title: Effects of angiotensin-converting-enzyme inhibitor therapy on the regulation of the plasma and cardiac tissue renin-angiotensin system in heart transplant patients.
abstract: BACKGROUND
  Angiotensin-converting enzyme (ACE) inhibitors (ACEis) are beneficial in patients with heart failure, yet their role after heart transplantation (HTx) remains ambiguous. Particularly, the effects of ACEis on plasma and cardiac metabolites of the "classical" and "alternative" renin-angiotensin system (RAS) in HTx patients are unknown.
  
  
  METHODS
  This cross-sectional study used a novel mass spectrometry-based approach to analyze plasma and tissue RAS regulation in homogenates of heart biopsy specimens from 10 stable HTx patients without RAS blockade and in 15 patients with ACEi therapy. Angiotensin (Ang) levels in plasma and Ang formation rates in biopsy tissue homogenates were measured.
  
  
  RESULTS
  Plasma Ang II formation is exclusively ACE dependent, whereas cardiac Ang II formation is primarily chymase dependent in HTx patients. ACEi therapy substantially increased plasma Ang-(1-7), the key effector of the alternative RAS, leaving plasma Ang II largely intact. Importantly, neprilysin and prolyl-carboxypeptidase but not angiotensin converting enzyme 2 are essential for cardiac tissue Ang-(1-7) formation.
  
  
  CONCLUSIONS
  ACE is the key enzyme for the generation of plasma Ang II, whereas chymase is responsible for cardiac tissue production of Ang II. Furthermore, our findings reveal that neprilysin and prolyl-carboxypeptidase are the essential cardiac enzymes for the alternative RAS after HTx. These novel insights into the versatile regulation of the RAS in HTx patients might affect future therapeutic avenues, such as chymase and neprilysin inhibition, beyond classical Ang II blockade.
authors: Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
authors: Johannes J
authors: JJ
authors: Kovarik
authors: Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
authors: Chantal
authors: C
authors: Kopecky
authors: Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
authors: Marlies
authors: M
authors: Antlanger
authors: Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
authors: Oliver
authors: O
authors: Domenig
authors: Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
authors: Christopher C
authors: CC
authors: Kaltenecker
authors: Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
authors: Johannes
authors: J
authors: Werzowa
authors: Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
authors: Manfred
authors: M
authors: Hecking
authors: Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria.
authors: Stephane
authors: S
authors: Mahr
authors: Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria.
authors: Martina
authors: M
authors: Grömmer
authors: Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
authors: Christoph
authors: C
authors: Wallner
authors: Department of Pathology, Medical University of Vienna, Vienna, Austria.
authors: Klaus
authors: K
authors: Aumayr
authors: Department of Pathology, Medical University of Vienna, Vienna, Austria.
authors: Renate
authors: R
authors: Kain
authors: Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria.
authors: Andreas
authors: A
authors: Zuckermann
authors: Attoquant Diagnostics GmbH, Vienna, Austria.
authors: Marko
authors: M
authors: Poglitsch
authors: Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria. Electronic address: marcus.saemann@meduniwien.ac.at.
authors: Marcus D
authors: MD
authors: Säemann
mesh_terms: D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D001317:Austria; D001707:Biopsy, Needle; D003430:Cross-Sectional Studies; D004452:Echocardiography; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D006333:Heart Failure / Q000097:blood* / Q000000981:diagnostic imaging / Q000601:surgery; D016027:Heart Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D012084:Renin-Angiotensin System / Q000187:drug effects*; D018570:Risk Assessment; D012380:Role; D016896:Treatment Outcome
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors
keywords: angiotensin-converting-enzyme; angiotensin-converting-enzyme inhibitors; chymase; heart transplantation; neprilysin; prolyl-carboxypeptidase; renin-angiotensin system