Project Title

Vagus Nerve Stimulation Mitigates Cardiac Symptoms and Alters Inflammatory Markers in Heart Failure Rats

Authors' Affiliations

Ariana Q Farrand, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Regenia Phillips-Campbell, Department of Medical Education, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Coty M Cooper, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Trenton E Banks, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Mary Katherine G Herndon, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Alexandre Hebert, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Bruce H KenKnight, Neuromodulation division, LivaNova PLC, Houston, TX. Eric Beaumont, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.

Location

Culp Ballroom

Start Date

4-7-2022 9:00 AM

End Date

4-7-2022 12:00 PM

Poster Number

17

Faculty Sponsor’s Department

Biomedical Sciences

Name of Project's Faculty Sponsor

Eric Beaumont

Classification of First Author

Post-doctoral Fellow

Competition Type

Competitive

Type

Poster Presentation

Project's Category

Neuroscience

Abstract or Artist's Statement

Chronic heart failure (HF) is estimated to affect 23 million people worldwide, and many patients show minimal improvement after treatment with high-potency medications. HF with reduced left ventricular ejection fraction makes up approximately half of cases and is associated with high mortality: a 5-year survival rate of only 25% after hospitalization. This disease is marked by autonomic and cardiac dysfunction, as well as increased inflammatory markers both in the brain and microbiota of the gastrointestinal tract. As a main component of the autonomic nervous system, the vagus nerve has been identified as a potential treatment target for HF. Vagus nerve stimulation (VNS) is thought to help re-balance the autonomic system and has shown promising results in clinical trials for treatment of HF. Although the mechanism of action for VNS remains partially understood, anti-inflammatory pathways have been shown to play a significant role, and these pathways may be enhanced by microbiota signaling via the vagus nerve. The goal of the current study is to provide insight into VNS treatment for HF with reduced ejection fraction via a pressure overload (PO) model. Male Sprague-Dawley rats were randomly divided into age-matched control (n=7), PO (n=6), and PO+VNS (n=11). PO rats underwent aortic constriction (~40%) to induce HF, and a subset of these had VNS leads implanted around the left cervical vagus nerve. Treatment was initiated for PO+VNS rats after reaching a 20% drop in left ventricular relative ejection fraction (EF, p<0.001). VNS was delivered using 1.0 mA pulses at 20 Hz, with 14 sec on-time followed by 66 sec off-time for 2 months to model settings used in successful clinical studies. Echocardiography to image the heart and fecal samples to assess microbiota were collected at regular intervals for all rats. Hearts were weighed at termination for a final heart to body weight ratio, and brains were processed to assess neuroinflammation. Findings indicate that while PO reduced EF ~40% at termination (p<0.05), VNS treatment restored EF back to control levels (p<0.0001 compared to study midpoint). Further, the heart/body weight ratio was increased for PO rats (p<0.05) compared to controls and PO+VNS rats. These data demonstrate that physiological markers of heart failure can be mitigated using these VNS settings. Notably, 66% of microbiota populations altered by PO were prevented with VNS treatment. Further, prolonged VNS significantly affected microbiota populations involved in inflammatory processes. Neuroinflammation was assessed in two key autonomic nuclei: paraventricular nucleus of the hypothalamus and locus coeruleus. PO displayed increased neuroinflammation as measured by microglial density in both regions, and VNS attenuated this effect (p<0.001). These findings indicate relevant contributions of inflammatory mechanisms and microbiome alterations for beneficial VNS effects leading to improved cardiac function in HF.

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Apr 7th, 9:00 AM Apr 7th, 12:00 PM

Vagus Nerve Stimulation Mitigates Cardiac Symptoms and Alters Inflammatory Markers in Heart Failure Rats

Culp Ballroom

Chronic heart failure (HF) is estimated to affect 23 million people worldwide, and many patients show minimal improvement after treatment with high-potency medications. HF with reduced left ventricular ejection fraction makes up approximately half of cases and is associated with high mortality: a 5-year survival rate of only 25% after hospitalization. This disease is marked by autonomic and cardiac dysfunction, as well as increased inflammatory markers both in the brain and microbiota of the gastrointestinal tract. As a main component of the autonomic nervous system, the vagus nerve has been identified as a potential treatment target for HF. Vagus nerve stimulation (VNS) is thought to help re-balance the autonomic system and has shown promising results in clinical trials for treatment of HF. Although the mechanism of action for VNS remains partially understood, anti-inflammatory pathways have been shown to play a significant role, and these pathways may be enhanced by microbiota signaling via the vagus nerve. The goal of the current study is to provide insight into VNS treatment for HF with reduced ejection fraction via a pressure overload (PO) model. Male Sprague-Dawley rats were randomly divided into age-matched control (n=7), PO (n=6), and PO+VNS (n=11). PO rats underwent aortic constriction (~40%) to induce HF, and a subset of these had VNS leads implanted around the left cervical vagus nerve. Treatment was initiated for PO+VNS rats after reaching a 20% drop in left ventricular relative ejection fraction (EF, p<0.001). VNS was delivered using 1.0 mA pulses at 20 Hz, with 14 sec on-time followed by 66 sec off-time for 2 months to model settings used in successful clinical studies. Echocardiography to image the heart and fecal samples to assess microbiota were collected at regular intervals for all rats. Hearts were weighed at termination for a final heart to body weight ratio, and brains were processed to assess neuroinflammation. Findings indicate that while PO reduced EF ~40% at termination (p<0.05), VNS treatment restored EF back to control levels (p<0.0001 compared to study midpoint). Further, the heart/body weight ratio was increased for PO rats (p<0.05) compared to controls and PO+VNS rats. These data demonstrate that physiological markers of heart failure can be mitigated using these VNS settings. Notably, 66% of microbiota populations altered by PO were prevented with VNS treatment. Further, prolonged VNS significantly affected microbiota populations involved in inflammatory processes. Neuroinflammation was assessed in two key autonomic nuclei: paraventricular nucleus of the hypothalamus and locus coeruleus. PO displayed increased neuroinflammation as measured by microglial density in both regions, and VNS attenuated this effect (p<0.001). These findings indicate relevant contributions of inflammatory mechanisms and microbiome alterations for beneficial VNS effects leading to improved cardiac function in HF.