抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

eMedicine创建于1996年，由近万名临床医师作为作者或编辑参与此临床医学知识库的建设，其中编辑均是来自美国哈佛、耶鲁、斯坦福、芝加哥、德克萨斯、加州大学等各分校医学院的教授或副教授。

eMedicine

Ventricular fibrillation (VF) is one of the main causes of death in the Western world. According to one hypothesis, the chaotic excitation dynamics during VF are the result of dynamical instabilities in action potential duration (APD) the occurrence of which requires that the slope of the APD restitution curve exceeds 1. Other factors such as electrotonic coupling and cardiac memory also determine whether these instabilities can develop. In this paper we study the conditions for alternans and spiral breakup in human cardiac tissue. Therefore, we develop a new version of our human ventricular cell model, which is based on recent experimental measurements of human APD restitution and includes a more extensive description of intracellular calcium dynamics. We apply this model to study the conditions for electrical instability in single cells, for reentrant waves in a ring of cells, and for reentry in two-dimensional sheets of ventricular tissue. We show that an important determinant for the onset of instability is the recovery dynamics of the fast sodium current. Slower sodium current recovery leads to longer periods of spiral wave rotation and more gradual conduction velocity restitution, both of which suppress restitution-mediated instability. As a result, maximum restitution slopes considerably exceeding 1 (up to 1.5) may be necessary for electrical instability to occur. Although slopes necessary for the onset of instabilities found in our study exceed 1, they are within the range of experimentally measured slopes. Therefore, we conclude that steep APD restitution-mediated instability is a potential mechanism for VF in the human heart.

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Alternans and spiral breakup in a human ventricular tissue model.

Cellular electrophysiology experiments, important for understanding cardiac arrhythmia mechanisms, are usually performed with channels expressed in non myocytes, or with non-human myocytes. Differences between cell types and species affect results. Thus, an accurate model for the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is needed. Such a model requires extensive experimental data, but essential elements have been unavailable. Here, we develop a human ventricular AP model using new undiseased human ventricular data: Ca2+ versus voltage dependent inactivation of L-type Ca2+ current (ICaL); kinetics for the transient outward, rapid delayed rectifier (IKr), Na+/Ca2+ exchange (INaCa), and inward rectifier currents; AP recordings at all physiological cycle lengths; and rate dependence and restitution of AP duration (APD) with and without a variety of specific channel blockers. Simulated APs reproduced the experimental AP morphology, APD rate dependence, and restitution. Using undiseased human mRNA and protein data, models for different transmural cell types were developed. Experiments for rate dependence of Ca2+ (including peak and decay) and intracellular sodium ([Na+]i) in undiseased human myocytes were quantitatively reproduced by the model. Early afterdepolarizations were induced by IKr block during slow pacing, and AP and Ca2+ alternans appeared at rates >200 bpm, as observed in the nonfailing human ventricle. Ca2+/calmodulin-dependent protein kinase II (CaMK) modulated rate dependence of Ca2+ cycling. INaCa linked Ca2+ alternation to AP alternans. CaMK suppression or SERCA upregulation eliminated alternans. Steady state APD rate dependence was caused primarily by changes in [Na+]i, via its modulation of the electrogenic Na+/K+ ATPase current. At fast pacing rates, late Na+ current and ICaL were also contributors. APD shortening during restitution was primarily dependent on reduced late Na+ and ICaL currents due to inactivation at short diastolic intervals, with additional contribution from elevated IKr due to incomplete deactivation.

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Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation

The heart is a rhythmic electromechanical pump, the functioning of which depends on action potential generation and propagation, followed by relaxation and a period of refractoriness until the next...

Molecular Physiology of Cardiac Repolarization

The experimental and clinical possibilities for studying cardiac arrhythmias in human ventricular myocardium are very limited. Therefore, the use of alternative methods such as computer simulations is of great importance. In this article we introduce a mathematical model of the action potential of human ventricular cells that, while including a high level of electrophysiological detail, is computationally cost-effective enough to be applied in large-scale spatial simulations for the study of reentrant arrhythmias. The model is based on recent experimental data on most of the major ionic currents: the fast sodium, L-type calcium, transient outward, rapid and slow delayed rectifier, and inward rectifier currents. The model includes a basic calcium dynamics, allowing for the realistic modeling of calcium transients, calcium current inactivation, and the contraction staircase. We are able to reproduce human epicardial, endocardial, and M cell action potentials and show that differences can be explained by differences in the transient outward and slow delayed rectifier currents. Our model reproduces the experimentally observed data on action potential duration restitution, which is an important characteristic for reentrant arrhythmias. The conduction velocity restitution of our model is broader than in other models and agrees better with available data. Finally, we model the dynamics of spiral wave rotation in a two-dimensional sheet of human ventricular tissue and show that the spiral wave follows a complex meandering pattern and has a period of 265 ms. We conclude that the proposed model reproduces a variety of electrophysiological behaviors and provides a basis for studies of reentrant arrhythmias in human ventricular tissue.

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A model for human ventricular tissue

In this paper, we formulate a model for human ventricular cells that is efficient enough for whole organ arrhythmia simulations yet detailed enough to capture the effects of cell level processes such as current blocks and channelopathies. The model is obtained from our detailed human ventricular cell model by using mathematical techniques to reduce the number of variables from 19 to nine. We carefully compare our full and reduced model at the single cell, cable and 2D tissue level and show that the reduced model has a very similar behaviour. Importantly, the new model correctly produces the effects of current blocks and channelopathies on AP and spiral wave behaviour, processes at the core of current day arrhythmia research. The new model is well over four times more efficient than the full model. We conclude that the new model can be used for efficient simulations of the effects of current changes on arrhythmias in the human heart.

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Cell model for efficient simulation of wave propagation in human ventricular tissue under normal and pathological conditions.

The His-Purkinje conduction system initiates the normal excitation of the ventricles and is a major component of the specialized conduction system of the heart. Abnormalities and propagation blocks in the Purkinje system result in abnormal excitation of the heart. Experimental findings suggest that the Purkinje network plays an important role in ventricular tachycardia and fibrillation, which is the major cause of sudden cardiac death. Nowadays an important area in the study of cardiac arrhythmias is anatomically accurate modelling. The majority of current anatomical models have not included a description of the Purkinje network. As a consequence, these models cannot be used to study the important role of the Purkinje system in arrhythmia initiation and maintenance. In this article we provide an overview of previous work on modelling of the Purkinje system and report on the development of a His-Purkinje system for our human ventricular model. We use the model to simulate the normal activation pattern as well as abnormal activation patterns resulting from bundle branch block and bundle branch reentry.

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Modelling of the ventricular conduction system.

Heterogeneity of cardiac tissue is an important factor determining the initiation and dynamics of cardiac arrhythmias. In this paper, we studied the effects of gradients of electrophysiological het...

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K. H. W. J. ten Tusscher

Papers

A model for human ventricular tissue

Alternans and spiral breakup in a human ventricular tissue model.

Cell model for efficient simulation of wave propagation in human ventricular tissue under normal and pathological conditions.

Modelling of the ventricular conduction system.

Reentry in heterogeneous cardiac tissue described by the Luo-Rudy ventricular action potential model