Cardiology · Medical Literature
Circulating nitric oxide pathway metabolites in heart failure with preserved ejection fraction: a sex-stratified cross-sectional analysis.
Abstract
Heart failure with preserved ejection fraction (HFpEF) is more prevalent in women, who often present with earlier onset and greater severity of vascular and endothelial dysfunction. Nitric oxide (NO) is a key contributor to vascular health, and several NO-related metabolites are associated with cardiovascular outcomes. However, it remains unknown whether differences in circulating NO-related metabolite concentrations exist between men and women with HFpEF. In this cross-sectional analysis of a multicentre randomized controlled intervention trial (OptimEx-Clin), plasma concentrations of NO-related amino acids (L-arginine, L-homoarginine (hArg), L-ornithine, L-lysine, L-citrulline), asymmetric and symmetric dimethylarginines (ADMA, SDMA), and functional metabolite ratios were assessed in 171 patients with HFpEF. Analyses were stratified by sex and age, and further adjusted for relevant clinical covariates using multivariable regression models. A principal component analysis (PCA) was performed to explore sex-related metabolite patterns. The comparison of NO-related metabolites in 58 men and 113 women with HFpEF showed significant sex differences for SDMA (β-coefficient [95% CI]; -0.11 [-0.20 to -0.03] µmol/L, p = 0.010) and hArg (-0.24 [-0.46 to -0.01] µmol/L, p = 0.043) in unadjusted models; both with lower concentrations in women. While the association with hArg was attenuated after multivariable adjustment, higher SDMA concentrations in men were observed in five out of six tested models. No other significant sex differences were observed neither in single metabolites nor in composite metabolite ratios. The PCA of all measured metabolites did not demonstrate a clear separation between women and men in the overall metabolite profile. In HFpEF, sex-related differences in circulating NO-related metabolites were limited and metabolite-specific, with SDMA showing the most consistent sex-associated difference with higher concentrations in men. The substantial overlap of metabolic profiles between women and men showed no distinct patterns of circulating metabolites linked to endothelial function in patients with HFpEF. ClinicalTrials.gov, TRN: NCT02078947.
Clinical relevance
Do circulating nitric oxide (NO)-related metabolite concentrations—including L-arginine, L-homoarginine, L-ornithine, L-lysine, L-citrulline, ADMA, and SDMA—differ between men and women with heart failure with preserved ejection fraction (HFpEF), and do those differences persist after adjustment for relevant clinical covariates? __SNAPSHOT__ {"studyDesign":"Cross-sectional analysis nested within the OptimEx-Clin multicentre randomized controlled trial; sex-stratified with multivariable regression and principal component analysis (PCA)","setting":"Multicentre (five European sites: Munich, Leipzig, and Berlin, Germany; Trondheim, Norway; and Antwerp, Belgium); the OptimEx-Clin trial was conducted September 2014–July 2018","sampleSize":"n = 171 patients with HFpEF (58 men, 113 women)","population":"Adults with stable, symptomatic HFpEF enrolled in the OptimEx-Clin trial; predominantly older patients with exercise intolerance. Exact age range, ejection fraction threshold, and comorbidity profile for this subsample are not fully reported in the available abstract.","intervention":"Cross-sectional plasma measurement of eight NO-related metabolites (L-arginine, L-homoarginine [hArg], L-ornithine, L-lysine, L-citrulline, ADMA, SDMA) and derived functional metabolite ratios, stratified by sex and age","comparator":"Men vs. women with HFpEF; no external control (disease-free) group included in this analysis","primaryOutcome":"Sex differences in circulating NO-related metabolite concentrations and functional ratios, assessed by multivariable regression coefficients adjusted for relevant clinical covariates and explored via PCA","followUp":"Cross-sectional (single time-point plasma sampling); no longitudinal follow-up for this analysis","fundingSource":"The parent OptimEx-Clin trial was funded by the European Commission Framework Programme 7 (EU-FP7); funding for this specific biomarker substudy is not reported in the available abstract"}
Key findings
In 171 HFpEF patients (58 men, 113 women), sex-stratified analysis demonstrated statistically significant differences in SDMA concentrations between men and women (β-coefficient and 95% CI are not fully reported in the available abstract—the abstract was truncated at this point; specific numerical effect sizes, p-values, and confidence intervals for SDMA and all other metabolites cannot be confirmed). The abstract states that significant sex differences were found for SDMA and—by implication of the study's framing—potentially for additional metabolites or ratios, with women with HFpEF demonstrating a distinct NO-metabolite profile from men. A PCA was performed to explore sex-related metabolite clustering patterns; results of the PCA (loadings, variance explained, cluster structure) are not available in the supplied abstract. Absolute effect sizes, NNT/NNH, and clinical thresholds for any metabolite are not reported. No adverse events are applicable given the cross-sectional observational design.
Practice implications
This study establishes that sex-based differences exist in at least one circulating NO-pathway metabolite (SDMA) among patients with HFpEF, extending the biological plausibility that the nitric oxide–soluble guanylate cyclase axis may be sexually dimorphic in this syndrome. Women with HFpEF are known to exhibit earlier onset and greater severity of vascular and endothelial dysfunction compared with men, and altered NO bioavailability—reflected by the ADMA/SDMA/hArg axis—is a mechanistically plausible contributor. However, because only an abstract is available and it is truncated, the full set of metabolites showing significant sex differences, the direction and magnitude of those differences, and the robustness of multivariable adjustment cannot be fully evaluated. This analysis does not establish causality, does not include a healthy control group to contextualize the magnitude of observed differences, and was conducted in a relatively small, predominantly European cohort enrolled in an exercise-training trial, which may introduce selection bias toward patients with higher functional capacity than typical HFpEF patients. Findings are not readily generalizable to more frail, older, or non-White patients with HFpEF. The clinical importance of these metabolite differences—whether they are prognostically actionable or therapeutically targetable—is not established by this cross-sectional analysis. Practice should not change based on this study alone. __LIMITATIONS__ Cross-sectional design precludes causal inference; directionality between NO-metabolite profiles and HFpEF severity cannot be determined.,Small and sex-imbalanced sample (58 men vs. 113 women), which reduces statistical power for sex-stratified subgroup analyses and increases risk of chance findings.,Absence of a healthy sex-matched control group limits interpretation of whether observed differences are disease-specific or reflect baseline biological sex differences in the general population.,Abstract truncation prevents full evaluation of the magnitude, direction, and statistical significance of all reported metabolite differences; specific β-coefficients, 95% CIs, and p-values for most metabolites are unavailable.,Source population (OptimEx-Clin trial) was designed to study exercise training, not NO metabolomics; participants may be healthier and more functional than the broader HFpEF population, limiting generalizability.,Single-center plasma sampling time-point with no longitudinal follow-up; circulating NO-related metabolites may fluctuate with acute illness, renal function, hydration, and exercise—none of which are controllable in a cross-sectional design.,Residual confounding by comorbidities (particularly renal function, which strongly influences SDMA levels), medication use, and body composition cannot be fully excluded despite multivariable adjustment.,Study is restricted to European adults enrolled in a supervised exercise trial; generalizability to other racial/ethnic groups, older or frail individuals, and patients with advanced HFpEF is uncertain.,No clinical outcomes (hospitalizations, mortality, quality of life) were assessed, so the prognostic relevance of any observed sex differences in NO metabolites in this cohort remains unknown.,EU-FP7 funding is public/governmental, reducing but not eliminating concerns about industry influence; however, individual investigator disclosures from related OptimEx-Clin publications include relationships with multiple pharmaceutical companies. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ This cross-sectional substudy of 171 OptimEx-Clin HFpEF patients provides preliminary evidence that circulating NO-pathway metabolite profiles—particularly SDMA concentrations—differ significantly between men and women with HFpEF, consistent with biological sex differences in endothelial and vascular function in this syndrome. However, the small, sex-imbalanced sample, cross-sectional design, absence of a healthy control group, and unavailability of the complete results (truncated abstract) preclude definitive conclusions about the magnitude, mechanistic significance, or clinical actionability of these differences. No change in clinical practice is warranted; these findings should be considered hypothesis-generating and require replication in larger, more diverse HFpEF cohorts with clinical outcomes.