Sympathetic remodeling and ventricular arrhythmia

University Of California At Davis, Davis CA

Investigators

Linked publications, trials & patents

Abstract

ABSTRACT: Myocardial infarction (MI) is a leading risk factor for ventricular arrhythmias. Due to significant MI- induced remodeling within the sympathetic nervous system and cardiac adrenergic signaling cascades, blocking cardiac b-adrenergic receptors (b-ARs) and downstream cyclic adenosine monophosphate (cAMP) signaling remains one of the most effective anti-arrhythmic strategies post-MI. In cardiomyocytes, cAMP is tightly controlled within a complex at the b-AR that includes phosphodiesterase 4D (PDE4D, cAMP degrading enzyme), and this complex may be impacted by sympathetic innervation. During the previous funding period, we developed a novel multi-parametric whole-heart imaging system and two transgenic mice expressing biosensors for cAMP and norepinephrine (NE) to assess cAMP and NE signaling in healthy and post-MI hearts. Using this approach, we found that cellular cAMP decay is significantly slowed in the post-MI heart following sympathetic stimulation, potentially implicating reduced PDE activity as an important – and previously unrecognized – contributor to arrhythmias. Preliminary data with the NE biosensor further suggest that reduced NE reuptake at the neuro- cardiac junction may also play an important role in slowing cAMP break-down. Finally, we found that restoring sympathetic innervation pharmacologically restored normal cAMP break-down and prevented arrhythmias during sympathetic stimulation. Therefore, this renewal application aims to test the hypotheses that: 1) the regulation and termination of cAMP signaling in the normal heart is governed by clearance of catecholamines from the synaptic cleft by the NE transporter (NET) and by PDE4D activity in the b-AR complex; 2) regional hypo-innervation post-MI leads to reduced NE reuptake and regional disruption of b-AR-cAMP signaling to promote arrhythmias; and 3) restoring sympathetic innervation to the infarct restores cAMP break-down to prevent arrhythmias. We will combine our multi-parametric whole-heart imaging system with cellular and biochemical analyses and functional optical mapping of transmembrane potential (Vm) and intracellular Ca2+. Aim 1 will characterize regional and sex differences in NE reuptake and PDE activity in modulating cAMP signaling and functional responses in the normal heart. In Aim 2, we will determine the role of NE reuptake vs. PDE activity in the termination of cAMP signaling in the post-MI heart and how this contributes to ventricular arrhythmias. Aim 3 will determine the mechanisms by which pharmacological sympathetic re-innervation post-MI accelerates and restores cAMP break-down to prevent arrhythmias. These studies will provide unprecedented insight into how changes to cAMP break-down contribute to arrhythmias from cellular signaling up to macro-scale multi-organ interactions. We will also determine detailed mechanisms of action of novel neuromodulatory drugs that may have therapeutic potential beyond the post-MI environment.