Effects of Angiotensin-Neprilysin Inhibition in Canines with Experimentally-Induced Cardiorenal Syndrome

BACKGROUND: Sacubitril/Valsartan (Sac/Val), a combined angiotensin-II receptor blocker (Val) and neprilysin inhibitor (Sac) in a 1:1 molar ratio, was shown to reduce the risk of cardiovascular death or heart failure (HF) hospitalization in patients with HF and reduced LV ejection fraction (EF). This study examined the effects of Sac/Val on LV structure, function and bioenergetics and on biomarkers of kidney injury and kidney function in dogs with experimental cardiorenal syndrome (CRS).METHODS AND RESULTS: 14 dogs with CRS (coronary microembolization-induced HF and renal dysfunction) were randomized to 3 months Sac/Val therapy (100 mg once daily, n=7) or no therapy (control, n=7). LV EF and troponin-I (TnI) as well as biomarkers of kidney injury/function including serum creatinine (sCr) and urinary kidney injury molecule-1 (KIM-1) were measured before and at end of therapy and the change (treatment effect Δ) calculated. Mitochondrial function measures including maximum rate of ATP synthesis (ATPsyn) were measured in isolated cardiomyocytes at end of therapy. In Sac/Val dogs, ΔEF increased compared to controls (6.9±1.4 vs. 0.7±0.6 %, p<0.002) while ΔTnI decreased (-0.16±0.03 vs. -0.03±0.02 ng/ml, p<0.001). Urinary ΔKIM-1 decreased in Sac/Val treated dogs compared to controls (-17.2±7.9 vs. 7.7±3.0 mg/ml, p<0.007) whereas ΔsCr was not significantly different. Treatment with Sac/Val increased ATPsyn compared to control (3,240±121 vs. 986±84 RLU/µg protein, p<0.05).CONCLUSIONS: In dogs with CRS, Sac/Val improves LV systolic function, improves mitochondrial function and decreases biomarkers of heart and kidney injury. The results offer mechanistic insights into the benefits of Sac/Val in HF with compromised renal function.