Redox balance and methylation are crucial to homeostasis and are linked by the methionine-homocysteine cycle. We examined whether differences in methylation potential, measured as plasma levels of S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH), occur at baseline and during anti-oxidant therapy with the xanthine oxidase inhibitor allopurinol in patients with heart failure with reduced ejection fraction. We analyzed plasma samples collected at baseline and 24 weeks in the Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) study, which randomized patients with heart failure with reduced ejection fraction to allopurinol or placebo. Associations between plasma levels of SAM, SAH, SAM/SAH ratio, and outcomes, including laboratory markers and clinical events, were assessed. Despite randomization, median SAM levels were significantly lower at baseline in the allopurinol group. SAH levels at 24 weeks, and change in SAM from baseline to week 24, were significantly higher in the group of patients randomized to allopurinol compared to the placebo group. A significant correlation was observed between change in SAH levels and change in plasma uric acid (baseline to 24-week changes) in the allopurinol group. There were no significant associations between levels of SAM, SAH, and SAM/SAH ratio and clinical outcomes. Our results demonstrate significant biological variability in SAM and SAH levels at baseline and during treatment with an anti-oxidant and suggest a potential mechanism for the lack of efficacy observed in trials of anti-oxidant therapy. These data also highlight the need to explore personalized therapy for heart failure.
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The authors gratefully acknowledge the EXACT-HF study investigators, coordinators, and patients for their time and effort on behalf of the clinical trial. We also thank the staff of the core biomarker laboratory at the University of Vermont, under the direction of Russel Tracy PhD, for their handling of clinical specimens. The authors would also like to acknowledge the Metabolomics Shared Resource at Georgetown University (Washington, DC, USA) that is partially supported by NIH/NCI/CCSG grant P30-CA051008.
This work was supported by grants from the National Institutes of Health: NHLBI coordinating center: U10HL084904; and regional clinical center: U10HL110337
Ethics approval and consent to participate
This is a sub-study utilizing data and blood samples collected as part of the primary study. No additional data or blood collection was performed as part of this study. This sub-study was approved by Institutional Review Boards of Brigham and Women’s Hospital and Duke University Medical Center. Informed consent was obtained from participants as part of the main study EXACT-HF.
The authors declare no competing interests.
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• Redox balance and methylation reactions are linked through the methionine-homocysteine cycle.
• The body’s methylation potential varies widely among individuals with heart failure.
• Methylation potential is altered by anti-oxidant therapy.
• These findings may explain the neutral results of clinical trials of anti-oxidant therapy.
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Joseph, J., Giczewska, A., Alhanti, B. et al. Associations of methyl donor and methylation inhibitor levels during anti-oxidant therapy in heart failure. J Physiol Biochem (2021). https://doi.org/10.1007/s13105-021-00797-x
- Redox balance
- Anti-oxidant therapy
- Heart failure