Biology subjects

Bueno-Orovio, A.

Publications and source records attributed to Bueno-Orovio, A..

3 recordsLinked to original sources

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↗

bioRxiv2020

ToR-ORd-dynCl: an update of the ToR-ORd model of human ventricular cardiomyocyte with dynamic intracellular chloride

Recently, our group published a new model of human ventricular cardiomyocyte named ToR-ORd (Tomek et al., 2019). Its development, calibration, and validation, were performed using a broad range of human experimental data and brought general insights into modelling of ionic channels. Model calibration ensured the reproduction of key physiological cellular features, with independent multiscale validation demonstrating a correct response to channel blocking drugs and pathophysiological remodelling. However, for very long simulations (several hours rather than minutes), the ToR-ORd simulations display a drift in its behaviour, caused by modelling chloride concentrations as constant values. This may be a limitation for simulations considering extremely long protocols, or for studies on model stability. To remedy this, we present here an updated version, termed ToR-ORd-dynCl, with dynamic representation of intracellular chloride. This model behaves very similarly to the original ToR-ORd, but with stable properties over long simulations and only a small increase in model complexity.

physiology↗

bioRxiv2019

Perlin Noise Generation of Physiologically Realistic Patterns of Fibrosis

Fibrosis, the pathological excess of fibroblast activity, is a significant health issue that hinders the function of many organs in the body, in some cases fatally. However, the severity of fibrosis-derived conditions depends on both the positioning of fibrotic affliction, and the microscopic patterning of fibroblast-deposited matrix proteins within afflicted regions. Variability in an individuals manifestation of a type of fibrosis is an important factor in explaining differences in symptoms, optimum treatment and prognosis, but a need for ex vivo procedures and a lack of experimental control over conflating factors has meant this variability remains poorly understood. In this work, we present a computational methodology for the generation of patterns of fibrosis microstructure, demonstrating the technique using histological images of four types of cardiac fibrosis. Our generator and automated tuning method prove flexible enough to capture each of these very distinct patterns, allowing for rapid generation of new realisations for high-throughput computational studies. We also demonstrate via simulation, using the generated fibrotic patterns, the importance of micro-scale variability by showing significant differences in electrophysiological impact even within a single class of fibrosis.

physiology↗