Entresto is a combination medication used to treat chronic heart failure with reduced ejection fraction (HFrEF). This condition occurs when the heart muscle is weakened and cannot pump sufficient blood to meet the body’s metabolic needs. Entresto is designed to counter the hormonal imbalances that drive the progression of this disease. By modulating the body’s natural regulatory systems, this pharmacological strategy alleviates chronic strain on the failing heart muscle, aiming to improve cardiac function and reduce serious outcomes.
Understanding the Body’s Hormonal Balance
In heart failure, the body activates the Renin-Angiotensin-Aldosterone System (RAAS), a powerful survival mechanism. While meant for short-term response, chronic RAAS activation is maladaptive. The final product, Angiotensin II, is a potent vasoconstrictor that narrows blood vessels, increasing blood pressure and the heart’s workload.
Angiotensin II promotes the retention of salt and water, increasing the volume of blood the weakened heart must pump. Aldosterone further promotes sodium and water retention. Chronic RAAS activation also triggers harmful cardiac remodeling, leading to the irreversible thickening and scarring of the heart muscle.
Counterbalancing the RAAS are beneficial hormones, primarily the Natriuretic Peptides (NPs), such as B-type Natriuretic Peptide (BNP). These peptides are released by the heart in response to stretching or volume overload. NPs oppose the RAAS by inducing vasodilation, which relaxes blood vessels and lowers blood pressure. They also promote natriuresis—the excretion of sodium and water by the kidneys—reducing fluid volume and pressure.
Valsartan’s Action: Blocking the Harmful Pathway
The valsartan component of Entresto is an Angiotensin Receptor Blocker (ARB). Valsartan targets the effects of Angiotensin II, the primary effector of the overactive RAAS. The drug occupies and blocks the Angiotensin II type 1 (AT1) receptors found on cells in the blood vessels and the heart.
Blocking these receptors prevents Angiotensin II from binding and initiating its signaling cascade. This action stops the downstream effects that lead to increased blood pressure and fluid retention. The physiological result is a relaxation of the blood vessels and a reduction in systemic vascular resistance.
This decreased resistance makes it easier for the heart to eject blood, lowering the strain on the failing muscle. Preventing chronic AT1 receptor stimulation also mitigates harmful cardiac remodeling. This inhibition slows the deposition of scar tissue within the heart muscle, preserving cardiac structure and function.
Sacubitril’s Action: Protecting the Beneficial Hormones
The novel aspect of Entresto is sacubitril, which targets the enzyme neprilysin. Neprilysin is a neutral endopeptidase responsible for the degradation of various vasoactive peptides. Its natural function includes metabolizing the beneficial Natriuretic Peptides (NPs), limiting their protective effects on the cardiovascular system.
Sacubitril is a prodrug metabolized into its active form, LBQ657, a potent neprilysin inhibitor. By blocking this enzyme, the drug prevents the rapid destruction of the NPs released by the heart. This inhibition leads to a sustained increase in circulating NP concentration, enhancing their protective effects.
The elevated NP levels stimulate increased vasodilation, relaxing the arteries and veins. Increased NP activity also promotes natriuresis and diuresis, enhancing the excretion of salt and water by the kidneys. This reduction in fluid volume decreases venous return to the heart, lowering the pressure and volume overload that stresses the weakened ventricles.
The Dual Mechanism: Achieving Synergistic Effect
Entresto is classified as an Angiotensin Receptor-Neprilysin Inhibitor (ARNI), reflecting its unique dual mechanism. The simultaneous use of sacubitril and valsartan is necessary due to the complex pathways involved. Inhibiting neprilysin alone would be counterproductive, as neprilysin also degrades Angiotensin II.
Blocking neprilysin alone would cause an undesirable rise in Angiotensin II levels, potentially overwhelming the beneficial effects of the preserved peptides. Valsartan is mandatory because it blocks the AT1 receptors, neutralizing any increase in Angiotensin II. This combination creates a powerful synergistic effect.
The valsartan component brakes the harmful, overactive RAAS, while sacubitril accelerates the beneficial Natriuretic Peptide system. This comprehensive hormonal modulation addresses the core pathophysiology of heart failure from two opposing directions. This dual action leads to enhanced fluid volume management, lower systemic blood pressure, and a reduction in chronic stress on the heart muscle. The combined impact results in better long-term outcomes, including decreased hospitalizations and improved survival rates for patients with HFrEF.