Molecular Basis of Ventricular Electrical Heterogeneity

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.