Alfonso Bueno-Orovio

Bio: Alfonso Bueno-Orovio is an academic researcher from University of Oxford. The author has contributed to research in topics: Population & Repolarization. The author has an hindex of 26, co-authored 89 publications receiving 2816 citations. Previous affiliations of Alfonso Bueno-Orovio include British Heart Foundation & University of Castilla–La Mancha.

Fourier spectral methods for fractional-in-space reaction-diffusion equations

Abstract: 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.

The 'Digital Twin' to enable the vision of precision cardiology.

Abstract: Providing therapies tailored to each patient is the vision of precision medicine, enabled by the increasing ability to capture extensive data about individual patients. In this position paper, we argue that the second enabling pillar towards this vision is the increasing power of computers and algorithms to learn, reason, and build the 'digital twin' of a patient. Computational models are boosting the capacity to draw diagnosis and prognosis, and future treatments will be tailored not only to current health status and data, but also to an accurate projection of the pathways to restore health by model predictions. The early steps of the digital twin in the area of cardiovascular medicine are reviewed in this article, together with a discussion of the challenges and opportunities ahead. We emphasize the synergies between mechanistic and statistical models in accelerating cardiovascular research and enabling the vision of precision medicine.

Experimentally calibrated population of models predicts and explains intersubject variability in cardiac cellular electrophysiology

Abstract: Cellular and ionic causes of variability in the electrophysiological activity of hearts from individuals of the same species are unknown. However, improved understanding of this variability is key to enable prediction of the response of specific hearts to disease and therapies. Limitations of current mathematical modeling and experimental techniques hamper our ability to provide insight into variability. Here, we describe a methodology to unravel the ionic determinants of intersubject variability exhibited in experimental recordings, based on the construction and calibration of populations of models. We illustrate the methodology through its application to rabbit Purkinje preparations, because of their importance in arrhythmias and safety pharmacology assessment. We consider a set of equations describing the biophysical processes underlying rabbit Purkinje electrophysiology, and we construct a population of over 10,000 models by randomly assigning specific parameter values corresponding to ionic current conductances and kinetics. We calibrate the model population by closely comparing simulation output and experimental recordings at three pacing frequencies. We show that 213 of the 10,000 candidate models are fully consistent with the experimental dataset. Ionic properties in the 213 models cover a wide range of values, including differences up to ±100% in several conductances. Partial correlation analysis shows that particular combinations of ionic properties determine the precise shape, amplitude, and rate dependence of specific action potentials. Finally, we demonstrate that the population of models calibrated using data obtained under physiological conditions quantitatively predicts the action potential duration prolongation caused by exposure to four concentrations of the potassium channel blocker dofetilide.

Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity.

Abstract: Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key challenges include consideration of inter-cellular variability in drug responses and integration of computational and experimental methods in safety pharmacology. Our aim is to evaluate the ability of in silico drug trials in populations of human action potential (AP) models to predict clinical risk of drug-induced arrhythmias based on ion channel information, and to compare simulation results against experimental assays commonly used for drug testing. A control population of 1,213 human ventricular AP models in agreement with experimental recordings was constructed. In silico drug trials were performed for 62 reference compounds at multiple concentrations, using pore-block drug models (IC50/Hill coefficient). Drug-induced changes in AP biomarkers were quantified, together with occurrence of repolarisation/depolarisation abnormalities. Simulation results were used to predict clinical risk based on reports of Torsade de Pointes arrhythmias, and further evaluated in a subset of compounds through comparison with electrocardiograms from rabbit wedge preparations and Ca2+-transient recordings in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). Drug-induced changes in silico vary in magnitude depending on the specific ionic profile of each model in the population, thus allowing to identify cell sub-populations at higher risk of developing abnormal AP phenotypes. Models with low repolarisation reserve (increased Ca2+/late Na+ currents and Na+/Ca2+-exchanger, reduced Na+/K+-pump) are highly vulnerable to drug-induced repolarisation abnormalities, while those with reduced inward current density (fast/late Na+ and Ca2+ currents) exhibit high susceptibility to depolarisation abnormalities. Repolarisation abnormalities in silico predict clinical risk for all compounds with 89% accuracy. Drug-induced changes in biomarkers are in overall agreement across different assays: in silico AP duration changes reflect the ones observed in rabbit QT interval and hiPS-CMs Ca2+-transient, and simulated upstroke velocity captures variations in rabbit QRS complex. Our results demonstrate that human in silico drug trials constitute a powerful methodology for prediction of clinical pro-arrhythmic cardiotoxicity, ready for integration in the existing drug safety assessment pipelines.

SU2: An Open-Source Suite for Multiphysics Simulation and Design

Abstract: This paper presents the main objectives and a description of the SU2 suite, including the novel software architecture and open-source software engineering strategy. SU2 is a computational analysis and design package that has been developed to solve multiphysics analysis and optimization tasks using unstructured mesh topologies. Its unique architecture is well suited for extensibility to treat partial-differential-equation-based problems not initially envisioned. The common framework adopted enables the rapid implementation of new physics packages that can be tightly coupled to form a powerful ensemble of analysis tools to address complex problems facing many engineering communities. The framework is demonstrated on a number, solving both the flow and adjoint systems of equations to provide a high-fidelity predictive capability and sensitivity information that can be used for optimal shape design using a gradient-based framework, goal-oriented adaptive mesh refinement, or uncertainty quantification.

Models of cardiac tissue electrophysiology: progress, challenges and open questions.

Abstract: Models of cardiac tissue electrophysiology are an important component of the Cardiac Physiome Project, which is an international effort to build biophysically based multi-scale mathematical models of the heart. Models of tissue electrophysiology can provide a bridge between electrophysiological cell models at smaller scales, and tissue mechanics, metabolism and blood flow at larger scales. This paper is a critical review of cardiac tissue electrophysiology models, focussing on the micro-structure of cardiac tissue, generic behaviours of action potential propagation, different models of cardiac tissue electrophysiology, the choice of parameter values and tissue geometry, emergent properties in tissue models, numerical techniques and computational issues. We propose a tentative list of information that could be included in published descriptions of tissue electrophysiology models, and used to support interpretation and evaluation of simulation results. We conclude with a discussion of challenges and open questions.

Nitric oxide signalling in cardiovascular health and disease

Abstract: Nitric oxide (NO) signalling has pleiotropic roles in biology and a crucial function in cardiovascular homeostasis. Tremendous knowledge has been accumulated on the mechanisms of the nitric oxide synthase (NOS)-NO pathway, but how this highly reactive, free radical gas signals to specific targets for precise regulation of cardiovascular function remains the focus of much intense research. In this Review, we summarize the updated paradigms on NOS regulation, NO interaction with reactive oxidant species in specific subcellular compartments, and downstream effects of NO in target cardiovascular tissues, while emphasizing the latest developments of molecular tools and biomarkers to modulate and monitor NO production and bioavailability.

Stanford University Unstructured (SU 2 ): An open-source integrated computational environment for multi-physics simulation and design

Abstract: This paper describes the history, objectives, structure, and current capabilities of the Stanford University Unstructured (SU 2 ) tool suite. This computational analysis and design software collection is being developed to solve complex, multi-physics analysis and optimization tasks using arbitrary unstructured meshes, and it has been designed so that it is easily extensible for the solution of Partial Differential Equation-based (PDE) problems not directly envisioned by the authors. At its core, SU 2 is an open-source collection of C++ software tools to discretize and solve problems described by PDEs and is able to solve PDE-constrained optimization problems, including optimal shape design. Although the toolset has been designed with Computational Fluid Dynamics (CFD) and aerodynamic shape optimization in mind, it has also been extended to treat other sets of governing equations including potential flow, electrodynamics, chemically reacting flows, and several others. In our experience, capabilities for computational analysis and optimization have improved considerably over the past two decades. However, the ability to integrate the resulting software packages into coupled multi-physics analysis and design optimization solvers has remained a challenge: the variety of approaches chosen for the independent components of the overall problem (flow solvers, adjoint solvers, optimizers, shape parameterization, shape deformation, mesh adaption, mesh deformation, etc) make it difficult to (a) expand the range of applicability to situations not originally envisioned, and (b) to reduce the overall burden of creating integrated applications. By leveraging well-established object-oriented software architectures (using C++) and by enabling a common interface for all the necessary components, SU 2 is able to remove these barriers for both the beginner and the seasoned analyst. In this paper we attempt to describe our efforts to develop SU 2 as an integrated platform. In some senses, the paper can also be used as a software reference manual for those who might be interested in modifying it to suit their own needs. We carefully describe the C++ framework and object hierarchy, the sets of equations that can be currently modeled by SU 2 , the available choices for numerical discretization, and conclude with a set of relevant validation and verification test cases that are included with the SU 2 distribution. We intend for SU 2 to remain open source and to serve as a starting point for new capabilities not included in SU 2 today, that will hopefully be contributed by users in both academic and industrial environments.