Genetic and Nongenetic Factors Influencing Pharmacokinetics of B-Type Natriuretic Peptide

•Study of 95 patients with heart failure receiving human recombinant B-type natriuretic peptide (BNP; nesiritide) infusion and measuring BNP elimination.•BNP clearance varied greatly across the cohort.•Heart failure type (ie, preserved vs reduced ejection fraction) correlated with BNP clearance rates.•Genetic variation in MME and NPR3 may affect BNP clearance rates; this needs replication.

BackgroundNatriuretic peptides (NPs) represent a critical pathway in heart failure (HF). However, there is wide individual variability in NP system activity, which could be partly genetic in origin. We explored genetic and nongenetic contributions to B-type natriuretic peptide (BNP) inactivation.MethodsChronic HF patients (n = 95) received recombinant human BNP (nesiritide) at standard doses, and BNP levels were measured at baseline, after 2 hours of infusion, and 30 minutes after discontinuation. Genomic DNA was genotyped for 91 single-nucleotide polymorphisms (SNP) in 2 candidate genes. We tested the association of patient characteristics and genotype with 5 pharmacokinetics (PK) parameters: elimination rate constant, ΔBNP, BNP clearance, adjusted BNP clearance, and half-life. Linear regression with pleiotropic analysis was used to test genotype associations with PK.ResultsParticipants' mean age was 63 years, 44% were female, and 46% were African American. PK parameters varied widely, some >10-fold. HF type (preserved vs reduced) was associated with PK (P < .01), whereas renal function, demographics, and body mass index and were not. Two SNPs in MME (rs989692, rs6798179) and 2 in NPR3 (rs6880564, rs2062708) also had associations with PK (P < .05).ConclusionsThe pharmacokinetics of BNP varies greatly in HF patients, differs by HF type, and possibly by MME or NPR3 genotype. Additional study is warranted.