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.

Conclusion: 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.

Keywords: angiotensin-converting-enzyme; angiotensin-converting-enzyme inhibitors; chymase; heart transplantation; neprilysin; prolyl-carboxypeptidase; renin-angiotensin system.