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Randomized Controlled Trial
. 2025 Aug 25;32(11):949-960.
doi: 10.1093/eurjpc/zwaf142.

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

Sophia Marie-Theres Dinges  1   2 , Edzard Schwedhelm  3   4 , Julia Schoenfeld  1   2 , Andreas B Gevaert  5   6 , Ephraim B Winzer  7 , Bernhard Haller  8 , Flavia Baldassarri  1   2 , Axel Pressler  1   9 , André Duvinage  1   2 , Rainer Böger  3   4 , Axel Linke  7 , Volker Adams  7 , Burkert Pieske  10 , Frank Edelmann  11   12 , Håvard Dalen  13   14   15 , Torstein Hole  13   16 , Alf Inge Larsen  17   18 , Patrick Feiereisen  19 , Trine Karlsen  13   20 , Eva Prescott  21 , Øyvind Ellingsen  13   14 , Emeline M Van Craenenbroeck  5   6 , Martin Halle  1   2 , Stephan Mueller  1   2
Affiliations
Randomized Controlled Trial

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

Sophia Marie-Theres Dinges et al. Eur J Prev Cardiol. .

Abstract

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 and results: Blood samples from two randomized controlled HF trials evaluating (i) high-intensity interval training (HIIT), (ii) moderate 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 (VO2peak) 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) (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; Endothelial function; Homoarginine; L-Arginine; NO bioavailability; SDMA.

Plain language 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).

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Conflict of interest statement

Conflict of interest: A.B.G. reported lecture/advisory fees paid to his institution by Abbott, AstraZeneca, Boehringer-Ingelheim, Johnson and Johnson, Novartis, Novo Nordisk, and Menarini, as well as grants paid to his institution by Abbott and Boehringer-Ingelheim, all outside the submitted work. E.B.W. reports grants from Boehringer-Ingelheim, and personal fees from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, CVRx, Daiichi-Sankyo, Pfizer, and Novartis outside the submitted work. A.I.L. reported honoraria from Pfizer for chairing a research meeting. A.L. reports honoraria or consultancy fees from Edwards Lifesciences, Boston Scientific, Abiomed, Novartis, Pfizer, Astra Zeneca, Boehringer, Abbott, MSD, Corvia, Daiichi and Meril; received grant support form Edwards Lifesciences and Novartis, and owns stock options from Transverse Medical, Picardia and Filterlex. B.P. reported institutional grants from Astra-Zeneca, Bayer Healthcare and Boston Scientific; personal fees for Steering Committee, consulting, and speaker services from Bayer Healthcare, MSD, Astra-Zeneca, Boehringer-Ingelheim, Novartis, Boston Scientific and Abbott outside the submitted work. B.P. holds minor shares in ICTS GmbH (Imaging in Clinical Trials Services). F.E. reported personal fees from Astra Zeneca, Bayer, Berlin Chemie, Boehringer-Ingelheim, CVRx, Medtronic, Merck, MSD, Novartis, Pfizer, PharmaCosmos, Resmed, Servier and Vifor Pharma, non-financial support from Novartis, and grants from Astra Zeneca, Boehringer-Ingelheim, Servier and Thermo Fischer outside the submitted work. E.M.V.C. reported consultancy fees paid to institution by Bristol-Myers Squibb, Novartis, Pfizer, Astra Zeneca and Boehringer-Ingelheim, and is an Associate Editor of EJPC. M.H. reported honoraria for lectures from Abbott, Amgen, Astra-Zeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Lilly, Medi, Novartis, Pfizer and Roche, consulting fees from Medical Park, and being the past-president of the European Association of Preventive Cardiology (presidency 2020–2022) outside the submitted work. S.M. reported personal fees from Bristol-Myers Squibb (consulting services) outside the submitted work and is a Deputy Editor of EJPC. No other potential conflicts of interest were reported.

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