Cellular bases for human atrial fibrillation

Atrial fibrillation (AF) causes substantial morbidity and mortality. It may be triggered and sustained by either reentrant or nonreentrant electrical activity. Human atrial cellular refractory period is shortened in chronic AF, likely aiding reentry. The ionic and molecular mechanisms are not fully understood and may include increased inward rectifier K<sup>+</sup> current and altered Ca<sup>2+</sup> handling. Heart failure, a major cause of AF, may involve arrhythmogenic atrial electrical remodeling, but the pattern is unclear in humans. Beta-blocker therapy prolongs atrial cell refractory period; a potentially antiarrhythmic influence, but the ionic and molecular mechanisms are unclear. The search for drugs to suppress AF without causing ventricular arrhythmias has been aided by basic studies of cellular mechanisms of AF. It remains to be seen whether such drugs will improve patient treatment

Na/K pump regulation of cardiac repolarization: Insights from a systems biology approach

The sodium-potassium pump is widely recognized as the principal mechanism for active ion transport across the cellular membrane of cardiac tissue, being responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients, crucial for cardiac cell electrophysiology. Importantly, sodium-potassium pump activity is impaired in a number of major diseased conditions, including ischemia and heart failure. However, its subtle ways of action on cardiac electrophysiology, both directly through its electrogenic nature and indirectly via the regulation of cell homeostasis, make it hard to predict the electrophysiological consequences of reduced sodium-potassium pump activity in cardiac repolarization. In this review, we discuss how recent studies adopting the Systems Biology approach, through the integration of experimental and modeling methodologies, have identified the sodium-potassium pump as one of the most\ud important ionic mechanisms in regulating key properties of cardiac repolarization and its rate-dependence, from subcellular to whole organ levels. These include the role of the pump in the biphasic modulation of cellular repolarization and refractoriness, the rate control of intracellular sodium and calcium dynamics and therefore of the adaptation of repolarization to changes in heart rate, as well as its importance in regulating pro-arrhythmic substrates through modulation of dispersion of repolarization and restitution. Theoretical findings are consistent across a variety of cell types and species including human, and widely in agreement with experimental findings. The novel insights and hypotheses on the role of the pump in cardiac electrophysiology obtained through this integrative approach could eventually lead to novel therapeutic and diagnostic strategies

Logistic regression analysis of populations of electrophysiological models to assess proarrythmic risk.

Population-based computational approaches have been developed in recent years and helped to gain insight into arrhythmia mechanisms, and intra- and inter-patient variability (e.g., in drug responses). Here, we illustrate the use of multivariable logistic regression to analyze the factors that enhance or reduce the susceptibility to cellular arrhythmogenic events. As an example, we generate 1000 model variants by randomly modifying ionic conductances and maximal rates of ion transports in our atrial myocyte model and simulate an arrhythmia-provoking protocol that enhances early afterdepolarization (EAD) proclivity. We then treat EAD occurrence as a categorical, yes or no variable, and perform logistic regression to relate perturbations in model parameters to the presence/absence of EADs. We find that EAD formation is sensitive to the conductance of the voltage-gated Na+, the acetylcholine-sensitive and ultra-rapid K+ channels, and the Na+/Ca2+ exchange current, which matches our mechanistic understanding of the process and preliminary sensitivity analysis. The described technique: •allows investigating the factors underlying dichotomous outcomes, and is therefore a useful tool improve our understanding of arrhythmic risk;•is valid for analyzing both deterministic and stochastic models, and various phenomena (e.g., delayed afterdepolarizations and Ca2+ sparks);•is computationally more efficient than one-at-a-time parameter sensitivity analysis

Atrial cellular electrophysiological changes in patients with ventricular dysfunction may predispose to AF

<b>Background:</b> Left ventricular systolic dysfunction (LVSD) is a risk factor for atrial fibrillation (AF), but the atrial cellular electrophysiological mechanisms in humans are unclear. Objective This study sought to investigate whether LVSD in patients who are in sinus rhythm (SR) is associated with atrial cellular electrophysiological changes that could predispose to AF. <b>Methods:</b> Right atrial myocytes were obtained from 214 consenting patients in SR who were undergoing cardiac surgery. Action potentials or ion currents were measured using the whole-cell-patch clamp technique. <b>Results:</b> The presence of moderate or severe LVSD was associated with a shortened atrial cellular effective refractory period (ERP) (209 ± 8 ms; 52 cells, 18 patients vs 233 ± 7 ms; 134 cells, 49 patients; P <0.05); confirmed by multiple linear regression analysis. The left ventricular ejection fraction (LVEF) was markedly lower in patients with moderate or severe LVSD (36% ± 4%, n = 15) than in those without LVSD (62% ± 2%, n = 31; P <0.05). In cells from patients with LVEF ≤ 45%, the ERP and action potential duration at 90% repolarization were shorter than in those from patients with LVEF > 45%, by 24% and 18%, respectively. The LVEF and ERP were positively correlated (r = 0.65, P <0.05). The L-type calcium ion current, inward rectifier potassium ion current, and sustained outward ion current were unaffected by LVSD. The transient outward potassium ion current was decreased by 34%, with a positive shift in its activation voltage, and no change in its decay kinetics. <b>Conclusion:</b> LVSD in patients in SR is independently associated with a shortening of the atrial cellular ERP, which may be expected to contribute to a predisposition to AF

Effect of myocyte-fibroblast coupling on the onset of pathological dynamics in a model of ventricular tissue

Managing lethal cardiac arrhythmias is one of the biggest challenges in modern cardiology, and hence it is very important to understand the factors underlying such arrhythmias. While early afterdepolarizations (EAD) of cardiac cells is known to be one such arrhythmogenic factor, the mechanisms underlying the emergence of tissue level arrhythmias from cellular level EADs is not fully understood. Another known arrhythmogenic condition is fibrosis of cardiac tissue that occurs both due to aging and in many types of heart diseases. In this paper we describe the results of a systematic insilico study, using the TNNP model of human cardiac cells and MacCannell model for (myo) fibroblasts, on the possible effects of diffuse fibrosis on arrhythmias occurring via EADs. We find that depending on the resting potential of fibroblasts (VFR), M-F coupling can either increase or decrease the region of parameters showing EADs. Fibrosis increases the probability of occurrence of arrhythmias after a single focal stimulation and this effect increases with the strength of the M-F coupling. While in our simulations, arrhythmias occur due to fibrosis induced ectopic activity, we do not observe any specific fibrotic pattern that promotes the occurrence of these ectopic sources

Duration of heart failure and the risk of atrial fibrillation: different mechanisms at different times?

Chronic heart failure increases the risk of atrial fibrillation (AF), with the prevalence of AF paralleling the severity of heart failure.1 Factors that underlie this increased susceptibility to AF may include electrical, structural, and neurohumoral changes.2 In AF, it is recognized that atrial electrophysiological remodelling occurs and contributes to the perpetuation of the arrhythmia, most notably the decrease of effective refractory period (ERP) which predisposes to re-entry by shortening the wavelength. Does heart failure cause similar changes in atrial electrophysiology that predispose to the arrhythmia

Rabbit models of heart disease.

Human heart disease is a major cause of death and disability. A variety of animal models of cardiac disease have been developed to better understand the etiology, cellular and molecular mechanisms of cardiac dysfunction and novel therapeutic strategies. The animal models have included large animals (e.g. pig and dog) and small rodents (e.g. mouse and rat) and the advantages of genetic manipulation in mice have appropriately encouraged the development of novel mouse models of cardiac disease. However, there are major differences between rodent and human hearts that raise cautions about the extrapolation of results from mouse to human. The rabbit is a medium-sized animal that has many cellular and molecular characteristics very much like human, and is a practical alternative to larger mammals. Numerous rabbit models of cardiac disease are discussed, including pressure or volume overload, ischemia, rapid-pacing, doxorubicin, drug-induced arrhythmias, transgenesis and infection. These models also lead to the assessment of therapeutic strategies which may become beneficial in human cardiac disease

Conditions for propagation and block of excitation in an asymptotic model of atrial tissue

Detailed ionic models of cardiac cells are difficult for numerical simulations because they consist of a large number of equations and contain small parameters. The presence of small parameters, however, may be used for asymptotic reduction of the models. Earlier results have shown that the asymptotics of cardiac equations are non-standard. Here we apply such a novel asymptotic method to an ionic model of human atrial tissue in order to obtain a reduced but accurate model for the description of excitation fronts. Numerical simulations of spiral waves in atrial tissue show that wave fronts of propagating action potentials break-up and self-terminate. Our model, in particular, yields a simple analytical criterion of propagation block, which is similar in purpose but completely different in nature to the `Maxwell rule' in the FitzHugh-Nagumo type models. Our new criterion agrees with direct numerical simulations of break-up of re-entrant waves.Comment: Revised manuscript submitted to Biophysical Journal (30 pages incl. 10 figures