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Patients with group 1 pulmonary hypertension and high HFpEF probability have a unique metabolome overlapping with clinical HFpEF, characterized by enhanced tryptophan-kynurenine pathway breakdown, lower serotonin, and decreased nitric oxide precursors.

This study stratified group 1 pulmonary hypertension (PH) patients by HFpEF probability and found that those with high probability (n=131) had significant metabolomic changes compared to low probability (n=62), including increased kynurenine metabolites and decreased serotonin, linoleate, arginine, and homoarginine. These changes overlapped with clinical HFpEF (n=240) and were abnormal relative to controls (n=85), suggesting biological overlap between the two conditions.

Last updated: Aug 26, 2026•0 RCTs•📖 Read as article →

Evidence Score

Evidence Score34/100
Human RCT☆☆☆☆☆
Meta-analysis☆☆☆☆☆
Mechanism★★★★★
Safety★★★★☆
Confidencelow

Study Evidence

Study 1. Metabolomic Evidence of Biological Overlap with Heart Failure with Preserved Ejection Fraction in a Subset of Pulmonary Arterial Hypertension.

observational

Reddy YNV, Asokan AK, Frantz RP, Hemnes A, Hassoun PM, Barnard J, Horn E, Leopold JA, Rischard F, Rosenzweig EB, Hill NS, Erzurum SC, Beck GJ, Finet JE, Grunig G, Jellis CL, Mathai SC, Simpson CE, Tang WHW, Nair KS, Borlaug BA · American journal of respiratory and critical care medicine (2025)

Participants: N/A
Duration: N/A
Intervention: Stratification of group 1 PH patients by HFpEF probability (low <25% vs high ≥75%) using the HFpEF-ABA score (age, body mass index, atrial fibrillation).
Outcome: Serum and transpulmonary metabolome profiles, including tryptophan-kynurenine pathway metabolites, serotonin, linoleate, arginine, homoarginine, glycine, and serine.
Effect Size: Fold change >1 or <1 for 438 metabolites (207 increased, 231 decreased) with FDR P<0.05; specific FDR P values <0.002 for tryptophan metabolites and <0.03 for linoleate and arginine.
Population: Patients with group 1 pulmonary hypertension (n=193), healthy controls (n=85), and clinical HFpEF subjects (n=240).

Result:

PubMed: 40504754DOI: 10.1164/rccm.202501-0034OC

Mechanism Graph

Enhanced tryptophan-kynurenine pathway breakdown in group 1 PH with high HFpEF probability
↓
Lower serotonin concentrations
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Deficiency of amino acids (glycine, serine) and precursors (linoleate, arginine, homoarginine)
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Result: Metabolome changes overlap with clinical HFpEF, indicating shared biological pathways

Limitations

  • ⚠Observational study design cannot establish causality
  • ⚠HFpEF probability was based on a clinical score (HFpEF-ABA) rather than direct hemodynamic or imaging confirmation
  • ⚠Metabolome changes may be influenced by medications or comorbidities not fully accounted for

Frequently Asked Questions

What is the HFpEF-ABA score?▼

It is a clinical probability score for heart failure with preserved ejection fraction based on age, body mass index, and atrial fibrillation.

What metabolomic changes were most significant in the high HFpEF probability group?▼

Enhanced tryptophan-kynurenine pathway breakdown, lower serotonin, and decreased linoleate, arginine, and homoarginine levels.

Did the metabolome changes originate from the lungs?▼

No, there was no evidence of differential transpulmonary uptake/release for most metabolites, except serotonin and kynurenine, suggesting a nonpulmonary origin.

How many patients were in each group?▼

Group 1 PH with high HFpEF probability: 131; low probability: 62; clinical HFpEF: 240; healthy controls: 85.

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References

  1. 1.Reddy YNV, Asokan AK, Frantz RP, Hemnes A, Hassoun PM, Barnard J, Horn E, Leopold JA, Rischard F, Rosenzweig EB, Hill NS, Erzurum SC, Beck GJ, Finet JE, Grunig G, Jellis CL, Mathai SC, Simpson CE, Tang WHW, Nair KS, Borlaug BA. "Metabolomic Evidence of Biological Overlap with Heart Failure with Preserved Ejection Fraction in a Subset of Pulmonary Arterial Hypertension.." American journal of respiratory and critical care medicine, 2025. PMID: 40504754 DOI: 10.1164/rccm.202501-0034OC
Disclaimer: This content is for educational purposes only and is not medical advice. Evidence scores reflect the quality and quantity of available research, not clinical recommendations. Always consult a healthcare professional before starting any supplement or intervention.