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Abstract Heart failure (HF) is a complex clinical syndrome that can occur due to various causes, including hypertension, coronary artery disease, valvular heart disease, diabetes, and obesity. The condition is characterized by a reduction in the heart’s ability to pump blood effectively, leading to symptoms such as shortness of breath, fatigue, and fluid retention. According to the World Health Organization, HF affects more than 26 million people globally, and its prevalence is projected to increase in the coming decades. In the United States alone, approximately 6.5 million adults have heart failure, with an estimated 960,000 new cases diagnosed each year. One of the key therapeutic targets for HF is the renin-angiotensinaldosterone system (RAAS), a complex hormonal system that regulates blood pressure and fluid balance in the body. The inhibition of this system with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) has been shown to improve outcomes in HF. However, the use of these agents is associated with limitations and side effects, leading to the development of novel agents with improved efficacy and tolerability. Broadly speaking, heart failure can be divided into heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). HFpEF occurs when the left ventricular ejection fraction (LVEF) is above 50%. HFrEF occurs when the left ventricular ejection fraction (LVEF) is 40% or less and is accompanied by progressive left ventricular dilatation and adverse cardiac remodeling. Patients with HF and an LVEF between the HFrEF and HFpEF range have been termed as “HF with mid-range EF,” or “HF with mildly reduced EF. Atrial function, in close interdependence with left ventricular (LV) function, plays a key role in maintaining an optimal cardiac performance. The left atrium (LA) modulates LV filling through its reservoir, conduit, and booster pump function, whereas LV function influences LA function throughout the cardiac cycle. The LA can react to increase LV filling pressure (in significant atrial disease). LA remodelling is related to LV remodelling, and LA function has a central role in maintaining optimal cardiac output despite impaired LV relaxation and reduced LV compliance. Sacubitril/valsartan (Entresto) is a novel medication approved by the US Food and Drug Administration (FDA) in 2015 for the treatment of HF with reduced ejection fraction (HFrEF). The drug is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an ARB. The combination of these agents provides dual inhibition of the RAAS and neprilysin pathways, leading to increased levels of natriuretic peptides and reduced levels of angiotensin II and aldosterone. This mechanism of action has been shown to improve hemodynamics, symptoms, and outcomes in patients with HFrEF. Sacubitril is a prodrug that is rapidly converted to its active metabolite, LBQ657, in the liver. LBQ657 is a potent inhibitor of neprilysin, an enzyme responsible for the degradation of natriuretic peptides, bradykinin, and other vasoactive peptides. By inhibiting neprilysin, sacubitril increases the levels of these peptides, leading to vasodilation, diuresis, and natriuresis. |