Summary of Study ST003686

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002286. The data can be accessed directly via it's Project DOI: 10.21228/M84N93 This work is supported by NIH grant, U2C- DK119886.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST003686
Study TitleCharacterization of the transpulmonary metabolome at the intersection of pulmonary vascular disease and exercise
Study SummaryPathologic implications of dysregulated pulmonary vascular metabolism to pulmonary arterial hypertension (PAH) are increasingly recognized, but their clinical applications have been limited. We hypothesized that metabolite quantification across the pulmonary vascular bed in connective tissue disease (CTD)-associated PAH would identify transpulmonary gradients of pathobiologically relevant metabolites, in an exercise stage-specific manner. 63 CTD patients with established or suspected PAH underwent exercise right heart catheterization. Using mass spectrometry-based metabolomics, metabolites were quantified in plasma samples simultaneously collected from the pulmonary and radial arteries at baseline and during resistance-free wheeling, peak exercise, and recovery. We identified uptake and excretion of metabolites across the pulmonary vascular bed, unique and distinct from single vascular site analysis. We demonstrated the physiological relevance of metabolites previously shown to promote disease in animal models and end-stage human lung tissues, including acylcarnitines, glycolytic intermediates, and tryptophan catabolites. Notably, pulmonary vascular metabolite handling was exercise stage-specific. Transpulmonary metabolite gradients correlated with hemodynamic endpoints largely during free-wheeling. Glycolytic intermediates demonstrated physiologic significance at peak exercise, including net uptake of lactate in those with more advanced disease. Contribution of pulmonary vascular metabolism to CTD-PAH pathogenesis and therapeutic candidacy of metabolism modulation must be considered in the context of physiologic stress.
Institute
University of Colorado Anschutz Medical Campus
Last NameHaines
First NameJulie
Address12801 E 17th Ave, Room 1303, Aurora, Colorado, 80045, USA
Emailjulie.haines@cuanschutz.edu
Phone3037243339
Submit Date2025-01-13
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2025-02-17
Release Version1
Julie Haines Julie Haines
https://dx.doi.org/10.21228/M84N93
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR002286
Project DOI:doi: 10.21228/M84N93
Project Title:Physiologic Relevance of Transpulmonary Metabolome in Connective Tissue Disease-Associated Pulmonary Vascular Disease
Project Summary:Previous studies attempted to deduce metabolic changes in the pulmonary vasculature of PAH patients by analyzing their plasma metabolome. The clinical applicability of these findings, however, has been limited by: (i) plasma collection from a single anatomic site reflecting metabolic disturbances of the whole body rather than the pulmonary vessels, and (ii) the incomprehension of how metabolism relates to exercise physiology in PAH. We therefore aimed to quantify the transpulmonary (i.e., across the pulmonary vascular bed via two collection sites per patient per exercise timepoint) plasma metabolome in exercising connective tissue disease patients with suspected or confirmed PAH, with the goal of identifying metabolic signatures specific to the pulmonary vasculature and defining how they relate to physiologic, clinical parameters.
Institute:University of Colorado Anschutz Medical Campus
Laboratory:Angelo D'Alessandro in collaboration with Michael Lee (UCSF)
Last Name:Haines
First Name:Julie
Address:12801 E 17th Ave, Room 1303, Aurora, Colorado, 80045, USA
Email:julie.haines@cuanschutz.edu
Phone:3037243339

Subject:

Subject ID:SU003818
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606
Gender:Male and female

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Site of blood draw Exercise_stage Sample source
SA402454FC123_381_r4-pulmonary artery free-wheel plasma
SA402455FC123-114_r36-pulmonary artery free-wheel plasma
SA402456FC123_365_r11-pulmonary artery free-wheel plasma
SA402457FC123-247_r48-pulmonary artery free-wheel plasma
SA402458FC123-55_r31-pulmonary artery free-wheel plasma
SA402459FC123_373_r18-pulmonary artery free-wheel plasma
SA402460FC123-119_r43-pulmonary artery free-wheel plasma
SA402461FC123-239_r24-pulmonary artery free-wheel plasma
SA402462FC123_357_r16-pulmonary artery free-wheel plasma
SA402463FC123-47_r47-pulmonary artery free-wheel plasma
SA402464FC123_389_r51-pulmonary artery free-wheel plasma
SA402465FC123-89_r6-pulmonary artery free-wheel plasma
SA402466FC123-126_r25-pulmonary artery free-wheel plasma
SA402467FC123_397_r11-pulmonary artery free-wheel plasma
SA402468FC123-223_r39-pulmonary artery free-wheel plasma
SA402469FC123-255_r32-pulmonary artery free-wheel plasma
SA402470FC123-63_r52-pulmonary artery free-wheel plasma
SA402471FC123_405_r37-pulmonary artery free-wheel plasma
SA402472FC123_333_r47-pulmonary artery free-wheel plasma
SA402473FC123-309_r23-pulmonary artery free-wheel plasma
SA402474FC123-301_r1-pulmonary artery free-wheel plasma
SA402475FC123-317_r14-pulmonary artery free-wheel plasma
SA402476FC123-293_r47-pulmonary artery free-wheel plasma
SA402477FC123-325_r5-pulmonary artery free-wheel plasma
SA402478FC123-99_r39-pulmonary artery free-wheel plasma
SA402479FC123-75_r9-pulmonary artery free-wheel plasma
SA402480FC123-263_r42-pulmonary artery free-wheel plasma
SA402481FC123-279_r39-pulmonary artery free-wheel plasma
SA402482FC123_341_r7-pulmonary artery free-wheel plasma
SA402483FC123-271_r36-pulmonary artery free-wheel plasma
SA402484FC123-70_r15-pulmonary artery free-wheel plasma
SA402485FC123-107_r48-pulmonary artery free-wheel plasma
SA402486FC123_349_r9-pulmonary artery free-wheel plasma
SA402487FC123-39_r15-pulmonary artery free-wheel plasma
SA402488FC123-231_r20-pulmonary artery free-wheel plasma
SA402489FC123-131_r10-pulmonary artery free-wheel plasma
SA402490FC123_466_r4-pulmonary artery free-wheel plasma
SA402491FC123_451_r19-pulmonary artery free-wheel plasma
SA402492FC123_459_r28-pulmonary artery free-wheel plasma
SA402493FC123-154_r34-pulmonary artery free-wheel plasma
SA402494FC123-10_r17-pulmonary artery free-wheel plasma
SA402495FC123-147_r16-pulmonary artery free-wheel plasma
SA402496FC123_443_r12-pulmonary artery free-wheel plasma
SA402497FC123-191_r3-pulmonary artery free-wheel plasma
SA402498FC123-23_r24-pulmonary artery free-wheel plasma
SA402499FC123_435_r43-pulmonary artery free-wheel plasma
SA402500FC123-199_r41-pulmonary artery free-wheel plasma
SA402501FC123-183_r31-pulmonary artery free-wheel plasma
SA402502FC123-175_r17-pulmonary artery free-wheel plasma
SA402503FC123-15_r19-pulmonary artery free-wheel plasma
SA402504FC123-159_r2-pulmonary artery free-wheel plasma
SA402505FC123_413_r46-pulmonary artery free-wheel plasma
SA402506FC123-3_r46-pulmonary artery free-wheel plasma
SA402507FC123-167_r13-pulmonary artery free-wheel plasma
SA402508FC123-215_r30-pulmonary artery free-wheel plasma
SA402509FC123-31_r51-pulmonary artery free-wheel plasma
SA402510FC123_421_r24-pulmonary artery free-wheel plasma
SA402511FC123-207_r42-pulmonary artery free-wheel plasma
SA402512FC123-139_r48-pulmonary artery free-wheel plasma
SA402513FC123-101_r38-pulmonary artery peak exercise plasma
SA402514FC123-155_r30-pulmonary artery peak exercise plasma
SA402515FC123-169_r39-pulmonary artery peak exercise plasma
SA402516FC123-281_r28-pulmonary artery peak exercise plasma
SA402517FC123-91_r4-pulmonary artery peak exercise plasma
SA402518FC123-273_r7-pulmonary artery peak exercise plasma
SA402519FC123-295_r4-pulmonary artery peak exercise plasma
SA402520FC123-177_r24-pulmonary artery peak exercise plasma
SA402521FC123-287_r37-pulmonary artery peak exercise plasma
SA402522FC123-149_r24-pulmonary artery peak exercise plasma
SA402523FC123-265_r4-pulmonary artery peak exercise plasma
SA402524FC123-141_r37-pulmonary artery peak exercise plasma
SA402525FC123-217_r3-pulmonary artery peak exercise plasma
SA402526FC123-225_r18-pulmonary artery peak exercise plasma
SA402527FC123-127_r47-pulmonary artery peak exercise plasma
SA402528FC123-209_r10-pulmonary artery peak exercise plasma
SA402529FC123-233_r15-pulmonary artery peak exercise plasma
SA402530FC123-241_r7-pulmonary artery peak exercise plasma
SA402531FC123-121_r3-pulmonary artery peak exercise plasma
SA402532FC123-109_r29-pulmonary artery peak exercise plasma
SA402533FC123-201_r22-pulmonary artery peak exercise plasma
SA402534FC123-249_r12-pulmonary artery peak exercise plasma
SA402535FC123-115_r49-pulmonary artery peak exercise plasma
SA402536FC123-193_r19-pulmonary artery peak exercise plasma
SA402537FC123-133_r35-pulmonary artery peak exercise plasma
SA402538FC123-257_r14-pulmonary artery peak exercise plasma
SA402539FC123-185_r38-pulmonary artery peak exercise plasma
SA402540FC123-303_r38-pulmonary artery peak exercise plasma
SA402541FC123-161_r27-pulmonary artery peak exercise plasma
SA402542FC123-33_r34-pulmonary artery peak exercise plasma
SA402543FC123-49_r16-pulmonary artery peak exercise plasma
SA402544FC123_423_r49-pulmonary artery peak exercise plasma
SA402545FC123_367_r8-pulmonary artery peak exercise plasma
SA402546FC123_445_r9-pulmonary artery peak exercise plasma
SA402547FC123-57_r16-pulmonary artery peak exercise plasma
SA402548FC123_375_r26-pulmonary artery peak exercise plasma
SA402549FC123_437_r3-pulmonary artery peak exercise plasma
SA402550FC123_383_r13-pulmonary artery peak exercise plasma
SA402551FC123-25_r12-pulmonary artery peak exercise plasma
SA402552FC123-65_r20-pulmonary artery peak exercise plasma
SA402553FC123_391_r33-pulmonary artery peak exercise plasma
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Collection:

Collection ID:CO003811
Collection Summary:Patient recruitment: Over a 24-month period, we prospectively and consecutively recruited CTD patients with suspected or confirmed diagnosis of PAH from the Pulmonary Hemodynamic Assessment Program at the Federal University of São Paulo (UNIFESP) in São Paulo, Brazil, with the following inclusion criteria: age ≥ 18 years; CTD diagnosis according to current guidelines using clinical presentation and serology; and ability to provide informed consent. Patients were excluded if any of the following criteria was met: New York Heart Association functional class IV (symptomatic at rest); syncope or change in PAH therapy within 30 days before study; anemia (serum hemoglobin < 10 g/dL); osteoarticular limitation precluding exercise on a cycle ergometer; and pregnancy. Exercise RHC and transpulmonary metabolomics: All consenting patients underwent clinically indicated, standardized, incremental, symptom-limited exercise RHC on a cycle ergometer with radial arterial lines, for the purpose of PAH diagnosis or risk stratification. All subjects were required to fast for at least four hours prior to study participation. Pulmonary vascular resistance (PVR) was calculated from hemodynamic variables as routinely performed and previously described. At the four sequential exercise stages – baseline (rest), free-wheeling (resistance-free pedaling), peak exercise, and two minutes into recovery (resistance-free pedaling) -- blood samples were simultaneously collected from the pulmonary artery and the systemic radial artery (i.e., across the pulmonary vascular bed), where both free-wheeling and recovery were done using resistance-free pedaling. The blood samples were immediately placed on ice upon collection, and isolated plasma was stored at -80°C until analyzed.
Sample Type:Blood (plasma)

Treatment:

Treatment ID:TR003827
Treatment Summary:Patients and blood samples were not treated as part of this study. Information on PAH medications used by the enrolled patients is included in a forthcoming manuscript.

Sample Preparation:

Sampleprep ID:SP003825
Sampleprep Summary:Plasma aliquots were thawed on ice then metabolites extracted from a 20 uL plasma aliquot using 480 uL of cold 5:3:2 MeOH:acetonitrile:water. Samples were vortexed 30 min at 4 degrees C then supernatants clarified by centrifugation (10 min, 10,000 g, 4 degrees C) and transferred to autosampler vials.
Processing Storage Conditions:4℃
Extract Storage:-80℃

Combined analysis:

Analysis ID AN006049 AN006050
Analysis type MS MS
Chromatography type Reversed phase Reversed phase
Chromatography system Thermo Vanquish Thermo Vanquish
Column Phenomenex Kinetex C18 (30 x 2.1mm, 1.7 um) Phenomenex Kinetex C18 (30 x 2.1mm, 1.7 um)
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Q Exactive Orbitrap Thermo Q Exactive Orbitrap
Ion Mode NEGATIVE POSITIVE
Units peak area peak area

Chromatography:

Chromatography ID:CH004597
Chromatography Summary:Negative C18
Instrument Name:Thermo Vanquish
Column Name:Phenomenex Kinetex C18 (30 x 2.1mm, 1.7 um)
Column Temperature:45
Flow Gradient:0-0.2 min 5-95% B at 0.3 mL/min, increase to 0.6 mL/min, 0.2 to 0.8 min hold at 95%B at 0.6 mL/min, 0.80-0.81 min 95-5%B and increase to 1 mL/min, 0.81-1.0 min hold at 5%B at 1 mL/min, at 1 min decrease flow to 0.3 mL/min
Flow Rate:Programmed flow rate, see gradient
Sample Injection:10 uL
Solvent A:100% water; 10 mM ammonium acetate
Solvent B:50% methanol/50% acetonitrile; 10 mM ammonium acetate
Chromatography Type:Reversed phase
  
Chromatography ID:CH004598
Chromatography Summary:Positive C18
Instrument Name:Thermo Vanquish
Column Name:Phenomenex Kinetex C18 (30 x 2.1mm, 1.7 um)
Column Temperature:45
Flow Gradient:0-0.3 min 5-95% B at 0.45 mL/min, 0.3 to 0.8 min hold at 95%B at 0.45 mL/min, 0.80-0.81 min 95-5%B and increase to 1 mL/min, 0.81-1.0 min hold at 5%B at 1 mL/min, at 1 min decrease flow to 0.45 mL/min
Flow Rate:Programmed flow rate, see gradient
Sample Injection:10 uL
Solvent A:100% water; 0.1% formic acid
Solvent B:100% acetonitrile; 0.1% formic acid
Chromatography Type:Reversed phase

MS:

MS ID:MS005758
Analysis ID:AN006049
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Resolution 70,000, scan range 65-900 m/z, maximum injection time 200 ms, microscans 2, automatic gain control (AGC) 3 x 10^6 ions, source voltage 4.0 kV, capillary temperature 320 C, and sheath gas 45, auxiliary gas 15, and sweep gas 0 (all nitrogen).
Ion Mode:NEGATIVE
  
MS ID:MS005759
Analysis ID:AN006050
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Resolution 70,000, scan range 65-900 m/z, maximum injection time 200 ms, microscans 2, automatic gain control (AGC) 3 x 10^6 ions, source voltage 4.0 kV, capillary temperature 320 C, and sheath gas 45, auxiliary gas 15, and sweep gas 0 (all nitrogen).
Ion Mode:POSITIVE
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