Changes in mid-regional pro-adrenomedullin during treatment with sacubitril/valsartan

Eur J Heart Fail. 2023 Aug;25(8):1396-1405. doi: 10.1002/ejhf.2957. Epub 2023 Jul 11.


Aims: Adrenomedullin is a vasodilatory peptide with a role in microcirculatory and endothelial homeostasis. Adrenomedullin is a substrate for neprilysin and may therefore play a role in beneficial effects of sacubitril/valsartan (Sac/Val) treatment.

Methods and results: Mid-regional pro-adrenomedullin (MR-proADM) was measured in 156 patients with heart failure with reduced ejection fraction (HFrEF) treated with Sac/Val and 264 patients with heart failure with preserved ejection fraction (HFpEF) randomized to treatment with Sac/Val or valsartan. Echocardiography and Kansas City Cardiomyopathy Questionnaire results were collected at baseline and after 6 and 12 months in the HFrEF cohort. Median (Q1-Q3) baseline MR-proADM concentrations were 0.80 (0.59-0.99) nmol/L in HFrEF and 0.88 (0.68-1.20) nmol/L in HFpEF. After 12 weeks of treatment with Sac/Val, MR-proADM increased by median 49% in HFrEF and 60% in HFpEF, while there were no significant changes in valsartan-treated patients (median 2%). Greater increases in MR-proADM were associated with higher Sac/Val doses. Changes in MR-proADM correlated weakly with changes in N-terminal pro-B-type natriuretic peptide, cardiac troponin T and urinary cyclic guanosine monophosphate. Increases in MR-proADM were associated with decreases in blood pressure, but not significantly associated with changes in echocardiographic parameters or health status.

Conclusions: MR-proAD concentrations rise substantially following treatment with Sac/Val, in contrast to no change from valsartan. Change in MR-proADM from neprilysin inhibition did not correlate with improvements in cardiac structure and function or health status. More data are needed regarding the role of adrenomedullin and its related peptides in the treatment of heart failure.

Clinical trial registration: PROVE-HF Identifier: NCT02887183, PARAMOUNT Identifier: NCT00887588.

Keywords: Angiotensin receptor-neprilysin inhibitors; Biomarker; MR-proADM; Neprilysin; Sacubitril/valsartan.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenomedullin
  • Aminobutyrates / therapeutic use
  • Angiotensin Receptor Antagonists / therapeutic use
  • Biphenyl Compounds / therapeutic use
  • Drug Combinations
  • Heart Failure* / diagnostic imaging
  • Heart Failure* / drug therapy
  • Humans
  • Microcirculation
  • Neprilysin
  • Stroke Volume / physiology
  • Tetrazoles / therapeutic use
  • Valsartan / therapeutic use


  • sacubitril
  • Adrenomedullin
  • Neprilysin
  • Tetrazoles
  • Angiotensin Receptor Antagonists
  • Valsartan
  • Aminobutyrates
  • Biphenyl Compounds
  • Drug Combinations

Associated data