PO-455617-7 CHRONIC SYMPATHETIC REMODELING IN HEART FAILURE IMPACTS WHOLE-HEART CAMP SIGNALING AND ARRHYTHMOGENESIS.

Abstract

Elevated sympathetic tone and b-AR desensitization are characteristics associated with heart failure (HF) and are contributors to the initiation of arrhythmia. Studies have shown that altered b-AR responsiveness in HF leads to altered compartmentalization and imparied sub-cellular cAMP signaling. Yet, if cAMP signaling is heterogeneously remodeled throughout the intact heart, and how this may contribute to arrhythmia is unknown. To assess whole-heart cAMP signaling and functional responses to adrenergic activation in HF. HF was induced via transverse aortic constriction in cardiac specific CAMPER reporter mice, expressing a FRET-based cAMP biosensor. HF was confirmed by echocardiography and hearts were Langendorff-perfused for simultaneous cAMP and Ca2+ imaging on an integrated whole-heart optical mapping FRET imaging system. Sham mice underwent the same procedure but without constriction of the aorta. Baseline cAMP levels, assessed as the FRET ratio, were uniform throughout the ventricles of male and female Sham hearts. Conversely, in HF, baseline levels of cAMP were higher in the apex vs. the base, particularly in female hearts. Low-dose b1-AR stimulation (100nM NE) led to greater cAMP response in male HF hearts vs. Sham, this response was uniform across the male heart. In female HF hearts, there was a trend toward a greater cAMP response in basal, but not apical regions. At high dose b1-AR stimulation (500nM NE), male and female HF hearts had reduced cAMP responses compared to Sham, mainly in the female apex, where dose-dependent responses were lost. Similar apex-base differences were evident following b1 and b2-AR stimulation (100-500nM Epi), with lower cAMP responses in the female apex in HF. Uniform cAMP responses in male and female Sham hearts were accompanied by uniform shortening of the Ca2+ transient duration (CaTD) in response to low dose b1-AR stimulation. Following HF, baseline CaTD was shorter than in Sham hearts and the response to b-AR stimulation was reduced. Moreover, CaTD responses were no longer spatially uniform, where apical CaTD shortened beyond that of basal regions in HF. At high dose b1-AR stimulation, ventricular arrhythmia was observed in 8/10 HF hearts, vs 0/4 Sham hearts. Using whole-heart cAMP and Ca2+ imaging, we have shown cAMP activity and responses became spatially heterogeneous in HF, mainly in female hearts. Heterogeneity in cAMP activity was associated with heterogenous Ca2+ responses and ventricular arrhythmia.