Self-restoration of cardiac excitation rhythm by anti-arrhythmic ion channel gating.

Homeostatic regulation protects organisms against hazardous physiological changes. However, such regulation is limited in certain organs and associated biological processes. For example, the heart fails to self-restore its normal electrical activity once disturbed, as with sustained arrhythmias. Here we present proof-of-concept of a biological self-restoring system that allows automatic detection and correction of such abnormal excitation rhythms. For the heart, its realization involves the integration of ion channels with newly designed gating properties into cardiomyocytes. This allows cardiac tissue to i) discriminate between normal rhythm and arrhythmia based on frequency-dependent gating and ii) generate an ionic current for termination of the detected arrhythmia. We show in silico, that for both human atrial and ventricular arrhythmias, activation of these channels leads to rapid and repeated restoration of normal excitation rhythm. Experimental validation is provided by injecting the designed channel current for arrhythmia termination in human atrial myocytes using dynamic clamp.

Arrhythmogenicity of fibro-fatty infiltrations.

The onset of cardiac arrhythmias depends on electrophysiological and structural properties of cardiac tissue. One of the most important changes leading to arrhythmias is characterised by the presence of a large number of non-excitable cells in the heart, of which the most well-known example is fibrosis. Recently, adipose tissue was put forward as another similar factor contributing to cardiac arrhythmias. Adipocytes infiltrate into cardiac tissue and produce in-excitable obstacles that interfere with myocardial conduction. However, adipose infiltrates have a different spatial texture than fibrosis. Over the course of time, adipose tissue also remodels into fibrotic tissue. In this paper we investigate the arrhythmogenic mechanisms resulting from the presence of adipose tissue in the heart using computer modelling. We use the TP06 model for human ventricular cells and study how the size and percentage of adipose infiltrates affects basic properties of wave propagation and the onset of arrhythmias under high frequency pacing in a 2D model for cardiac tissue. We show that although presence of adipose infiltrates can result in the onset of cardiac arrhythmias, its impact is less than that of fibrosis. We quantify this process and discuss how the remodelling of adipose infiltrates affects arrhythmia onset.

Effects of Heterogeneous Diffuse Fibrosis on Arrhythmia Dynamics and Mechanism.

Myocardial fibrosis is an important risk factor for cardiac arrhythmias. Previous experimental and numerical studies have shown that the texture and spatial distribution of fibrosis may play an important role in arrhythmia onset. Here, we investigate how spatial heterogeneity of fibrosis affects arrhythmia onset using numerical methods. We generate various tissue textures that differ by the mean amount of fibrosis, the degree of heterogeneity and the characteristic size of heterogeneity. We study the onset of arrhythmias using a burst pacing protocol. We confirm that spatial heterogeneity of fibrosis increases the probability of arrhythmia induction. This effect is more pronounced with the increase of both the spatial size and the degree of heterogeneity. The induced arrhythmias have a regular structure with the period being mostly determined by the maximal local fibrosis level. We perform ablations of the induced fibrillatory patterns to classify their type. We show that in fibrotic tissue fibrillation is usually of the mother rotor type but becomes of the multiple wavelet type with increase in tissue size. Overall, we conclude that the most important factor determining the formation and dynamics of arrhythmia in heterogeneous fibrotic tissue is the value of maximal local fibrosis.

Conditions for Waveblock Due to Anisotropy in a Model of Human Ventricular Tissue.

Waveblock formation is the main cause of reentry. We have performed a comprehensive numerical modeling study of block formation due to anisotropy in Ten Tusscher and Panfilov (2006) ionic model for human ventricular tissue. We have examined the border between different areas of myocardial fiber alignment and have shown that blockage can occur for a wave traveling from a transverse fiber area to a longitudinal one. Such blockage occurs for reasonable values of the anisotropy ratio (AR): from 2.4 to 6.2 with respect to propagation velocities. This critical AR decreases by the suppression of INa and ICa, slightly decreases by the suppression of IKr and IKs, and substantially increases by the suppression of IK1. Hyperkalemia affects the block formation in a complex, biphasic way. We provide examples of reentry formation due to the studied effects and have concluded that the suppression of IK1 should be the most effective way to prevent waveblock at the areas of abrupt change in anisotropy.

Effect of global cardiac ischemia on human ventricular fibrillation: insights from a multi-scale mechanistic model of the human heart.

Acute regional ischemia in the heart can lead to cardiac arrhythmias such as ventricular fibrillation (VF), which in turn compromise cardiac output and result in secondary global cardiac ischemia. The secondary ischemia may influence the underlying arrhythmia mechanism. A recent clinical study documents the effect of global cardiac ischaemia on the mechanisms of VF. During 150 seconds of global ischemia the dominant frequency of activation decreased, while after reperfusion it increased rapidly. At the same time the complexity of epicardial excitation, measured as the number of epicardical phase singularity points, remained approximately constant during ischemia. Here we perform numerical studies based on these clinical data and propose explanations for the observed dynamics of the period and complexity of activation patterns. In particular, we study the effects on ischemia in pseudo-1D and 2D cardiac tissue models as well as in an anatomically accurate model of human heart ventricles. We demonstrate that the fall of dominant frequency in VF during secondary ischemia can be explained by an increase in extracellular potassium, while the increase during reperfusion is consistent with washout of potassium and continued activation of the ATP-dependent potassium channels. We also suggest that memory effects are responsible for the observed complexity dynamics. In addition, we present unpublished clinical results of individual patient recordings and propose a way of estimating extracellular potassium and activation of ATP-dependent potassium channels from these measurements.

A study of early afterdepolarizations in a model for human ventricular tissue.

Sudden cardiac death is often caused by cardiac arrhythmias. Recently, special attention has been given to a certain arrhythmogenic condition, the long-QT syndrome, which occurs as a result of genetic mutations or drug toxicity. The underlying mechanisms of arrhythmias, caused by the long-QT syndrome, are not fully understood. However, arrhythmias are often connected to special excitations of cardiac cells, called early afterdepolarizations (EADs), which are depolarizations during the repolarizing phase of the action potential. So far, EADs have been studied mainly in isolated cardiac cells. However, the question on how EADs at the single-cell level can result in fibrillation at the tissue level, especially in human cell models, has not been widely studied yet. In this paper, we study wave patterns that result from single-cell EAD dynamics in a mathematical model for human ventricular cardiac tissue. We induce EADs by modeling experimental conditions which have been shown to evoke EADs at a single-cell level: by an increase of L-type Ca currents and a decrease of the delayed rectifier potassium currents. We show that, at the tissue level and depending on these parameters, three types of abnormal wave patterns emerge. We classify them into two types of spiral fibrillation and one type of oscillatory dynamics. Moreover, we find that the emergent wave patterns can be driven by calcium or sodium currents and we find phase waves in the oscillatory excitation regime. From our simulations we predict that arrhythmias caused by EADs can occur during normal wave propagation and do not require tissue heterogeneities. Experimental verification of our results is possible for experiments at the cell-culture level, where EADs can be induced by an increase of the L-type calcium conductance and by the application of I[Formula: see text] blockers, and the properties of the emergent patterns can be studied by optical mapping of the voltage and calcium.

Action potential duration heterogeneity of cardiac tissue can be evaluated from cell properties using Gaussian Green's function approach.

Action potential duration (APD) heterogeneity of cardiac tissue is one of the most important factors underlying initiation of deadly cardiac arrhythmias. In many cases such heterogeneity can be measured at tissue level only, while it originates from differences between the individual cardiac cells. The extent of heterogeneity at tissue and single cell level can differ substantially and in many cases it is important to know the relation between them. Here we study effects from cell coupling on APD heterogeneity in cardiac tissue in numerical simulations using the ionic TP06 model for human cardiac tissue. We show that the effect of cell coupling on APD heterogeneity can be described mathematically using a Gaussian Green's function approach. This relates the problem of electrotonic interactions to a wide range of classical problems in physics, chemistry and biology, for which robust methods exist. We show that, both for determining effects of tissue heterogeneity from cell heterogeneity (forward problem) as well as for determining cell properties from tissue level measurements (inverse problem), this approach is promising. We illustrate the solution of the forward and inverse problem on several examples of 1D and 2D systems.

Atrium-specific Kir3.x determines inducibility, dynamics, and termination of fibrillation by regulating restitution-driven alternans.

BACKGROUND: Atrial fibrillation is the most common cardiac arrhythmia. Ventricular proarrhythmia hinders pharmacological atrial fibrillation treatment. Modulation of atrium-specific Kir3.x channels, which generate a constitutively active current (I(K,ACh-c)) after atrial remodeling, might circumvent this problem. However, it is unknown whether and how I(K,ACh-c) contributes to atrial fibrillation induction, dynamics, and termination. Therefore, we investigated the effects of I(K,ACh-c) blockade and Kir3.x downregulation on atrial fibrillation. METHODS AND RESULTS: Neonatal rat atrial cardiomyocyte cultures and intact atria were burst paced to induce reentry. To study the effects of Kir3.x on action potential characteristics and propagation patterns, cultures were treated with tertiapin or transduced with lentiviral vectors encoding Kcnj3- or Kcnj5-specific shRNAs. Kir3.1 and Kir3.4 were expressed in atrial but not in ventricular cardiomyocyte cultures. Tertiapin prolonged action potential duration (APD; 54.7±24.0 to 128.8±16.9 milliseconds; P<0.0001) in atrial cultures during reentry, indicating the presence of I(K,ACh-c). Furthermore, tertiapin decreased rotor frequency (14.4±7.4 to 6.6±2.0 Hz; P<0.05) and complexity (6.6±7.7 to 0.6±0.8 phase singularities; P<0.0001). Knockdown of Kcnj3 or Kcnj5 gave similar results. Blockade of I(K,ACh-c) prevented/terminated reentry by prolonging APD and changing APD and conduction velocity restitution slopes, thereby altering the probability of APD alternans and rotor destabilization. Whole-heart mapping experiments confirmed key findings (e.g., >50% reduction in atrial fibrillation inducibility after I(K,ACh-c) blockade). CONCLUSIONS: Atrium-specific Kir3.x controls the induction, dynamics, and termination of fibrillation by modulating APD and APD/conduction velocity restitution slopes in atrial tissue with I(K,ACh-c). This study provides new molecular and mechanistic insights into atrial tachyarrhythmias and identifies Kir3.x as a promising atrium-specific target for antiarrhythmic strategies.

Prolongation of minimal action potential duration in sustained fibrillation decreases complexity by transient destabilization.

AIMS: Sustained ventricular fibrillation (VF) is maintained by multiple stable rotors. Destabilization of sustained VF could be beneficial by affecting VF complexity (defined by the number of rotors). However, underlying mechanisms affecting VF stability are poorly understood. Therefore, the aim of this study was to correlate changes in arrhythmia complexity with changes in specific electrophysiological parameters, allowing a search for novel factors and underlying mechanisms affecting stability of sustained VF. METHODS AND RESULTS: Neonatal rat ventricular cardiomyocyte monolayers and Langendorff-perfused adult rat hearts were exposed to increasing dosages of the gap junctional uncoupler 2-aminoethoxydiphenyl borate (2-APB) to induce arrhythmias. Ion channel blockers/openers were added to study effects on VF stability. Electrophysiological parameters were assessed by optical mapping and patch-clamp techniques. Arrhythmia complexity in cardiomyocyte cultures increased with increasing dosages of 2-APB (n > 38), leading to sustained VF: 0.0 ± 0.1 phase singularities/cm(2) in controls vs. 0.0 ± 0.1, 1.0 ± 0.9, 3.3 ± 3.2, 11.0 ± 10.1, and 54.3 ± 21.7 in 5, 10, 15, 20, and 25 µmol/L 2-APB, respectively. Arrhythmia complexity inversely correlated with wavelength. Lengthening of wavelength during fibrillation could only be induced by agents (BaCl(2)/BayK8644) increasing the action potential duration (APD) at maximal activation frequencies (minimal APD); 123 ± 32%/117 ± 24% of control. Minimal APD prolongation led to transient VF destabilization, shown by critical wavefront collision leading to rotor termination, followed by significant decreases in VF complexity and activation frequency (52%/37%). These key findings were reproduced ex vivo in rat hearts (n = 6 per group). CONCLUSION: These results show that stability of sustained fibrillation is regulated by minimal APD. Minimal APD prolongation leads to transient destabilization of fibrillation, ultimately decreasing VF complexity, thereby providing novel insights into anti-fibrillatory mechanisms.