Chronic Therapy with Sacubitril/Valsartan Reduces Plasma Troponin-I Level in Dogs with Experimentally-Induced Cardiorenal Syndrome

Abstract

Introduction Ongoing loss of cardiomyocytes occurs in heart failure (HF) and contributes to progressive worsening of the HF state. Sacubitril/Valsartan (S/Val), a combined angiotensin-II receptor blocker (Val) and neprilysin inhibitor (S) in a 1:1 molar ratio, was shown to reduce the risk of cardiovascular death or HF hospitalization in patients with HF and reduced left ventricular (LV) ejection fraction (EF). Chronic therapy with S/VAL was also shown to improve LV systolic function in dogs with experimentally-induced cardiorenal syndrome. Objective This study tested the hypothesis that chronic therapy with S/Val in dogs with cardiorenal syndrome ameliorates ongoing loss of cardiomyocytes as evidenced by lowering plasma levels of troponin-I (TnI). Methods 14 dogs with coronary microembolization-induced HF and renal dysfunction induced by unilateral nephrectomy with imposed stenosis of the contralateral renal vein, were randomized to 3 months therapy with S/Val (100 mg once daily, n=7) or no therapy (control, CON, n=7). LV EF was measured before (PRE) and at 12 weeks after initiating therapy with S/Val (POST). High sensitivity plasma TnI was measured when animals were normal (NL) and again after induction of cardiorenal syndrome and subsequently at 2, 4, and 12 weeks after initiating S/Val therapy. TnI levels were determined using a commercially available Ultra-Sensitive Dog Cardiac Troponin-I Elisa kit and the concentration was expressed in ng/ml. Results In CON dogs, LV EF was unchanged from PRE to POST (35 ± 1 vs. 36 ± 1 %) but increased significantly from PRE to POST in S/Val-treated dogs (34 ± 1 vs. 41 ± 2 %, p Table ) and remained elevated throughout the follow-up period. In contrast, in S/Val-treated dogs, TnI levels decreased gradually during the therapy period ( Table ). Conclusions In dogs with cardiorenal syndrome, S/Val reduces plasma TnI levels compared to untreated CON. This observations suggests that chronic therapy with S/Val attenuates or prevents ongoing loss cardiomyocytes, a characteristic feature of the HF state.