Vagus Nerve Stimulation Suppresses Atrial Fibrillation
Vagus Nerve Stimulation Suppresses Atrial Fibrillation
We randomized 40 patients to either LLTS (n = 20) or sham control (n = 20) groups. No statistically significant differences were observed in the baseline clinical and echocardiographic characteristics between the 2 groups (Table 1); the discomfort threshold and threshold for slowing the sinus rate or AV conduction were also similar. During threshold determination, the sinus rate decreased by 2.6 ± 1.0 beats/min in the LLTS group and by 2.7 ± 1.3 in the control group. The AH interval increased by 1.4 ± 0.5 ms in the LLTS group and by 1.5 ± 0.5 ms in the control group. There was no difference in the subtle changes of sinus rate and AH interval between the 2 groups. During LLTS or sham stimulation, there was no appreciable effect on either the sinus rate or AH interval. Under general anesthesia, we found no change in bispectral index levels when LLTS was applied, indicating no effect of LLTS on level of awareness.
Summarized in Table 2, there were no statistically significant differences in the baseline electrophysiological parameters between the 2 groups. AF was inducible in all but 1 patient in whom, after LLTS, AF was not inducible after 15 attempts. Pacing-induced AF duration decreased significantly by 6.3 ± 1.9 min in the LLTS group versus baseline levels and increased by 1.4 ± 1.8 min in the control group (between-group comparison p = 0.002; Central Illustration). Likewise, pacing-induced AF cycle length increased significantly (28.8 ± 6.5 ms) in the LLTS group compared with baseline, but decreased (8.7 ± 6.5 ms) in the control group (between-group comparison p = 0.0002) (Figure 3). More attempts were required to induce AF in the LLTS group compared with baseline, whereas fewer attempts were required in the control group compared with baseline (LLTS: 2 attempts before vs. 4 attempts after; control: 2 attempts before vs. 1 attempt after; between-group comparison p = 0.005). The AERP at the right atrium and the distal coronary sinus increased in the LLTS group and decreased in the control group (both p = 0.04 for comparison between groups) (Figure 4).
(Enlarge Image)
Figure 3.
Effect of LLTS on Cycle Length
There was a significant increase in AF cycle length compared with baseline in the LLTS group, but not in the control group. Abbreviations as in Figure 1.
(Enlarge Image)
Figure 4.
Effect of LLTS on AERP
Both the right atrial (RA) and coronary sinus (CS) atrial effective refractory period (AERP) increased in the low-level tragus stimulation (LLTS) group and decreased in the control group.
(Enlarge Image)
Central Illustration.
Neuromodulation Suppresses Inflammation and AF
This study examined the antiarrhythmic and anti-inflammatory effects of low-level electrical stimulation of the auricular branch of the right vagus nerve at the tragus (LLTS) in patients referred for atrial fibrillation (AF) ablation. We demonstrated for the first time in humans that LLTS compared with control (sham) stimulation (A) decreased AF duration and (B) suppressed inflammatory cytokines. LLTS = low- level tragus stimulation; TNF = tumor necrosis factor.
There were no significant differences in any of the cytokines measured at baseline between the 2 groups (Table 3). Systemic TNF-α levels were suppressed significantly (2.3 ± 0.3 pg/ml) compared with baseline in the LLTS group but not in the control group (between-group comparison p = 0.006) (Central Illustration). Importantly, the magnitude of decrease in TNF-α levels by LLTS was comparable with the difference between patients with active versus inactive inflammatory diseases. Systemic CRP levels decreased significantly in the LLTS group (1.9 ± 1.4 ng/l) but not in the control group (between-group comparison p = 0.001) (Figure 5). Of note, the decrease in TNF-α and CRP levels was similar in patients who did or did not undergo cardioversion. On the contrary, no difference was observed in the coronary sinus TNF-α or CRP levels between the 2 groups, indicating that the effect of LLTS was mediated through the systemic circulation. Systemic and coronary sinus IL-6 and IL-10 levels did not differ significantly between the 2 groups.
(Enlarge Image)
Figure 5.
Effect of LLTS on Systemic CRP Levels
There was a significant decrease in systemic C-reactive protein (CRP) levels compared with baseline in the low-level tragus stimulation (LLTS) group, but not in the control group.
No major adverse events were noted in the study, including no effect on blood pressure or heart rate during stimulation. In 2 patients, a mild burn on the right ear was observed at the site of the stimulating electrode, which resolved with conservative measures. This adverse effect was not observed after adjusting the tension of the metal clip delivering LLTS.
Patients were followed at 1 month, 3 months, and approximately every 3 months thereafter. Median follow-up was 6 months (interquartile range: 4 to 10 months). During follow-up, 5 patients (25%) in each group experienced recurrence of AF or atrial tachycardia (p = 0.93 by log-rank test).
Results
We randomized 40 patients to either LLTS (n = 20) or sham control (n = 20) groups. No statistically significant differences were observed in the baseline clinical and echocardiographic characteristics between the 2 groups (Table 1); the discomfort threshold and threshold for slowing the sinus rate or AV conduction were also similar. During threshold determination, the sinus rate decreased by 2.6 ± 1.0 beats/min in the LLTS group and by 2.7 ± 1.3 in the control group. The AH interval increased by 1.4 ± 0.5 ms in the LLTS group and by 1.5 ± 0.5 ms in the control group. There was no difference in the subtle changes of sinus rate and AH interval between the 2 groups. During LLTS or sham stimulation, there was no appreciable effect on either the sinus rate or AH interval. Under general anesthesia, we found no change in bispectral index levels when LLTS was applied, indicating no effect of LLTS on level of awareness.
Summarized in Table 2, there were no statistically significant differences in the baseline electrophysiological parameters between the 2 groups. AF was inducible in all but 1 patient in whom, after LLTS, AF was not inducible after 15 attempts. Pacing-induced AF duration decreased significantly by 6.3 ± 1.9 min in the LLTS group versus baseline levels and increased by 1.4 ± 1.8 min in the control group (between-group comparison p = 0.002; Central Illustration). Likewise, pacing-induced AF cycle length increased significantly (28.8 ± 6.5 ms) in the LLTS group compared with baseline, but decreased (8.7 ± 6.5 ms) in the control group (between-group comparison p = 0.0002) (Figure 3). More attempts were required to induce AF in the LLTS group compared with baseline, whereas fewer attempts were required in the control group compared with baseline (LLTS: 2 attempts before vs. 4 attempts after; control: 2 attempts before vs. 1 attempt after; between-group comparison p = 0.005). The AERP at the right atrium and the distal coronary sinus increased in the LLTS group and decreased in the control group (both p = 0.04 for comparison between groups) (Figure 4).
(Enlarge Image)
Figure 3.
Effect of LLTS on Cycle Length
There was a significant increase in AF cycle length compared with baseline in the LLTS group, but not in the control group. Abbreviations as in Figure 1.
(Enlarge Image)
Figure 4.
Effect of LLTS on AERP
Both the right atrial (RA) and coronary sinus (CS) atrial effective refractory period (AERP) increased in the low-level tragus stimulation (LLTS) group and decreased in the control group.
(Enlarge Image)
Central Illustration.
Neuromodulation Suppresses Inflammation and AF
This study examined the antiarrhythmic and anti-inflammatory effects of low-level electrical stimulation of the auricular branch of the right vagus nerve at the tragus (LLTS) in patients referred for atrial fibrillation (AF) ablation. We demonstrated for the first time in humans that LLTS compared with control (sham) stimulation (A) decreased AF duration and (B) suppressed inflammatory cytokines. LLTS = low- level tragus stimulation; TNF = tumor necrosis factor.
There were no significant differences in any of the cytokines measured at baseline between the 2 groups (Table 3). Systemic TNF-α levels were suppressed significantly (2.3 ± 0.3 pg/ml) compared with baseline in the LLTS group but not in the control group (between-group comparison p = 0.006) (Central Illustration). Importantly, the magnitude of decrease in TNF-α levels by LLTS was comparable with the difference between patients with active versus inactive inflammatory diseases. Systemic CRP levels decreased significantly in the LLTS group (1.9 ± 1.4 ng/l) but not in the control group (between-group comparison p = 0.001) (Figure 5). Of note, the decrease in TNF-α and CRP levels was similar in patients who did or did not undergo cardioversion. On the contrary, no difference was observed in the coronary sinus TNF-α or CRP levels between the 2 groups, indicating that the effect of LLTS was mediated through the systemic circulation. Systemic and coronary sinus IL-6 and IL-10 levels did not differ significantly between the 2 groups.
(Enlarge Image)
Figure 5.
Effect of LLTS on Systemic CRP Levels
There was a significant decrease in systemic C-reactive protein (CRP) levels compared with baseline in the low-level tragus stimulation (LLTS) group, but not in the control group.
No major adverse events were noted in the study, including no effect on blood pressure or heart rate during stimulation. In 2 patients, a mild burn on the right ear was observed at the site of the stimulating electrode, which resolved with conservative measures. This adverse effect was not observed after adjusting the tension of the metal clip delivering LLTS.
Patients were followed at 1 month, 3 months, and approximately every 3 months thereafter. Median follow-up was 6 months (interquartile range: 4 to 10 months). During follow-up, 5 patients (25%) in each group experienced recurrence of AF or atrial tachycardia (p = 0.93 by log-rank test).
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