Genotype-dependent NT-proBNP, cardiac remodeling and pharmacokinetic marker dynamics after acute decompensation in heart failure: insights from the BeLove study

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Abstract Background and Aims N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a key biomarker for heart failure (HF) severity and recovery following acute decompensation. Genetic factors may influence NT-proBNP clearance and overall cardiac recovery. Protease-activated receptor 2 (PAR2), a coagulation receptor activated by factor Xa, has been implicated in cardiovascular inflammation and remodeling. This study examines NT-proBNP trajectories, proteomic markers and clinical outcome data in relation to rs1529505 genotype associated with increased PAR2 expression to better understand molecular influences on HF progression after acute decompensation. Methods Patients with acute HF (n=182) from the prospective BeLove (Berlin Long-Term Observation of Vascular Events) study were assessed. Genotyping was performed using DNA extracted from whole blood samples. Patients were stratified based on rs1529505 genotype (wild-type vs. carriers). NT-proBNP levels and proteomic markers were measured at the acute phase (V1) and after 90 days of follow-up (V3). Longitudinal changes for biomarkers were analyzed using a linear mixed model with time as a categorical variable, adjusting for sex and multiple comparisons (Tukey’s method). Type III ANOVA with Satterthwaite’s method was used to assess whether the change in NTproBNP from V1 to V3 differs between rs1529505 and wild-type. Results At baseline (V1), NT-proBNP levels were similar between wild-type and rs1529505 carriers (2237 [861-5745] ng/ml vs. 2080 [1436-3451] ng/ml, p = 0.7335). After 90 days (V3), wild-type individuals showed a significant NT-proBNP reduction (F(1, 111.76) = 5.37, p = 0.0223), indicating impaired biomarker decline in rs1529505 carriers. Glycoprotein Ib Alpha Chain (GP1BA) (+0.18, p = 0.047) and Tenascin-C (TNC) (+0.23, p = 0.044) exhibited persistent upregulation, indicating increased thrombotic risk and cardiac remodeling/fibrosis, respectively. Carboxylesterase 1 (CES1) (+0.52, p = 0.029) showed a genotype-dependent increase after decompensation, potentially altering bioactivation of ACE inhibitors, clopidogrel and ASS. Additionally, Protein Tyrosine Phosphatase Receptor Type S (PTPRS) (+0.02, p = 0.007) increased genotype-dependently post-decompensation, suggesting a role in modulating JAK/STAT and RAS/ERK signaling, which may influence immune regulation. Preliminary analysis of clinical outcomes showed a higher one-year MACE incidence (0.53 [0.36-0.66] vs. 0.37 [0.26-0.47]) and five-year all-cause mortality (0.61 [0.40-0.74] vs. 0.43 [0.30-0.54]) in rs1529505 carriers. Conclusion These findings suggest that rs1529505 influences adverse cardiac remodeling following acute decompensation (i.e. no significant decline in NT-proBNP levels), and pharmacokinetics, which may impact heart failure recovery and treatment efficacy. Further research is needed to determine the clinical significance of these genotype-driven differences for heart failure management and personalized therapy.

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