Exploring The Mechanism Of Myocardial Ischemia And Heart Failure By Computer Models

Cardiovascular diseases have become the killer to people’s health and life. Common cardiovascular diseases such as myocardial ischemia and heart failure will damage the contraction-relaxation dynamics, which further affects the metabolism. Relative to the damage by disturbed cardiac mechanics, cardiac arrhythmias is more fatal because of its sudden and unexpected occurrence. Heart is a transmural heterogeneous tissue, with different properties in local regions. After cardiac disease, the transmural heterogeneous electrical properties will be selectively remodeled. The selective remodeling exaggerates the transmural action potential difference, proving the basis for cardiac arrhythmias like reentry. Therefore, it is really necessary for us to examine the ionic basis underlying the transmural heterogeneous electrical properties.Cardiac myocyte is a biological system with many components interacting with each other. Due to their bi-directional coupling and the present level of experimental methods, it is difficult for researchers to explore the underlying mechanisms of some diseases. By using computer models, we can change the components in isolation, which has become an important tool to find the disease mechanisms.In this thesis, based on experimental data, we developed cardiac models which can recreate the properties of cardiac dynamics. The models can be used to find the disease mechanisms and optimize the strategy to cure patients with cardiac diseases. It includes the following parts:1) Investigating the mechanism of myocardial ischemiaThe hyperkalemia, anoxia and acidosis of myocardial ischemia have been implemented to simulate their role in the shortened action potential duration. According to experimental data, the transmural heterogeneous electrical and mechanical properties of cardiac cells have been recreated. The selective changes of transmural distributed cardiac myocytes and ECG alterations after myocardial ischemia are simulated.2) Theoretically investigating the mechanism of heart failureBased on the available canine ventricular cell data, we developed a new canine ventricular cell model. The prolonged action potential, decreased Ca2+transient, Na+elevation and the alternans phenomenon are simulated. By quantitative analysis,we come to the following conclusions: Although CaMKⅡ affects the AP profile, it does not contribute to APD prolongation. The prolonged APD is caused by the down-regulation of K currents. The down-regulated SERCA protein plays a little role in decreased Ca2+transient due to the enhaced role of CaMKⅡ and prolonged APD. In contrary, increased SR Ca2+leak current makes a big contribution to the decreased Ca2+transient. Other Na+elevation factors should be considered because enhanced late Na+current alone could not account for the degree of Na+elevation. The enhanced CaMKⅡ makes the fractional SR Ca2+release more steepened, which facilitates the occurrence of alternans. Partial CaMKII inhibition combined with SR Ca2+leak current blockade may be a new way to cure patients with HF.3) The ionic basis of transmural heterogeneous electrical properties and their different responsiveness to drugsThe contribution of the transient outward potassium current to ventricular repolarization has been controversial. It is difficult for experiments to identify its exact role because there is lack of selective Ito blockers. By computer models, we can find that Ito has little effect on canine ventricular repolarization in the physiological range. Transmural distributed Na+/K+pump current affects both the transmural APD dispersion and the regional Ca2+transients. Transmural heterogeneous Ca2+transient and Na+forms a different chemical gradient for local NCX. That accounts for why NCX is transmural different while the NCX protein is homogeneously distributed. According to experimental data, we have constructed a platform consisted of epicardial, midmyocardial and endocardial cells. We have simulated the easier EADs in the midmyocardial cells compared with epicardial and endocardial cells in response to AP prolonged factors such as E-4031. The essential underlying mechanism is the long plateau phase for midmyocardial cells. This platform could be used as a tool to study the selective remodeling and different responsiveness to drugs.4) Cardiac fiber mechanics simulationCardiac fiber mechanics has been simulated to recreate the preload-afterload experiment. The five phases of cardiac work including filling, isovolumetric contraction, ejection, isovolumetric relaxation and isotonic relaxation are simulated. It provides a platform for the future cardiac mechanics simulation to test the effect of cardiac diseases.