| The development of biology has been greatly accelerated by advanced biotechnology and the extensive use of computer technique in recent decades. The Human Genome, Proteome and Physiome Project provided a biological "parts list" and technologies such as parallel DNA sequencing, expression microarrays, and spectrometric analyses of proteins and metabolites have made high-throughput measurements, enables us to collect comprehensive data sets on system performance and identify the components of complex systems at system level. Differ from traditional biological and biochemical studies which deal with relatively few components, allowing intuitive reasoning to guide hypotheses and experiments, the system-based approches, which seeks to investigate biology system’s structure and dynamics from multi-scale level, is likely to play an increasingly important role in modeling and analyzing physiological systems.On the other hand, given the complexity of the cardiovascular system and of cardiovascular diseases, system-based approches are encouraged in elucidating the higher-order interactions underlying traits such as atherosclerosis, cardiac hypertrophy, heart failure, and arrhythmias. Take the familial hypertrophic cardiomyopathy (FHC) for example, it is an complex inherited heart disease wich is caused by sarcomeric protein gene mutations and characterized by exceptional ion channels, alterant cardiac metabolism, impaired myocardial contractile function and ventricular hypertrophy. Traditional studies alone are not sufficient to explain complex processes of how these complex processes together (quantitatively, temporally, and spatially). For this, a more global analysis, in which the activities of all of the relevant proteins are tracked over time and then integrated into a quantitative mathematical model, is required to provide a deeper level of understanding of the pathogenesis.In this study, we used a multi-scale model that links electrophysiology, contractile activity and energy metabolism of heart to analyze the mechanisms by which CTnI mutations of FHC effects contractility and metabolism through excitation-contraction coupling. The main research contents and results have been listed here:(1) Based on a mass of experimental data, we constructed a multi-scale quantificational platform which can quantitatively compute the calcium transient, metabolism concentrations, isometric force, and left ventricle wall movement in FHC mutation group and normal type heart. The platform incorporated various kind of modeling approaches at different levels (cell, tissue and organ). We combined the Luo-Rudy model which was one of the standard models of cardiac ventricular myocyte and a spatially approximate model of cooperative activation and cross-bridge cycling in cardiac muscle to study the relationship between Ca2+ transient of cardiac cell and force development of muscle in normal and mutation tissue. The energy demand were used as an input to a simplified cardiac metabolic network using minimization of metabolic adjustment dynamic flux balance analysis to simulate alter of cardiac energetic metabolism as the raising of energy cost. The cardiac muscles force was used into a finite element model of left ventricle, which is constructed from the Visual Chinese Human (VCH) dataset, to study how the molecular level disorder fairs will change the organ level issues, such as left ventricle wall movement. The simulation results reasonably mimicked experimental observations, and we obtained new insight into the mechanisms of diastolic dysfunction and low coupling of glucose oxidation to glycolysis in hypertrophied hearts.(2) We used an integrated simulation to investigate alterations in myocardial contractile function and energy metabolism regulation as a result of increased Ca2+-sensitivity in CTnI mutations. Simulation results reproduced typical features of the FHC:1. slower relaxation (diastolic dysfunction) caused by prolonged [Ca2+]i and force transients;2. higher energy consumption with the increase in Ca2+-sensitivity; and 3. reduced fatty acid oxidation and enhanced glucose utilization in hypertrophied heart metabolism. Furthermore, the simulation indicated that under high-energy-consumption conditions (that is, more than an 18.3% increase in total energy consumption), the myocardial energetic metabolic network switched from a net consumer to a net producer of lactate, resulting in a low coupling of glucose oxidation to glycolysis, which is a common feature of hypertrophied hearts. This study provides a novel systematic myocardial contractile and metabolic analysis to help elucidate the pathogenesis of FHC and suggests that the alterations in resting heart energy supply and demand could contribute to disease progression.(3) A lumped parameter model of the cardiovascular system and a 3D model of the heart configurations and interior structures have been constructed based on the Dataset of Visible Chinese Human. The finite element model of left ventricular is obtained from the heart structure model. Both ventricular wall and blood in the cavity are modeled by finite element mesh. The fluid-structure coupling of the left ventricle and blood has been constructed using an arbitrary Lagrange-Euler algorithm. Based on the models, the fluid-structure interaction of the left ventricle and blood of the FHC mutation group and normal type heart in the filling phase is simulated. Simulation result successfully reproduced the biphasic filling flow consisting of early rapid filling and atrial contraction similar to the clinical observation. This study provides a feasible method to analyse the structure and haemodynamics properties of heart using image-based fluid-structure simulation. It could be applied in heart function investigations and clinical applications. |
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