Molecular mechanisms of sacubitril/valsartan in cardiac remodeling

Abstract

Cardiovascular diseases have become a major clinical burden globally. Heart failure is one of the diseases that commonly emanates from progressive uncontrolled hypertension. This gives rise to the need for a new treatment for the disease. Sacubitril/valsartan is a new drug combination that has been approved for patients with heart failure. This review aims to detail the mechanism of action for sacubitril/valsartan in cardiac remodeling, a cellular and molecular process that occurs during the development of heart failure. Accumulating evidence has unveiled the cardioprotective effects of sacubitril/valsartan on cellular and molecular modulation in cardiac remodeling, with recent large-scale randomized clinical trials confirming its supremacy over other traditional heart failure treatments. However, its molecular mechanism of action in cardiac remodeling remains obscure. Therefore, comprehending the molecular mechanism of action of sacubitril/valsartan could help future research to study the drug’s potential therapy to reduce the severity of heart failure.

Clinical and Hemodynamic Improvement in Pulmonary Hypertension After Switching to Sacubitril/Valsartan in Patients With Heart Failure With Preserved Ejection Fraction

“…Presacubitril/valsartan RHC [performed on hospital day 1 (1-4)] showed significantly elevated PAP (systolic/diastolic/ mean) in both groups of pulmonary hypertension [IpcPH: 47 (40-55)/18 (15-23)/31 (26)(27)(28)(29)(30)(31)(32)(33)(34)(35) mm Hg; CpcPH: 61 (50-79)/ 24 (19-30)/40 mm Hg] (Figs. 1, 2).…”

“…In this context, the bestknown effect is related to the inhibition of BNP degradation by neprilysin, thereby reactivating the NO-pGC-cGMP-PKG signaling pathway, which induces natriuresis, diuresis, suppression of the renin-angiotensin-aldosterone system, and vasodilatory effects. 31,32 Importantly, reduced left ventricular filling pressures with a reduction in back transmission to the pulmonary vasculature can now be linked to a reduction in titin stiffness because the NO-pGC-cGMP-PKG pathway has been subcellular colocalized with the I-band, which houses the regulatory sites of titin. 10 Another important but neglected substrate of neprilysin is apelin, which has been shown to be involved in the regulation of both cardiac and vascular contractility and is known to be less expressed in endothelial cells from patients with pulmonary hypertension.…”

Signaling Pathways and Potential Therapeutic Strategies in Cardiac Fibrosis

“…Sacubitril/Valsartan treatment was well tolerated, and hypotension was the major observed adverse effect [ 159 , 160 , 161 , 162 ]. In heart failure patients, Sacubitril/Valsartan treatment was demonstrated to improve cardiac function and decrease myocardial hypertrophy, suggesting an effect on cardiac fibrosis [ 163 , 164 , 165 ]. There is a lack of proof concerning the effect of RNA interference (RNAi) treatment on cardiac fibrosis in the myocardium of patients.…”

Loop diuretic management after sacubitril/valsartan initiation in heart failure with preserved ejection fraction: deceptively simple or more than meets the eye?

“…Although the direct effects of sacubitril/valsartan appear to be haemodynamic and neurohormonal in nature, it is possible that the therapy's effects are more diverse than previously anticipated and could differ by HF subtype. Although sacubitril/valsartan consistently decreases myocardial fibrosis through regulation of the transforming growth factor (TGF)‐β1 signalling pathway in both murine models of HFpEF and HFrEF, 12 circulating proteomic analyses of human HF suggest differential responses to sacubitril/valsartan by HF subtype. In HFpEF, sacubitril/valsartan significantly altered 14 of 369 circulating proteins over 5 weeks, and 9 of these 14 proteins were reflecting of the TGF‐β signalling pathway 13 .…”