ORCID Profile
0000-0002-1634-3601
Current Organisation
University of Oxford
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Publisher: Elsevier BV
Date: 04-2020
Publisher: Elsevier BV
Date: 2023
Publisher: Cold Spring Harbor Laboratory
Date: 19-06-2019
DOI: 10.1101/668848
Abstract: 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 in idual’s 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.
Publisher: Public Library of Science (PLoS)
Date: 02-12-2015
Publisher: The Open Journal
Date: 13-03-2020
DOI: 10.21105/JOSS.01848
Publisher: Elsevier BV
Date: 2016
Publisher: Frontiers Media SA
Date: 28-08-2018
Publisher: American Physiological Society
Date: 05-2018
DOI: 10.1152/AJPHEART.00477.2017
Abstract: Variability refers to differences in physiological function between in iduals, 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 s les 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 Ca 2+ 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 Ca 2+ transient phenotypes, differing in intracellular Ca 2+ handling and Na + /Ca 2+ 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 + /Ca 2+ exchanger is identified as a primary mechanism underlying diastolic Ca 2+ fluctuations in human atrial myocytes.
Publisher: Springer Science and Business Media LLC
Date: 04-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-01-2016
DOI: 10.1161/CIRCRESAHA.115.307836
Abstract: Repolarization alternans (RA) are associated with arrhythmogenesis. Animal studies have revealed potential mechanisms, but human-focused studies are needed. RA generation and frequency dependence may be determined by cell-to-cell variability in protein expression, which is regulated by genetic and external factors. To characterize in vivo RA in human and to investigate in silico using human models, the ionic mechanisms underlying the frequency-dependent differences in RA behavior identified in vivo. In vivo electrograms were acquired at 240 sites covering the epicardium of 41 patients at 6 cycle lengths (600–350 ms). In silico investigations were conducted using a population of biophysically detailed human models incorporating variability in protein expression and calibrated using in vivo recordings. Both in silico and in vivo, 2 types of RA were identified, with Fork- and Eye-type restitution curves, based on RA persistence or disappearance, respectively, at fast pacing rates. In silico simulations show that RA are strongly correlated with fluctuations in sarcoplasmic reticulum calcium, because of strong release and weak reuptake. Large L-type calcium current conductance is responsible for RA disappearance at fast frequencies in Eye-type (30% larger in Eye-type versus Fork-type P .01), because of sarcoplasmic reticulum Ca 2+ ATPase pump potentiation caused by frequency-induced increase in intracellular calcium. Large Na + /Ca 2+ exchanger current is the main driver in translating Ca 2+ fluctuations into RA. In human in vivo and in silico, 2 types of RA are identified, with RA persistence/disappearance as frequency increases. In silico, L-type calcium current and Na + /Ca 2+ exchanger current determine RA human cell-to-cell differences through intracellular and sarcoplasmic reticulum calcium regulation.
Location: Spain
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Alfonso Bueno-Orovio.