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

Abstract

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.

Keywords: autonomic modulation; heart failure with preserved ejection fraction; inflammation.

Figures

Figure 1. Device and location of active and sham stimulation.

A, The Parasym device was used for stimulation. B, For active stimulation, the ear clip was attached to the tragus, which is innervated by the auricular branch of the vagus nerve. C, For sham control stimulation, the ear clip was attached to the earlobe, which is devoid of vagal innervation.

Figure 2. Screening and enrollment of patients.

Figure 3. Effect of treatment on the co‐primary outcomes.

A, Changes in the ratio of the early mitral inflow Doppler velocity to the early diastolic mitral annulus velocity (E/e′). B, Changes in global longitudinal strain (GLS). The absolute values of GLS are plotted. LLTS indicates low‐level transcutaneous vagus nerve stimulation; and ns, nonsignificant. *P<0.05.

Figure 4. Changes in functional outcomes during the 3 months of treatment.

A, 6‐minute walk distance. B, Minnesota Living with Heart Failure Questionnaire (MLHFQ) score. LLTS indicates low‐level transcutaneous vagus nerve stimulation; and ns, nonsignificant. *P<0.05.

Figure 5. Changes in inflammatory biomarkers during the 3 months of treatment.

A, Tumor necrosis factor (TNF)‐α. B, Interleukin (IL)‐8. LLTS indicates low‐level transcutaneous vagus nerve stimulation; and ns, nonsignificant. *P<0.05.

Figure 6. Linear association between the interval change of TNF‐α and the change in absolute GLS.

Logarithmic transformation of TNF‐α was performed to satisfy the modeling assumptions. The association was significant, with 54% of the variation in the change in GLS being explained by the change in TNF‐α levels (r=−0.73, R2=0.54, P=0.001). GLS indicates global longitudinal strain; LLTS, low‐level transcutaneous vagus nerve stimulation; and TNF‐α, tumor necrosis factor α.