Elevated 5-oxoproline levels and adverse outcomes in heart failure: Association with renal cortical OPLAH loss in a multi-comorbidity model.
BACKGROUND: Heart failure (HF) progression is closely linked to oxidative stress. 5-Oxoproline (5-OP), a product of glutathione degradation, is normally metabolized by 5-oxoprolinase (OPLAH) but accumulates when the gamma-glutamyl cycle is disrupted. Here, we investigated the clinical characteristics of circulating 5-OP, its proteomic correlates, and the associations to outcome in HF. METHODS: In serum of 823 BIOSTAT-CHF patients, 5-OP was quantified by validated liquid chromatography-mass spectrometry and analyzed for associations with clinical outcomes. Proteomic correlates were identified across 355 OLINK proteins using stability selection with Minimax Concave Penalty regression. Mechanistic context was evaluated in a multi-comorbidity, large-animal cardio-kidney-metabolic (CKM) model with regional OPLAH assessment. RESULTS: Higher 5-OP was associated with worse renal function (eGFR declining across 5-OP tertiles, 67.9 to 60.2 mL/min/1.73 m2; p = 0.0012) and higher all-cause mortality (HR 1.55, 95% CI 1.11-2.17, p = 0.010). Per SD increase in log-5-OP, risk for the 2-year composite endpoint increased (HR 1.27, 95% CI 1.05-1.53), with broadly similar associations across CKD strata (interaction p = 0.63). TGF-α was the most robust proteomic correlate (π = 0.70; empirical permutation p = 0.001). In CKM swine, circulating 5-OP was elevated and renal cortical OPLAH protein, but not cardiac OPLAH, was selectively reduced, consistent with a renal contribution to systemic 5-OP elevation. CONCLUSION: Circulating 5-OP identifies HF patients at higher risk and is robustly associated with TGF-α. In a translational swine model, selective loss of renal cortical OPLAH provides tissue context supporting a renal contribution to systemic 5-OP elevation in cardiorenal syndrome.