Abstract 2429: Distinct Mechanisms Underlying Moderate and Severe Conduction Abnormalities During the Course of Hypertrophic Remodeling
Mechanisms by which structural, mechanical, and molecular alterations predispose to arrhythmias at the tissue level prior to the onset of LV dysfunction remain unclear. Here, we investigate the nature of conduction abnormalities and their molecular correlates during early hypertrophic remodeling.
Methods and Results: In a rat model of concentric LV hypertrophy (LVH) produced by ascending aortic banding, we correlate mechanical and structural changes measured in vivo with key electrophysiological changes measured ex vivo using high resolution optical AP mapping. We find that AP prolongation, a hallmark of electrical remodeling, is highly correlated with changes in LV wall thickness (septum p=0.003; free wall p=0.0056) but not mechanical function (p=0.820). In contrast, conduction delays are neither predicted by mechanical nor structural (NS) remodeling. Instead, dynamic changes in the expression of Cx45 and the phosphorylation of Cx43 are associated with moderate (−21.4%) and severe (−62.1%) conduction slowing, respectively (Figure⇓). Specifically, moderate conduction slowing during early LVH progression is associated with increased (>1.5X) Cx45 and preserved Cx43 expression. Severe conduction slowing which occur when stroke volume is significantly (p<0.01) reduced (by 36%) are caused by Cx43 dephosphorylation and loss of interaction with the cytoskeletal protein ZO-1.
Conclusion: Repolarization but not conduction delays are predicted by structural remodeling in LVH. A transient increase in Cx45 expression is associated with moderate conduction slowing whereas dephosphorylation of Cx43 and loss of interaction with ZO-1 form severe conduction delays.
This research has received full or partial funding support from the American Heart Association, National Center.