Cardiac Resynchronization Therapy Restores Sympathovagal Balance in the Failing Heart by Differential Remodeling of Cholinergic Signaling

Abstract

Rationale Cardiac resynchronization therapy (CRT) is the only heart failure (HF) therapy documented to improve left ventricular (LV) function and reduce mortality. The underlying mechanisms are incompletely understood. While β-adrenergic signaling has been studied extensively, the effect of CRT on cholinergic signaling is unexplored. Objective We hypothesized that remodeling of cholinergic signaling plays an important role in the aberrant calcium signaling and depressed contractile and β-adrenergic responsiveness in dyssynchronous HF (DHF) that are restored by CRT. Methods and Results Canine tachypaced DHF and CRT models were generated to interrogate responses specific to dyssynchronous vs. resynchronized ventricular contraction during hemodynamic decompensation. Echocardiographic, electrocardiographic and invasive hemodynamic data were collected from normal controls, DHF and CRT models. LV tissue was used for biochemical analyses and functional measurements (calcium transient, sarcomere shortening) from isolated myocytes (N=42–104 myocytes/model; 6–9 hearts/model). Human LV myocardium was obtained for biochemical analyses from explanted failing (N=18) and non-failing (N=7) hearts. The M2 subtype of muscarinic acetylcholine receptors (M2-mAChR) was upregulated in human and canine HF compared to non-failing controls. CRT attenuated the increased M2-mAChR expression and Gαi-coupling, and enhanced M3-mAChR expression in association with enhanced calcium cycling, sarcomere shortening and β-adrenergic responsiveness. Despite model-dependent remodeling, cholinergic stimulation completely abolished isoproterenol-induced triggered activity in both DHF and CRT myocytes. Conclusions Remodeling of cholinergic signaling is a critical pathological component of human and canine HF. Differential remodeling of cholinergic signaling represents a novel mechanism for enhancing sympathovagal balance with CRT and may identify new targets for treatment of systolic HF.

Muscarinic Stimulation Facilitates Sarcoplasmic Reticulum Ca Release by Modulating Ryanodine Receptor 2 Phosphorylation Through Protein Kinase G and Ca/Calmodulin-Dependent Protein Kinase II

“…26,27 Accordingly, selective inhibitors of the aforementioned MR subtypes (AF-DX 116 (specific for M2R), J 104129 fumarate (specific for M3R)) 27,28 were used to examine the role of these receptor subtypes in mediating RyR2 phosphorylation in response to cholinergic stimulation. Inhibition of M2R (but not inhibition of M3R) prevented changes in RyR2 phosphorylation at Ser-2808 in mouse myocytes (Fig.…”

Parasympathetic dysfunction and antiarrhythmic effect of vagal nerve stimulation following myocardial infarction

“…Given the decrease in central drive, this increase in response may be due to upreguation of muscarinic receptors in the heart. Although an increase in receptor density has not been evaluated in ischemic cardiomyopathy, in a guinea pig model of pacing-induced heart failure, M2 receptors have been shown to be upregulated, and VNS is able to normalize these receptor levels (42).…”

Cardiac Innervation and the Autonomic Nervous System in Sudden Cardiac Death

“…79 In addition, while heart failure increases muscarinic receptor subtype 2 and its Gαi counterpart, CRT upregulates known protective muscarinic receptor subtype 3. 80 …”