Cardiovascular research · 2026
Differential metabolomic prediction of outcomes in HFpEF and HFrEF: a prospective international multi-ethnic cohort study.
СтатьяМногоцентровое исследованиеСравнительное исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Wu Lik Hang, Pakkiri Leroy Sivappiragasam, Tromp Jasper, Lim Poh Leong, Liu Xinyi, Chan Siew Pang, Yang Jielin, Samant Rishikesh, Dong Jiangwen, Goh Eugene, Lee Jieun, Ling Lieng Hsi, Gamble Greg D, Sim David, Gerard Leong Kui Toh, Yeo Poh Shuan Daniel, Ong Hean Yee, Jaufeerally Fazlur, Ng Tze Pin, Lund Mayanna, Devlin Gerry, Troughton Richard, Cameron Vicky, Lam Carolyn Su Ping, Doughty Robert, Richards Arthur Mark, Drum Chester Lee
Аннотация
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.
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.