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Proteomic Profiling for Cardiovascular Biomarker Discovery in Orthostatic Hypotension

Johansson, Madeleine LU ; Ricci, Fabrizio LU ; Aung, Nay; Sutton, Richard; Melander, Olle LU and Fedorowski, Artur LU (2018) In Hypertension 71(3). p.465-472
Abstract

Orthostatic hypotension (OH) has been linked with higher incidence of cardiovascular disease, but little is known about the mechanisms behind this association. We aimed to identify cardiovascular disease biomarkers associated with OH through a proteomic profiling approach. Seven hundred seventy-eight patients with unexplained syncope or orthostatic intolerance underwent head-up tilt test and supine blood samples. Of these, 220 met diagnostic criteria of OH, and 179 demonstrated normal hemodynamic response during head-up tilt test. Blood samples were analyzed by antibody-based Proximity Extension Assay technique simultaneously measuring 92 cardiovascular disease-related human protein biomarkers. The discovery algorithm was a sequential... (More)

Orthostatic hypotension (OH) has been linked with higher incidence of cardiovascular disease, but little is known about the mechanisms behind this association. We aimed to identify cardiovascular disease biomarkers associated with OH through a proteomic profiling approach. Seven hundred seventy-eight patients with unexplained syncope or orthostatic intolerance underwent head-up tilt test and supine blood samples. Of these, 220 met diagnostic criteria of OH, and 179 demonstrated normal hemodynamic response during head-up tilt test. Blood samples were analyzed by antibody-based Proximity Extension Assay technique simultaneously measuring 92 cardiovascular disease-related human protein biomarkers. The discovery algorithm was a sequential 2-step process of biomarker signature identification by supervised, multivariate, principal component analysis and verification by univariate ANOVA with Bonferroni correction. Patients with OH were older (67 versus 60 years;P<0.001) and more likely to be women (48% versus 41%;P>0.001) but did not differ from OH-negative patients in medical history. Principal component analysis identified MMP-7 (matrix metalloproteinase-7), TM (thrombomodulin), MB (myoglobin), TIM-1 (T-cell immunoglobulin and mucin domain-1), CASP-8 (caspase-8), CXCL-1 (C-X-C motif chemokine-1), Dkk-1 (dickkopf-related protein-1), lectin-like LOX-1 (oxidized low-density lipoprotein receptor-1), PlGF (placenta growth factor), PAR-1 (proteinase-activated receptor-1), and MCP-1 (monocyte chemotactic protein-1) as the most robust proteomic signature for OH. From this proteomic feature selection, MMP-7 and TIM-1 met Bonferroni-adjusted significance criteria in univariate and multivariate regression analyses. Proteomic profiling in OH reveals a biomarker signature of atherothrombosis and inflammation. Circulating levels of MMP-7 and TIM-1 are independently associated with OH and may be involved in cardiovascular disease promotion.

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author
organization
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type
Contribution to journal
publication status
published
subject
keywords
Journal Article
in
Hypertension
volume
71
issue
3
pages
8 pages
publisher
Lippincott Williams & Wilkins
external identifiers
  • scopus:85044118059
ISSN
1524-4563
DOI
10.1161/HYPERTENSIONAHA.117.10365
language
English
LU publication?
yes
id
58c5dca9-c12f-4765-86f9-e9c050a76dd5
date added to LUP
2018-04-04 12:35:51
date last changed
2018-10-28 14:20:31
@article{58c5dca9-c12f-4765-86f9-e9c050a76dd5,
  abstract     = {<p>Orthostatic hypotension (OH) has been linked with higher incidence of cardiovascular disease, but little is known about the mechanisms behind this association. We aimed to identify cardiovascular disease biomarkers associated with OH through a proteomic profiling approach. Seven hundred seventy-eight patients with unexplained syncope or orthostatic intolerance underwent head-up tilt test and supine blood samples. Of these, 220 met diagnostic criteria of OH, and 179 demonstrated normal hemodynamic response during head-up tilt test. Blood samples were analyzed by antibody-based Proximity Extension Assay technique simultaneously measuring 92 cardiovascular disease-related human protein biomarkers. The discovery algorithm was a sequential 2-step process of biomarker signature identification by supervised, multivariate, principal component analysis and verification by univariate ANOVA with Bonferroni correction. Patients with OH were older (67 versus 60 years;P&lt;0.001) and more likely to be women (48% versus 41%;P&gt;0.001) but did not differ from OH-negative patients in medical history. Principal component analysis identified MMP-7 (matrix metalloproteinase-7), TM (thrombomodulin), MB (myoglobin), TIM-1 (T-cell immunoglobulin and mucin domain-1), CASP-8 (caspase-8), CXCL-1 (C-X-C motif chemokine-1), Dkk-1 (dickkopf-related protein-1), lectin-like LOX-1 (oxidized low-density lipoprotein receptor-1), PlGF (placenta growth factor), PAR-1 (proteinase-activated receptor-1), and MCP-1 (monocyte chemotactic protein-1) as the most robust proteomic signature for OH. From this proteomic feature selection, MMP-7 and TIM-1 met Bonferroni-adjusted significance criteria in univariate and multivariate regression analyses. Proteomic profiling in OH reveals a biomarker signature of atherothrombosis and inflammation. Circulating levels of MMP-7 and TIM-1 are independently associated with OH and may be involved in cardiovascular disease promotion.</p>},
  author       = {Johansson, Madeleine and Ricci, Fabrizio and Aung, Nay and Sutton, Richard and Melander, Olle and Fedorowski, Artur},
  issn         = {1524-4563},
  keyword      = {Journal Article},
  language     = {eng},
  number       = {3},
  pages        = {465--472},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Hypertension},
  title        = {Proteomic Profiling for Cardiovascular Biomarker Discovery in Orthostatic Hypotension},
  url          = {http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.10365},
  volume       = {71},
  year         = {2018},
}