Plasma concentration of choline: A potential biomarker of acetylcholine release by neurostimulation
Sabbah HN, Gupta RC. Plasma concentration of choline: A potential biomarker of acetylcholine release by neurostimulation. Heart Rhythm. 2018;15(5):S364-S365.
Background: Autonomic imbalance occurs in heart failure (HF) and is characterized by sympathetic overdrive and parasympathetic withdrawal Electrical cervical Vagus nerve stimulation (VNS) can restore autonomic balance in HF bypromoting the release of acetylcholine (ACh). Because ACh cannot be directly measured in the circulation due to its very short half-life, major diffculties were encountered in clinical trials in assessing whether appropriate VNS stimulation currents were applied to ensure adequate release of ACh. Once ACh is released and has served its function, it is rapidly broken down by the enzyme acetylcholinesterase (AChE) into choline and acetic acid that are subsequently recycled to form more Ach. Objective: This study tested the hypothesis that plasmaconcentrations of choline (Ch) serves as an indicator or biomarker of ACh release during VNS. Methods: Studies were performed in plasma samples obtained from 26 dogs with chronic HF produced by intracoronary microembolizations (LV ejection fraction ≤35%) and from 14 normal (NL) dogs. HF dogs were randomized to 3 months therapy with VNS at a stimulation current of 4-6 mA (n=6), VNS stimulation current ≤ 2 mA (n=8), β-blocker therapy alone (BB, metoprolol succinate 100 mg once daily, n=6), or to no therapy at all (Controls, n=6). Choline levels in plasmawere measured using a commercially available fuorometric choline quantifcation kit and quantifed in fmols/ml. Results: In NL dogs, plasma Ch levels were 5926 ± 459 fmols/ml and signifcantly decreased to 3335 ± 133 fmols/ml in HF Controls (p<0.05). Compared to HF Controls, plasma Ch increased modestly but not signifcantly to 4226 ± 175 fmols/ml in HF dogs treated with BB alone and to 4117 ± 702 fmols/ml in HF dogs treated with low current (≤ 2 mA) VNS. In contrast, treatment of HF dogs with high current (4-6 mA) VNS elicited a normalization of Ch levels (6205 ± 617 fmols/ml, p<0.05 vs. HF Controls). Conclusion: Plasma Ch levels and, hence, Ach levels are signifcantly reduced in dogs with chronic HF compared to NL dogs. Treatment with either BB or low current VNS does not restore normal Ch levels. Treatment with higher stimulation VNS current is necessary to elicit normal Ach release and, therefore, essential for achieving effective therapy from chronic VNS.