Introduction

Higher blood pressure (BP) variability (BPV) was shown to be strong predictors of poor cardiovascular outcomes in heart failure (HF) with reduced ejection fraction (HFrEF) [1] and HF with preserved ejection fraction (HFpEF) [2]. Early drop in systolic BP (SBP) was associated with worsening renal function [3, 4] and outcome in acute HF (AHF) patients [3]. Even in the AHF, excessive fluctuations in BP are considered to be an important factor for target organ damage and poor prognosis. In addition to arterial remodeling, increased sympathetic nervous system (SNS) activity is associated with elevated BPV [5]. Suppression of SNS activity or up regulation of the parasympathetic nervous activity in HF is expected to contribute to hemodynamic stability and reduce BPV.

Low-level tragus stimulation (LLTS) is a simple, non-invasive emergency treatment with few side effects that stimulates the auricular branch of the vagus nerve in the tragus [6]. Selective vagus nerve stimulation (VNS) is associated with an increase in baroreflex sensitivity (BRS) [7] and LLTS is effective in reducing certain frequency domain parameters that are reflective of SNS activity. In clinical studies, LLTS significantly reduced LV afterload in acute HF (AHF) patients [6].

From these perspectives, we hypothesized that active LLTS could significantly reduce BPV in HF. To date, no previous study has shown a relationship between vagally-mediated neuromodulation and BPV in HF. In this study, acute active stimulation and sham stimulation was performed to investigate the effect of active LLTS on BPV in AHF patients.

Methods

Study Design and Data Source

This study was conducted as a single-center randomized controlled trial at Hiroshima City Asa Hospital from June 2021 to June 2022 in Japan. We performed a post hoc analysis of the earlier study in which the relationship between LLTS and LV afterload was investigated in AHF (University Hospital Medical Information Network Clinical Trials Registry, UMIN000044121). We considered a patient as eligible for study enrollment if he or she were hospitalized for AHF during this study. The patients hospitalized for AHF were randomized after initial stabilization after admission. The rationale, design and outcomes of the study were previously published [6]. After informed consent, patients were randomly assigned to active or sham LLTS group (1:1). Active LLTS or sham stimulation was then performed for 1 h per day between 2:00 PM and 4:00 PM for 5 days.

Inclusion criteria included (i) patients with an on-admission systolic BP (SBP) of > 100 mmHg; (ii) consenting to participate in this study. Exclusion criteria included (i) patients with multiple organ failure (possibility of unclear relationship between VNS and HF); (ii) patients in shock (possibility of excessive hypotension): (iii) patients with severe bradycardia, excluding those with a pacemaker (possibility of promoting bradycardia): (iv) patients with sepsis (possibility of excessive hypotension): (v) patients who did not consent to participate in this study [6].

Measurement of Symptoms and BPV

At each occasion before and after stimulation, the 100-point visual analog scales (VAS, from 0 = “worst you can imagine” to 100 = “best you can imagine” with labeled hash marks at increments of 5 was recorded for HF symptoms. Brachial BP was measured three times after 5 min rest with an automated oscillometric device [6], and the average, standard deviation (SD), coefficient of variation (CV) and δ at each occasion were calculated in SBP, diastolic BP (DBP) and heart rate (HR) [6, 8].

BPV was measured among three measurements at each occasion according to the following equations: SD (mmHg) = square root [sum of (individual reading value—sample average value)2/3], CV (%) = SD/average value × 100, and δ (mmHg) = Maximum value – minimum value. These BPV indicators are widely used in the numerous clinical studies in which BPV were in investigated [9]. To eliminate the influence of average value, CV was calculated [8]. Five-day average values of SD, CV and δ in SBP, DBP and HR were compared before and after stimulation in each group, and the changes in the values of SD, CV and δ were also compared between two groups.

Statistical Analysis

The data were expressed as medians and interquartile ranges. Measurements of VAS score and variability in SBP, DBP and HR before and after stimulation in each active and sham group were analyzed through paired Wilcoxon signed-rank test. Changes in measurements of VAS score and variability in SBP, DBP and HR between the two groups were compared through Mann-Whiteney U test. p-values less than 0.05 were considered statistically significant. All analyses were performed using SPSS version 11.5 J statistical software (SPSS, Chicago, IL).

Results

Study Population

The baseline characteristics of the patients were balanced between the 2 groups, and that information was presented elsewhere [6]. At admission, median BNP in the active group was 402 pg/ml compared to 495 pg/ml in the sham group (p = 0.33). Baseline EF (60.6 vs 63.1%, p = 0.72) and E/e’ (23.2 vs 16.9, p = 0.44) were not significantly between active LLTS and sham groups. Most of the patients were elderly, and HFpEF was observed in 75% of the active stimulation group and 87.5% of the sham stimulation group. And ischemic etiology was observed in 12.5% of the active stimulation group and 12.5% of the sham stimulation group. Chronic arial fibrillation was observed in 50% of the active stimulation group and 50% of the sham stimulation group.

Measurements of VAS Score and Variability in Blood Pressure and Heart Rate Before and After Stimulation

There was a significant change in VAS score in the active LLTS (52.5 to 62.5, p = 0.02) while there was no significant change in VAS score in sham stimulation group (52.5 to 50.0, p = 1.0) (Table 1). There were significant differences in variability in SBP and DBP before and after stimulation. In the active group, each of SD (6.63 vs 3.15 mmHg), CV (4.31 vs 2.40%) and δ (12.6 vs 5.8 mmHg) in SBP was significantly decreased after stimulation (all p < 0.05) (Fig. 1a, b and c), while each of SD (3.82 vs 5.71 mmHg) and δ (7.20 vs 11.0 mmHg) in SBP was significantly increased after stimulation in the sham group (all p < 0.05). In the active group, δ in DBP was significantly increased after stimulation (p < 0.05), while each of SD, CV and δ in DBP was significantly increased after stimulation in the sham group (all p < 0.05). There were not significant differences in SD, CV and δ in HR both in both the active LLTS and sham groups (Table 1).

Table 1 Measurements of variability in blood pressure and heart rate before and after stimulation
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Fig. 1
figure 1

Effect of active vs sham LLTS on measurements of variability in systolic blood pressure. a Standard deviation. b Coefficient of variation. c δ. A. Active stimulation. B. Sham stimulation

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Changes in Measurements of VAS Score and Variability in Blood Pressure and Heart Rate Between Two Groups

There was significant difference in the changes in VAS score between active LLTS and sham stimulation groups (12.5 vs 0.0, p = 0.01) (Table 2). When the changes in measurements of variability in SBP, DBP and HR before and after stimulation were compared between active and sham groups, there were significant differences in changes in SD, CV and δ in SBP (all p < 0.001), and in SD and CV in DBP (all p < 0.05) between two groups. There were no significant differences in the changes in SD, CV and δ in HR between the active LLTS group and the sham group (Table 2).

Table 2 Changes in measurements of variability in blood pressure and heart rate between active and sham stimulation groups
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Discussion

In this study, 1 h of LLTS significantly reduced BPV and improved HF symptom compared to sham stimulation in AHF patients. This study suggests that non-invasive vagally-mediated neuromodulation is useful and safe for reducing BPV in AHF.

LLTS and BPV

BPV indices of SD, CV, and δ are widely used in numerous clinical studies [9]. And in this study, LLTS suppressed the BPV in patients with AHF. Generally, BPV tends to be influenced by the average BP value, but in this study, LLTS suppressed CV for which the average BP value had minimally influence. This suggests that LLTS might be effective to stabilize hemodynamics via BPV reduction.

Baroreflex plays a vital role in short-term regulation of BP, and impaired BRS could have resulted in increased BPV. Acute VNS therapy has shown beneficial effects on BP dynamics in hypertensive rats [7]. Electrical stimulation of vagus nerve fibers has shown to increase BRS and consequently lower BP [7]. Although HF is suggested to be associated with autonomic dysfunction characterized by decreased BRS gain, increased SNS activity, and withdrawal of parasympathetic activity [6], LLTS for AHF patients might stabilize the sympatho-vagal imbalance and increase BRS gain resulting in BPV reduction.

Sham Stimulation and BPV

Contrary to our hypothesis, in this study, sham stimulation significantly increased systolic and diastolic BPV compared to before stimulation.

The earlobe is considered a reliable site for sham stimulation because of its innervation without vagus nerve fibers [10]. Therefore, it is thought that earlobe stimulation has almost no effect derived from the parasympathetic nervous system. In fact, distinct vagus evoked potentials were seen only after stimulation inside the tragus, but not after stimulation of the earlobe [11]. Almost all controlled LLTS trials investigate the earlobe as a sham region, presumably the site that produces the biological activity of stimuli in terms of physiological responses.

Changes in blood oxygenation level dependent (BOLD) signal induced by earlobe transcutaneous stimulation in healthy subjects has been documented through functional magnetic resonance (fMRI) imaging studies [12]. While BOLD signal activation of the nucleus tractus solitarius, where vagus nerve afferents gathered, was not observed under the left earlobe stimulation as sham conditions [13], earlobe stimulation produced activation in the insular cortex in fMRI study. Recent studies have supported the notion that the cardiovascular system is regulated by a central autonomic network (CAN) including insular cortex, anterior cingulate gyrus and amygdala [14, 15]. The changes in hemodynamics during sham stimulation in this study might be influenced by sympathetic physiological responses due to CAN activity.

LLTS and Dyspnea

In this study, active LLTS improved HF symptom of dyspnea. In HF patients, dyspnea is associated with high CO2 exposure or an extreme cardiac output increase. In AHF patients, active LLTS reduced average HR [6]. If it were assumed that the stroke volume was constant, the cardiac output would decrease due to active LLTS [6].

Recently, fMRI studies have shown that insular cortex, cingulate cortex and hippocampus play an important role in mediating the perception of dyspnea [16, 17]. In HF patients, these brain areas were also damaged, that might also contribute to perception of dyspnea [18]. On the other hand, LLTS were associated with activation of the insular cortex and improved viscerosensory perception [10, 19].

Improved dyspnea in the active group of this study is suggested to be due to LV load reduction and improved function of central autonomic network via active LLTS. Relief of acute LV load-induced dyspnea might be associated with brain activation regarding breathing regulation [20].

Limitations

This is the post hoc analysis of a previously published study which may raise concerns about the robustness of the findings. Additionally, this study was conducted as a single-center randomized controlled trial in Japan, which may limit the generalizability of the findings to other populations. Furthermore, this study was conducted on AHF patients whose hemodynamic was stabilized after admission, as this may influence the interpretation of the results.

Conclusion

While increased BPV in patients with HF has been shown to be a poor prognostic marker, there have been few clinical investigations from the perspective of the autonomic nervous system instability. In this study, non-invasive neuromodulation of the vagus nervous system in patients with AHF reduced BPV, and clinically relevant findings were reported in the standpoints of elucidating pathophysiology and therapeutic intervention. In the future, studies into vagally-mediated non-invasive neuromodulation for patients with AHF will progress as a large-scale, multicenter, international research.