N-terminal pro-B-type natriuretic peptide (NT-proBNP) reflects heart failure severity and post-discharge prognosis following acute decompensation. The rs1529505 variant in F2RL1 (protease-activated receptor 2, PAR2) has been associated with enhanced inflammatory responses in cardiovascular disease. Carboxylesterase 1 (CES1), a hepatic enzyme essential for activating cardiac prodrugs (e.g. ACE inhibitors) and clearing circulating biomarkers, is itself regulated by inflammatory signals. We investigated whether variation at the F2RL1 locus influences NT-proBNP and troponin trajectories through CES1-dependent clearance mechanisms during acute heart failure (AHF) recovery.
We analyzed 135 AHF patients from the prospective BeLOVE cohort stratified by rs1529505 genotype (wild-type vs. carriers). NT-proBNP, troponin, and plasma proteins were measured at acute presentation (V1) and 90-day follow-up (V3). Longitudinal changes were analyzed using linear mixed-effects models, including fixed effects for genotype, visit, and their interaction, adjusted for age, sex, anticoagulation, and smoking. Post-hoc contrasts used Tukey adjustment. Three-way interactions between Visit×Genotype×CES1 were evaluated. MACE (hospitalization for heart failure, non-fatal stroke, or vascular death) and all-cause mortality were assessed using competing-risk models with cause-specific Cox regression over one- and five-year follow-up respectively.
Carriers exhibited significantly attenuated NT-proBNP decline (genotype×visit: F~1,111.26~=5.17, p=0.025; interaction effect β=376.5, p<0.001) with elevated levels at V3 (p=0.040). Troponin showed similar impairment (F~1,18~=5.12, p=0.036). CES1 demonstrated genotype-dependent dynamics (β=0.57, p=0.019), revealing rs1529505 modulation of the CES1–NT-proBNP relationship (p=0.008). At 12-month and 5-year follow-up, cumulative MACE incidence was 0.53 [0.36–0.66] in carriers versus 0.37 [0.26–0.47] in wild-type (HR 1.44 [0.84–2.46]); all-cause mortality was 0.61 [0.40–0.74] versus 0.43 [0.30–0.54] (HR 1.34 [0.78–2.28]).
The rs1529505 variant impairs biomarker resolution through CES1-dependent mechanisms linking PAR2-inflammatory pathways to cardiac clearance capacity, supporting genotype-directed acute heart failure management strategies.
