الفهرس 
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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.