Effects of Low-Level Tragus Stimulation on Endothelial Function in Heart Failure With Reduced Ejection Fraction

https://doi.org/10.1016/j.cardfail.2020.12.017Get rights and content

Highlights

Abstract

Background

Autonomic dysregulation in heart failure with reduced ejection fraction plays a major role in endothelial dysfunction. Low-level tragus stimulation (LLTS) is a novel, noninvasive method of autonomic modulation.

Methods and Results

We enrolled 50 patients with heart failure with reduced ejection fraction (left ventricular ejection fraction of ≤40%) in a randomized, double-blinded, crossover study. On day 1, patients underwent 60 minutes of LLTS with a transcutaneous stimulator (20 Hz, 200 μs pulse width) or sham (ear lobule) stimulation. Macrovascular function was assessed using flow-mediated dilatation in the brachial artery and cutaneous microcirculation with laser speckle contrast imaging in the hand and nail bed. On day 2, patients were crossed over to the other study arm and underwent sham or LLTS; vascular tests were repeated before and after stimulation. Compared with the sham, LLTS improved flow-mediated dilatation by increasing the percent change in the brachial artery diameter (from 5.0 to 7.5, LLTS on day 1, P = .02; and from 4.9 to 7.1, LLTS on day 2, P = .003), compared with no significant change in the sham group (from 4.6 to 4.7, P = .84 on day 1; and from 5.6 to 5.9 on day 2, P = .65). Cutaneous microcirculation in the hand showed no improvement and perfusion of the nail bed showed a trend toward improvement.

Conclusions

Our study demonstrated the beneficial effects of acute neuromodulation on macrovascular function. Larger studies to validate these findings and understand mechanistic links are warranted.

Section snippets

Patient Characteristics and Study Protocol

In this pilot randomized prospective study (NCT03380156), we enrolled 50 patients (>18 years of age) with HFrEF (with a left ventricular ejection fraction of ≤40%) on guideline-directed medical therapies. Patients with acute congestive heart failure/recent acute myocardial infarction (<4 weeks) or unstable angina, active malignancy, women on estrogen hormone supplements, unilateral or bilateral vagotomy, bilateral upper extremity amputation, pregnancy, end-stage renal disease, recurrent

Results

Fifty patients were enrolled in this study and 45 patients were able to complete both days of the study (NCT03380156). No adverse effects were reported, except for mild tingling of the external ear in 3 patients. The frequency and pulse width of stimulation was set at 20 Hz and 200 µs. The stimulation strength for individual patients (4–65 mA) was set at 3–5 mA below the level that caused discomfort. Mean age was 58 ± 8 years. Demographic and clinical characteristics are outlined in Table 1.

Discussion

To our knowledge, this is the first-in-human study to demonstrate the beneficial effects of acute noninvasive neuromodulation via LLTS on macrovascular endothelial function in patients with HFrEF. We showed that 1 hour of LLTS improves FMD based on brachial artery reactivity testing. Blood perfusion over the nail beds, but not cutaneous perfusion, as assessed by LSCI, showed a trend toward improvement in microvascular endothelial function with 1 hour of LLTS.

Despite use of evidence-based

Limitations

The chronic effects of neuromodulation on EnD are currently unknown, but are being investigated in a randomized clinical trial at our center. In addition, there is a great deal of interest in determining the impact of LLTS on clinical measures such as symptoms, quality of life, exercise capacity, cognition, and biomarkers such as NT-Pro-BNP in patients with HFrEF. Improvement in EnD may potentially lead to improvement in such outcomes in HFrEF. Our sample size also does not permit a secondary

Conclusions

Our study using LLTS in patients with HFrEF demonstrated an improvement in macrovascular endothelial function and showed a trend toward improvement in the microcirculatory function in the nailbed. This holds great promise in the future trials of noninvasive neuromodulation to improve not only endothelial function but to also investigate effects of LLTS on HFrEF end points such as symptoms, exercise capacity, biomarkers, quality of life, and hospitalizations.

Declaration of Competing Interest

The authors declare no conflicts of interest.

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      Citation Excerpt :

      Patients included in the trials of autonomic modulation had a higher proportion of NYHA class III to IV compared with the trials of CRT (Table 1), and patients with symptomatic heart failure are more likely to derive a meaningful improvement in functional capacity from the intervention.28 Furthermore, autonomic modulation and exercise have shown to improve flow-mediated vasodilatation, which is associated with a higher exercise capacity.31,32 In chronologic sequence, the trials of autonomic modulation were conducted after the trials of medical therapy and CRT.

    Supported by the Heart Rhythm Institute, Oklahoma Center for the Advancement of Science and Technology, Presbyterian Health Foundation, Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (GM104938), & Cellular and Molecular GeroScience CoBRE (P20GM125528). This research was also supported by the Oklahoma Shared Clinical and Translational Resources (U54GM104938) with an Institutional Development Award (IDeA) from NIGMS. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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