NR3C2 genotype is associated with response to spironolactone in diastolic heart failure patients from the Aldo‐DHF trial

Abstract Study Objective This study aimed to determine if variants in NR3C2 , which codes the target protein of spironolactone, or CYP11B2 , which is involved in aldosterone synthesis, were associated with spironolactone response, focused on the primary end point of diastolic function (E/e′), in Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo‐DHF) participants. Design Post‐hoc genetic analysis. Data Source Data and samples were derived from the multi‐center, randomized, double‐blind, placebo‐controlled Aldo‐DHF trial. Patients Aldo‐DHF participants treated with spironolactone ( n = 184) or placebo ( n = 178) were included. Intervention Participants were genotyped for NR3C2 rs5522, NR3C2 rs2070951 and CYP11B2 rs1799998 via pyrosequencing. Measurements In the placebo and spironolactone arms, separate multivariable linear regression analyses were performed for change in E/e′ with each single nucleotide polymorphism (SNP), adjusted for age, sex, and baseline E/e′. To discern potential mechanisms of a genotype effect, associated SNPs were further examined for their association with change in blood pressure, circulating procollagen type III N‐terminal peptide (PIIINP), and left atrial area. Main Results Carriers of the rs5522 G allele in the placebo arm had a greater increase in E/e′ over the 12‐month course of the trial compared to noncarriers (β = 1.10; 95% confidence interval CI: 0.05–2.16; p = 0.04). No corresponding E/e′ worsening by rs5522 genotype was observed in the spironolactone arm. None of the other genotypes were associated with change in E/e′. Compared to noncarriers, rs5522 G carriers also had a greater increase in left atrial area with placebo (β = 0.83; 95% CI: 0.17–1.48; p = 0.01) and a greater reduction in diastolic blood pressure with spironolactone (β = −3.56; 95% CI: −6.73 to −0.39; p = 0.03). Serum PIIINP levels were similar across rs5522 genotypes. Conclusions Our results suggest that spironolactone attenuates progression of diastolic dysfunction associated with the NR3C2 rs5522 G allele. Validation of our findings is needed.