Neuromodulation of Inflammation to Treat Heart Failure With Preserved Ejection Fraction: A Pilot Randomized Clinical Trial.

Background A systemic proinflammatory state plays a central role in the development of heart failure with preserved ejection fraction. Low-level transcutaneous vagus nerve stimulation suppresses inflammation in humans. We conducted a sham-controlled, double-blind, randomized clinical trial to examine the effect of chronic low-level transcutaneous vagus nerve stimulation on cardiac function, exercise capacity, and inflammation in patients with heart failure with preserved ejection fraction. Methods and Results Patients with heart failure with preserved ejection fraction and at least 2 additional comorbidities (obesity, diabetes, hypertension, or age ≥65 years) were randomized to either active (tragus) or sham (earlobe) low-level transcutaneous vagus nerve stimulation (20 Hz, 1 mA below discomfort threshold), for 1 hour daily for 3 months. Echocardiography, 6-minute walk test, quality of life, and serum cytokines were assessed at baseline and 3 months. Fifty-two patients (mean age 70.4±9.2 years; 70% female) were included (active, n=26; sham, n=26). Baseline characteristics were balanced between the 2 arms. Adherence to the protocol of daily stimulation was >90% in both arms (P>0.05). While the early mitral inflow Doppler velocity to the early diastolic mitral annulus velocity ratio did not differ between groups, global longitudinal strain and tumor necrosis factor-α levels at 3 months were significantly improved in the active compared with the sham arm (-18.6%±2.5% versus -16.0%±2.4%, P=0.002; 8.9±2.8 pg/mL versus 11.3±2.9 pg/mL, P=0.007, respectively). The reduction in tumor necrosis factor-α levels correlated with global longitudinal strain improvement (r=-0.73, P=0.001). Quality of life was better in the active arm. No device-related side effects were observed. Conclusions Neuromodulation with low-level transcutaneous vagus nerve stimulation over 3 months resulted in a significant improvement in global longitudinal strain, inflammatory cytokines, and quality of life in patients with heart failure with preserved ejection fraction. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03327649.

Non-invasive vagus nerve stimulation attenuates proinflammatory cytokines and augments antioxidant levels in the brainstem and forebrain regions of Dahl salt sensitive rats.

The anti-inflammatory effects of vagus nerve stimulation are well known. It has recently been shown that low-level, transcutaneous stimulation of vagus nerve at the tragus (LLTS) reduces cardiac inflammation in a rat model of heart failure with preserved ejection fraction (HFpEF). The mechanisms by which LLTS affect the central neural circuits within the brain regions that are important for the regulation of cardiac vagal tone are not clear. Female Dahl salt-sensitive rats were initially fed with either low salt (LS) or high salt (HS) diet for a period of 6 weeks, followed by sham or active stimulation (LLTS) for 30 min daily for 4 weeks. To study the central effects of LLTS, four brainstem (SP5, NAb, NTS, and RVLM) and two forebrain sites (PVN and SFO) were examined. HS diet significantly increased the gene expression of proinflammatory cytokines in the SP5 and SFO. LLTS reversed HS diet-induced changes at both these sites. Furthermore, LLTS augmented the levels of antioxidant Nrf2 in the SP5 and SFO. Taken together, these findings suggest that LLTS has central anti-inflammatory and antioxidant properties that could mediate the neuromodulation of cardiac vagal tone in the rat model of HFpEF.

Spatial memory formation differentially affects c-Fos expression in retrosplenial areas during place avoidance training in rats.

The retrosplenial cortex is involved in spatial memory function, but the contribution of its individual areas is not well known. To elucidate the involvement of retrosplenial cortical areas 29c and 30 in spatial memory, we analyzed the expression of c-Fos in these areas in the experimental group of rats that were trained in a spatial place avoidance task, i.e. to avoid shocks presented in an unmarked sector of a stable arena under light conditions. Control rats were trained in the same context as the experimental rats either without (Control-noUS) or with shocks (Control-US) that were delivered in a random, noncontingent manner for three days. On the first day of place avoidance learning, the experimental group exhibited c-Fos induction in area 29c, similar to both control groups. In area 30, similarly high levels of c-Fos expression were observed in the experimental and Control-US groups. On the third day of training, when the experimental group efficiently avoided c-Fos expression in areas 29c and 30 was lower compared with the first day of training. In area 29c c-Fos level was also lower in the experimental than in comparison to the Control-US group. In area 30, c-Fos expression in the experimental group was lower than in both control groups. In conclusion, areas 29c and 30 appear to be activated during spatial memory acquisition on the first day of training, whereas area 30 seems suppressed during long-term memory functioning on the third day of training when rats effectively avoid.