Beschreibung

Nowadays, heart diseases are the most common diseases in the western world. Many people suffer from different heart diseases and die of them. Recent studies have shown that in most cases sudden cardiac death is caused by cardiac arrhythmias, mainly ventricular tachycardia (VT) degenerating into ventricular fibrillation (VF) or immediately occurring VF. On the other hand, the basis of cellular physiology and also electromechanical coupling in the heart failure is still largely unknown.

In the last decades, human heart used to be considered homogeneous across the ventricle wall, but recent studies have established three distinct cell types in the ventricular myocardium: subepicardial (Epi), midmyocardial (M) and subendocardial (Endo) cells. They differ from each other with respect to the morphology of action potential (AP), the AP duration (APD), and the frequency dependence of APD shortening. The ionic bases were proposed later in different species. Recent research of calcium activity in canine left ventricle has proved that the heterogeneity in ventricle exists not only in electrophysiology but also in mechanical functions.

Due to the limitation of experiments on heart, especially on failed heart, computational modeling plays an important role in understanding the physiology and mechanics in the heart. The first human ventricular model was presented by Priebe and Beuckelmann. It was mainly based on the Luo-Rudy phase II ventricular myocyte model for guinea pig and developed using parameter variation. Ten Tusscher et al. subsequently presented a human ventricular model in which parameters are based on more recent whole-cell current data in isolated human ventricular myocytes. In 2005 a new model was developed by Iyer et al. to present the epicardial cell in human left ventricle, which used continuous-time Markov chain models to describe transmembrane ion channels and intracellular ion handling and was based on recent experimental data. Theses models describe the properties of various ion channels and handling of intracellular ion concentration, and can represent the action potential properties and the cellular properties.

Though much attention has been focused on the mathematical description of the cell model of human ventricular myocyte, the heterogeneity in the ventricular wall has not gained much attention. Ten Tusscher et al. have developed a model to present different APs in different layers of human ventricle, but only transient outward current and the slow component of the delayed rectifier current were concerned. Seemann et al. have developed a model to reconstruct the heterogeneity in human ventricular myocardium, in which the parameters and conductance of Ito, IKs, IK1 and INaCa were adjusted according to the recent experimental data.

This diploma thesis was focused on the electromechanical heterogeneity in human left ventricular myocytes. The Iyer et al. model was used and modified to reconstruct the inhomogeneous transmembrane electrophysiology and intracellular calcium activities. The modified model was able to simulate the heterogeneous densities or properties of late sodium current (late INa), transient outward current (Ito), slow component of delayed rectifier current (IKs), inwardly rectifier current (IK1) and sodium-calcium exchange current (I), as well as calcium release (Irel) and uptake (Iup) currents of sarcoplasmic reticulum in calcium handling. With these modifications, the difference in APs, calcium transients and tension development of Epi, M and Endo cell in human left ventricle can be reconstructed. Cordeiro et al. have published the heterogeneous AP and calcium activity in

canine left ventricle. The tendency of the regional difference in AP, calcium transient, as well as mechanical function, in this simulation work showed good agreement to their experiment. This work can explain how heterogeneous transmembrane ion currents and intracellular calcium handling lead to an inhomogeneous electrophysiology of human left ventricular myocytes but a more homogenized contraction of the ventricular wall. Heterogeneity is such an important characteristic of human left ventricle, that it might determine the electromechanical properties of ventricle, furthermore, its abnormality might be the crucial basis of some kind of heart failing. Myocytes with mishandling of calcium are the central cause of both contractile dysfunction and arrhythmias in pathophysiological conditions. This simulation could contribute to the simulation of calcium handling in failing heart and the research of human cardiac diseases in the future.