INTRODUCTION

In the pathophysiology of chronic heart failure with reduced ejection fraction, neurohormonal regulation plays a fundamental role. The treatment of heart failure has been centered for decades on the inhibition of vasoconstrictive substances (renin-angiotensin-aldosterone system and sympathetic nervous system)^1-3, yielding good results in terms of reducing morbidity and mortality^4-8. However, the prognosis of heart failure remains poor, with persistently elevated rates of mortality and hospitalizations^9-11. Therefore, it has been important to explore the other side of the neurohormonal model, focusing on vasodilatory substances (natriuretic peptide system) and their potential benefit in the treatment of heart failure^12,13. The objective of this work is to review the main clinical studies focused on modulating the natriuretic peptide system as a treatment for chronic heart failure with reduced ejection fraction and its evolution over time, explaining the reasons for successive failures until the arrival of LCZ696.

SEARCH STRATEGY

From January to March 2021, a literature review was conducted on Pubmed, ScienceDirect, and Clinical Key. The search terms used were: heart failure, neprilysin, LCZ 696, and natriuretic peptides. Boolean operators AND and OR were employed. The review included narrative reviews, books, and clinical trials. There was no time limit imposed, as a historical review was necessary. Articles not focused on heart failure with reduced ejection fraction or its pathophysiology, as well as those not available in Spanish or English, were excluded. Titles and abstracts were reviewed, and a secondary search was performed using the bibliographic references of the included articles.

NEUROHORMONAL REGULATION IN HEART FAILURE

In the early stages of the pathophysiology of heart failure with reduced left ventricular systolic function, the activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system play a fundamental, compensatory, and beneficial role. These mechanisms, through vasoconstriction, lead to an increase in systemic vascular resistance, ensuring adequate perfusion to important organs despite the decrease in cardiac output. Additionally, they cause sodium and water retention, increasing preload and enhancing stroke volume through the Frank-Starling mechanism. However, prolonged vasoconstriction leads to well-known harmful effects, particularly at the level of the heart, kidneys, and vasculature, contributing to disease progression and a poor prognosis^1-3. Pharmacological strategies aimed at blocking the chronic activation of these two systems through angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, beta-blockers, and aldosterone antagonists have demonstrated a reduction in morbidity and mortality and are widely accepted^4-8.

THE NATRIURETIC PEPTIDE SYSTEM

In contrast to the adverse effects of these two systems, there is a third system, known as the natriuretic peptide system, which is composed of substances with predominantly vasodilatory function. These substances produce favorable effects such as increased natriuresis and diuresis, reduced sympathetic tone, decreased vasopressin and aldosterone activation, and decreased cardiac remodeling^2,3,12-14. (Figure 1)

Figure 1 Interaction of the natriuretic peptide system with the sympathetic nervous system and the renin-angiotensin-aldosterone system, and its counterregulatory effects on key organs. ACE = angiotensin converting enzyme; Ang = angiotensin; ANP = atrial natriuretic peptide; BNP = B-type natriuretic peptide; BP = blood pressure; NP = natriuretic peptide; RAAS = renin-angiotensin-aldosterone system; SNS = sympathetic nervous system.(Adapted from Volpe M. Natriuretic peptides and cardio-renal disease. Int J Cardiol. 2014;176(3):630-9). 

The most important ones are atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). ANP is stored in the atrium and is released in response to atrial distension. BNP, on the other hand, is only produced in abnormal states of ventricular hemodynamic stress, as seen in heart failure. In the endothelium, C-type natriuretic peptide (CNP) is produced, which has a limited natriuretic effect but plays a significant role in vasodilation².

Additionally, there are three types of natriuretic peptide receptors. ANP and BNP bind to the type A natriuretic peptide receptor, leading to its activation via guanylate cyclase. CNP is activated upon binding to the natriuretic peptide receptor type B. Natriuretic peptide receptor type C degrades peptides¹⁴(Figure 2)

Figure 2 Interaction of natriuretic peptides with their receptors and their effects. AC, adenylyl cyclase; ANP, atrial natriuretic peptide; AVP, arginine-vasopressin; BNP, brain natriuretic peptide; cGMP, cyclic guanosine monophosphate; CNP, C‐type natriuretic peptide; GTP, guanosine triphosphate; NPR, natriuretic peptide receptor; PKG, protein kinase G; PLC, phospholipase C; sGC, soluble guanylate cyclase.”(Adapted from Díez J. Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy. Eur J Heart Fail. 2017;19(2):167-76.). 

FIRST FAILED ATTEMPT: USE OF SYNTHETIC NATRIURETIC PEPTIDES

Once the beneficial effects of natriuretic peptides were known, it seemed reasonable to synthesize exogenous peptides to enhance the effects of endogenous peptides. The main one was nesiritide, a recombinant type B natriuretic peptide, approved by the FDA in 2001 for the treatment of acute decompensated heart failure, as it reduced dyspnea and fatigue compared to placebo¹⁵. However, its safety came into question when an increased risk of renal failure and death was reported with its use¹⁶. In the ASCEND-HF study, nesiritide was not associated with worsening renal function but showed no beneficial impact on mortality or hospitalization for heart failure, nor significant improvement in dyspnea at 30 days¹⁷. Carperitide, a recombinant type A peptide, was used in Japan with some benefits for acute heart failure, but it did not consistently improve long-term mortality or morbidity¹⁸. Therefore, the strategy of using synthetic peptides proved to be ineffective in the management of chronic heart failure.

WHY DID THE USE OF SYNTHETIC NATRIURETIC PEPTIDES FAIL? THE ROLE OF NEPRILYSIN

We must remember that natriuretic peptide levels are already elevated in heart failure, and their levels increase as the disease progresses¹⁴. In fact, elevated levels of natriuretic peptides are associated with worse functional class¹⁹and correlate directly with a worse prognosis, being associated with higher all-cause mortality, heart failure mortality, sudden death, and higher rates of hospitalizations²⁰. So, why do elevated natriuretic peptide levels associate with higher morbidity and mortality when they have been described to have beneficial effects in heart failure? The answer is simple: these large amounts of natriuretic peptides do not have adequate effectiveness; they represent quantity, but not quality. The reduced effectiveness of natriuretic peptides is mainly due to excessive activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system, which counterregulate and mitigate their effects, even at the renal and vascular levels. Therefore, in heart failure, the effects of vasoconstrictive substances prevail over vasodilators¹⁴(Figure 3).

Figure 3 Consequences of the reduced effectiveness of natriuretic peptides in heart failure (Adapted from Díez J. Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy. Eur J Heart Fail. 2017;19(2):167-76.) 

But why did the use of drugs that block the renin-angiotensin-aldosterone system and the sympathetic system not imply greater effectiveness of natriuretic peptides? This is because, in heart failure, in addition to having elevated levels of natriuretic peptides, there is also an increase in the enzyme responsible for degrading natriuretic peptides through a mechanism different from the type C natriuretic peptide receptor^21-23. This enzyme, called neprilysin, is a zinc- dependent metalloproteinase. It is widely distributed in the body, mainly in the kidney at the level of the proximal convoluted tubule but also in the brain, lung, endothelium, cardiomyocytes, fibroblasts, adipocytes, and neutrophils^{24 25}. In summary, despite having increased levels of natriuretic peptides, they were not effective because they were degraded by neprilysin before reaching their target site.

SECOND FAILED ATTEMPT: ISOLATED NEPRILYSIN INHIBITION

The next reasonable step was to use neprilysin inhibitors to decrease the degradation of natriuretic peptides. Phosphoramidon was shown to prevent the elimination of ANP in the renal tissue of mice at the level of the proximal convoluted tubule and glomerulus²¹.

Oral candoxatril, used in humans, was expected to lower blood pressure by increasing the bioavailability of natriuretic peptides. However, in a study in hypertensive patients, despite increasing ANP levels, the reduction in blood pressure was not sustained²⁶. In a later study, also conducted in hypertensive patients, candoxatril significantly increased angiotensin II levels, leading to greater vasoconstriction. It was concluded that its effects on arterial hypertension were unpredictable, as it could increase, decrease, or have no effect on blood pressure, depending on the balance of its vasoconstrictive and vasodilatory effects²⁷.

WHY DID THE USE OF NEPRILYSIN INHIBITORS FAIL? NEPRILYSIN, A "VERY PROMISCUOUS" ENZYME

In the scientific literature, neprilysin behaves like a "promiscuous" enzyme because it has many substrates. It not only degrades vasodilatory peptides, such as natriuretic peptides, adrenomedullin, and bradykinin, but also vasoconstrictive peptides, such as angiotensin I and II, and endothelin-1. Therefore, the use of neprilysin inhibitors functions as a double-edged sword, as it increases the level of natriuretic peptides on one hand, but also raises the levels of angiotensin II, potentially mitigating the beneficial effects of natriuretic peptides^28-32.

THIRD FAILED ATTEMPT: USE OF VASOPEPTIDASES, DUAL INHIBITION OF NEPRILYSIN AND ANGIOTENSIN-CONVERTING ENZYME

In response to this new failure, a solution was proposed to enhance the effect of neprilysin inhibition by using an angiotensin-converting enzyme inhibitor to block the effects of the renin-angiotensin-aldosterone system. This dual combination was named vasopeptidase³³. The most widely used was omapatrilat, which showed a decrease in cardiac remodeling in rats³⁴. The OCTAVE study demonstrated better blood pressure control compared to enalapril in untreated hypertensive patients, but it also reported a higher rate of angioedema³⁵. On the other hand, the OVERTURE clinical trial compared omapatrilat with enalapril in patients with systolic heart failure and showed a decrease in all-cause mortality and cardiovascular hospitalization. However, it was also associated with high rates of angioedema, leading to the abandonment of this strategy³⁶.

THE FAILURE OF DUAL NEPRILYSIN AND ANGIOTENSIN-CONVERTING ENZYME INHIBITION: WHY DID VASOPEPTIDASES LEAD TO A HIGHER RATE OF ANGIOEDEMA?

Angioedema has been described to be primarily associated with an increase in bradykinin levels³⁷. Both angiotensin-converting enzyme and neprilysin degrade bradykinins. Moreover, omapatrilat also inhibits aminopeptidase P, which in turn metabolizes bradykinin³⁸. Consequently, the excessive increase in bradykinin levels led to the high rate of angioedema and resulted in the failure of this drug³⁹.

FOURTH ATTEMPT: ARNI AND THE EMERGENCE OF A NEW PARADIGM

With the goal of overcoming this new failure and reducing the potentiation of bradykinin, a new drug was designed, initially known as LCZ696. Currently called sacubitril/valsartan, it is a unique drug as it is an inhibitor of both neprilysin and the angiotensin receptor (ARNI, angiotensin receptor-neprilysin inhibitor). Sacubitril, its active metabolite, does not inhibit aminopeptidase P, which implies that there is no increased risk of angioedema, as seen with omapatrilat^40,41. When tested in hypertensive patients, sacubitril/valsartan showed greater reduction in blood pressure compared to valsartan⁴². Its effects are summarized in figure 4.

Figure 4 Mechanism of action of ARNI. Sacubitril inhibits neprilysin, improving the levels of natriuretic peptides, which are beneficial in heart failure. On the other hand, valsartan, by blocking the AT receptor, inhibits the renin-angiotensin-aldosterone system, counteracting the harmful effects of elevated angiotensin II. Ang II = angiotensin II; ARNI = angiotensin receptor neprilysin inhibitor; AT1 = angiotensin type 1 receptor; CV = cardiovascular; NEP = neprilysin; NP = natriuretic peptide; NPR = natriuretic peptide receptor; RAAS = renin-angiotensin-aldosterone system.”(Adapted from Volpe M. Natriuretic peptides and cardio-renal disease. Int J Cardiol. 2014;176(3):630-9.) 

The expectations of success for this new medication were greatly exceeded. In 2014, the results of the PARADIGM-HF study were published, a double-blind trial that involved 8,442 patients with chronic heart failure and a reduced ejection fraction of less than 40%, with functional class II to IV and optimal medical treatment. The study had to be terminated early because sacubitril/valsartan, as compared to enalapril, demonstrated a 20% reduction in the primary end point of cardiovascular death and hospitalization for heart failure; it also resulted in a 16% reduction in all-cause mortality, a 20% reduction in sudden death, a 21% reduction in death due to worsening heart failure, a 23% reduction in the risk of hospitalization for heart failure, an 18% reduction in intensive care unit admissions, and an improvement in quality of life. There were no significant differences in the rate of angioedema⁴³. The results of this trial are so consistent (p <0.00125.29) that they would be equivalent to at least four clinical trials with the same results ^₍₁₃₎ . Undoubtedly, these findings led to a paradigm shift in the management of heart failure, resulting in strong recommendations in the latest versions of the heart failure guidelines^44,45.

CONCLUSION

Heart failure is a complex syndrome with significant residual morbidity and mortality rates, despite the use of optimal medical treatment aimed at inhibiting the effects of vasoconstrictor substances. After years of research and numerous failures, we have reached a paradigm shift in the modulation of the neurohormonal system, led by a new class of drug, the ARNI sacubitril/valsartan, which enhances the effects of vasodilator substances and mitigates the effects of vasoconstrictor substances. In this way, the results obtained are compelling in reducing morbidity and mortality in patients with heart failure and reduced ejection fraction.