Molecular Basis of Ventricular Electrical Heterogeneity

心室肌细胞的电学特性有系统的变化。在动作电位持续时间和离子通道表达方面存在一致的差异，这取决于心肌细胞在心室壁内的位置。复极化色散的一个主要决定因素是瞬态向外电流的不均匀分布。这影响了正常和异常心脏的复极决定因素，在临床上可以在心电图的ST段和T波中看到。我们以前已经描述了两个基因编码的瞬时外通道亚单位是在脑室差异表达。KChlP2基因在大型（犬和人）哺乳动物左心室游离壁上以大的跨壁梯度表达，Kv4.2基因在大鼠中以跨壁梯度表达。在这两种情况下，这些基因的差异调节似乎是瞬时外向电流表达水平的主要决定因素，并直接影响电性

Ventricular myocytes show systematic variation in their electrical properties. There are consistent differences in action potential duration and in ion channel expression that depend upon the location of the myocyte within the ventricular walls. A major determinant of dispersion of repolarization is the non-uniform distribution of the transient outward current. This impacts on the determinants of repolarization in normal and abnormal hearts and is seen clinically in the ST segment and T wave of the ECG. We have previously described two genes encoding subunits of the transient outward channel that are differentially expressed in the ventricles. The KChlP2 gene is expressed in a large transmural gradient across the left ventricular free wall of large (canine and human) mammals and the Kv4.2 gene is expressed in a transmural gradient in rat. In both cases, differential regulation of these genes appears to be a primary determinant of the level of transient outward current expression and directly contributes to the electrical heterogeneity of ventricular myocytes. The overall aim of this proposal is to use molecular and biophysical techniques to further characterize the relationship between the differential expression of the KChlP2 and Kv4.2 genes and expression of the transient outward current, and to begin to determine the cellular and genetic mechanisms underlying the differential expression of these genes. The results of this study should permit a greater understanding of the mechanisms that determine repolarization in different species and, in collaboration with Project 1, at different ages. The understanding that evolves ultimately should be applicable to the modification of abnormal repoiarization in settings of cardiac disease.