Biology subjects

Doste, R.

Publications and source records attributed to Doste, R..

6 recordsLinked to original sources

bioRxiv2025

MonoAlg3D: Enabling Cardiac Electrophysiology Digital Twins with an Efficient Open Source Scalable Solver on GPU Clusters

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 (MO_SCPLOWONOC_SCPLOWAO_SCPLOWLGC_SCPLOW3D), 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 10.94x 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.

bioengineering↗

bioRxiv2025

Sex-specific human electromechanical multiscale in-silico models for virtual therapy evaluation

Background and AimWomen 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. MethodsProtein 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. ResultsSex-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. ConclusionSimulations 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 ContributionsO_LIDevelopment, calibration and validation of sex-specific human ventricular electromechanical, multiscale models. C_LIO_LIAn 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. C_LIO_LIConsideration of both sex-specific electrophysiology and anatomy explains sex-specific differences on the impact of drugs on ECG and mechanics. C_LIO_LISimulations 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. C_LI

physiology↗

bioRxiv2025

Calibration and validation strategy for electromechanical cardiac digital twins

State-of-the-art cardiac electromechanical modelling and simulation form the basis for recent developments in cardiac Digital Twin technologies. However, a comprehensive evaluation of electromechanical models at cellular, tissue, and organ level has yet to be performed that addresses both ECG and pressure-volume biomarkers. Such an evaluation would build credibility for applications of cardiac Digital Twins in clinical research and therapy development. We aimed to follow ASME V&V40 standards for calibration, validation, and sensitivity analysis of ventricular electromechanical models under healthy conditions, to progress towards the Digital Twin vision. We performed a multi-scaled review of ventricular electromechanics and compiled a dataset for calibration and validation incorporating ECG, pressure-volume, displacement, and strain biomarkers. When applied to a biventricular multiscale model, we achieved healthy calibrated values for the QRS duration (89 ms), QT interval (360 ms), left ventricular ejection fraction (LVEF) (51 %), peak systolic pressure (14 kPa), end diastolic (105 mL) and end systolic volumes (51 mL), peak ejection flow rate (180 mL/ms). Model validation was performed by comparison to displacement and strain biomarkers including systolic atrioventricular plane displacement (1.5 cm), systolic fibre strain (-0.18) and longitudinal strain (-0.15). Sensitivity analysis of model parameters at cellular and ventricular scales was also performed to inform model calibration and as a first step towards uncertainty quantification. We quantified the effects of variability in ionic conductance, mechanical stiffness, cross-bridge cycling dynamics, and systemic circulation on action potential and active tension dynamics at the cellular scale, and on ECG, pressure-volume, displacement, and strain biomarkers at the ventricular scale. Simulations showed that the relationship between healthy LVEF and T wave biomarkers was primarily underpinned by variability in L-type calcium channel conductance and SERCA activity through multi-scale effects. In this study, we provide a systematic framework for credibility assessment of cardiac electromechanical models based on both ECG and mechanical biomarkers, as a foundational step towards the cardiac Digital Twin vision.

bioengineering↗

bioRxiv2023

In Silico Evaluation of Cell Therapy in Acute versus Chronic Infarction: Role of Automaticity, Heterogeneity and Purkinje in Human

Human-based modelling and simulation offer an ideal testbed for novel medical therapies to guide experimental and clinical studies. Myocardial infarction (MI) is a common cause of heart failure and mortality, for which novel therapies are urgently needed. Although cell therapy offers promise, electrophysiological heterogeneity raises pro-arrhythmic safety concerns, where underlying complex spatio-temporal dynamics cannot be investigated experimentally. After demonstrating credibility of the modelling and simulation framework, we investigate cell therapy in acute versus chronic MI, and the role of cell heterogeneity, scar size and the Purkinje system. Simulations agreed with experimental and clinical recordings from ionic to ECG dynamics in acute and chronic infarction. Following cell delivery, spontaneous beats were facilitated by heterogeneity in cell populations, chronic MI due to tissue depolarisation, and slow sinus rhythm. Subsequent re-entrant arrhythmias occurred, in some instances with Purkinje involvement, and their susceptibility was enhanced by impaired Purkinje-myocardium coupling, large scars, and acute infarction. We conclude that homogeneity in injected cell populations minimises their spontaneous beating, which is enhanced by chronic MI, whereas a healthy Purkinje-myocardium coupling is key to prevent subsequent re-entrant arrhythmias, particularly for large scars.

bioengineering↗

bioRxiv2022

Human iPSC-CMs and in-silico technologies define mechanisms and accelerate targeted pharmacogenetics in hypertrophic cardiomyopathy

Cardiomyopathies have unresolved genotype-phenotype relationships and lack disease-specific treatments. Here we identify genotype-specific pathomechanisms and therapeutic targets combining experimental hiPSC-CM modelling and human-based cardiac electromechanical in-silico modelling and simulation bridging from specific mutations to 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. We show that destabilisation of myosin super relaxation drives disease in MYH7R403Q/+ with secondary effects on thin filament activation, which are corrected by Mavacamten. Thin filament variants TNNT2R92Q/+ and TNNI3R21C/+ share calcium regulation-related pathomechanisms, for which Mavacamten provides incomplete salvage. 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.

bioengineering↗

bioRxiv2022

Remodelling of potassium currents underlies arrhythmic action potential prolongation under beta-adrenergic stimulation in hypertrophic cardiomyopathy

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 {beta}-adrenergic receptor stimulation ({beta}-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 {beta}-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 {beta}-ARS using experimental measurements of human adult cardiomyocytes from control and HCM patients. Our major findings include: (1) the developed in silico models of {beta}-ARS capture the behaviour observed in the experimental data, including the aberrant response of HCM cardiomyocytes to {beta}-ARS; (2) the reduced increase of potassium currents under {beta}-ARS was identified as the main mechanism of action potential prolongation in HCM, rather than a more sustained inward calcium current; (3) dispersion of repolarisation between healthy and HCM tissue was increased upon {beta}-ARS, while transmural dispersion in HCM tissue was 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 {beta}-ARS through the downregulation of potassium currents.

physiology↗