Aims: Exercise has been shown to affect the nitric oxide (NO) pathway, which is involved in the pathophysiology of endothelial dysfunction in heart failure (HF) with reduced (HFrEF) and preserved ejection fraction (HFpEF). However, the effects of different exercise modes on NO metabolites in patients with HF are uncertain.
Methods: Blood samples from two randomized controlled HF trials evaluating 1.) high-intensity-interval-training (HIIT), 2.) moderate-continuous-training (MCT) or 3.) a control group (CG) in HFrEF (SMARTEX-HF) and HFpEF (OptimEx-Clin) were analysed for NO metabolites L-arginine, homoarginine (hArg), asymmetric and symmetric dimethylarginine (ADMA; SDMA). Metabolite plasma concentrations were compared between HFrEF and HFpEF at baseline and within each HF type after 3 months of supervised exercise training and 12 month-follow-up.
Results: Overall, 206 patients with HFrEF (61±12 years, 18.9% females) and 160 with HFpEF (70±8 years, 65.6% females) were investigated. Baseline hArg (1.74±0.78 vs. 1.31±0.69 µmol/l) and ADMA (0.68±0.15 vs. 0.62±0.09 µmol/l) were significantly higher in HFrEF (p<0.001). NO metabolites showed several significant associations with markers of HF severity like exercise capacity (VO2peak) and NT-proBNP, but not with measures of endothelial function (reactive hyperaemia index, flow-mediated dilation). After 3 months of exercise and 12-month-follow-up, changes in metabolite plasma levels were not significantly different between study groups (HIIT, MCT or CG) (pgroup*time >0.05), neither in HFrEF nor HFpEF.
Conclusion: Baseline NO metabolite profile was unfavourable in patients with HF and lower VO2peak or higher NT-proBNP. We did not find a significant influence of HIIT or MCT on NO metabolites at 3 and 12 months.
Keywords: ADMA; L-Arginine; NO bioavailability; SDMA; endothelial function; homoarginine.
In our study, we measured the metabolites L-arginine, homoarginine, asymmetric and symmetric dimethylarginine (ADMA, SDMA), which are considered important regulators of the nitric oxide (NO) mediated endothelial function and associated with cardiovascular outcome, in patients with heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) and investigated whether exercise, in particular a 3-month supervised high-intensity-interval (HIIT) or a moderate continuous training (MCT) has an effect on their systemic plasma concentrations. Baseline NO metabolites were associated with parameters of HF severity, linking less favourable metabolite profiles with an increasing disease severity, but not with clinical measures of endothelial function. Contrary to our expectations, microvascular endothelial dysfunction was more frequent in HFrEF than in HFpEF.Exercise training did not significantly influence circulating NO metabolites plasma concentrations, regardless of exercise mode (HIIT or MCT), follow-up time (3 or 12 months) or type of HF (HFrEF or HFpEF).
© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.