Abstract P421: The Effects of Dual Angiotensin Receptor and Neprilysin Inhibitor on Organoprotection in Experimental Model of Chronic Heart Failure

Abstract

The cardiac effects of dual angiotensin receptor and neprilysin inhibitor (LCZ696) as a novel therapeutic approach for inhibition of renin-angiotensin system was assessed in volume overload-induced chronic heart failure (CHF) in hypertensive Ren2 transgenic rats (TGR) with aorto-caval fistula (ACF) and compared with valsartan (VAL). CHF model was induced by ACF in male TGR at 8 weeks of age. After 5 weeks of ACF induction, LCZ696 was administered in standard dosing at 68 mg/kg/day and VAL at 31 mg/kg/day for next 15 weeks to assess the effect on mortality. In second series, 12 weeks after ACF, the animals were anaesthetized and echocardiography was performed using a 7.5 MHz probe (Vivid 7, GE) to determine left ventricular internal dimensions (LVIDd), fractional shortening (FS) and stroke volume (SV). Animals were euthanized to determine heart weight and left ventricular mass (LVm). Untreated ACF group displayed 100 % mortality till 17 weeks after ACF induction. On the other hand, LCZ696-treated ACF TGR exhibited only 12 % mortality at the end of experiment. Valsartan also markedly reduce mortality in these animals to 21 %. In comparison to intact animals, ACF significantly increased LVIDd (10,2 ± 1,1 vs. 7,6 ± 0,4 mm). Only LCZ significantly lowered LVIDd in ACF TGR (8,2 ± 0,7 mm). We also observed significantly altered ventricular function in ACF group compared to intact TGR: FS 37 ± 5 vs. 53 ± 4 % and SV 763 ± 124 vs. 395 ± 36 ml/beat. There was a significant improvement of the left ventricular function in both treated groups, where FS was increased in ACF LCZ (52 ± 4 %) or in ACF VAL (47 ± 3 %) and SV significantly decreased in LCZ (509 ± 62 ml/beat) and ACF VAL (591 ± 78 ml/beat). Compared to untreated ACF group, the LVm was significantly reduced in ACF LCZ (1958 ± 97 vs. 1697 ± 69 mg). We did not observe any adverse effect during the treatments with VAL or LCZ confirming the safety of these drugs in this model. LCZ696 treatment resulted in significant reverse left ventricular remodeling. However, we did not observe any additional effects of treatment on cardiac function with LCZ696 compared to VAL in short term follow-up. Prolonged treatment period is advised to verify possible cardioprotective benefits of LCZ696 in this model.