Vagus Nerve Stimulation and Atrial Fibrillation: Revealing the Paradox

Kharbanda, Rohit K.; Does, Willemijn F. B. van der; Staveren, Lianne N. van; Taverne, Yannick J.H.J.; Bogers, Ad J.J.C.; Groot, Natasja M.S. de

doi:10.1016/j.neurom.2022.01.008

Cited by 19 publications

(15 citation statements)

References 85 publications

(124 reference statements)

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“…Therefore, the HR rebound after the termination of stimulation in Experiment 1 was not due to homeostatic plasticity, but rather to the physiological reaction to the verbal NRS response. In animal studies on the application of tVNS for cardiac disease, high-intensity stimulation to vagal efferent fibers induces atrial fibrillation and low-intensity VNS has been shown to suppress atrial fibrillation [ 7 , 10 , 24 , 30 , 33 , 34 , 35 , 36 ]. However, atrial fibrillation cannot be induced unless the HR is reduced by 40% or more [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Afferent information from the vagus nerve enters the nucleus tractus solitarius (NTS) and then spreads through the locus coeruleus (LC) to the various cortical regions, such as the sensorimotor cortex, anterior cingulate cortex (ACC), and insular cortex (Ins) [ 2 ]. Transcutaneous Vagus Nerve Stimulation (tVNS) enables noninvasive electrical stimulation of vagal afferents and has been reported to improve symptoms of seizures, depression, migraine headaches, COVID-19, cardiac disease, and stroke [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. Neurophysiological changes underpinning the effects of tVNS reveal that stimulation either to the tragus or cymba conchae, the auricular branches of the vagus nerve, changes heart rate (HR) and heart rate variability (HRV) [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Changes in autonomic nervous system activity have also been observed at both low- and high-stimulation intensities [ 18 ]. In an animal study, high-intensity VNS delayed atrial conduction speed and induced atrial fibrillation [ 7 ]. Interestingly, low-intensity VNS has been reported to be effective in suppressing atrial fibrillation [ 10 , 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Effects of Stimulus Frequency, Intensity, and Sex on the Autonomic Response to Transcutaneous Vagus Nerve Stimulation

et al. 2022

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This study aimed to determine how transcutaneous vagus nerve stimulation (tVNS) alters autonomic nervous activity by comparing the effects of different tVNS frequencies and current intensities. We also investigated the sex-dependent autonomic response to tVNS. Thirty-five healthy adult participants were stimulated using a tVNS stimulator at the left cymba conchae while sitting on a reclining chair; tVNS-induced waveform changes were then recorded for different stimulus frequencies (Experiment 1: 3.0 mA at 100 Hz, 25 Hz, 10 Hz, 1 Hz, and 0 Hz (no stimulation)) and current intensities (Experiment 2: 100 Hz at 3.0 mA, 1.0 mA, 0.2 mA (below sensory threshold), and 0 mA (no stimulation)) using an electrocardiogram. Pulse widths were set at 250 µs in both experiment 1 and 2. Changes in heart rate (HR), root-mean-square of the difference between two successive R waves (RMSSD), and the ratio between low-frequency (LF) (0.04–0.15 Hz) and high-frequency (HF) (0.15–0.40 Hz) bands (LF/HF) in spectral analysis, which indicates sympathetic and parasympathetic activity, respectively, in heart rate variability (HRV), were recorded for analysis. Although stimulation at all frequencies significantly reduced HR (p = 0.001), stimulation at 100 Hz had the most pronounced effect (p = 0.001) in Experiment 1 and was revealed to be required to deliver at 3.0 mA in Experiment 2 (p = 0.003). Additionally, participants with higher baseline sympathetic activity experienced higher parasympathetic response during stimulation, and sex differences may exist in the autonomic responses by the application of tVNS. Therefore, our findings suggest that optimal autonomic changes induced by tVNS to the left cymba conchae vary depending on stimulating parameters and sex.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of Stimulus Frequency, Intensity, and Sex on the Autonomic Response to Transcutaneous Vagus Nerve Stimulation

et al. 2022

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“…With a change in the activity of the vagal nerve, in the atria, the ACh concentration changes significantly (e.g., it increases by 9 times at 20 Hz vagal stimulation and by 20 times at 40 Hz stimulation [ 8 ]). Both ACh infusion at high concentration and high-level vagal stimulation promote the inducibility of atrial fibrillation (AF) [ 9 , 10 , 11 , 12 ]. The arrhythmogenic effects of ACh are related to the ACh-activated K + current (I K,ACh ), which hyperpolarizes the membrane and shortens action potential duration (APD) in atrial cardiomyocytes facilitating the onset and maintenance of AF by reducing the wavelength for re-entry [ 11 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Peculiarities of the Acetylcholine Action on the Contractile Function of Cardiomyocytes from the Left and Right Atria in Rats

Butova

Myachina

Simonova

et al. 2022

Cells

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Acetylcholine (ACh) is the neurotransmitter of the parasympathetic nervous system that modulates cardiac function, and its high concentrations may induce atrial fibrillation. We compared the ACh action on the mechanical function of single cardiomyocytes from the left atria (LA) and the right atria (RA). We exposed single rat LA and RA cardiomyocytes to 1, 10, and 100 µM ACh for 10–15 min and measured the parameters of sarcomere shortening–relengthening and cytosolic calcium ([Ca2+]i) transients during cell contractions. We also studied the effects of ACh on cardiac myosin function using an in vitro motility assay and analyzed the phosphorylation level of sarcomeric proteins. In LA cardiomyocytes, ACh decreased the time to peak sarcomere shortening, time to 50% relengthening, and time to peak [Ca2+]i transients. In RA cardiomyocytes, ACh affected the time of shortening and relengthening only at 10 µM. In the in vitro motility assay, ACh reduced to a greater extent the sliding velocity of F-actin over myosin from LA cardiomyocytes, which was accompanied by a more pronounced decrease in phosphorylation of the myosin regulatory light chain (RLC) in LA cardiomyocytes than in RA cardiomyocytes. Our findings indicate that ACh plays an important role in modulating the contractile function of LA and RA, provoking more pronounced changes in the time course of sarcomere shortening–relengthening and the kinetics of actin–myosin interaction in LA cardiomyocytes.

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“…Bradycardia and SAN dysfunction have been linked to AF. Stimulating the vagus nerve to increase parasympathetic signaling can be both proarrhythmic and anti-arrhythmic (50). While low level vagus nerve stimulation, which does not induce bradycardia, can be anti-arrhythmic, parasympathetic over-stimulation that induces bradycardia can lead to proarrhythmic effects on the atrium (32,(51)(52)(53).…”

Section: Discussionmentioning

confidence: 99%

Neonatal Scn1b-null mice have sinoatrial node dysfunction, altered atrial structure, and atrial fibrillation

Ramos-Mondragón¹,

Edokobi²,

Hodges³

et al. 2022

JCI Insight

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Author contributionsNE performed tissue isolation, whole mount preparation and imaging/analysis, and ECG recordings. RRM performed intracardiac recordings, ECG recordings, patch clamp electrophysiology, and analysis of echocardiography and provided mentoring support to NE. SH and CS performed RNA isolations and qPCR experiments and analyses. SW performed cardiac myocyte isolation, picrosirius red staining, imaging, and analysis, and qPCR and analysis. AAB performed the RNA isolation for RNA-Seq. CC performed picrosirius red staining and analysis. LJ and WRA contributed to whole mount image analysis. SN mentored and trained NE in whole mount preparation and imaging analysis. NRM and MSR provided mentorship and funding to RRM. LLI contributed to experimental design and interpretation and provided funding. LFLS provided mentoring and training to NE. NE, RRM, LFLS, and LLI cowrote the manuscript. NE and RRM are recognized as co-first authors. NE and RRM performed equal amounts of work and so their authorship is listed in alphabetical order.

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Vagus Nerve Stimulation and Atrial Fibrillation: Revealing the Paradox

Cited by 19 publications

References 85 publications

Effects of Stimulus Frequency, Intensity, and Sex on the Autonomic Response to Transcutaneous Vagus Nerve Stimulation

Effects of Stimulus Frequency, Intensity, and Sex on the Autonomic Response to Transcutaneous Vagus Nerve Stimulation

Peculiarities of the Acetylcholine Action on the Contractile Function of Cardiomyocytes from the Left and Right Atria in Rats

Neonatal Scn1b-null mice have sinoatrial node dysfunction, altered atrial structure, and atrial fibrillation

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