Trans-right ventricle and transpulmonary metabolite gradients in human pulmonary arterial hypertension
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ..
OBJECTIVE: While metabolic dysfunction occurs in several pulmonary arterial hypertension (PAH) animal models, its role in the human hypertensive right ventricle (RV) and lung is not well characterised. We investigated whether circulating metabolite concentrations differ across the hypertensive RV and/or the pulmonary circulation, and correlate with invasive haemodynamic/echocardiographic variables in patients with PAH.
METHODS: Prospective EDTA blood collection during cardiac catheterisation from the superior vena cava (SVC), pulmonary artery (PA) and ascending aorta (AAO) in children with PAH (no shunt) and non-PAH controls (Con), followed by unbiased screens of 427 metabolites and 836 lipid species and fatty acids (FAs) in blood plasma (Metabolon and Lipidyzer platforms). Metabolite concentrations were correlated with echocardiographic and invasive haemodynamic variables.
RESULTS: Metabolomics/lipidomics analysis of differential concentrations (false discovery rate<0.15) revealed several metabolite gradients in the trans-RV (PA vs SVC) setting. Notably, dicarboxylic acids (eg, octadecanedioate: fold change (FC)_Control=0.77, FC_PAH=1.09, p value=0.044) and acylcarnitines (eg, stearoylcarnitine: FC_Control=0.74, FC_PAH=1.21, p value=0.058). Differentially regulated metabolites were also found in the transpulmonary (AAO vs PA) setting and between-group comparisons, that is, in the SVC (PAH-SVC vs Con-SVC), PA and AAO. Importantly, the differential PAH-metabolite concentrations correlated with numerous outcome-relevant variables (e.g., tricuspid annular plane systolic excursion, pulmonary vascular resistance).
CONCLUSIONS: In PAH, trans-RV and transpulmonary metabolite gradients exist and correlate with haemodynamic determinants of clinical outcome. The most pronounced differential trans-RV gradients are known to be involved in lipid metabolism/lipotoxicity, that is, accumulation of long chain FAs. The identified accumulation of dicarboxylic acids and acylcarnitines likely indicates impaired β-oxidation in the hypertensive RV and represents emerging biomarkers and therapeutic targets in PAH.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:106 |
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| Enthalten in: |
Heart (British Cardiac Society) - 106(2020), 17 vom: 20. Sept., Seite 1332-1341 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chouvarine, Philippe [VerfasserIn] |
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| Links: |
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| Themen: |
β-oxidation |
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| Anmerkungen: |
Date Completed 28.06.2021 Date Revised 28.06.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1136/heartjnl-2019-315900 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM30673429X |
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| 100 | 1 | |a Chouvarine, Philippe |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Trans-right ventricle and transpulmonary metabolite gradients in human pulmonary arterial hypertension |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 28.06.2021 | ||
| 500 | |a Date Revised 28.06.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. | ||
| 520 | |a OBJECTIVE: While metabolic dysfunction occurs in several pulmonary arterial hypertension (PAH) animal models, its role in the human hypertensive right ventricle (RV) and lung is not well characterised. We investigated whether circulating metabolite concentrations differ across the hypertensive RV and/or the pulmonary circulation, and correlate with invasive haemodynamic/echocardiographic variables in patients with PAH | ||
| 520 | |a METHODS: Prospective EDTA blood collection during cardiac catheterisation from the superior vena cava (SVC), pulmonary artery (PA) and ascending aorta (AAO) in children with PAH (no shunt) and non-PAH controls (Con), followed by unbiased screens of 427 metabolites and 836 lipid species and fatty acids (FAs) in blood plasma (Metabolon and Lipidyzer platforms). Metabolite concentrations were correlated with echocardiographic and invasive haemodynamic variables | ||
| 520 | |a RESULTS: Metabolomics/lipidomics analysis of differential concentrations (false discovery rate<0.15) revealed several metabolite gradients in the trans-RV (PA vs SVC) setting. Notably, dicarboxylic acids (eg, octadecanedioate: fold change (FC)_Control=0.77, FC_PAH=1.09, p value=0.044) and acylcarnitines (eg, stearoylcarnitine: FC_Control=0.74, FC_PAH=1.21, p value=0.058). Differentially regulated metabolites were also found in the transpulmonary (AAO vs PA) setting and between-group comparisons, that is, in the SVC (PAH-SVC vs Con-SVC), PA and AAO. Importantly, the differential PAH-metabolite concentrations correlated with numerous outcome-relevant variables (e.g., tricuspid annular plane systolic excursion, pulmonary vascular resistance) | ||
| 520 | |a CONCLUSIONS: In PAH, trans-RV and transpulmonary metabolite gradients exist and correlate with haemodynamic determinants of clinical outcome. The most pronounced differential trans-RV gradients are known to be involved in lipid metabolism/lipotoxicity, that is, accumulation of long chain FAs. The identified accumulation of dicarboxylic acids and acylcarnitines likely indicates impaired β-oxidation in the hypertensive RV and represents emerging biomarkers and therapeutic targets in PAH | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a PAH | |
| 650 | 4 | |a biomarker | |
| 650 | 4 | |a hemodynamics | |
| 650 | 4 | |a human | |
| 650 | 4 | |a lipidomics | |
| 650 | 4 | |a metabolites | |
| 650 | 4 | |a metabolomics | |
| 650 | 4 | |a omics | |
| 650 | 4 | |a trans-RV gradient | |
| 650 | 4 | |a transpulmonary gradient | |
| 650 | 4 | |a β-oxidation | |
| 650 | 7 | |a Biomarkers |2 NLM | |
| 650 | 7 | |a Lipids |2 NLM | |
| 700 | 1 | |a Giera, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Kastenmüller, Gabi |e verfasserin |4 aut | |
| 700 | 1 | |a Artati, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Adamski, Jerzy |e verfasserin |4 aut | |
| 700 | 1 | |a Bertram, Harald |e verfasserin |4 aut | |
| 700 | 1 | |a Hansmann, Georg |e verfasserin |4 aut | |
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| 773 | 1 | 8 | |g volume:106 |g year:2020 |g number:17 |g day:20 |g month:09 |g pages:1332-1341 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1136/heartjnl-2019-315900 |3 Volltext |
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