Abstract 309: Long-Term Therapy with Ivabradine Increases ACE-2 Activity in Left Ventricular Myocardium of Dogs with Chronic Heart Failure
Background: Angiotensin converting enzyme 2 (ACE2) is a homolog of ACE. ACE2 removes the terminal amino-acid from angiotensin-II (Ang II) to form Ang(1-7) which antagonizes the effects of Ang-II by activating the Mas receptor. We showed that ivabradine (IVA), a novel inhibitor of the cardiac pacemaker current If, improves left ventricular (LV) function and prevents progressive LV remodeling in dogs with microembolization-induced heart failure (HF). Because RAAS system overactivity contributes to the progression of HF, we assessed changes in Ang-II level and ACE and ACE2 activity in LV of dogs treated with IVA.
Methods: Studies were performed in LV tissue from 24 HF dogs randomized to 3 months therapy with high dose (HD) IVA (30 mg twice daily, n=8), low dose (LD) IVA (15 mg twice daily, n=8) or to no therapy at all (Control, CON, n=8). LV tissue from 6 normal (NL) dogs was used for comparison. A fluorogenic peptide, captopril (ACE inhibitor) and DX600 (ACE2 inhibitor) were used to quantify the activity of ACE and ACE2 in LV homogenate. Activity was expressed as fluorescence unit (FU)/μ g protein/hour. Ang II level was determined by ELISA.
Results: IVA reduced heart rate (HR) and significantly increased LV ejection fraction in a dose-dependent manner. Ang II level and ACE and ACE2 activities were up-regulated in HF CON compared to NL dogs. Compared to CON, treatment with IVA reduced ACE activity and Ang II level but increased ACE2 activity in a dose-dependent manner (Table).
Conclusions: In dogs with HF, therapy with IVA reduces activation of ACE and Ang II level but increases activation of ACE2. The latter may contribute to the observed beneficial effects of IVA on LV function and remodeling in HF.
- © 2012 by American Heart Association, Inc.