title: Roles of Angiotensin Peptides and Recombinant Human ACE2 in Heart Failure.
abstract: BACKGROUND
  The renin-angiotensin system (RAS) is activated in heart failure (HF) and inhibition of RAS is a mainstay therapy for HF. Angiotensin-converting enzyme 2 (ACE2) and its product, angiotensin 1-7 (Ang-[1-7]), are important negative regulators of the RAS.
  
  
  OBJECTIVE
  A comprehensive examination of angiotensin peptide levels and therapeutic effects of recombinant human ACE2 (rhACE2) on peptide metabolism was evaluated in human plasma and explanted heart tissue from patients with HF.
  
  
  METHODS
  Using prospective cohorts with chronic (n = 59) and acute (n = 42) HF, plasma angiotensin analysis was performed using a unique liquid chromatography-mass spectrometry/mass spectroscopy method quantifying circulating and equilibrium levels. Angiotensin II (Ang II) metabolism was examined in human explanted hearts with dilated cardiomyopathy (n = 25).
  
  
  RESULTS
  The dynamic range of the RAS was large, with equilibrium angiotensin levels being 8- to 10-fold higher compared with circulating angiotensin levels. In chronic HF patients receiving ACE inhibition, plasma Ang II was suppressed and plasma Ang-(1-7) was elevated, whereas acute HF and patients receiving angiotensin receptor blocker had higher plasma Ang II with lower Ang-(1-7) levels. Suppressed Ang-(1-7)/Ang II ratio was associated with worsening HF symptoms and longer hospitalization. Recombinant human ACE2 effectively metabolized Ang-(1-10) and Ang II into Ang-(1-9) and Ang-(1-7), respectively. Myocardial Ang II levels in explanted human hearts with dilated cardiomyopathy were elevated despite ACE inhibition with elevated chymase activity, and Ang II was effectively converted to Ang-(1-7) by rhACE2.
  
  
  CONCLUSIONS
  Plasma angiotensin peptides represent a dynamic network that is altered in HF and in response to rhACE2. An increased plasma Ang-(1-7) level is linked to ACE inhibitor use, whereas acute HF reduced Ang-(1-7) levels and suppressed the Ang-(1-7)/Ang II ratio. Increased chymase activity elevated Ang II levels in failing human hearts. Use of rhACE2 effectively normalized elevated Ang II while increasing Ang-(1-7) and Ang-(1-9) levels.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.affiliation: Attoquant Diagnostics, Vienna, Austria.
authors.forename: Marko
authors.initials: M
authors.lastname: Poglitsch
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
authors.forename: Haran
authors.initials: H
authors.lastname: Yogasundaram
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
authors.forename: Jissy
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Department of Emergency Medicine and School of Public Health, University of Alberta, Edmonton, Canada.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Rowe
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada. Electronic address: gavin.oudit@ualberta.ca.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000809:Angiotensins / Q000502:physiology*; D016022:Case-Control Studies; D002908:Chronic Disease; D005260:Female; D006333:Heart Failure / Q000097:blood* / Q000150:complications / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins
keywords: angiotensin II; angiotensin-(1–7); chymase; dilated cardiomyopathy; renin-angiotensin system