Urinary proteomic signature of exercise intolerance in patients at risk of heart failure: evidence from the HOMAGE trial

BACKGROUND: Urinary proteomic profiling (UPP) provides insights in disease mechanisms and origin of symptoms. Using UPP, this study aimed at deepening insight in the biology of exercise tolerance. METHODS: In the HOMAGE trial, 268 patients at risk of heart failure underwent the incremental shuttle walk test (SWT) and UPP by capillary electrophoresis coupled with mass spectrometry at baseline (discovery) and the 9-month final visit (replication). Sequencing of 1498 urinary peptides identified 170 non-collagen and 40 collagen-derived proteins. Ten exercise-related variables, including heart rate and blood pressure responses, symptoms and walking distance were summarised into a single factor, higher values indicating exercise intolerance. In exploratory analyses, exercise intolerance was related to the UPP, first in linear and logistic regression models, considering one peptide at a time, and next by elastic net regression considering the peptides retained in the previous step. Replicated proteins were subjected to pathway analysis. FINDINGS: Twenty-nine non-collagen and 31 collagen-derived peptides were associated with reduced exercise capacity with correction for multiple testing. In elastic net regression, exercise intolerance was in >50% of 1000 bootstrap runs associated with the non-collagen proteins FXYD2, GAPDH, HBB, KCNB1, MB, MYOCD, SECTM1, SNX9, TACC3, TMSB4X, and TTN and with collagens COL5A1, COL6A1, COL11A2, and COL28A1. Enriched pathways involved oxygen homoeostasis, oxidative stress regulation, metabolic and developmental processes, and muscle biology. INTERPRETATION: In HOMAGE patients, UPP identified parent proteins regulating exercise endurance, which are involved in oxygenation, vascular and muscle structure and function, maintenance of the circulating volume, and protection against oxidative stress. FUNDING: European Union.

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Journal
EBioMedicine
Published
2026-07-30
DOI
https://doi.org/10.1016/j.ebiom.2026.106406
Primary Topic
Cardiovascular and exercise physiology
Type
article
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article

Urinary proteomic signature of exercise intolerance in patients at risk of heart failure: evidence from the HOMAGE trial

Agnieszka Latosińska, Arantxa González, Johannes Petutschnigg, Erwan Bozec et al.
EBioMedicine
Cardiovascular and exercise physiology
article

Urinary proteomic signature of exercise intolerance in patients at risk of heart failure: evidence from the HOMAGE trial

Agnieszka Latosińska, Arantxa González, Johannes Petutschnigg, Erwan Bozec, Nicolas Girerd, Fang‐Fei Wei, John G.F. Cleland, Roberto Latini, Dries S. Martens, Gladys E. Maestre, Philippe Rouet, De‐Wei An, Pierpaolo Pellicori, Jan A. Staessen, Beatrice Mariottoni, Harald Mischak, K. Asayama, Anne Pizard, Stéphanie Grojean, Yu‐Ling Yu, Fozia Ahmed, Patrick Rossignol, Dong‐Yan Zhang, João P. Ferreira, Andrew L. Clark, Joe Cuthbert, Franco Cosmi, S. R. B. Heymans, Justyna Siwy, Joe Cuthbert, Peter Verhamme, Tine W. Hansen, Job A.J. Verdonschot, María U. Moreno, Yan Li, Ken McDonald, Katarzyna Stolarz-Skrzypek, Tim Collier, Andrew L. Clark, Tim S. Nawrot, John GF. Cleland, Faiez Zannad, Begoñia López, L. Thijs, Javed Khan, Chu-Hao Liu, Suzanna Ravassa, Hans P. Brunner La Rocca, Mamas A. Mamas, Mark Hazebroek, Job AJ. Verdonschot, Pierpaolo Pellicori, Burkert Pieske, Faiez Zannad, Nicolas Girerd, Frank Edelmann, Javier Díez
article en

Abstract

BACKGROUND: Urinary proteomic profiling (UPP) provides insights in disease mechanisms and origin of symptoms. Using UPP, this study aimed at deepening insight in the biology of exercise tolerance. METHODS: In the HOMAGE trial, 268 patients at risk of heart failure underwent the incremental shuttle walk test (SWT) and UPP by capillary electrophoresis coupled with mass spectrometry at baseline (discovery) and the 9-month final visit (replication). Sequencing of 1498 urinary peptides identified 170 non-collagen and 40 collagen-derived proteins. Ten exercise-related variables, including heart rate and blood pressure responses, symptoms and walking distance were summarised into a single factor, higher values indicating exercise intolerance. In exploratory analyses, exercise intolerance was related to the UPP, first in linear and logistic regression models, considering one peptide at a time, and next by elastic net regression considering the peptides retained in the previous step. Replicated proteins were subjected to pathway analysis. FINDINGS: Twenty-nine non-collagen and 31 collagen-derived peptides were associated with reduced exercise capacity with correction for multiple testing. In elastic net regression, exercise intolerance was in >50% of 1000 bootstrap runs associated with the non-collagen proteins FXYD2, GAPDH, HBB, KCNB1, MB, MYOCD, SECTM1, SNX9, TACC3, TMSB4X, and TTN and with collagens COL5A1, COL6A1, COL11A2, and COL28A1. Enriched pathways involved oxygen homoeostasis, oxidative stress regulation, metabolic and developmental processes, and muscle biology. INTERPRETATION: In HOMAGE patients, UPP identified parent proteins regulating exercise endurance, which are involved in oxygenation, vascular and muscle structure and function, maintenance of the circulating volume, and protection against oxidative stress. FUNDING: European Union.

EBioMedicineVol. 130
Inserm (FR), Sun Yat-sen University (CN), Manchester Academic Health Science Centre (GB), Maastricht University Medical Centre (NL), Castle Hill Hospital (GB), Karolinska Institutet (SE), Mosaiques Diagnostics and Therapeutics (Germany) (DE), The First Affiliated Hospital, Sun Yat-sen University (CN), Shanghai Institute of Hypertension (CN), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Charité - Universitätsmedizin Berlin (DE), University of Glasgow (GB), Hasselt University (BE), Université de Lorraine (FR), KU Leuven (BE)
Good health and well-being
Openalex Percentile: Top 6%
Cardiovascular and exercise physiology
DOIOpen Access PDFOpenAlex
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