Effect of Low-Level Tragus Stimulation on Cardiac Metabolism in Heart Failure with Preserved Ejection Fraction: A Transcriptomics-Based Analysis.

Abnormal cardiac metabolism precedes and contributes to structural changes in heart failure. Low-level tragus stimulation (LLTS) can attenuate structural remodeling in heart failure with preserved ejection fraction (HFpEF). The role of LLTS on cardiac metabolism is not known. Dahl salt-sensitive rats of 7 weeks of age were randomized into three groups: low salt (0.3% NaCl) diet (control group; n = 6), high salt diet (8% NaCl) with either LLTS (active group; n = 8), or sham stimulation (sham group; n = 5). Both active and sham groups received the high salt diet for 10 weeks with active LLTS or sham stimulation (20 Hz, 2 mA, 0.2 ms) for 30 min daily for the last 4 weeks. At the endpoint, left ventricular tissue was used for RNA sequencing and transcriptomic analysis. The Ingenuity Pathway Analysis tool (IPA) was used to identify canonical metabolic pathways and upstream regulators. Principal component analysis demonstrated overlapping expression of important metabolic genes between the LLTS, and control groups compared to the sham group. Canonical metabolic pathway analysis showed downregulation of the oxidative phosphorylation (Z-score: -4.707, control vs. sham) in HFpEF and LLTS improved the oxidative phosphorylation (Z-score = -2.309, active vs. sham). HFpEF was associated with the abnormalities of metabolic upstream regulators, including PPARGC1α, insulin receptor signaling, PPARα, PPARδ, PPARGC1ß, the fatty acid transporter SLC27A2, and lysine-specific demethylase 5A (KDM5A). LLTS attenuated abnormal insulin receptor and KDM5A signaling. HFpEF is associated with abnormal cardiac metabolism. LLTS, by modulating the functioning of crucial upstream regulators, improves cardiac metabolism and mitochondrial oxidative phosphorylation.

Noninvasive Vagus Nerve Stimulation in Postural Tachycardia Syndrome: A Randomized Clinical Trial.

BACKGROUND: Low-level transcutaneous stimulation of the auricular branch of the vagus nerve at the tragus is antiarrhythmic and anti-inflammatory in animals and humans. Preliminary studies show that transcutaneous vagus nerve stimulation (tVNS) is beneficial in animal models of postural tachycardia syndrome (POTS). OBJECTIVES: In this study the authors conducted a sham-controlled, double-blind, randomized clinical trial to examine the effect of tVNS on POTS over a 2-month period relative to sham stimulation. METHODS: tVNS (20 Hz, 1 mA below discomfort threshold) was delivered using an ear clip attached to either the tragus (active; n = 12) or the ear lobe (sham; n = 14) for 1 hour daily over a 2-month period. Postural tachycardia was assessed during the baseline and 2-month visit. Heart rate variability based on 5-minute electrocardiogram, serum cytokines, and antiautonomic autoantibodies were measured at the respective time points. RESULTS: Mean age was 34 ± 11 years (100% female; 81% Caucasian). Adherence to daily stimulation was 83% in the active arm and 86% in the sham arm (P > 0.05). Postural tachycardia was significantly less in the active arm compared with the sham arm at 2 months (mean postural increase in heart rate 17.6 ± 9.9 beats/min vs 31.7 ± 14.4 beats/min; P = 0.01). Antiadrenergic autoantibodies and inflammatory cytokines were lower in the active arm compared with the sham arm at 2 months (P < 0.05). Heart rate variability was better in the active arm. No device-related side effects were observed. CONCLUSIONS: Our results support the emerging paradigm of noninvasive neuromodulation to treat POTS. Mechanistically, this effect appears to be related to reduction of antiautonomic autoantibodies and inflammatory cytokines, and improvement in autonomic tone. Further studies are warranted. (Autoimmune Basis for Postural Tachycardia Syndrome; NCT05043051).

Non-invasive Vagus Nerve Simulation in Postural Orthostatic Tachycardia Syndrome.

Postural orthostatic tachycardia syndrome (POTS) is a chronic debilitating condition of orthostatic intolerance, predominantly affecting young females. Other than postural tachycardia, symptoms of POTS include a spectrum of non-cardiac, systemic and neuropsychiatric features. Despite the availability of widespread pharmacological and non-pharmacological therapeutic options, the management of POTS remains challenging. Exaggerated parasympathetic withdrawal and sympathetic overdrive during postural stress are principal mechanisms of postural tachycardia in POTS. Non-invasive, transcutaneous, vagus nerve stimulation (tVNS) is known to restore sympathovagal balance and is emerging as a novel therapeutic strategy in cardiovascular conditions including arrhythmias and heart failure. Furthermore, tVNS also exerts immunomodulatory and anti-inflammatory effects. This review explores the effects of tVNS on the pathophysiology of POTS and its potential as an alternative non-pharmacological option in this condition.

Transcutaneous Vagus Nerve Stimulation Ameliorates the Phenotype of Heart Failure With Preserved Ejection Fraction Through Its Anti-Inflammatory Effects.

BACKGROUND: A systemic proinflammatory state plays a central role in the development of heart failure with preserved ejection fraction (HFpEF). Low-level transcutaneous vagus nerve stimulation (LLTS) suppresses inflammation in animals and humans, mediated by an α7nAchR (alpha7 nicotinic acetylcholine receptor)-dependent pathway. We examined the effects of LLTS on cardiac function, inflammation, and fibrosis in the presence of α7nAchR pharmacological blockade in a rat model of HFpEF. METHODS: Dahl salt-sensitive rats at 7 weeks of age were treated with high-salt diet for 6 weeks to induce HFpEF, followed by 4 weeks of (1) LLTS, (2) LLTS with the α7nAchR blocker methyllycaconitine, (3) sham, and (4) olmesartan. Blood pressure, cardiac function by echocardiography, heart rate variability, and serum cytokines were measured at 13 and 17 weeks of age. Cardiac fibrosis, inflammatory cell infiltration, and gene expression were determined at 17 weeks. RESULTS: LLTS attenuated the increase in blood pressure; improved cardiac function; decreased inflammatory cytokines, macrophage infiltration, and fibrosis; and improved survival compared with other groups. Methyllycaconitine attenuated these effects, whereas olmesartan did not improve cardiac function or fibrosis despite maintaining similar blood pressure as LLTS. Heart rate variability was similarly improved in the LLTS and LLTS plus methyllycaconitine groups but remained low in the other groups. LLTS reversed the dysregulated inflammatory signaling pathways in HFpEF hearts. CONCLUSIONS: Neuromodulation with LLTS improved cardiac function in a rat model of HFpEF through its anti-inflammatory and antifibrotic effects. These results provide the basis for further clinical trials in humans.