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-a 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-a 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.