Molecular Basis of Ventricular Electrical Heterogeneity

心室肌细胞的电特性表现出系统性的变化。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，这取决于心室壁内肌细胞的位置。复极化离散度的一个主要决定因素是瞬时外向电流的不均匀分布。这影响了正常和异常心脏中复极的决定因素，临床上见于ECG的ST段和T波。我们以前已经描述了两个基因编码的瞬时外向通道的亚基，差异表达的心室。KChIP2基因在大型（犬和人）哺乳动物的左心室游离壁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，并直接促进了电刺激。 心室肌细胞的异质性。本提案的总体目标是使用分子和生物物理技术来进一步表征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。本研究的结果应该可以更好地了解决定不同物种以及与项目1合作的不同年龄复极的机制。最终发展的理解应该适用于心脏病背景下异常复极的修改。

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.