Combined Angiotensin Receptor–Neprilysin Inhibitors Improve Cardiac and Vascular Function Via Increased NO Bioavailability in Heart Failure

Abstract

BackgroundThere is a paucity of data about the mechanisms by which sacubitril/valsartan (also known as LCZ696) improves outcomes in patients with heart failure. Specifically, the effects of sacubitril/valsartan on vascular function and NO bioavailability have not been investigated. We hypothesized that sacubitril/valsartan therapy increases circulating NO levels and improves vascular function in the setting of heart failure.Methods and ResultsMale spontaneously hypertensive rats underwent myocardial ischemia/reperfusion surgery to induce heart failure and were followed for up to 12 weeks with serial echocardiography. Rats received sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), or vehicle starting at 4 weeks after reperfusion. At 8 or 12 weeks of reperfusion, animals were euthanized and tissues were collected for ex vivo analyses of NO bioavailability, aortic vascular reactivity, myocardial and vascular histology, and cardiac molecular assays. Left ventricular structure and function were improved by both valsartan and sacubitril/valsartan compared with vehicle. Sacubitril/valsartan resulted in superior cardiovascular benefits, as evidenced by sustained improvements in left ventricular ejection fraction and end‐diastolic pressure. Ex vivo vascular function, as measured by aortic vasorelaxation responses to acetylcholine and sodium nitroprusside, was significantly improved by valsartan and sacubitril/valsartan, with more sustained improvements afforded by sacubitril/valsartan. Furthermore, myocardial NO bioavailability was significantly enhanced in animals receiving sacubitril/valsartan therapy.ConclusionsSacubitril/valsartan offers superior cardiovascular protection in heart failure and improves vascular function to a greater extent than valsartan alone. Sacubitril/valsartan‐mediated improvements in cardiac and vascular function are likely related to increases in NO bioavailability and explain, in part, the benefits beyond angiotensin receptor blockade.

LCZ696 Therapy Reduces Ventricular Tachyarrhythmia Inducibility in a Myocardial Infarction-Induced Heart Failure Rat Model

“…In this study, we demonstrated that both enalapril and LCZ696 improved LVEF and that LCZ696 therapy led to a greater effect on LVEF. As compared with enalapril therapy, the additional effects of LCZ696 may be attributed to inhibition of cardiac fibrosis [15], suppression of proinflammatory cytokine [16], and enhancement of nitric oxide (NO) bioavailability [17]. In a report by von Lueder et al, LCZ696 therapy reduced degree of fibrosis in noninfarct remote myocardium in the peri-infarct zone [15].…”

Hydrogen Sulfide Attenuates Renin Angiotensin and Aldosterone Pathological Signaling to Preserve Kidney Function and Improve Exercise Tolerance in Heart Failure

“…Vascular function was measured in isolated segments (3 mm in length) of thoracic aorta as previously described (27) at 18 weeks following TAC in all study groups. Vascular rings were equilibrated for 60 min and then pre-contracted with phenylephrine (1 μM).…”

Differential Effects of Sacubitril/Valsartan on Diastolic Function in Mice With Obesity-Related Metabolic Heart Disease

“…Relatively little is known about the effects of SAC/VAL on diastolic function, and in particular, about the effects on diastolic function in MHD or models of HFpEF. In 1 study, SAC/VAL improved LV relaxation in spontaneously hypertension rats with heart failure induced by myocardial ischemia/reperfusion ( 22 ).…”