Effects of exercise training on nitric oxide metabolites in heart failure with reduced or preserved ejection fraction: a secondary analysis of the SMARTEX-HF and OptimEx-Clin trials

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 (i) high-intensity interval training (HIIT), (ii) moderate and results continuous training (MCT), or (iii) 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 a 12-month follow-up. 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 (VO_2peak) and NT-proBNP, but not with measures of endothelial function (reactive hyperaemia index, flow-mediated dilation). After 3 months of exercise and a 12-month follow-up, changes in metabolite plasma levels were not significantly different between study groups (HIIT, MCT, or CG) (p_group×time > 0.05), neither in HFrEF nor HFpEF. Conclusion Baseline NO metabolite profile was unfavourable in patients with HF and lower VO_2peak or higher NT-proBNP. We did not find a significant influence of HIIT or MCT on NO metabolites at 3 and 12 months. Lay summary 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).