Cargando…

Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction

AIMS: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronar...

Descripción completa

Detalles Bibliográficos
Autores principales: Ford, Thomas J, Corcoran, David, Padmanabhan, Sandosh, Aman, Alisha, Rocchiccioli, Paul, Good, Richard, McEntegart, Margaret, Maguire, Janet J, Watkins, Stuart, Eteiba, Hany, Shaukat, Aadil, Lindsay, Mitchell, Robertson, Keith, Hood, Stuart, McGeoch, Ross, McDade, Robert, Yii, Eric, Sattar, Naveed, Hsu, Li-Yueh, Arai, Andrew E, Oldroyd, Keith G, Touyz, Rhian M, Davenport, Anthony P, Berry, Colin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557475/
https://www.ncbi.nlm.nih.gov/pubmed/31972008
http://dx.doi.org/10.1093/eurheartj/ehz915
_version_ 1783594429217505280
author Ford, Thomas J
Corcoran, David
Padmanabhan, Sandosh
Aman, Alisha
Rocchiccioli, Paul
Good, Richard
McEntegart, Margaret
Maguire, Janet J
Watkins, Stuart
Eteiba, Hany
Shaukat, Aadil
Lindsay, Mitchell
Robertson, Keith
Hood, Stuart
McGeoch, Ross
McDade, Robert
Yii, Eric
Sattar, Naveed
Hsu, Li-Yueh
Arai, Andrew E
Oldroyd, Keith G
Touyz, Rhian M
Davenport, Anthony P
Berry, Colin
author_facet Ford, Thomas J
Corcoran, David
Padmanabhan, Sandosh
Aman, Alisha
Rocchiccioli, Paul
Good, Richard
McEntegart, Margaret
Maguire, Janet J
Watkins, Stuart
Eteiba, Hany
Shaukat, Aadil
Lindsay, Mitchell
Robertson, Keith
Hood, Stuart
McGeoch, Ross
McDade, Robert
Yii, Eric
Sattar, Naveed
Hsu, Li-Yueh
Arai, Andrew E
Oldroyd, Keith G
Touyz, Rhian M
Davenport, Anthony P
Berry, Colin
author_sort Ford, Thomas J
collection PubMed
description AIMS: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD). METHODS AND RESULTS: Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects [allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10–0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (OR) 2.33, 95% CI 1.10–4.96; P = 0.027]. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; −3.0 units in Duke Exercise Treadmill Score; −5.8 to −0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ET(A)) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ET(A) antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status. CONCLUSION: We identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ET(A) antagonist therapy in patients with microvascular angina. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03193294.
format Online
Article
Text
id pubmed-7557475
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-75574752020-10-20 Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction Ford, Thomas J Corcoran, David Padmanabhan, Sandosh Aman, Alisha Rocchiccioli, Paul Good, Richard McEntegart, Margaret Maguire, Janet J Watkins, Stuart Eteiba, Hany Shaukat, Aadil Lindsay, Mitchell Robertson, Keith Hood, Stuart McGeoch, Ross McDade, Robert Yii, Eric Sattar, Naveed Hsu, Li-Yueh Arai, Andrew E Oldroyd, Keith G Touyz, Rhian M Davenport, Anthony P Berry, Colin Eur Heart J Clinical Research AIMS: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD). METHODS AND RESULTS: Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects [allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10–0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (OR) 2.33, 95% CI 1.10–4.96; P = 0.027]. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; −3.0 units in Duke Exercise Treadmill Score; −5.8 to −0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ET(A)) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ET(A) antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status. CONCLUSION: We identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ET(A) antagonist therapy in patients with microvascular angina. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03193294. Oxford University Press 2020-01-23 /pmc/articles/PMC7557475/ /pubmed/31972008 http://dx.doi.org/10.1093/eurheartj/ehz915 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Clinical Research
Ford, Thomas J
Corcoran, David
Padmanabhan, Sandosh
Aman, Alisha
Rocchiccioli, Paul
Good, Richard
McEntegart, Margaret
Maguire, Janet J
Watkins, Stuart
Eteiba, Hany
Shaukat, Aadil
Lindsay, Mitchell
Robertson, Keith
Hood, Stuart
McGeoch, Ross
McDade, Robert
Yii, Eric
Sattar, Naveed
Hsu, Li-Yueh
Arai, Andrew E
Oldroyd, Keith G
Touyz, Rhian M
Davenport, Anthony P
Berry, Colin
Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction
title Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction
title_full Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction
title_fullStr Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction
title_full_unstemmed Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction
title_short Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction
title_sort genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction
topic Clinical Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557475/
https://www.ncbi.nlm.nih.gov/pubmed/31972008
http://dx.doi.org/10.1093/eurheartj/ehz915
work_keys_str_mv AT fordthomasj geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT corcorandavid geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT padmanabhansandosh geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT amanalisha geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT rocchicciolipaul geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT goodrichard geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT mcentegartmargaret geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT maguirejanetj geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT watkinsstuart geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT eteibahany geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT shaukataadil geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT lindsaymitchell geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT robertsonkeith geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT hoodstuart geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT mcgeochross geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT mcdaderobert geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT yiieric geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT sattarnaveed geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT hsuliyueh geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT araiandrewe geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT oldroydkeithg geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT touyzrhianm geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT davenportanthonyp geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction
AT berrycolin geneticdysregulationofendothelin1isimplicatedincoronarymicrovasculardysfunction