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

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.

The role of age-associated autonomic dysfunction in inflammation and endothelial dysfunction.

Aging of the cardiovascular regulatory function manifests as an imbalance between the sympathetic and parasympathetic (vagal) components of the autonomic nervous system (ANS). The most characteristic change is sympathetic overdrive, which is manifested by an increase in the muscle sympathetic nerve activity (MSNA) burst frequency with age. Age-related changes that occur in vagal nerve activity is less clear. The resting tonic parasympathetic activity can be estimated noninvasively by measuring the increase in heart rate occurring in response to muscarinic cholinergic receptor blockade; animal study models have shown this to diminish with age. Humoral, cellular, and neural mechanisms work together to prevent non-resolving inflammation. This review focuses on the mechanisms underlying age-related alternations in the ANS and how an imbalance in the ANS, evaluated by MSNA and heart rate variability (HRV), potentially facilitates inflammation when the homeostatic mechanisms between reflex neural circuits and the immune system are compromised, particularly the dysfunction of the cholinergic anti-inflammatory reflex. Physiologically, the efferent arm of this reflex acts via the [Formula: see text] 7 nicotinic acetylcholine receptors expressed in macrophages, monocytes, dendritic cells, T cells, and endothelial cells to curb the release of inflammatory cytokines, in which inhibition of NF­κB nuclear translocation and activation of a JAK/STAT-mediated signaling cascade in macrophages and other immune cells are implicated. This reflex is likely to become less adequate with advanced age. Consequently, a pro-inflammatory state induced by reduced vagus output with age is associated with endothelial dysfunction and may significantly contribute to the development and propagation of atherosclerosis, heart failure, and hypertension. The aim of this review is to summarize the relationship between ANS dysfunction, inflammation, and endothelial dysfunction in the context of aging. Meanwhile, this review also attempts to describe the role of HRV measures as a predictor of the level of inflammation and endothelial dysfunction in the aged population and explore the possible therapeutical effects of vagus nerve stimulation.

Meta-analysis Analyzing the Effect of Therapies on 6-Minute Walk Distance in Heart Failure With Reduced Ejection Fraction.

The 6-minute walk distance (6MWD) carries prognostic value in patients with heart failure with reduced ejection fraction (HFrEF). We performed this systematic review and meta-analysis to evaluate the effect of heart failure therapies on improvement in 6MWD. A systematic search of MEDLINE and Embase was conducted for randomized controlled trials measuring 6MWD at baseline and at follow-up in at least 50 patients with HFrEF across both arms. The primary outcome was improvement in 6MWD at follow-up. Meta-analysis was stratified in groups on the basis of medical therapy, device-based therapy, autonomic modulation, and exercise. Mean differences (MDs) with 95% confidence interval (CI) were reported across multiple studies that were included in the meta-analysis. A total of 44 studies met the inclusion criteria for systematic review; 17 of which were included for meta-analysis. Statistical analysis showed a statistically significant improvement in 6MWD in meters (m) at follow-up for device-based therapy (MD 20.01 m, 95% CI 18.71 to 21.31), autonomic modulation (MD 76.64 m, 95% CI 54.10 to 99.19), and exercise group (MD 39.52 m, 95% CI 19.68 to 59.35). Pooled analysis of medical therapy did not show statistically significant improvement in 6MWD at follow-up (MD 31.69 m, 95% CI -6.52 to 69.91). Device-based therapy (cardiac resynchronization therapy and cardiac contractility modulation), autonomic modulation, and exercise training programs are associated with improvement in 6MWD in patients with HFrEF. 6MWD is a useful test to gauge improvement in functional capacity among patients with HFrEF, especially those with severe symptomatic heart failure.

Non-invasive Low-level Tragus Stimulation in Cardiovascular Diseases.

Low-level tragus stimulation (LLTS) is a non-invasive approach of transcutaneous vagus nerve stimulation. LLTS has applications in diseases of multiple systems, including epilepsy, depression, headache and potentially several cardiovascular diseases. LLTS has shown promising results in suppressing AF, alleviating post-MI ventricular arrhythmias and ischaemia-reperfusion injury along with improving diastolic parameters in heart failure with preserved left ventricular ejection fraction (HFpEF). Preliminary pilot clinical studies in patients with paroxysmal AF, HFpEF, heart failure with reduced ejection fraction and acute MI have demonstrated promising results. The beneficial effects are likely secondary to favourable alteration of the sympathovagal imbalance. On-going exploratory work focused on underlying mechanisms of LLTS in cardiovascular disease states and larger scale clinical trials will shed more light on the non-invasive modulation of the neuro-immune axis.