Atorvastatin Attenuates Atrial Remodeling by Its Anti-Oxidant and Anti-Inflammatory Action

Abstract

Introduction: Infusion of nesiritide (recombinant human B-type natriuretic peptide (BNP)) lowers blood pressure and may cause natriuresis, but these effects are highly variable between individuals. How much of this variability is genetic is unknown. Hypothesis: Genetic variants in BNP clearance mechanisms will affect drug elimination rate and may thus impact its clinical effects. Methods: Patients with heart failure (n537, 24 men, 19 African Americans) who received nesiritide infusion at standard doses (0.005-0.01 mcg/kg/min) were studied. Subjects were closely monitored during a 1 hour baseline period and a 2 hour infusion period. BNP levels were measured during the baseline and infusion periods, as was urine sodium (Na) excretion and mean arterial pressure (MAP). DNA was extracted from blood and genotyped for 71 sequence variants in membrane metallo-endopeptidase (MME) and natriuretic peptide receptor 3 (NPR3), the two key clearance mechanisms for BNP. Elimination rate constant (K) was calculated using the difference in BNP level from baseline to 2-hours of infusion (C), the infusion rate (k0), and the estimated volume of distribution (0.073 L/kg, V) according to the equation K5k0/(C*V). We first tested the association of NPR3 and MME genotypes (additive model) with K, then examined changes in Na excretion and MAP for variants of interest. P!0.01 was considered significant. Results: Two NPR3 sites, rs11749133 and rs16890196 were associated K (p50.0055, 0.0092, respectively) with O4 fold difference in K between homozygous genotype groups (median K 5 0.06 vs. 0.3 for AA vs. GG). These genotypes were also associated with differences in sodium excretion (p50.0017, 0.0096, respectively); While Na excretion declined overall with nesiritide, it was better preserved in the AA group (slower elimination) compared to GG group (rapid elimination) with median decline in Na excretion of 3,300meq/hr vs. 13,000meq/hr. There was no significant difference in MAP changes between genotype groups. Conclusions: This small pilot study suggests that NPR3 genotype affects BNP elimination, and possibly natriuresis during BNP infusion. Further investigation with larger cohorts is needed to illuminate genetic sources of variability in BNP response.