Objective: Clinical trials investigating the benefits of vagus nerve stimulation (VNS) in heart failure have shown mixed results. This variation maybe due to inconsistent stimulation parameters, which may fail to adequately stimulate cardiomotor fibers required for cardio-protection. However, overstimulation of the vagus nerve may cause adverse off-target effects. Thus, the aim of this study was to assess the beneficial effects of moderate frequency VNS in patients with structurally normal hearts (SNH) and those with cardiomyopathy (CM).
Hypothesis: Moderate frequency VNS (10 Hz) confers ventricular electrophysiological effects.
Methods: Patients with SNH and supraventricular tachycardia (n = 5) and cardiomyopathy patients with ventricular tachycardia (CM, n = 5) undergoing electrophysiology procedures were recruited. A multi-electrode circular electrophysiology catheter was advanced from the femoral to the right internal jugular vein via a long sheath. Bipolar electrode pairs were serially stimulated and capture/stimulation of the vagus nerve identified by a negative chronotropic response. Threshold current was defined as a 10-15% decrease in heart rate (HR) at 20 Hz and 1 ms pulse-width. Stimulation was then performed at threshold current for 10 seconds at 10 and 20 Hz. Endocardial unipolar electrograms were continuously recorded using ventricular multielectrode mapping catheters and used to calculate activation recovery intervals (ARI), a validated surrogate of local action potential duration (APD). Electrodes were designated as overlying scar, border zone, or viable myocardium based on standard bipolar voltage mapping criteria in CM patients. ARIs were corrected for HR by the Framingham method.
Results: The current of stimulation was 13.2 ± 1.7 mA in SNH and 14.4 ± 3.1 mA in CM (p = ns). VNS at 20 Hz significantly decreased HR (p ≤ 0.01) in both SNH and CM patients (12.6 ± 1.4% in SNH vs 12.9 ± 1.7% in CM, p = ns) while significantly prolonging global ventricular ARIs (2.2 ± 0.4% in SNH vs 4.6 ± 1.0% in CM, p = ns). The chronotropic effects of 10 Hz VNS were similar to 20 Hz in SNH (12.0 ± 1.4% at 10 Hz vs 12.6 ± 1.4% at 20 Hz, p = ns) but blunted in CM patients (12.0 ± 1.4% in SNH vs 4.9 ± 2.4% in CM, p ≤ 0.05). Surprisingly, despite reduced chronotropic responses, global ARI prolongation persisted (4.0 ± 0.7% at 10 Hz vs 4.6 ± 1.0% at 20 Hz, p = ns) in CM patients. Importantly, ARI prolongation was observed in scar (326 ± 23 to 340 ± 22 ms, p ≤ 0.05) and border zone regions (312 ± 18 ms to 323 ± 17 ms, p ≤ 0.05). Moreover, after correcting ARI for heart rate (ARIc), 10 Hz VNS in CM patients caused significantly greater prolongation in ARIc than 20 Hz (1.8 ± 0.6% at 10 Hz vs -1.0 ± 0.6% at 20 Hz, p ≤ 0.05), suggesting that higher frequency VNS may potentially cause a net shortening of ventricular APD.
Conclusions: Acute application of moderate frequency VNS (10 Hz) demonstrated ventricular electrophysiological effects, with ARI prolongation observed in scar and border zone regions in diseased hearts. This human data validates previously reported effects of moderate frequency VNS in large animal infarct models. Stimulation at 20 Hz is unnecessary and may have negative ventricular electrophysiological effects. Further clinical trials assessing electrophysiological effects of chronic VNS in humans are required.
SPARC Program, OT2OD028201-01 and R01 HL148190-01
Figure 1. Effects of frequency on VNS in SNH and CM. A) A circular electrophysiology catheter was positioned in the internal jugular vein for transvascular VNS. B-C) VNS lowered HR at both 10 and 20 Hz in SNH, but HR effects of 10 Hz VNS were blunted in CM. D) Unipolar electrograms were acquired via endocardial multi-electrode electrophysiology catheters for ARI measurement. E-F) Global ARIs were prolonged by VNS in both SNS and CM patients, but not significantly different between 10 and 20 Hz.; Figure 2. Regional effects of VNS in CM patients. A) Representative bipolar voltage map of a CM patient and mapping catheter with electrodes overlying viable (purple, voltage >1.5 mV), border zone (multicolor, between 0.5-1.5 mV) and scar (grey, <0.5 mV) regions. B) ARIs prolonged in scar and border zone areas, regions known to play a key role in arrhythmogenesis. C) Correcting for HR, ARI parameters revealed that 10 Hz VNS may have greater ventricular electrophysiologic effects than 20 Hz.
