Milan David J, MacRae Calum A
Cardiovascular Research Center, Massachusetts General Hospital, 149 13th Street, Charlestown, MA, USA.
Cardiovasc Res. 2005 Aug 15;67(3):426-37. doi: 10.1016/j.cardiores.2005.06.012.
The complex pathophysiology of human arrhythmias has proven difficult to model. Direct correlations between the traditional arrhythmia mechanisms, including abnormal excitability, conduction, or repolarization and underlying molecular or cellular biology are poorly defined, as the primary etiologies of many human arrhythmias remain unknown. Since the causes of several arrhythmic syndromes have been identified, genetic models reproducing the mechanisms of these arrhythmias have become feasible. Initial murine modeling has revealed that in many cases the pathophysiology of the respective human disease is more complex than had been suspected. Insights from human genetic studies and animal models strongly suggest that the primary molecular defects may contribute at many stages in the causal chain leading to arrhythmia. The comprehensive analysis of each arrhythmia will require knowledge not only of the membrane effects of the primary defects, but also downstream intracellular signals, the developmental results of these perturbations, and the integration of compensatory responses and environmental factors. Precise modeling will require not only the mutation of specific residues in known disease genes, but also the systematic study of each of the many steps in arrhythmogenesis. Ultimately, such models will enable unbiased screens for disease mechanisms and novel therapies.
人类心律失常复杂的病理生理学已被证明难以建模。传统心律失常机制（包括异常兴奋性、传导或复极化）与潜在分子或细胞生物学之间的直接关联定义不明确，因为许多人类心律失常的主要病因仍然未知。自从几种心律失常综合征的病因被确定以来，重现这些心律失常机制的遗传模型已变得可行。最初的小鼠建模表明，在许多情况下，相应人类疾病的病理生理学比之前怀疑的更为复杂。人类遗传学研究和动物模型的见解强烈表明，主要分子缺陷可能在导致心律失常的因果链的多个阶段起作用。对每种心律失常的全面分析不仅需要了解主要缺陷的膜效应，还需要了解下游细胞内信号、这些扰动的发育结果以及代偿反应和环境因素的整合。精确建模不仅需要对已知疾病基因中的特定残基进行突变，还需要对心律失常发生过程中许多步骤中的每一步进行系统研究。最终，这样 的模型将能够对疾病机制和新疗法进行无偏筛选。
