S2 pacing protocols were used to quantify arrhythmic risk in scenarios of (i) untreated HCM-remodelled myocardium and (ii) myocardium treated with 3µM, 6µM and 10µM ranolazine, for variable repolarisation heterogeneity sizes and pacing rates. ECGs were derived from biventricular simulations to identify ECG biomarkers linked to antiarrhythmic effects.Results: 10µM ranolazine given to models manifesting ventricular tachycardia (VT) at baseline led to a 40% reduction in number of VT episodes on pooled analysis of >40,000 re-entry inducibility simulations. Antiarrhythmic efficacy and safety were dependent on the degree of repolarisation impairment, with optimal benefit in models with maximum JT_c interval Conclusion: Ranolazine efficacy and safety may be critically dependent upon the degree of repolarisation impairment in HCM. For moderate repolarisation impairment, reductions in refractoriness heterogeneity by ranolazine may prevent conduction blocks and re-entry. With severe-extreme disease substrates, reductions of the refractory period can increase re-entry sustainability.

The aim of this work was to analyze the influence of sex hormones and anatomical details (trabeculations and false tendons) on the electrophysiology of healthy human hearts. Additionally, sex- and anatomy-dependent effects of ventricular tachycardia (VT) inducibility are presented. To this end, four anatomically normal, human, biventricular geometries (two male, two female), with identifiable trabeculations, were obtained from high-resolution, ex-vivo MRI and represented by detailed and smoothed geometrical models (with and without the trabeculations). Additionally one model was augmented by a scar. The electrophysiology finite element model (FEM) simulations were carried out, using O’Hara-Rudy human myocyte model with sex phenotypes of Yang and Clancy. A systematic comparison between detailed vs smooth anatomies, male vs female normal hearts was carried out. The heart with a myocardial infarction was subjected to a programmed stimulus protocol to identify the effects of sex and anatomical detail on ventricular tachycardia inducibility. All female hearts presented QT-interval prolongation however the prolongation interval in comparison to the male phenotypes was anatomy-dependent and was not correlated to the size of the heart. Detailed geometries showed QRS fractionation and increased T-wave magnitude in comparison to the corresponding smoothed geometries. A variety of sustained VTs were obtained in the detailed and smoothed male geometries at different pacing locations, which provide evidence of the geometry-dependent differences regarding the prediction of the locations of reentry channels. In the female phenotype, sustained VTs were induced in both detailed and smooth geometries with RV apex pacing, however no consistent reentry channels were identified. Anatomical and physiological cardiac features play an important role defining risk in cardiac disease. These are often excluded from cardiac electrophysiology simulations. The assumption that the cardiac endocardium is smooth may produce inaccurate predictions towards the location of reentry channels in in-silico tachycardia inducibility studies.