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Dysregulated neurovascular control underlies declining microvascular functionality in people with non-alcoholic fatty liver disease (NAFLD) at risk of liver fibrosis

Dysregulated neurovascular control underlies declining microvascular functionality in people with non-alcoholic fatty liver disease (NAFLD) at risk of liver fibrosis
Dysregulated neurovascular control underlies declining microvascular functionality in people with non-alcoholic fatty liver disease (NAFLD) at risk of liver fibrosis

Background/Aims: Increasing evidence shows that non-alcoholic fatty liver disease (NAFLD) is associated with dysregulation of microvascular perfusion independently of established cardio-metabolic risk factors. We investigated whether hepatic manifestations of NAFLD such as liver fibrosis and liver fat are associated with microvascular hemodynamics through dysregulation of neurovascular control. Methods: Microvascular dilator (post-occlusive reactive hyperemia) and sympathetically mediated constrictor (deep inspiratory breath-hold) responses were measured at the forearm and finger, respectively, using laser Doppler fluximetry. Non-linear complexity-based analysis was used to assess the information content and variability of the resting blood flux (BF) signals, attributable to oscillatory flow-motion activity, and over multiple sampling frequencies. Results: Measurements were made in 189 adults (113 men) with NAFLD, with (n = 65) and without (n = 124) type 2 diabetes mellitus (T2DM), age = 50.9 ± 11.7 years (mean ± SD). Microvascular dilator and constrictor capacity were both negatively associated with age (r = −0.178, p = 0.014, and r = −0.201, p = 0.007, respectively) and enhanced liver fibrosis (ELF) score (r = −0.155, p = 0.038 and r = −0.418, p < 0.0001, respectively). There was no association with measures of liver fat, obesity or T2DM. Lempel-Ziv complexity (LZC) and sample entropy (SE) of the BF signal measured at the two skin sites were associated negatively with age (p < 0.01 and p < 0.001) and positively with ELF score (p < 0.05 and p < 0.0001). In individuals with an ELF score ≥7.8 the influence of both neurogenic and respiratory flow-motion activity on LZC was up-rated (p < 0.0001). Conclusion: Altered microvascular network functionality occurs in adults with NAFLD suggesting a mechanistic role for dysregulated neurovascular control in individuals at risk of severe liver fibrosis.

NAFLD, blood flow, flow-motion, liver fibrosis, microcirculation, non-linear complexity analysis, skin, sympathetic nervous system
1664-042X
Clough, Geraldine
9f19639e-a929-4976-ac35-259f9011c494
Chipperfield, Andrew
524269cd-5f30-4356-92d4-891c14c09340
Thanaj, Marjola
fb9baacc-4255-483d-8efa-e4fa983a9b2f
Scorletti, Eleonora
4e896544-2974-4f81-9696-1595d3c36814
Calder, Philip
1797e54f-378e-4dcb-80a4-3e30018f07a6
Byrne, Christopher
1370b997-cead-4229-83a7-53301ed2a43c
Clough, Geraldine
9f19639e-a929-4976-ac35-259f9011c494
Chipperfield, Andrew
524269cd-5f30-4356-92d4-891c14c09340
Thanaj, Marjola
fb9baacc-4255-483d-8efa-e4fa983a9b2f
Scorletti, Eleonora
4e896544-2974-4f81-9696-1595d3c36814
Calder, Philip
1797e54f-378e-4dcb-80a4-3e30018f07a6
Byrne, Christopher
1370b997-cead-4229-83a7-53301ed2a43c

Clough, Geraldine, Chipperfield, Andrew, Thanaj, Marjola, Scorletti, Eleonora, Calder, Philip and Byrne, Christopher (2020) Dysregulated neurovascular control underlies declining microvascular functionality in people with non-alcoholic fatty liver disease (NAFLD) at risk of liver fibrosis. Frontiers in Physiology, 11, [551]. (doi:10.3389/fphys.2020.00551).

Record type: Article

Abstract

Background/Aims: Increasing evidence shows that non-alcoholic fatty liver disease (NAFLD) is associated with dysregulation of microvascular perfusion independently of established cardio-metabolic risk factors. We investigated whether hepatic manifestations of NAFLD such as liver fibrosis and liver fat are associated with microvascular hemodynamics through dysregulation of neurovascular control. Methods: Microvascular dilator (post-occlusive reactive hyperemia) and sympathetically mediated constrictor (deep inspiratory breath-hold) responses were measured at the forearm and finger, respectively, using laser Doppler fluximetry. Non-linear complexity-based analysis was used to assess the information content and variability of the resting blood flux (BF) signals, attributable to oscillatory flow-motion activity, and over multiple sampling frequencies. Results: Measurements were made in 189 adults (113 men) with NAFLD, with (n = 65) and without (n = 124) type 2 diabetes mellitus (T2DM), age = 50.9 ± 11.7 years (mean ± SD). Microvascular dilator and constrictor capacity were both negatively associated with age (r = −0.178, p = 0.014, and r = −0.201, p = 0.007, respectively) and enhanced liver fibrosis (ELF) score (r = −0.155, p = 0.038 and r = −0.418, p < 0.0001, respectively). There was no association with measures of liver fat, obesity or T2DM. Lempel-Ziv complexity (LZC) and sample entropy (SE) of the BF signal measured at the two skin sites were associated negatively with age (p < 0.01 and p < 0.001) and positively with ELF score (p < 0.05 and p < 0.0001). In individuals with an ELF score ≥7.8 the influence of both neurogenic and respiratory flow-motion activity on LZC was up-rated (p < 0.0001). Conclusion: Altered microvascular network functionality occurs in adults with NAFLD suggesting a mechanistic role for dysregulated neurovascular control in individuals at risk of severe liver fibrosis.

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Accepted/In Press date: 30 April 2020
Published date: 3 June 2020
Additional Information: Funding Information: We would like to thank the WELCOME and INSYTE Trial Investigators who helped with recruitment and data collection; the research nurses at Southampton General Hospital (Gillian Wise, Bridget Clancy, Sanchia Triggs, Gemma Rood, Andria Staniford, Norma Diaper, and Jennifer Hedges); and Lucinda England for research governance administration. We would also like to thank the WELCOME and INSYTE Trial participants. Funding. This work was supported by the National Institute of Health Research through the NIHR Southampton Biomedical Research Centre and Diabetes United Kingdom (BDA 09/0003937). CB, ES, and PC were supported in part by the Southampton NIHR Biomedical Research Centre. MT was supported by an EPSRC DTP Studentship. Publisher Copyright: © Copyright © 2020 Clough, Chipperfield, Thanaj, Scorletti, Calder and Byrne.
Keywords: NAFLD, blood flow, flow-motion, liver fibrosis, microcirculation, non-linear complexity analysis, skin, sympathetic nervous system

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Local EPrints ID: 439758
URI: http://eprints.soton.ac.uk/id/eprint/439758
ISSN: 1664-042X
PURE UUID: 0ff24c12-de44-4d21-8a7b-951951734b36
ORCID for Geraldine Clough: ORCID iD orcid.org/0000-0002-6226-8964
ORCID for Andrew Chipperfield: ORCID iD orcid.org/0000-0002-3026-9890
ORCID for Marjola Thanaj: ORCID iD orcid.org/0000-0002-1789-7112
ORCID for Philip Calder: ORCID iD orcid.org/0000-0002-6038-710X
ORCID for Christopher Byrne: ORCID iD orcid.org/0000-0001-6322-7753

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Date deposited: 01 May 2020 16:39
Last modified: 29 Sep 2022 01:38

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Contributors

Author: Marjola Thanaj ORCID iD
Author: Eleonora Scorletti
Author: Philip Calder ORCID iD

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