Exercise-induced biomolecular changes and cardiovascular effects in heart failure: a systematic review and meta-analysis

AIM: This meta-analysis aimed to (1) evaluate exerkines, signalling molecules secreted by tissues such as skeletal muscle, heart, and adipose tissue, as biomarkers or mediators of exercise-induced benefits in heart failure (HF), and (2) compare the impact of training on exerkine expression. METHODS: We systematically searched four databases up to August 31, 2025, for randomised and non-randomised controlled trials evaluating the effects of exercise training on exerkines (e.g., IL-6, TNF-α, lactate, IGF-1, and adiponectin) in patients with HF. Risk of bias and quality of reporting data were assessed using the Cochrane Collaboration tool and the Robins-I scale. RESULTS: Pooled data from 29 studies (n=1,278) showed that exercise training significantly reduced circulating IL-6 (g=-0.27, 95% CI -0.52 to -0.01) and TNF-α (g=-0.26, 95% CI -0.40 to -0.12) compared to the controls. An exploratory multivariate meta-analysis yielded an overall effect of g=-0.38 (95% CI: -0.55 to -0.21), indicating a global decrease in exerkines after the intervention. Greater declines in exerkines were associated with larger increases in peak oxygen consumption (β=-0.16, 95% CI -0.28 to -0.04) and left ventricular ejection fraction (β=-0.12, 95% CI -0.17, -0.07). By phenotype, HF with reduced ejection fraction (HFrEF) exhibited a clear, robust reduction (g=-0.37, 95% CI -0.56 to -0.19), whereas HF with preserved ejection fraction (HFpEF) and mixed HFrEF/HFpEF did not show this reduction. CONCLUSIONS: Exercise training modulates circulating exerquines levels. Notably, it reduces pro-inflammatory responses in HF, linking molecular adaptations to improved functional gain. These molecular adaptations are linked to functional improvements, supporting exercise training as a safe and effective anti-inflammatory and metabolic therapy in HF.