Michael Alan Colman

University of Leeds · Division of Cardiovascular and Diabetes

Key points • Previous studies have shown that atrial electrical properties are altered (remodelled) by atrial fibrillation (AF) and that the recurrence of AF is high following remodelling. However, demonstrating a causal link between atrial remodelling in experimental models and the increased risk of AF is a challenge.• AF-induced electrical remode...

Atrial fibrillation (AF), the commonest cardiac arrhythmia, has been strongly linked with arrhythmogenic sources near the pulmonary veins (PVs), but underlying mechanisms are not fully understood. We aim to study the generation and sustenance of wave sources in a model of the PV tissue. A previously developed biophysically detailed three-dimensiona...

Rapid atrial arrhythmias such as atrial fibrillation (AF) predispose to ventricular arrhythmias, sudden cardiac death and stroke. Identifying the origin of atrial ectopic activity from the electrocardiogram (ECG) can help to diagnose the early onset of AF in a cost-effective manner. The complex and rapid atrial electrical activity during AF makes i...

Atrial fibrillation (AF) is the world's most common cardiac arrhythmia. Due to the complexity of the heart and highly irregular electrical activity during AF it is a grand challenge to underpin the mechanisms underlying the initiation and maintenance of AF. Complimentary to experimental physiology, biophysically detailed models of the heart provide...

Despite a vast amount of experimental and clinical data on the underlying ionic, cellular and tissue substrates, the mechanisms of common atrial arrhythmias (such as atrial fibrillation, AF) arising from the functional interactions at the whole atria level remain unclear. Computational modelling provides a quantitative framework for integrating suc...

Inter-cellular electrical coupling in the heart is a major determinant of excitation patterns in health and disease. Cardiac arrhythmias, in particular rapid arrhythmias such as tachycardia and fibrillation, are characterised by spatially complex and heterogeneous conduction patterns. In disease conditions, these complex excitation patterns may res...

Regulation of intracellular calcium is a critical component of cardiac electrophysiology and excitation-contraction coupling. The calcium spark, the fundamental element of the intracellular calcium transient, is initiated in specialized nanodomains which co-locate the ryanodine receptors and L-type calcium channels. However, calcium homeostasis is...

The intracellular calcium handling system of cardiomyocytes is responsible for controlling excitation-contraction coupling (ECC) and has been linked to pro-arrhythmogenic cellular phenomena in conditions such as heart failure (HF). SERCA2a, responsible for intracellular uptake, is a primary regulator of calcium homeostasis, and remodelling of its f...

Cycling of calcium ions is a critical component of the link between the electrical activity and mechanical contraction of heart-muscle cells, and depends on complex, microscopic structures within each cell

Understanding of the mechanisms driving the regular beating of the heart is a major challenge.

Cardiac alternans, referring to beat-to-beat alternations to the action potential (AP) duration (APD) of cardiomyocytes (Fig. 1), are associated with contractile dysfunction and arrhythmogenesis in multiple disease conditions. In tissue, these cellular phenomena can manifest as spatially concordant alternans (SCA), wherein all regions alternate wit...

Computational models of the heart at multiple spatial scales, from sub-cellular nanodomains to the whole-organ, are a powerful tool for the simulation of cardiac electrophysiology. Application of these models has provided remarkable insight into the normal and pathological functioning of the heart. In these two articles, we present methods for mode...

Computational models of the heart, from cell-level models, through one-, two- and three-dimensional tissue-level simplifications, to biophysically-detailed three-dimensional models of the ventricles, atria or whole heart, allow the simulation of excitation and propagation of this excitation, and have provided remarkable insight into the normal and...

Cardiac electrical excitation-propagation is influenced by myocyte orientations (cellular organisation). Quantitatively understanding this relationship presents a significant research challenge, especially during arrhythmias where excitation patterns become complex. Tissue-scale simulations of cardiac electrophysiology, incorporating both dynamic a...

Spontaneous sub-cellular calcium release events (SCRE) are conjectured to promote rapid arrhythmias associated with conditions such as heart failure and atrial fibrillation: they can underlie the emergence of spontaneous action potentials in single cells which can lead to arrhythmogenic triggers in tissue. The multi-scale mechanisms of the developm...

Key points: Early-afterdepolarizations (EADs) are abnormal action potential oscillations and a known cause of cardiac arrhythmias. Ventricular EADs involve reactivation of a Ca2+ current (ICaL ) in its 'window region' voltage range. However, electrical mechanisms of atrial EADs, a potential cause of atrial fibrillation, are poorly understood. Atri...

Quantitative prediction over multiple space and time scales using computer models of the electrical activity in the mammalian heart, based on membrane and intracellular ion transport and binding dynamics, digital histology, and three-dimensional cardiac anatomy and architecture.

Background: Non-invasive cardiac mapping—also known as Electrocardiographic imaging (ECGi)—is a novel, painless and relatively economic method to map the electrical activation and repolarization patterns of the heart, providing a valuable tool for early identification and diagnosis of conduction abnormalities and arrhythmias. Moreover, the ability...

Aims: Action potential duration (APD) alternans is an established precursor or arrhythmia and sudden cardiac death. Important differences in fundamental electrophysiological properties relevant to arrhythmia exist between experimental models and the diseased in vivo human heart. To investigate mechanisms of APD alternans using a novel approach com...

Nanodomains are intracellular foci which transduce signals between major cellular compartments. One of the most ubiquitous signal transducers, the ryanodine receptor (RyR) calcium channel, is tightly clustered within these nanodomains. Super-resolution microscopy has previously been used to visualise RyR clusters near the cell surface. A majority o...

The system of transverse and longitudinal sarcolemmal tubules (T-system) is observed to remodel in atrial fibrillation (AF) and heart failure (HF). The resulting calcium dysregulation has been suggested to underlie disruptions in excitation-contraction coupling, and increase the frequency of arrhythmic events at the cellular scale; however, these m...

Aberrant intracellular calcium handling, as observed in diseases such as heart failure, promotes lethal ventricular arrhythmias and sudden cardiac death. Recent data from our laboratory suggests that reduced expression of the inward rectifier current in failing rat myocytes increases spontaneous calcium release, however existing computational model...

The propagation of cardiac electrical excitation is influenced by tissue microstructure. Reaction-diffusion computational models of cardiac electrophysiology incorporating both dynamic action potential (AP) behaviour and image-based myocardial architecture provide an approach to study the complex organisation of excitation waves within variable myo...

Motivation Spontaneous sub-cellular calcium release events (SCRE), controlled by microscopic stochastic fluctuations of the proteins responsible for intracellular calcium release, are conjectured to promote the initiation and perpetuation of rapid arrhythmia associated with conditions such as heart failure and atrial fibrillation: SCRE may underlie...

Motivation The role of sub-cellular spontaneous calcium release events (SCRE) in the development of arrhythmia associated with atrial and ventricular tachycardia and fibrillation has yet to be investigated in detail. SCRE may underlie the emergence of spontaneous excitation in single cells, resulting in arrhythmic triggers in tissue. Furthermore, t...

Atrial fibrillation (AF) and sinus bradycardia have been reported in patients with short QT syndrome variant 2 (SQT2), which is underlain by gain-of-function mutations in KCNQ1 encoding the α subunit of channels carrying slow delayed rectifier potassium current, IKs. However, the mechanism(s) underlying the increased atrial arrhythmogenesis and imp...

Introduction: The development of improved diagnosis, management, and treatment strategies for human atrial fibrillation (AF) is a significant and important challenge in order to improve quality of life for millions and reduce the substantial social-economic costs of the condition. As a complex condition demonstrating high variability and relation t...

The poster our work on the computation methods in pediatric cardiac electrophysiological changes during severe malaria infection.

Background: Prolongation of the QT interval of the electrocardiogram (ECG), underlain by prolongation of the action potential duration (APD) at the cellular level, is linked to increased vulnerability to cardiac arrhythmia. Pharmacological management of arrhythmia associated with QT prolongation is typically achieved through attempting to restore A...

Intracellular calcium cycling is a vital component of cardiac excitation-contraction coupling. The key structures responsible for controlling calcium dynamics are the cell membrane (comprising the surface sarcolemma and transverse-tubules), the intracellular calcium store (the sarcoplasmic reticulum), and the co-localisation of these two structures...

Rate dependence of the Ca2+ transient. (PDF)

Code and documentation. Code provided in C/C++ and includes the structural datasets used in this study. Documentation is provided on use of and updating the code. Updates may also be available on Michael Colman’s website, http://www.physicsoftheheart.com and github repository: https://github.com/michaelcolman/CODE---PLOS-Comp-Biol-2017-Model-SR. (Z...

Comparison between full-sized and cross-sectional portion models. (PDF)

Spatio-temporal dynamics in a model without a subspace. (PDF)

Model description. Contains all equations, variables and parameters describing the developed model. (PDF)

Redistribution of INaCa to the TTs. (PDF)

Further renders of Ca2+ gradients in the cytoplasm. (PDF)

Jrel and single-dyad dynamics. (PDF)

Spatio-temporal dynamics during a single beat of cardiac excitation. Left panels: Whole cell membrane potential, cytoplasm and SR Ca2+ concentration during a single beat. Centre panels: cytoplasm Ca2+ concentration in a small portion of the cell in 3-D (upper) and a longitudinal slice (lower) scaling. Right panels: nSR Ca2+ concentration in 3D (upp...

Spatio-temporal dynamics during Ca2+ transient alternans. Left panels: Whole cell cytoplasm and SR Ca2+ concentration during multiple beats undergoing Ca2+ transient alternans. Upper panels: cytoplasm Ca2+ concentration in a small portion of the cell. Lower panels: nSR Ca2+ concentration. Colours are according to the colour bar in Figs 11 and 12. (...

Spontaneous Ca2+ waves in the whole cell. Upper panel shows whole cell proportion of open RyRs and intracellular Ca2+ concentration. Middle and lower panels show the 3D Ca2+ concentration in the whole cell at normal and enhanced scaling. Video corresponds to the condition illustrated in Fig 14B. (AVI)

A recent experimental study investigating patients with lone atrial fibrillation identified six novel mutations in the KCNA5 gene. The mutants exhibited both gain- and loss-of-function of the atrial specific ultra-rapid delayed rectifier K+ current, IKur. The aim of this study is to elucidate and quantify the functional impact of these KCNA5 mutati...

Vulnerability windows in the Courtemanche et al. model. (DOCX)

Effects of beta-adrenergic stimulation on human atrial myocytes. (DOCX)

Regional cell models. (DOCX)

Modelling chronic-AF induced electrical remodelling. (DOCX)

Human SAN model. (DOCX)

Analysis of the role of IKur in human atrial AP morphology. (DOCX)

3D anatomical model of the human atria. (DOCX)

Numerical methods. (DOCX)

Effects of chronic AF remodelling on single cell electrophysiology. (DOCX)

Simulated re-entrant spiral wave in the 3D human atria. (DOCX)

Validations to the updated Colman et al. model with a new formulation of IKur. (DOCX)

Atrial tachy-arrhytmias, such as atrial fibrillation (AF), are characterised by irregular electrical activity in the atria, generally associated with erratic excitation underlain by re-entrant scroll waves, fibrillatory conduction of multiple wavelets or rapid focal activity. Epidemiological studies have shown an increase in AF prevalence in the de...

Perez-Alday et al. algorithm. (DOCX)

Table of conductivities. (DOCX)

2D and 3D view files. (ZIP)

Female Torso. (DOCX)

Atrial Model. (DOCX)

Colman_2013_single_cell_function. (C)

White Noise. (DOCX)

Dipole Validation. (DOCX)