Elsevier

Translational Research

Volume 213, November 2019, Pages 100-111
Translational Research

Splenic artery denervation: target micro-anatomy, feasibility, and early preclinical experience

https://doi.org/10.1016/j.trsl.2019.07.012Get rights and content

This study sought to evaluate perisplenic artery nerve distribution and the feasibility of splenic artery denervation (SDN). The NEXION radiofrequency catheter was used to perform SDN in healthy and inflammatory arthritis pigs. Splenic artery anatomy, nerve distribution, and splenic norepinephrine (NEPI) levels were evaluated before and after SDN. Perisplenic artery nerves were primarily distributed within 2.5 mm of the arterial lumen and were largely sympathetic on the basis of tyrosine hydroxylase expression. The pancreas, tended to be circumferentially positioned around the proximal splenic artery, typically >2.5 mm from the lumen, ensuring that most of the nerves could be targeted without affecting this sensitive organ. The mid segment of the splenic artery was relatively free of contact with the adjacent pancreas. Splenic NEPI levels and nerve abundance followed a decreasing gradient from the proximal to distal splenic artery. SDN resulted in significant reductions in splenic NEPI levels at day 14 (60.7%, P = 0.024) in naïve pigs and day 45 (100%, P = 0.001) in inflammatory arthritis pigs. There was no significant effect of SDN on joint soft tissue injury or circulating inflammatory markers in the inflammatory arthritis model. The majority of perisplenic arterial nerves are within close proximity of the lumen and are primarily sympathetic efferent fibers. Nerves in the mid-segment may be the preferred SDN target given their proximity to the artery and paucity of periarterial off-target organs. SDN appears safe and effective at reducing splenic NEPI levels.

Section snippets

INTRODUCTION

The spleen plays an important role in the immune response to inflammatory conditions including cancer, myocardial infarction, and atherosclerosis (Fig 1).1 The autonomic nervous system responds to inflammatory stimuli, in part, by upregulating sympathetic nerve trafficking to the spleen, which can mobilize monocytes to sites of tissue injury and release cytokines that modulate the inflammatory response.2, 3 Device-based neuromodulation of the spleen's neural pathways is an emerging therapeutic

Animal models and experimental overview

All animal experiments were performed at CBSET, Inc. (Lexington, Massachusetts) and adhered to the Guide for the Care and Use of Laboratory Animals20 an institutional animal care and use committee approved protocol. In total, 27 castrated male Yorkshire swine (68.0 ± 24.8 kg) were studied. A detail outline of the experimental groups and study design can be found in the Supplement (Table S1).

Group 1 consisted of N = 5 control pigs evaluated for splenic artery anatomy and histology and baseline

Splenic artery anatomy and histology

Splenic artery anatomy was grossly and microscopically evaluated in untreated healthy swine to elucidate the relationship of the spleen and splenic artery to surrounding organs and structures including the pancreas and lymph nodes (Fig 2, A). For the purposes of mapping interventional targets for SDN, the proximal splenic artery was defined as the segment coursing along the pancreas, and the distal splenic artery was defined as the segment coursing along the splenic hilus. The mid splenic

DISCUSSION

The nervous system is an important regulator of inflammation,3, 25 and the spleen is an important reservoir of monocytes2 that can be mobilized in response to sympathetic nervous system9 and cytokine26, 27 signaling pathways. Device-based neuromodulation is a promising therapeutic approach for managing disease-states characterized by dysregulated immune responses. Percutaneous endovascular SDN is a highly novel approach to disrupting the mobilization of inflammatory cells from the spleen

ACKNOWLEDGMENTS

Conflicts of Interest: The authors have no conflicts of interest to declare. All authors have read the journal's policy on disclosure of potential conflicts of interest and authorship agreement.

This work was supported by unrestricted research sponsorship from Lavita. The manuscript was prepared independently by CBSET Inc, a private nonprofit research organization, which also provided partial support for this work.

REFERENCES (49)

  • A.R. Tzafriri et al.

    Innervation patterns may limit response to endovascular renal denervation

    J Am Coll Cardiol

    (2014)
  • F.K. Swirski et al.

    Identification of splenic reservoir monocytes and their deployment to inflammatory sites

    Science

    (2009)
  • F.A. Koopman et al.

    Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis

    Proc Natl Acad Sci U S A

    (2016)
  • K. Murray et al.

    Neuroanatomy of the spleen: mapping the relationship between sympathetic neurons and lymphocytes

    PloS One

    (2017)
  • T. Heidt et al.

    Chronic variable stress activates hematopoietic stem cells

    Nature Med

    (2014)
  • P. Dutta et al.

    Myocardial infarction accelerates atherosclerosis

    Nature

    (2012)
  • H.M. Hsiao et al.

    Spleen-derived classical monocytes mediate lung ischemia-reperfusion injury through IL-1beta

    J Clin Invest

    (2018)
  • D. Carnevale et al.

    A cholinergic-sympathetic pathway primes immunity in hypertension and mediates brain-to-spleen communication

    Nat Commun

    (2016)
  • G. Matteoli et al.

    A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen

    Gut

    (2014)
  • M. Rosas-Ballina et al.

    Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit

    Science

    (2011)
  • T. Inoue et al.

    Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through alpha7nAChR+ splenocytes

    J Clin Invest

    (2016)
  • L.V. Borovikova et al.

    Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin

    Nature

    (2000)
  • D.L. Bellinger et al.

    Sympathetic nerve hyperactivity in the spleen: causal for nonpathogenic-driven chronic immune-mediated inflammatory diseases (IMIDs)?

    Int J Mol Sci

    (2018)
  • G. Heusch

    The spleen in myocardial infarction

    Circ Res

    (2019)
  • Cited by (3)

    Mazen Albaghdadi, MD is an Instructor in the Department of Medicine in the Division of Cardiology at Massachusetts General Hospital, Harvard Medical School. Dr. Albaghdadi is interventional cardiologist and physician-scientist with a research interest in translating novel diagnostic and therapeutic medical devices to improve patient care.

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