Abstract 068: Age-associated, Vinculin-mediated Remodeling of the Intercalated Disc Results in Localized Myocardial Stiffening but Preserved Mechanical Function

Abstract

Molecular and ultrastructural remodeling of the intercalated disc occurs with advanced age and onset of cardiomyopathy, yet the precise effect of this remodeling on mechanical function remains unclear. We employed recently-developed biophysical techniques to measure passive and active cardiac mechanics to investigate how intercalated disc remodeling affects structure and mechanical function with age. Nanoindentation of intact, living Drosophila heart reveals that juvenile myocytes are mechanically homogeneous; however, aging induces mechanical heterogeneity, indicated by increased transverse passive stiffness proximal to the intercalated disc (ID). Localized stiffening up to a 111% increase correlates with an 18% age-related decline in diastolic dimension (DD) as well as increased fascia adherens expression. On the other hand, aged specimens with stiffened IDs were found to have preserved systolic function, assessed by measuring shortening velocity under acute hemodynamic load, as compared to their juvenile counterparts. Aged specimens with no change in ID stiffness experienced reduced shortening velocities at all loads. Cardiac-specific vinculin overexpression stiffened IDs and increased shortening velocity and fractional shortening at all hemodynamic loads. Cardiac specific, RNAi-mediated knockdown of vinculin softened the IDs of intact hearts and reduced fractional shortening at all loads. These data indicate that increased expression of vinculin at the ID results in a stiffer cortical cytoskeleton which acts as a more stable anchor against which the myocytes can shorten. These findings have potential implications for geriatric patients with diastolic heart failure, in whom increased vinculin expression at the intercalated disc, concomitant with increased diastolic stiffness but preserved ejection fraction, has been observed.