Differential metabolomic prediction of outcomes in HFpEF and HFrEF: a prospective international multi-ethnic cohort study
Year: 2026
Type: article
Study design: Observational Study
Abstract: AIMS: Metabolic dysregulation accompanies heart failure (HF), yet coordinated biochemical shifts are rarely quantified for prognostication. We investigated whether early metabolic profiles predict morbidity and mortality in HF with preserved (HFpEF) or reduced ejection fraction (HFrEF). METHODS AND RESULTS: In the PEOPLE and SHOP cohorts (n = 1520), 288 plasma metabolites were quantified by tandem mass spectrometry. Weighted co-expression network analysis produced metabolic indices that were regressed against all-cause mortality and composite outcomes (death or readmission) using multivariable proportional hazards and win-ratio models. In HFpEF, metabolic indices of nitric oxide signalling and glycaemic control (netNO-pEF) and purine metabolism (netPurine-pEF) predicted outcomes. In HFrEF, indices of acylcarnitine (netACa-rEF) and amino acids (netAA-rEF) predicted outcomes. Every 20% higher netNO-pEF was associated with adjusted hazard ratios (HR20%higher) of 0.64 [95% CI 0.49-0.84] in PEOPLE-HFpEF and 0.40 [0.20-0.83] in SHOP-HFpEF; HR20%higher for netPurine-pEF were 1.71 [1.30-2.24] in PEOPLE-HFpEF and 1.96 [1.08-3.55] in SHOP-HFpEF; HR20%higher for netACa-rEF were 1.48 [1.23-1.79] in PEOPLE-HFrEF and 1.39 [1.15-1.68] in SHOP-HFrEF; HR20%higher for netAA-rEF were 0.75 [0.62-0.91] in PEOPLE-HFrEF and 0.51 [0.39-0.67] in SHOP-HFrEF. Adjusted inverse win-ratios were concordant: 1/WR20%higher for netACa-rEF were 1.40 [1.19-1.64] in PEOPLE-HFrEF and 1.17 [1.02-1.34] in SHOP-HFrEF; 1/WR20%higher for netNO-pEF were 0.74 [0.54-1.00] in PEOPLE-HFrEF and 0.55 [0.33-0.89] in SHOP-HFrEF. netNO-pEF was negatively associated with body surface area among HFpEF with concomitant hypertension and diabetes, but only in SHOP-HFpEF. Adding orotic acid, a constituent metabolite of netNO-pEF, to a base model containing five risk indices (MAGGIC score, NT-proBNP, hsTnT, GDF15, and E/e' ratio) incrementally improved 2-year mortality prediction (AUROC: 0.82→0.83 in PEOPLE; 0.74→0.79 in SHOP). CONCLUSION: Differential metabolic signatures tied to metabolic inflammation in HFpEF and impaired energy metabolism in HFrEF enhance risk stratification and point to therapeutic targets.
Source: Cardiovascular Research
DOI: 10.1093/cvr/cvag090
Authors: Lik Hang Wu, Leroy Sivappiragasam Pakkiri, Jasper Tromp, Poh Leong Lim, Xinyi Liu, Siew Pang Chan, Jielin Yang, Rishikesh Samant, Jiangwen Dong, Eugene Goh, Jieun Lee, Lieng Hsi Ling, Greg D Gamble, David Sim, Kui Toh Gerard Leong, Poh Shuan Daniel Yeo, Hean Yee Ong, Fazlur Jaufeerally, Tze Pin Ng, Mayanna Lund, Gerry Devlin, Richard Troughton, Vicky Cameron, Carolyn Su Ping Lam, Robert Doughty, Arthur Mark Richards, Chester Lee Drum
Institutions: National University of Singapore, National University Health System, Kitasato University, Duke-NUS Medical School, National University Heart Centre Singapore, University of Auckland, Changi General Hospital, Tan Tock Seng Hospital, Khoo Teck Puat Hospital, Singapore General Hospital, Middlemore Hospital, Waikato Hospital, University of Otago
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,329
Funders: National Research Foundation, Agency for Science, Technology and Research, National University of Singapore, National Research Foundation Singapore, Singapore General Hospital, Auckland Medical Research Foundation, National Heart Foundation of New Zealand, Waikato Medical Research Foundation, Changi General Hospital, Medical Research Council, National Medical Research Council, Health Research Council of New Zealand, Society of Transnational Academic Researchers Scholars Network
OpenAlex ID: W7155702907