Electrical vagus nerve stimulation for the treatment of chronic heart failure
ABSTRACTAutonomic dysregulation is a feature of chronic heart failure (HF) and is characterized by a sustained increase of sympathetic drive and by withdrawal of parasympathetic activity. Both sympathetic overdrive and increased heart rate are predictors of poor long-term outcome in patients with HF. Pharmacologic agents that partially inhibit sympathetic activity, such as beta-adrenergic receptor blockers, effectively reduce mortality and morbidity in patients with chronic HF. In contrast, modulation of parasympathetic activation as a potential therapy for HF has received only limited attention because of its inherent complex cardiovascular effects. This review examines results of experimental animal studies that provide support for the possible use of electrical vagus nerve stimulation (VNS) as a long-term therapy for the treatment of chronic HF. The review also addresses the effects of VNS on potential modifiers of the HF state, including proinflammatory cytokines, nitric oxide elaboration, and myocardial expression of gap junction proteins. Finally, the safety, feasibility, and efficacy trends of VNS in patients with advanced HF are reviewed.
VNS IN DOGS WITH RAPID PACING–INDUCED HEART FAILURE
Electrical VNS as a potential therapy for HF was examined in dogs with HF secondary to high-rate ventricular pacing using the Cyberonics VNS system (Cyberonics Inc., Houston, TX), which does not operate on a negative feedback mechanism.15 In this study, VNS therapy was delivered continuously for the duration of the study with a duty cycle of 14 seconds on and 12 seconds off. VNS signals were delivered to the right cervical vagus nerve at a frequency of 20 Hz and a pulse width of 0.5 msec.15 Dogs were randomized to control (n = 7) or to monotherapy with VNS (n = 8) and followed for 8 weeks. All measurements were made approximately 15 minutes after temporarily turning off the ventricular pacemaker and the vagus nerve stimulator.15 VNS therapy resulted in a significant decrease in LV end-diastolic and end-systolic volumes and a significant increase in LV ejection fraction compared with controls.15 This improvement was associated with significant reduction in plasma levels of norepinephrine, angiotensin II, and C-reactive protein. The study also demonstrated the effectiveness of VNS in restoring baroreflex sensitivity, thus improving cardiac autonomic control.15 Because rapid pacing was maintained throughout the study except for short periods when measurements were made, one can argue that the benefits of VNS therapy in this model of HF are independent of heart rate.15
SAFETY AND TOLERABILITY OF VNS IN PATIENTS WITH ADVANCED HEART FAILURE
In patients with HF, reduced vagal activity is associated with increased mortality.1 Vagal withdrawal has also been shown to precede episodes of acute decompensation.32 In a recently published study, De Ferrari et al, on behalf of the CardioFit Multicenter Trial Investigators, examined the safety and tolerability of chronic VNS in 32 patients with symptomatic HF and severe LV dysfunction using the CardioFit system.16 The CardioFit system used in this study differed from that used in dogs with microembolization-induced HF in that it did not operate on a negative feedback principle. A bradycardia limit causing interruption of VNS was set at 55 beats/min. A 3-week uptitration period was used to maximize current amplitude and duty cycle based on patient sensation. The intensity of the stimulation reached 4.1 ± 1.2 mA at the end of the titration period.16
This multicenter, open-label, phase 2 trial involved 3 to 6 months of followup with an optional 1 year followup. The results suggested that VNS may be safe and tolerable in HF patients with severe LV dysfunction. Trends for efficacy were also favorable, bearing in mind the nonrandomized and unblinded nature of the study design. The study showed significant improvements in New York Heart Association HF classification, 6-minute walk test, LV ejection fraction, and LV systolic volumes.16
CONCLUSIONS
A wealth of preclinical and clinical studies supports the concept that electrical VNS can favorably modify the underlying pathophysiology and course of evolving HF. In animals with HF, VNS improves LV function, attenuates LV remodeling and may prevent arrhythmias that provoke sudden cardiac death. VNS derives these potential clinical benefits from multiple mechanisms of action that include reduced heart rate and normalization of sympathetic overdrive. VNS also appears to have a favorable impact on other signaling pathways that are likely to elicit beneficial effects in patients with HF. These include restoration of baroreflex sensitivity, suppression of proinflammatory cytokines, normalization of NO signaling pathways, and suppression of gap junction remodeling. At present, there is no evidence to implicate a single mechanism of action for the benefits derived from VNS. Instead, it is likely that all of the mechanisms listed above act in concert to elicit the global benefit seen with VNS. In humans with HF, VNS may be safe, feasible, and apparently well tolerated. Full appreciation of its efficacy in treating chronic HF must await completion of pivotal randomized clinical trials.
