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

Leanne Dumeny, Orly Vardeny, Frank Edelmann, Burkert Pieske, Julio D. Duarte, Larisa H. Cavallari

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)978-987
Number of pages10
Issue number12
StatePublished - Dec 2021
Externally publishedYes

Bibliographical note

Funding Information:
We would like to acknowledge Shitalben Patel for her work on the PIIINP radioimmunoassay. This work was supported by the National Institutes of Health [F31HL154563 and K23GM112014]. Effort by LHC was supported in part by NIH grant UL1 TR001427. Aldo‐DHF was funded by the Federal Ministry of Education and Research (grant no. 01GI0205) [Clinical trial program Aldo‐DHF (FKZ 01KG0506)].

Publisher Copyright:
© 2021 Pharmacotherapy Publications, Inc.


  • aldosterone receptor antagonists
  • diastolic
  • heart failure
  • pharmacogenetics
  • spironolactone


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