Chronic Low-Level Vagus Nerve Stimulation Improves Long-Term Survival in Salt-Sensitive Hypertensive Rats

Elizabeth M Annoni, Dusty Van Helden, Yugene Guo, Brett Levac, Imad Libbus, Bruce H KenKnight, John W Osborn, Elena G Tolkacheva, Elizabeth M Annoni, Dusty Van Helden, Yugene Guo, Brett Levac, Imad Libbus, Bruce H KenKnight, John W Osborn, Elena G Tolkacheva

Abstract

Chronic hypertension (HTN) affects more than 1 billion people worldwide, and is associated with an increased risk of cardiovascular disease. Despite decades of promising research, effective treatment of HTN remains challenging. This work investigates vagus nerve stimulation (VNS) as a novel, device-based therapy for HTN treatment, and specifically evaluates its effects on long-term survival and HTN-associated adverse effects. HTN was induced in Dahl salt-sensitive rats using a high-salt diet, and the rats were randomly divided into two groups: VNS (n = 9) and Sham (n = 8), which were implanted with functional or non-functional VNS stimulators, respectively. Acute and chronic effects of VNS therapy were evaluated through continuous monitoring of blood pressure (BP) and ECG via telemetry devices. Autonomic tone was quantified using heart rate (HR), HR variability (HRV) and baroreflex sensitivity (BRS) analysis. Structural cardiac changes were quantified through gross morphology and histology studies. VNS significantly improved the long-term survival of hypertensive rats, increasing median event-free survival by 78% in comparison to Sham rats. Acutely, VNS improved autonomic balance by significantly increasing HRV during stimulation, which may lead to beneficial chronic effects of VNS therapy. Chronic VNS therapy slowed the progression of HTN through an attenuation of SBP and by preserving HRV. Finally, VNS significantly altered cardiac structure, increasing heart weight, but did not alter the amount of fibrosis in the hypertensive hearts. These results suggest that VNS has the potential to improve outcomes in subjects with severe HTN.

Keywords: autonomic; heart; hypertension; rat; survival; vagus nerve stimulation.

Figures

FIGURE 1
FIGURE 1
(A) Experimental design. HTN was induced using a high salt diet (8% NaCl). At Week 4, the rats were implanted with vagal nerve stimulators and DSI transmitters, and randomly divided into Sham (n = 8) and VNS (n = 9) groups. VNS therapy was turned on at Week 6 and continuous BP and ECG were recorded until the end of the study. (B) Kaplan-Meier event-free survival curves for Sham and VNS rats are statistically different (P < 0.05). The dashed vertical line indicates the start of VNS therapy at Week 6. The number of rats remaining in each group is included along the x-axis.
FIGURE 2
FIGURE 2
Acute cardiovascular and hemodynamic response of VNS rats (n = 6) at Week 9. (A) A representative example of VNS stimulation, BP and the BP derivative (dP/dt) traces showing segmentation into “Pre,” “VNS On,” Post 1,” and “Post 2” intervals. Acute SBP (B), BPV (C), contractility (dP/dtmax) (D), HR (E), and HRV (F) responses during VNS therapy in hypertensive rats for “Pre,” “VNS On,” “Post 1,” and “Post 2” intervals shown as percent change with respect to the “Pre” interval. †Indicates statistical significance between intervals.
FIGURE 3
FIGURE 3
Relative changes in SBP (ΔSBP) as HTN progresses. ΔSBP as a function of time and slopes of the linear regressions are shown for Sham and VNS rats during the (A)Day12h and (B)Night12h intervals. Circadian rhythm of SBP for Sham and VNS rats are shown for Week 6 (C) and Week 9 (D). ∗Indicates statistical significance between Sham and VNS rats.
FIGURE 4
FIGURE 4
Relative changes in HR (ΔHR) as HTN progresses. ΔHR as a function of time and slopes of the linear regressions are shown for Sham and VNS rats during the (A)Day12h interval and (B)Night12h intervals. Circadian rhythm analysis of HR for Sham and VNS rats are shown for Week 6 (C) and Week 9 (D). ∗Indicates statistical significance between Sham and VNS rats.
FIGURE 5
FIGURE 5
Relative changes in HRV (ΔHRV) as HTN progresses. ΔHRV as a function of time and slopes of the linear regressions are shown for Sham and VNS rats during the (A)Day12h interval and (B)Night12h intervals. BRS was quantified during the Day4h(C) and Night4h(D) intervals for Week 6 through Week 9. ∗Indicates statistical significance between Sham and VNS rats.
FIGURE 6
FIGURE 6
Gross morphology and histology studies for Sham (n = 8) and VNS (n = 6) hypertensive rats. The effects of VNS on cardiac structural properties – (A) HW/TL, (B) HW/diameter, (C) percent fibrosis, (D) right ventricle (RV) and (E) left ventricle (LV) free wall thickness, and (F) septum thickness – as a function of survival rate along with corresponding linear regression fits.

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