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Phosphodiesterase-5 inhibition with sildenafil compared with a placebo had no effect on the exercise capacity or clinical status of patients with heart failure with preserved ejection fraction (HFpEF) in the PhosphodiesteRasE-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure with Preserved Ejection Fraction (RELAX) clinical trial. Metabolic impairments may explain the neutral results.To test the hypothesis that profiling metabolites in the RELAX trial would clarify the mechanisms of sildenafil effects and identify metabolites associated with clinical outcomes in HFpEF.Paired baseline and 24-week plasma samples of 160 stable outpatient individuals with HFpEF enrolled in the RELAX clinical trial were analyzed using flow injection tandem mass spectrometry (60 metabolites) and conventional assays (5 metabolites).Sildenafil (n = 79) or a placebo (n = 81) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks.The primary measure was metabolite level changes between baseline and 24 weeks stratified by treatments. Secondary measures included correlations between metabolite level changes and clinical biomarkers and associations between baseline metabolite levels and the composite clinical score.No metabolites changed between baseline and 24 weeks in the group treated with a placebo; however, 7 metabolites changed in the group treated with sildenafil, including decreased amino acids (alanine and proline; median change [25th-75th], −38.26 [−100.3 to 28.19] and −28.24 [−56.29 to 12.08], respectively; false discovery rate–adjusted P = .01 and .03, respectively), and increased short-chain dicarboxylacylcarnitines glutaryl carnitine, octenedioyl carnitine, and adipoyl carnitine (median change, 6.19 [−3.37 to 14.18], 2.72 [−3 to 12.57], and 10.72 [−11.23 to 29.57], respectively; false discovery rate–adjusted P = .01, .04, and .05, respectively), and 1 long-chain acylcarnitine metabolite (palmitoyl carnitine; median change, 7.83 [−5.64 to 26.99]; false discovery rate–adjusted P = .03). The increases in long-chain acylarnitine metabolites and short-chain dicarboxylacylcarnitines correlated with increases in endothelin-1 and creatinine/cystatin C, respectively. Higher baseline levels of short-chain dicarboxylacylcarnitine metabolite 3-hydroxyisovalerylcarnitine/malonylcarnitine and asparagine/aspartic acid were associated with worse clinical rank scores in both treatment groups (β, −96.60, P = .001 and β, −0.02, P = .01; after renal adjustment, P = .09 and .02, respectively).Our study provides a potential mechanism for the effects of sildenafil that, through adverse effects on mitochondrial function and endoplasmic reticulum stress, could have contributed to the neutral trial results in RELAX. Short-chain dicarboxylacylcarnitine metabolites and asparagine/aspartic acid could serve as biomarkers associated with adverse clinical outcomes in HFpEF.