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. Copyright (c) 2026 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).