Abnormal Conduction in the Diseased Heart - Enhanced fibrosis due to reduced gap junction and sodium channel expression

The velocity with which the impulse is conducted is dependent on three different factors: excitability, cell-to-cell coupling and tissue characteristics. Excitability is mainly determined by Nav1.5 channels, determining the upstroke-velocity of the action potential, but also by Kir2.1 channels. Gap junctions, in the ventricles of the heart mainly Cx43, enable low resistance communication between adjacent cells, thereby increasing cell-to-cell coupling. The last determinant of impulse conduction, the tissue architecture, is largely dependent on the amount of collagen. Thin fibers of collagen between cardiomyocytes provide essential strength, but an excessive deposition of collagen, called fibrosis, can hamper impulse conduction. A decreased expression of Kir2.1, Nav1.5, Cx43 and / or an increase in collagen is found in many cardiac disorders. Although these proteins are considered as individual parameters, their remodeling generally occurs in concert in the diseased hearts, which suggests a close relation among these proteins. In this thesis we have focused on the interrelations among the different conduction determinants, and their effects on the vulnerability for arrhythmias. We hypothesized that abnormal sodium channel function results in abnormal Cx43 expression which in turn leads to enhanced collagen deposition.By using different types of stress in mice with a genetically abnormal expression of Nav1.5 or Cx43, we analyzed their interaction and effects on collagen deposition and subsequent effects on impulse propagation and arrhythmia inducibility. First, the effect of aging and pressure-overload on mice with a genetically 50% reduction in Cx43 expression was investigated and compared to mice with normal Cx43 expression. Reduced expression of Cx43 resulted in more excessive fibrosis in both aged and pressure-overloaded mice, due to an increased activity of fibroblasts. Besides, this enhanced fibrosis, combined with a heterogeneously reduced expression of Cx43, made the heart highly arrhythmogenic due to dispersed conduction. Pressure-overload in mice with a mutated sodium channel resulted in almost half of the animals in a typical Lev / Lenègre phenotype: progressively slowed impulse conduction through the specific conduction system, eventually evolving into AV-block. Surviving mice showed no abnormalities in vivo, but AV-conduction was delayed ex vivo, and tissue analysis showed increased collagen deposition. Besides, the Cx43 expression levels were decreased. If Cx43 expression is reduced to extremely low levels (~5%) in mice, conduction is disturbed, increasing the susceptibility for arrhythmias. However, arrhythmias could not be induced in all animals, suggesting important differences between arrhythmogenic (VT+) and non-arrhythmogenic (VT-) mice. We found that in VT+ mice, arrhythmia vulnerability was associated with lower Cx43 expression and higher macroscopic Cx43 heterogeneity. Besides, Nav1.5 expression was reduced in VT+ compared to VT- mice. In conclusion, the studies in this thesis have shown that Nav1.5 and Cx43 expression are strongly interrelated, and that abnormal expression of one of those proteins enhances the formation of fibrosis. The resultant is an electrically unstable heart, prone to arrhythmias.