Gradual reactivation over time of vascular tissue angiotensin I to angiotensin II conversion during chronic lisinopril therapy in chronic heart failure

OBJECTIVES This study was designed to fully characterize vascular tissue angiotensin I (AI)/angiotensin II (AII) conversion changes over time in vivo in humans during chronic angiotensin-converting enzyme (ACE) inhibitor therapy. BACKGROUND Plasma AII does not remain fully suppressed during chronic ACE inhibitor therapy. However, the plasma renin angiotensin system (RAS) might be dissociated from the vascular tissue RAS. We therefore set out to characterize the time course of vascular RAS reactivation during chronic ACE inhibitor therapy. METHODS Vascular AI/AII conversion was studied in patients with chronic heart failure (CHF) taking chronic lisinopril therapy by the differential infusion of AI and AII into the brachial artery. A cross-sectional study was done to see whether there were differences in vascular AI/AII conversion according to New York Heart Association (NYHA) class. A second longitudinal study followed 28 patients with NYHA I to II CHF serially over 18 months to see whether vascular ACE inhibition was progressively lost with time despite ACE inhibitor therapy. A third study examined whether increasing the dose of lisinopril affected subsequent vascular ACE inhibition. RESULTS In the cross-sectional study, vascular AI-to-AII conversion was significantly reduced in NYHA class III compared with class I/II (p < 0.05). In the longitudinal study, vascular ACE inhibition was significantly reduced at 18 months as compared with baseline (p < 0.001), suggesting gradual reactivation of vascular ACE in CHF over time. In the third study, tissue ACE inhibition could be restored by increasing the ACE inhibitor dose. CONCLUSIONS Vascular AI/AII conversion reactivates over time during chronic ACE inhibitor therapy even if the CHF disease process is clinically stable. It also occurs as the CHF disease process progresses. Even if vascular AI/AII conversion has reactivated, it can be suppressed by increasing the dose of the ACE inhibitor.