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Sex Differences in NO Metabolites Are Limited and Metabolite-Specific in HFpEF
In a sex-stratified analysis of 171 HFpEF patients, circulating symmetric dimethylarginine (SDMA) was consistently higher in men than in women, with a small absolute difference of approximately 0.11 µmol/L (β −0.11 µmol/L, 95% CI −0.20 to −0.03), while the broader nitric oxide metabolite profile showed substantial overlap between sexes. The overall pattern suggests that sex-based divergence in circulating NO-related metabolites is narrow and metabolite-specific, rather than reflecting a broadly distinct endothelial biochemistry in HFpEF.
What Was Studied
This study examined whether men and women with heart failure with preserved ejection fraction (HFpEF) differ in the concentrations of circulating nitric oxide (NO)-related metabolites — including amino acids and dimethylarginines — that are linked to vascular and endothelial function. Given that women with HFpEF are reported to present with earlier onset and greater severity of vascular dysfunction, the analysis sought to determine whether these clinical differences are reflected in measurable differences in NO-pathway metabolite profiles.
How It Was Studied
This was a cross-sectional analysis nested within the OptimEx-Clin multicentre randomized controlled intervention trial (ClinicalTrials.gov NCT02078947). Plasma concentrations of seven NO-related metabolites — L-arginine, L-homoarginine (hArg), L-ornithine, L-lysine, L-citrulline, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) — as well as functional metabolite ratios, were measured in 171 patients with confirmed HFpEF. The analytical cohort comprised 58 men and 113 women, and comparisons were stratified by sex and age. Multivariable regression models adjusting for relevant clinical covariates were applied across six model specifications, and a principal component analysis (PCA) was conducted to evaluate whether distinct metabolite clustering patterns existed between sexes.
What Was Observed
- SDMA was the most consistently sex-differentiated metabolite, with men showing higher concentrations than women by approximately 0.11 µmol/L (β −0.11 µmol/L, 95% CI −0.20 to −0.03, p = 0.010). This difference remained directionally consistent in five out of six multivariable-adjusted models, making it the most robust sex-associated finding in the dataset.
- L-homoarginine (hArg) was also lower in women in unadjusted analyses, with a difference of approximately 0.24 µmol/L (β −0.24 µmol/L, 95% CI −0.46 to −0.01, p = 0.043). However, this association was attenuated and lost statistical significance after multivariable adjustment for clinical covariates, suggesting that confounding factors may explain much of the unadjusted difference.
- No other metabolites or composite ratios showed significant sex-related differences, including L-arginine, L-citrulline, ADMA, L-ornithine, and L-lysine. This null result across the majority of measured analytes indicates that the NO metabolite landscape in HFpEF is largely shared between men and women.
- Principal component analysis revealed no clear metabolite-based separation between sexes, confirming at a multivariate level that the overall circulating NO-related metabolite profile does not form distinct sex-specific clusters in this HFpEF population.
Why This Matters
HFpEF is described in this study as more prevalent in women, who also present with earlier onset and greater severity of vascular and endothelial dysfunction — yet this analysis found that these clinical differences are not mirrored by broadly divergent circulating NO metabolite profiles. This challenges the assumption that sex-based differences in HFpEF disease expression would be detectable through these specific circulating markers. The findings imply that endothelial dysfunction in HFpEF may not be adequately captured by NO-pathway metabolites measured in plasma alone, and that sex-specific mechanistic drivers may operate through pathways not represented in this metabolite panel.
How to Read This Result
This cross-sectional, secondary analysis with a moderately sized and unequally distributed sex cohort supports a largely neutral conclusion — the data suggest minimal sex stratification in NO metabolites — but the design precludes causal interpretation, and residual confounding cannot be excluded.
Limitations
The cross-sectional design prevents any causal inference about the relationship between sex, NO metabolites, and HFpEF. As a secondary analysis of the OptimEx-Clin RCT, the study population was not originally selected for this metabolomic question, which may introduce selection bias and limit generalizability. The unequal distribution between men (n = 58) and women (n = 113) may reduce statistical power for detecting sex differences in the smaller male subgroup. Finally, while multivariable models adjusted for available clinical covariates, unmeasured or residual confounders — such as medication use or hormonal status — may still influence the observed metabolite concentrations.