Differential Cardiac Effects of an AT1R Biased Ligand, AT1R Antagonist and ACE Inhibitor in Mouse Models of Post-Myocardial Infarction Heart Failure

Introduction: Stimulation of the renin-angiotensin-system plays a fundamental role in heart failure (HF) pathophysiology. Angiotensin II (Ang II) stimulates multiple signaling pathways via AT1 receptors that mediate both deleterious and beneficial responses. AT1R antagonists (ARB) and inhibition of Ang II production by ACE inhibitors (ACEi) are the current standard of care for patients with HF post myocardial infarction (MI). Methods and Results: In these studies, we compared the activity of an AT1R biased agonist peptide (TRV-120027), an ARB (valsartan) and an ACEi (enalapril) on cardiac function in mouse models of MI induced by permanent ligation of the left anterior descending coronary artery in C57BL/6 mice. In vitro activity of TRV-120027 was confirmed in CHO cells expressing the mouse AT1R. Both Ang II and TRV-120027 potently stimulated β-arrestin accumulation (EC50 = 0.25 ± 0.05 nM and 0.38 ± 0.07 nM, respectively). Ang II stimulated IP1 accumulation with an EC50 = 1.04 ± 0.17 nM. TRV-120027 did not stimulate IP1 accumulation to an appreciable degree but completely blocked Ang II- dependent IP1 accumulation. The ARB displayed no agonistic activity at the mAT1R but completely inhibited both Ang II-dependent β-arrestin recruitment and IP1 accumulation. Test compounds were administered to mice via subcutaneous osmotic mini-pumps, and cardiac function and hemodynamics was assessed under isoflurane anesthesia by echocardiography and intra-arterial/left ventricular (LV) catheter, respectively. In an acute HF model, animals were randomized to either vehicle or valsartan (30 mg/kg/day) administered 24 hours post MI for 2 weeks. Compared to vehicle, administration of valsartan reduced heart weight (LV mass: 129.2 ± 7.2 vs. 94.3 ± 6.5 mg, P < .05) and cardiac output (CO: 31.2 ± 2.0 vs. 22.7 ± 1.4 ml/min, P < .05). In a more chronic HF model, animals were randomized to either vehicle, enalapril (20 mg/kg/day) or TRV-120027 (9.8 and 28.8 mg/kg/day) administered 7 days post MI for 6 weeks. Chronic treatment with enalapril reduced LV mass and CO (35.3 ± 1.8 vs. 22.4 ± 1.9 ml/min, P < .05). TRV-120027 at the low dose reduced LV mass and CO (35.3 ± 1.8 vs. 28.5 ± 2.2 ml/min, P < .05) to a lesser extent than enalapril, whereas TRV-120027 at the high dose maintained LV mass and CO accompanied with a trend to increase cardiac contractility. Following 6 weeks of treatment, TRV-120027 reduced blood pressure (BP) to a lesser degree than enalapril (P < .05). Conclusion: In summary, these results suggest that an AT1R biased agonist has a more favorable cardiac and hemodynamic profile (preserved CO and less BP lowering) than an ARB or ACEi in mouse models of acute and chronic HF post MI.