Elucidation of the cellular basis of arrhythmias in ion channelopathy disorders is complicated by the inherent difficulties in studying human cardiac tissue. Thus we used a computer modeling approach to study the mechanisms of cellular dysfunction induced by mutations in inward rectifier potassium channel (Kir)2.1 that cause Andersen-Tawil syndrome (ATS). ATS is an autosomal dominant disorder associated with ventricular arrhythmias that uncommonly degenerate into the lethal arrhythmia torsade de pointes. We simulated the cellular and tissue effects of a potent disease-causing mutation D71V Kir2.1 with mathematical models of human ventricular myocytes and a bidomain model of transmural conduction. The D71V Kir2.1 mutation caused significant action potential duration prolongation in subendocardial, midmyocardial, and subepicardial myocytes but did not significantly increase transmural dispersion of repolarization. Simulations of the D71V mutation at shorter cycle lengths induced stable action potential alternans in midmyocardial, but not subendocardial or subepicardial cells. The action potential alternans was manifested as an abbreviated QRS complex in the transmural ECG, the result of action potential propagation failure in the midmyocardial tissue. In addition, our simulations of D71V mutation recapitulate several key ECG features of ATS, including QT prolongation, T-wave flattening, and QRS widening. Thus our modeling approach faithfully recapitulates several features of ATS and provides a mechanistic explanation for the low frequency of torsade de pointes arrhythmia in ATS.
The anticholinergic antiparkinson drug orphenadrine is an antagonist at central and peripheral muscarinic receptors. Orphenadrine intake has recently been linked to QT prolongation and Torsade-de-Pointes tachycardia. So far, inhibitory effects on I Kr or cloned HERG channels have not been examined. HERG channels were heterologously expressed in a HEK 293 cell line and in Xenopus oocytes and HERG current was measured using the whole cell patch clamp and the double electrode voltage clamp technique. Orphenadrine inhibits cloned HERG channels in a concentration dependent manner, yielding an IC50 of 0.85 μM in HEK cells. Onset of block is fast and reversible upon washout. Orphenadrine does not alter the half-maximal activation voltage of HERG channels. There is no shift of the half-maximal steady-state-inactivation voltage. Time constants of direct channel inactivation are not altered significantly and there is no use-dependence of block. HERG blockade is attenuated significantly in mutant channels lacking either of the aromatic pore residues Y652 and F656. In conclusion, we show that the anticholinergic agent orphenadrine is an antagonist at HERG channels. These results provide a novel molecular basis for the reported proarrhythmic side effects of orphenadrine
D. L. Weiss, D. U. J. Keller, O. Dössel, and G. Seemann. The influence of fibre orientation, extracted from different segments of the human left ventricle, on the activation and repolarization sequence: a simulation study. In Europace, vol. 9(suppl 6) , pp. vi96-vi104, 2007
Aims This computational study examined the influence of fibre orientation on the electrical processes in the heart. In contrast to similar previous studies, human diffusion tensor magnetic resonance imaging measurements were used.Methods The fibre orientation was extracted from distinctive regions of the left ventricle. It was incorporated in a single tissue segment having a fixed geometry. The electrophysiological model applied in the computational units considered transmural heterogeneities. Excitation was computed by means of the monodomain model; the accompanying pseudo-electrocardiograms (ECGs) were calculated.Results The distribution of fibre orientation extracted from the same transversal section showed only small variations. The fibre information extracted from the equal circumferential but different longitudinal positions showed larger differences, mainly in the imbrication angle. Differences of the endocardial myocyte orientation mainly affected the beginning of the activation sequence. The transmural propagation was faster in areas with larger imbrication angles leading to a narrower QRS complex in pseudo-ECGs.Conclusion The model can be expanded to simulate electrophysiology and contraction in the whole heart geometry. Embedded in a torso model, the impact of fibre orientation on body surface ECGs and their relation to local pseudo-ECGs can be identified.
A computer model of the human heart is presented, that starts with the electrophysiology of single myocardial cells including all relevant ion channels, spans the de- and repolarization of the heart including the generation of the Electrocardiogram (ECG) and ends with the contraction of the heart that can be measured using 4D Magnetic Resonance Imaging (MRI). The model can be used to better understand physiology and pathophysiology of the heart, to improve diagnostics of infarction and arrhythmia and to enable quantitative therapy planning. It can also be used as a regularization tool to gain better solutions of the ill-posed inverse problem of ECG. Movies of the evolution of electrophysiology of the heart can be reconstructed from Body Surface Potential Maps (BSPM) and MRI, leading to a new non-invasive medical imaging technique.
The congenital long-QT syndrome is commonly associated with a high risk for polymorphic ventricular tachy-cardia and sudden cardiac death. This is probably due to an intensification of the intrinsic heterogeneities present in ventricular myocardium. Increasing the electrophysiological heterogeneities amplifies the dispersion of repolarization which directly affects the morphology of the T wave in the ECG. The aim of this work is to investigate the effects of LQT2, a specific subtype of the long-QT syndrome (LQTS), on the Body Surface Potential Maps (BSPM) and the ECG. In this context a three-dimensional, heterogeneous model of the human ventricles is used to simulate both physiological and pathological excitation propagation. The results are used as input for the forward calculation of the BSPM and ECG. Characteristic QT prolongation is simulated correctly. The main goal of this study is to prepare and evaluate a simulation environment that can be used prospectivley to find features in the ECG or the BSPM that are characteristic for the LQTS. Such features might be used to facilitate the identification of LQTS patients.
D. U. J. Keller, D. L. Weiss, O. Dössel, and G. Seemann. Transferring ventricular myocyte orientation to individual patient data based on diffusion tensor MRI measurements. In Tagungsband 6. Jahrestagung der Deutschen Gesellschaft für Computer- und Roboterassistierte Chirurgie e. V., pp. 255-258, 2007
Atrial fibrillation (AF) induced electrical remodelling of ionic channels shortens action potential duration and reduces atrial excitability. Experimental data of AF-induced electrical remodelling (AFER) from two previous studies on human atrial myocytes were incorporated into a human atrial cell computer model to simulate their effects on atrial electrical behaviour. The dynamical behaviors of excitation scroll waves in an anatomical 3D homogenous model of human atria were studied for control and AF conditions. Under control condition, scroll waves meandered in large area and became persistent when entrapped by anatomical obstacles. In this case, a mother rotor dominated atrial excitation. Action potentials from several sites behaved as if the atrium were paced rapidly. Under AF conditions, AFER increased the stability of re-entrant scroll waves by reducing meander. Scroll wave break up leads to wavelets underpinning sustained chronic AF. Our simulation results support the hypothesis that AF-induced electrical remodelling perpetuates and sustains AF.
M. W. Krueger, D. L. Weiss, O. Dössel, and G. Seemann. Die Begrenztheit theoretischer Modelle der menschlichen Biologie und ihr großer Nutzen für das Verständnis des Körpers. In Challenges and Limitations of Models in Science and Theology, 2007
D. L. Weiss, G. Seemann, and O. Doessel. A framework for incorporation of arbitrary 3D electrophysiological heterogeneities in simulations of the human heart. In 41. Jahrestagung der DGBMT im VDE. Proceedings BMT 2007, vol. 52, 2007
D. L. Weiss, O. Dössel, and G. Seemann. The end of T wave need not coincide with final repolarization in tissue: a simulation study. In Heart Rhythm, vol. 4(5s) , pp. 159, 2007
Heterogeneity of ion channel properties within human ventricular tissue determines the sequence of repolarization under healthy conditions. In this computational study, the impact of different extend of electrophysiological heterogeneity in both human ventricles on the ECG was investigated by a forward calculation of the cardiac electrical signals on the body surface. The gradients ranged from solely transmural, interventricular and apico-basal up to full combination of these variations. As long interventricular heterogeneities were neglected, the transmural gradient generated a positive T wave that was increased when apico-basal variations were considered. Inclusion of interventricular changes necessitated the incorporation of both transmural and apico-basal heterogeneities to reproduce the positive T wave.