Myocardial Angiotensin Metabolism in End-Stage Heart Failure

Noemi Pavo, Suriya Prausmüller, Georg Spinka, Georg Goliasch, Philipp E Bartko, Raphael Wurm, Henrike Arfsten, Guido Strunk, Marko Poglitsch, Oliver Domenig, Julia Mascherbauer, Keziban Uyanik-Ünal, Christian Hengstenberg, Andreas Zuckermann, Martin Hülsmann

Research output: Journal article (peer-reviewed)Journal article

15 Citations (Scopus)

Abstract

BACKGROUND: The myocardium exhibits an adaptive tissue-specific renin-angiotensin system (RAS), and local dysbalance may circumvent the desired effects of pharmacologic RAS inhibition, a mainstay of heart failure with reduced ejection fraction (HFrEF) therapy.

OBJECTIVES: This study sought to investigate human myocardial tissue RAS regulation of the failing heart in the light of current therapy.

METHODS: Fifty-two end-stage HFrEF patients undergoing heart transplantation (no RAS inhibitor: n = 9; angiotensin-converting enzyme [ACE] inhibitor: n = 28; angiotensin receptor blocker [ARB]: n = 8; angiotensin receptor neprilysin-inhibitor [ARNi]: n = 7) were enrolled. Myocardial angiotensin metabolites and enzymatic activities involved in the metabolism of the key angiotensin peptides angiotensin 1-8 (AngII) and Ang1-7 were determined in left ventricular samples by mass spectrometry. Circulating angiotensin concentrations were assessed for a subgroup of patients.

RESULTS: AngII and Ang2-8 (AngIII) were the dominant peptides in the failing heart, while other metabolites, especially Ang1-7, were below the detection limit. Patients receiving an ARB component (i.e., ARB or ARNi) had significantly higher levels of cardiac AngII and AngIII (AngII: 242 [interquartile range (IQR): 145.7 to 409.9] fmol/g vs 63.0 [IQR: 19.9 to 124.1] fmol/g; p < 0.001; and AngIII: 87.4 [IQR: 46.5 to 165.3] fmol/g vs 23.0 [IQR: <5.0 to 59.3] fmol/g; p = 0.002). Myocardial AngII concentrations were strongly related to circulating AngII levels. Myocardial RAS enzyme regulation was independent from the class of RAS inhibitor used, particularly, a comparable myocardial neprilysin activity was observed for patients with or without ARNi. Tissue chymase, but not ACE, is the main enzyme for cardiac AngII generation, whereas AngII is metabolized to Ang1-7 by prolyl carboxypeptidase but not to ACE2. There was no trace of cardiac ACE2 activity.

CONCLUSIONS: The failing heart contains considerable levels of classical RAS metabolites, whereas AngIII might be an unrecognized mediator of detrimental effects on cardiovascular structure. The results underline the importance of pharmacologic interventions reducing circulating AngII actions, yet offer room for cardiac tissue-specific RAS drugs aiming to limit myocardial AngII/AngIII peptide accumulation and actions.

Original languageEnglish
Pages (from-to)1731-1743
Number of pages13
JournalJournal of the American College of Cardiology
Volume77
Issue number14
DOIs
Publication statusPublished - 13 Apr 2021

Keywords

  • Angiotensin I/blood
  • Angiotensin II/blood
  • Angiotensin Receptor Antagonists/pharmacology
  • Angiotensin-Converting Enzyme Inhibitors/pharmacology
  • Disease Progression
  • Female
  • Heart Failure/drug therapy
  • Heart Transplantation/methods
  • Humans
  • Male
  • Mass Spectrometry/methods
  • Middle Aged
  • Myocardium/enzymology
  • Peptide Fragments/blood
  • Renin-Angiotensin System/drug effects
  • Stroke Volume/drug effects
  • heart failure
  • angiotensin receptor neprilysin inhibition
  • RAS
  • ARNI
  • renin
  • angiotensin
  • renin-angiotensin system

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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