Optimal Titration Is Important to Maximize the Beneficial Effects of Vagal Nerve Stimulation in Chronic Heart Failure

Nishizaki, Akiko; Sakamoto, Kazuo; Saku, Keita; Hosokawa, Kazuya; Sakamoto, Takafumi; Oga, Yasuhiro; Akashi, Takuya; Murayama, Yuichi; Kishi, Takuya; Ide, Tomomi; Sunagawa, Kenji

doi:10.1016/j.cardfail.2016.04.021

Cited by 16 publications

(17 citation statements)

References 23 publications

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“…The current intensity of VNS was adjusted at just below the symptom threshold (97 ± 6 μA). Chronic VNS did not directly affect heart rate or arterial pressure (AP) under a conscious state, as we previously reported (22) . There was no implantation-related death in this study, but 11 rats were excluded from the protocol because of mechanical failure of the VNS system.…”

Section: Methodssupporting

confidence: 60%

Electrical Vagal Nerve Stimulation Ameliorates Pulmonary Vascular Remodeling and Improves Survival in Rats With Severe Pulmonary Arterial Hypertension

Yoshida

Saku

Kamada

et al. 2018

JACC: Basic to Translational Science

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Section: Methodssupporting

confidence: 60%

Electrical Vagal Nerve Stimulation Ameliorates Pulmonary Vascular Remodeling and Improves Survival in Rats With Severe Pulmonary Arterial Hypertension

Yoshida

Saku

Kamada

et al. 2018

JACC: Basic to Translational Science

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“…We ligated the left coronary artery with 5-0 silk. To select only the rats with established heart failure prior to initiate ICV infusion, among the survived rats at one week after coronary ligation, I excluded the rats defined by the prior exclusion criteria; (1) LV wall motion did not have asynergy, or LVEF was over 50%, or LV diastolic diameter was under 9.0 mm assessed by echocardiography (SSA-380A, TOSHIBA, Tokyo, Japan), (2) body weight did not increase when compared to that before coronary ligation, (3) 24-h averaged mean left atrial pressure was under 10 mmHg, (4) food and water intake were subjectively poor, and (5) activity was subjectively decreased, as in our previous study [ 21 ]. After the experimental protocols, the brain and heart of rats were removed with an over dose of pentobarbital, and the harvested heart fixed with 10% formaldehyde was sliced and stained with Masson’s trichrome stain to calculate infarct size.…”

Section: Methodsmentioning

confidence: 52%

Disruption of Central Antioxidant Property of Nuclear Factor Erythroid 2-Related Factor 2 Worsens Circulatory Homeostasis with Baroreflex Dysfunction in Heart Failure

Kishi

2018

IJMS

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Heart failure is defined as a disruption of circulatory homeostasis. We have demonstrated that baroreflex dysfunction strikingly disrupts circulatory homeostasis. Moreover, previous many reports have suggested that central excess oxidative stress causes sympathoexcitation in heart failure. However, the central mechanisms of baroreflex dysfunction with oxidative stress has not been fully clarified. Our hypothesis was that the impairment of central antioxidant property would worsen circulatory homeostasis with baroreflex dysfunction in heart failure. As the major antioxidant property in the brain, we focused on nuclear factor erythroid 2-related factor 2 (Nrf2; cytoprotective transcription factor). Hemodynamic and baroreflex function in conscious state were assessed by the radio-telemetry system. In the heart failure treated with intracerebroventricular (ICV) infusion of angiotensin II type 1 receptor blocker (ARB), sympathetic activation and brain oxidative stress were significantly lower, and baroreflex sensitivity and volume tolerance were significantly higher than in heart failure treated with vehicle. ICV infusion of Nrf2 activator decreased sympathetic activation and brain oxidative stress, and increased baroreflex sensitivity and volume tolerance to a greater extent than ARB. In conclusion, the disruption of central antioxidant property of Nrf2 worsened circulatory homeostasis with baroreflex dysfunction in heart failure.

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“…This is of particular importance when VNS is delivered therapeutically, wherein standardized doses are desirable within and in between animals, and across time. Previous reports from rat and large animal models implemented a similar approach to adjust stimulation intensity using respiratory twitching [15,71], and heart rate [40,72,73] to standardize stimulation protocols, but not on a dose-by-dose basis. Notably, electrical impedance, which is commonly used as a measure of electrode integrity and performance [74], did not correlate well with changes in HRT on an individual implant basis as implants aged (Fig 3E).…”

Section: Discussionmentioning

confidence: 99%

An implant for long-term cervical vagus nerve stimulation in mice

Mughrabi

Hickman

Jayaprakash

et al. 2020

Preprint

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Vagus nerve stimulation (VNS) is a neuromodulation therapy with the potential to treat a wide range of chronic conditions in which inflammation is implicated, including type 2 diabetes, obesity and atherosclerosis. Many of these diseases have well-established mouse models, but due to the significant surgical and engineering challenges that accompany a reliable interface for long-term VNS in mice, the therapeutic implications of this bioelectronic therapy remain unexplored. Here, we describe a long-term VNS implant in mice, developed at 3 research laboratories and validated for across-lab reproducibility. Implant functionality was evaluated over 3-8 weeks in 81 anesthetized or behaving mice by determining the stimulus intensity required to elicit a change in heart rate (heart rate threshold, HRT). HRT was also used as a method to standardize stimulation dosing. Overall, 60-90% of implants produced stimulusevoked physiological responses for at least 4 weeks, with HRT values stabilizing after the second week of implantation. Furthermore, stimulation delivered through 6-week-old implants decreased TNF levels in a subset of mice with acute inflammation caused by endotoxemia. Histological examination of 4-to 6-weekold implants revealed fibrotic encapsulation and no gross fiber loss. This implantation and dosing approach provides a tool to systematically investigate the therapeutic potential of long-term VNS in chronic diseases modeled in the mouse, the most widely used vertebrate species in biomedical research.

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Optimal Titration Is Important to Maximize the Beneficial Effects of Vagal Nerve Stimulation in Chronic Heart Failure

Abstract: The optimal titration of VNS would maximize benefits for CHF and minimize adverse effects.

Cited by 16 publications

References 23 publications

Electrical Vagal Nerve Stimulation Ameliorates Pulmonary Vascular Remodeling and Improves Survival in Rats With Severe Pulmonary Arterial Hypertension

Electrical Vagal Nerve Stimulation Ameliorates Pulmonary Vascular Remodeling and Improves Survival in Rats With Severe Pulmonary Arterial Hypertension

Disruption of Central Antioxidant Property of Nuclear Factor Erythroid 2-Related Factor 2 Worsens Circulatory Homeostasis with Baroreflex Dysfunction in Heart Failure

An implant for long-term cervical vagus nerve stimulation in mice

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