Abstract Body (Do not enter title and authors here): Introduction Resting-state plasma proteins are predictive of exercise performance, but limited data exist regarding acute changes in the plasma proteome with exercise.

Hypothesis Prominent changes in the plasma proteome occur with acute exercise, a subset of which also relate to peak VO₂ as an objective measure of cardiorespiratory fitness.

Methods Among community-based participants in the multi-ethnic Dallas Heart Study who participated in the third study phase (2020-2024) and underwent protocol cardiopulmonary exercise testing, we measured aptamer-based plasma proteomics (SomaLogic; 7172 aptamers corresponding to 6490 unique proteins) at rest and immediately post-exercise in 73 participants (146 paired samples). We tested for associations between log2 protein levels and rest/exercise status using linear mixed effects models adjusted for age, sex, BMI, rest and exercise heart rate and systolic blood pressure. For proteins that changed with exercise, we assessed associations of rest protein values with percent peak VO2 using linear regression models adjusted for age, sex, and BMI. Finally, associations with HF were assessed in a case-control study of 58 prevalent cases and matched controls using logistic regression. The Bonferroni method was used for multiple testing correction.

Results Mean age was 54±11 years, 64% were male, BMI was 28.3±8.7 kg/m², and percent peak VO2 was 85±33%. After multiple testing correction, 415 protein aptamers changed from rest to exercise: 242 increased and enriched for pathways related to RNA processing and translation; 173 decreased and enriched for pathways related to extracellular matrix organization, and immune response. Of these, 4 proteins were also associated with peak VO2 after multiple test correction: higher peak VO₂ associated with decrease in LEP consistent with prior reports, and with increases in CIB1, ITGB1|ITGA11, and CYB5R3. In addition to proteins involved in metabolism (LEP, CYB5R3), these proteins reflect processes related to signal transduction (ITGB1, LEP), extracellular matrix organization (ITGB1|ITGA11) and biological pathway regulation (CIB1). Higher resting ITGB1|ITGA11 value was also associated with decreased odds of HF (OR per 1-sd 0.20 [95% CI 0.067-0.55], p= 0.003).

Conclusions Acute exercise impacts the plasma proteome, with exercise-induced changes in LEP, CIB1, ITGB1|ITGA11, and CYB5R3 associated with cardiorespiratory fitness. Higher resting values of ITGB1|ITGA11 associate with lower HF risk.