Abstract 14985: Enhanced Angiotensin-(1-7) Positive Modulation on Left Ventricular Functional Performance in Conscious Dog With Pacing-Induced Heart Failure: Assessment by Pressure-Volume Analysis
Background: Angiotensin1-7 [A-(1-7)] opposes various actions of angiotensin II (AII) and has emerged as a key protective pathway against heart failure (HF). However, its effect on LV contractility is unclear. We previously demonstrated that in HF, AII decreases LV contractility. Whether A-(1-7) might antagonize AII-induced cardiac depression, thereby contributing to its cardioprotection in HF remains undefined. We assessed the hypothesis that A-(1-7) may enhance LV contraction and relaxation, independent of loading conditions in HF.
Methods: We studied the responses to A-(1-7) (600 ng/kg plus 150 ng/kg/min, iv) administration in 8 instrumented conscious dogs before and after pacing-induced HF.
Results: Compared with normal, after HF, not only the basal circulating A-(1-7) were significantly higher, A-(1-7) infusion also resulted greater increase in plasma levels of A-(1-7) (Normal: 175.6 vs 4.4 pg/ml; HF: 267.4 vs 23.4 pg/ml). A-(1-7) caused no changes in heart rate, but significantly decreased LV end-systolic pressure (PES) in both normal and HF. Prior to HF, A-(1-7) had no direct effects on LV contractility (EES, 6.6 vs 6.9 mmHg/ml) and the time constant of LV relaxation (τ, 27.5 vs 26.6 ms). In contrast, after HF, A-(1-7) significantly decreased LV end-diastolic pressure (P) (39.0 vs 42.3 mmHg), end-diastolic volume (V), arterial elastance (EA, 6.2 vs 8.8 mmHg/ml) and τ (34.2 vs 38.9 ms), but increased stroke volume. Importantly, A-(1-7) augmented LV contractility with significantly increased EES (5.2 vs 4.3 mmHg/ml) and MSW (60.9 vs 54.8 mmHg). LV-arterial (A) coupling, EES/EA (0.54 vs 0.42) improved. The mechanical efficiency quantitated as the ratio of stroke work and total P-V area also improved (0.50 vs 0.41). These effects were not modified with autonomic blockade, but were prevented by an A-(1-7) selective antagonist, A-779 (6 μg/kg, iv.).
Conclusions: Before HF, levels of A-(1-7) seen with ACE-inhibition have no direct cardiac effects. After HF, A-(1-7) antagonizes AII-induced cardiac depression. A-(1-7) produces arterial vasodilatation, improves LV relaxation, LV contractility, LV-A coupling, and mechanical efficiency. This study provides new evidence for a critical counter-regulatory role of A-(1-7) on the activated RAS in HF.
Author Disclosures: X. Zhang: None. A. Morimoto: None. H. Cheng: None. T. Li: None. N. Ohte: None. D.M. Herrington: None. C. Cheng: None.
- © 2016 by American Heart Association, Inc.