Neurohumoral activation in heart failure and the implications for treatment

Br J Cardiol 2016;23(suppl 1):S1–S16doi:10.5837/bjc.2016.s01 Leave a comment
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Sponsorship Statement: This sponsored supplement was initiated and funded by Novartis. Editorial control, however, was retained by the authors and editors but Novartis reviewed the supplement for technical accuracy only before publication.

ENT16-CO51; May 2016
Entresto™ (sacubitril/valsartan) prescribing information is available here

The pathophysiology of heart failure is complex. This article describes the neurohumoral pathways that are active in chronic heart failure with left ventricular systolic dysfunction (also known as heart failure with reduced ejection fraction [HFREF]). It also explains the rationale behind the development of therapies to favourably modulate the neurohumoral imbalance seen in this condition.


An acute pathological insult to the heart leads to a reduction in cardiac output (i.e. any cause of left ventricular systolic dysfunction [LVSD]), which activates a series of innate protective mechanisms. In the short term, activation of neurohumoral systems aim to preserve central arterial pressure and thereby vital organ perfusion, and include the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system (RAAS). The net main effects of this process are: i) vasoconstriction; ii) sodium and water retention by the kidneys. While in the acute setting these adaptive responses may be beneficial, long-term overactivation, such as that seen in patients with chronic heart failure, results in maladaptive processes, such as left ventricular remodelling and disease progression. Opposing counter-regulatory vasodilatory pathways, such as the natriuretic peptide system, contribute to physiological homeostasis.

The neurohumoral hypothesis1,2 of heart failure development/progression has been tested in a number of landmark studies. This has resulted in combined antagonism of the RAAS and SNS with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), beta blockers, and mineralocorticoid receptor antagonists (MRAs), forming the evidence-based treatment for patients with chronic heart failure secondary to LVSD.3,4

Recent results from the PARADIGM-HF study5 have enhanced our understanding of the counter regulatory pathways provided by other vasoactive peptides, particularly, the natriuretic peptide system.

Sensing mechanisms

A failure in the pumping capacity of the heart leads to haemodynamic changes that activate various sensing mechanisms. These, in turn, activate and regulate various neurohumoral pathways in an attempt to maintain circulatory integrity. Afferent sensing mechanisms triggered in heart failure can be subdivided into:

  • low-pressure volume receptors – present mainly in the cardiac atria
  • high-pressure mechanoreceptors – located in the left ventricle, aortic arch, carotid sinus and renal juxtaglomerular apparatus.6

Low-pressure receptors

In heart failure, atrial stretch – caused by either volume expansion or increased transmural pressures – activates the low-pressure mechanoreceptors. This leads to release of natriuretic peptides, suppression of sympathetic outflow and decrease in renin and vasopressin release, ultimately leading to diuresis and natriuresis.7

High-pressure mechanoreceptors

A decrease in arterial pressure sensed at the high-pressure mechanoreceptors located in the aortic arch and carotid sinus, results in a reduction in the tonic inhibition of the sympathetic system. The net result is activation of the SNS and RAAS and non-osmotic release of vasopressin.

The mechanoreceptors in the renal juxtaglomerular apparatus respond to the reduction in renal perfusion or tubular sodium load typically seen in heart failure by enhancing renin release.6

Pathophysiological RAAS and SNS activation in chronic heart failure (figure 1)

Activation of the SNS with release of endogenous catecholamines results in increased myocardial contractility, heart rate, vasoconstriction, sodium and water retention and RAAS activation. These all work to increase cardiac output and vital organ perfusion by linked pathways, which include expansion of the circulatory volume. Activation of the SNS, for example, plays an important stimulatory role in renal tubular sodium and water re-absorption;8 SNS renal nerve stimulation leads to RAAS activation by stimulating renin release.5,9 While these mechanisms help maintain cardiac output, they also increase strain on an already
failing heart.

Figure 1. Summary of the complex interaction between key neurohumoral pathways involved in the pathophysiology of heart failure. In heart failure, arterial under filling due to diminished cardiac output and/or reduced peripheral vascular resistance activates various mechanoreceptors, resulting in RAAS and SNS activation and vasopressin release. These, in turn, cause sodium and water retention and vasoconstriction, which have beneficial effects in the initial stages of heart failure. In the long term, these effects along with cardiac hypertrophy and remodelling and renal parenchymal fibrosis, have a detrimental effect culminating in the progression of heart failure. Natriuretic peptides secreted in response to myocyte stretch have a beneficial counter-regulatory effect. This includes increased water and sodium excretion, vasodilatation and reduced cardiac hypertrophy and fibrosis.9 These pathways interact with each other in a complex fashion
Figure 1

As cardiac output decreases, increased sympathetic stimulation and decreased renal perfusion leads to an increase in secretion of renin by the kidneys. Renin acts on a circulating substrate called angiotensinogen to form angiotensin I. Cleavage of angiotensin I to form angiotensin II primarily occurs by the actions of ACE, which is found predominantly in the vascular endothelium, especially in
the lungs.

Cardiac myocytes release two of the natriuretic peptides that play a significant role in water and salt homeostasis
Cardiac myocytes release two of the natriuretic peptides that play a significant role in water and salt homeostasis

Angiotensin II has a number of key functions, including:

  • increasing systemic vascular resistance and arterial pressure (potent vasoconstrictor)
  • sodium and water retention by directly stimulating sodium transport at renal tubular sites, promoting the release of aldosterone and vasopressin and activation of the SNS. The subsequent release of aldosterone results in a further important contribution to sodium retention.

It is apparent that these neurohumoral systems also influence each other and the net result after chronic activation is adverse loading of the left ventricle. This is both by increased afterload (vasoconstriction) and pre-load as a consequence of circulating volume expansion (sodium and water retention). However, aldosterone, angiotensin II and the SNS, are also potent stimulants for myocardial hypertrophy and fibrosis, adverse vascular remodelling and renal parenchymal fibrosis.10-12 When left unchecked, these systems contribute to heart failure disease progression.

SNS and RAAS blockade

Therapeutic manipulation of these pathways with beta blockers, ACE inhibitors, ARBs and MRAs has become the cornerstone of the management of chronic heart failure with LVSD. Manipulation of these neurohumoral pathways results in beneficial reduction in ventricular afterload and reverse cardiac remodelling.12,13

ACE inhibitors

The landmark trials that established ACE inhibitors as the cornerstone for heart failure management were CONSENSUS (1987),14 SOLVD-Treatment (1991),15 V-HeFT II (1991)16 and SOLVD-Prevention (1992).17 The CONSENSUS14 and SOLVD-Treatment15 trials showed that treatment with enalapril reduced overall mortality by 16–40% in patients with heart failure as compared with placebo. V-HeFT II16 showed that enalapril was superior to the combination of hydralazine and isosorbide dinitrate, which had previously been established as beneficial in the V-HeFT I trial (1986).18 The SOLVD-Prevention trial17 confirmed that enalapril was also beneficial in asymptomatic patients with reduced ejection fraction.


ARBs are only generally used in patients who cannot tolerate ACE inhibitors due to side effects, such as cough. They have not been proven to be superior to ACE inhibitors. The concept of using ARBs in heart failure was introduced in the Val-HeFT trial (2001).19

Beta blockers

The role of beta blockers in heart failure was initially viewed with scepticism due to concerns of further worsening inotropy. Evidence from a number of large trials, such as COPERNICUS (2001),20 showed that carvedilol led to a 35% reduction in mortality in patients with chronic heart failure compared to placebo. A substantial mortality benefit has also been demonstrated with bisoprolol and sustained release metoprolol (CIBIS-II,21 MERIT-HF22); these trials have greatly aided our understanding of the role of the SNS in heart failure.


Spironolactone, was evaluated in the RALES trial (1999)23 and was associated with a 30% reduction in mortality among patients with severe heart failure already receiving an ACE inhibitor and a loop diuretic. These results were further strengthened by the EMPHASIS-HF trial (2011),24 which evaluated eplerenone, another MRA, in patients with mild symptoms of heart failure and LVSD and demonstrated marked additional benefit when added to patients receiving optimal therapy with ACE inhibitors and beta blockers.

Current guidelines recommend combination therapy with both an ACE inhibitor and beta blocker as first line for management of chronic heart failure. A MRA is generally added to patients with symptomatic LVSD.3,4

Natriuretic peptide modulation – new to the armamentarium (figure 1)

Natriuretic peptides are a group of peptide hormones that play a significant role in water and salt homeostasis. They provide counter-regulatory balance to the neurohumoral pathways already discussed; beneficial effects include direct vasodilatation, lowering of blood pressure, natriuresis, diuresis, lowering the release of renin from the kidneys, increasing renal blood flow and decreasing cardiac hypertrophy and fibrosis.25

The natriuretic peptide system consists of three main peptides:

  • atrial natriuretic peptide (ANP)
  • B-type natriuretic peptide (BNP)
  • C-type natriuretic peptide (CNP).

ANP and BNP are released from myocytes in response to cardiac stretch (elevated filling pressures). CNP is mainly released from endothelial cells.25

Elevated circulating levels of natriuretic peptides are found in patients with chronic heart failure and assessment of BNP (or its inactive N-terminal fragment, NTproBNP) is now a key component of the diagnostic pathway for patients with suspected heart failure.4 As such, it might seem counter-intuitive that there could be merit in enhancing natriuretic peptide activity in chronic heart failure. Yet data suggest that the natriuretic peptide system functions abnormally in people with cardiovascular diseases, such as hypertension and chronic heart failure.25

Recent studies using sensitive mass spectrometric techniques have shown that there are both active and inactive components of BNP. It appears that patients with chronic heart failure often exhibit an abnormal pattern of circulating BNP – with a relative deficiency of the protective (active) BNP and elevation of the inactive form.25 As a consequence of this, research has focused on increasing active BNP in heart failure, with a view to establishing if this can translate into improved patient outcomes.

Augmentation of natriuretic peptides in chronic heart failure

Exogenous administration of recombinant natriuretic peptide (neseritide) was assessed in the ASCEND-HF trial,26 and showed some benefit in symptoms (dyspnoea) in the acute phase but did not show any reduction in mortality or rehospitalisation rates, or improvement of renal function. Due to additional safety concerns this drug is not used in the UK.

Another method of increasing natriuretic peptide concentration is to reduce its degradation through the inhibition of neprilysin or neutral endopeptidase (NEP) – an enzyme that breaks down several peptide hormones including natriuretic peptides. In mammals, NEP is widely expressed in organs, such as the kidney, lung, endothelial cells, vascular smooth muscle cells and cardiac myocytes, with the highest concentrations being present in the renal proximal tubule.25

Several NEP inhibitors have been developed and tested in clinical trials; one of the earliest ones to be developed for clinical use was candoxatril, an orally administered prodrug.25 Candoxatril produced favourable effects in heart failure patients such as natriuresis and increased plasma ANP. However it was also found to increase angiotensin II and endothelin I levels.25 This was one of the limitations of using NEP inhibitors alone; while there is an increase in beneficial vasodilatory peptides, such as natriuretic peptides and bradykinin, there is also an increase in unwanted peptides such as angiotensin II and endothelin I (vasoconstrictors). These unwanted peptides counterbalance the beneficial effects (figure 2).27

Figure 2. Impact of NEP (neprilysin) inhibition on various endogenous vasoactive peptides27
Figure 2. Impact of NEP (neprilysin) inhibition on various endogenous vasoactive peptides27

Combining inhibitors

This led to the idea of combining a NEP inhibitor with an inhibitor of the RAAS system; a combination often referred to as vasopeptidase inhibition.25,28 The rationale for combining an NEP inhibitor with a RAAS inhibitor is that the former can increase endogenous naturietic peptide levels while the latter can counteract the undesired increases in angiotensin II.

Omapatrilat, a dual blocker of NEP and ACE, was evaluated in the IMPRESS trial29 with lisinopril as the comparator in patients with heart failure. The data suggested potential benefits with omapatrilat and led onto a further study OVERTURE30 (versus enalapril in patients with chronic heart failure). It proved non-superior in comparison to enalapril in terms of lowering the primary end point of death and hospital admission requiring intravenous treatment. Further concerns were raised from the OCTAVE31 trial, where omapatrilat was tested against enalapril for the treatment of 25,302 hypertensive patients. Although omapatrilat was found to help patients reach the target blood pressure more quickly, as compared with enalapril, the likelihood of early-onset of angioedema was significantly higher in patients treated with omapatrilat compared with those treated with enalapril. These concerns were highlighted in a review of omapatrilat conducted by the US Food and Drug Administration (FDA) body. Cases of angioedema were higher in African-American patients and those with a history of smoking. These findings led to omapatrilat not receiving FDA approval.25

The advent of ARNIs

The cause for angioedema with vasopeptidase inhibitors was initially thought to be secondary to increased levels of bradykinin from dual ACE and NEP inhibition. Newer data, however, suggest that inhibition of aminopeptidase P also plays an important role in bradykinin degradation when ACE is inhibited.25 This led to the development of an alternative strategy which combined an ARB and a NEP inhibitor – in this situation the ARB offers the advantage of not interfering with bradykinin metabolism as much as ACE inhibitors with the hope of reduced risk of angioedema.32 This group of drugs were collectively called ARB with NEP inhibition – or the angiotensin-receptor–neprilysin inhibitors (ARNIs).

The development molecule LCZ696 was the first of the ARNI class of drugs and combines valsartan (an ARB) with sacubitril (a NEP inhibitor). The key pathways targeted by the ARNI class of drugs are shown in figure 3.33 Pharmacokinetic and pharmacodyamic studies34 indicated sacubitril/valsartan is a potent dual-acting angiotensin receptor and NEP inhibitor. Following oral administration in healthy participants, it was shown to rapidly deliver NEP inhibition and angiotensin-receptor blockade.

Figure 3. Heart failure is a state of neurohumoral imbalance
Figure 3. Heart failure is a state of neurohumoral imbalance

These early clinical studies paved the way for the large, randomised, double-blind, controlled trial, PARADIGM-HF, where the safety and efficacy of sacubitril/valsartan was tested over the ACE inhibitor, enalapril, an established therapy in patients with chronic heart failure and LVSD.5

Key messages

  • Chronic activation of the sympathetic nervous and renin–angiotensin–aldosterone systems contribute to disease progression in patients with chronic heart failiure
  • Pharmacological therapies proven to improve prognosis in chronic heart failure (ACE inhibitors, beta blockers, MRAs) antagonise these activated neurohumoral systems
  • The natriuretic peptide family provides counter-regulatory vasodilatory and natriuretic pathways and, therefore, is a target for potential beneficial pharmacological modulation


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Dosing of sacubitril/valsartan: Throughout this supplement, the dosing of sacubitril/ valsartan (Entresto™, Novartis Pharmaceuticals) has been split to show the constituent doses.

In clinical trials, sacubitril/ valsartan – initially known as the investigational agent LCZ696 – was used in 100 mg and 200 mg doses. These translate to the licensed doses of 49 mg sacubitril/51 mg valsartan and 97 mg sacubitril/103 mg of valsartan, respectively.

A smaller 50 mg dose, which equates to 24 mg sacubitril/26 mg valsartan, is also available.

Disclaimer: Medinews Cardiology Limited advises healthcare professionals to consult up-to-date Prescribing Information and the full Summary of Product Characteristics available from the manufacturers before prescribing any product. Medinews Cardiology Limited cannot accept responsibility for any errors in prescribing which may occur.