Molecular Basis of Ventricular Electrical Heterogeneity

心室肌细胞表现出系统性的电学特性变化。在动作电位时程和离子通道表达上有一致的差异，这取决于心肌细胞在室壁内的位置。复极化分散的一个主要决定因素是瞬时外向电流的不均匀分布。这会影响正常和异常心脏的复极决定因素，临床上可以在心电图的ST段和T波上看到。我们之前已经描述了两个编码瞬时外向通道亚单位的基因，它们在脑室中差异表达。KChlP2基因在大型哺乳动物(犬和人)的左心室游离壁中以跨壁梯度表达，Kv4.2基因在大鼠中以跨壁梯度表达。在这两种情况下，这些基因的不同调控似乎是瞬时外向电流表达水平的主要决定因素，并直接对电 心肌细胞的异质性。该方案的总体目标是利用分子和生物物理技术进一步表征KChlP2和Kv4.2基因的差异表达与瞬时外向电流表达之间的关系，并开始确定这些基因差异表达的细胞和遗传机制。这项研究的结果应该能够更好地理解决定不同物种复极化的机制，并与项目1合作，在不同的年龄确定复极化。这种最终演变的理解应该适用于心脏疾病环境中异常再定位的修改。

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.