Heart failure with preserved ejection fraction in older adults
Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich in Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
The natriuretic peptides play a crucial role in fluid homeostasis. Neprilysin is a zinc-dependent metalloprotease that degrades biologically active natriuretic peptides and does not affect the biologically inactive NT-proBNP (42). LCZ696 is a new combination drug of the angiotensin II type-1 receptor blocker valsartan and the neprilysin inhibitor pro-drug AHU377. This angiotensin receptor-neprilysin inhibitor (ARNI) combination exerts a powerful vasodilatory and natriuretic effect by blocking angiotensin II activity while augmenting plasma levels of natriuretic peptides, such as BNP. In the Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) trial, LCZ696 significantly lowered NT-proBNP levels, and at 36 weeks decreased LA size and showed a trend toward improved functional class (42). The promising findings of this phase-2 study led to an ongoing large, multicenter trial, Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF (PARAGON), which is comparing LCZ696 to valsartan in patients with HFpEF with the primary composite outcome of CV death or first hospitalization for HF (ClinicalTrials.gov NCT01920711). Other novel therapies tried in HFpEF are summarized in Table 22.3.
Circulatory controls
Burt B. Hamrell in Cardiovascular Physiology, 2018
Patients with aortic valvular stenosis and left ventricular hypertrophy eventually develop heart failure that is characterized by myocardial and vascular remodeling, and myocardial apoptosis and fibrosis. Relatively recent findings show that ANP and BNP act to reduce these adverse myocardial and vascular changes in heart failure. The clinical use of these beneficial effects of ANP and BNP is currently being investigated. The action of natriuretic peptides, particularly ANP, is terminated by enzymatic degradation by neprilysin. Neprilysin is produced in vascular endothelial cells and the tubular cells of the kidney. Clinical testing of neprilysin inhibitors have been carried out recently and show promise for heart failure treatment.
Pathophysiology of Heart Failure with Reduced Ejection Fraction
Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler in Heart Failure, 2023
Based on their physiological mechanisms, multiple natriuretic peptide analogues and endopeptidase inhibitors have progressed through preclinical studies to human trials. Nesiritide, a recombinant BNP, although showing hemodynamic benefits in earlier studies, did not reduce death or rehospitalization compared to placebo in a large long-term trial. Neprilysin is a membrane-bound metalloproteinase that cleaves and inactivates various peptide hormones, including natriuretic peptides, bradykinin, substance P, and beta amyloids. Early neprilysin inhibitors were shown to promote natriuresis, but the effect was not sustained, likely because AT II breakdown was also inhibited. Consequently, dual blockade of neprilysin and ACE was thought to be the solution. The neprilysin-ACE inhibitor omapatrilat was compared with ACE inhibitor alone in the phase III trial OVERTURE,4 showing no reduction in the composite primary endpoint of all-cause mortality and HF hospitalization, but causing a reduction in the secondary endpoint of all-cause mortality and cardiovascular hospitalization. However, on account of the unacceptable rise in the angioedema rate in the treatment group, related to omapatrilat inhibition of bradykinin breakdown, further development of this agent was ceased. The more recently developed agent sacubitril-valsartan carries the dual advantage that sacubitrilat (active metabolite of sacubitril) does not inhibit aminopeptidase P, which breaks down bradykinin, and that valsartan does not inhibit ACE, which also contributes to bradykinin inactivation (Figure 3.2). Accordingly, sacubitril-valsartan was compared with enalapril for HFrEF patients in the recent phase III trial PARADIGM-HF,5 demonstrating the marked superiority of sacubitril-valsartan in terms of all-cause mortality, cardiovascular mortality, and HF hospitalization, with a non-significant rise in non-serious angioedema. Replacing ACE inhibitor or ARB with sacubitril-valsartan now holds a level I class of recommendation in all major international guidelines for HFrEF.6,7Sacubitril-valsartan mechanism of action in heart failure. (Reproduced with permission from: Vardeny, Miller, and Solomon, JACC Heart Fail 2014;2:663–70.)
New pharmacotherapy for heart failure with reduced ejection fraction
Published in Expert Review of Cardiovascular Therapy, 2020
Sara Sotirakos, Peter Wheen, James Spiers, Richard Armstrong
Atrial Natriuretic Peptide (ANP), or A-type, and Brain Natriuretic Peptide (BNP), or B-type, originate within myocardial cells and act antagonistically to the ANG-II mediated effects of the RAAS [5]. C-type Natriuretic Peptide (CNP) originates within the endothelium of blood vessels [5]. Activity of the RAAS system and circulating levels of ANP are both elevated in HF [5,9]. To note, the levels of natriuretic peptides are often assessed by measuring the N-terminus Pro-ANP (NT-proANP) or N-terminus Pro-BNP (NT-proBNP), which are the non-active prohormones that circulate longer and serve as an estimate of ANP or BNP levels [9]. Why would we want to increase levels of natriuretic peptides further using sacubitril/valsartan? As shown in Figure 1, natriuretic peptides mediate anti-RAAS effects such as vasodilation, lowered sympathetic tone, and natriuresis. Neprilysin is one of the key enzymes in the breakdown of these peptides [10]. Neprilysin has the highest affinity for ANP, CNP, ANG-I, and ANG-II; and lower affinities for BNP, endothelin-1, and bradykinin [11]. Inhibition of the breakdown of these natriuretic peptides allows this system to run at a higher capacity to the RAAS system. However, inhibition of neprilysin as a monotherapy has shown ineffective as neprilysin also breaks down ANG-II [10]. Sacubitril is therefore used in combination with valsartan, achieving an enhanced effect by decreasing activity of the RAAS system via the ARB valsartan and increasing activity of the natriuretic peptides via the NEP-I Sacubitril [12].
Safety and efficacy considerations amongst the elderly population in the updated treatment of heart failure: a review
Published in Expert Review of Cardiovascular Therapy, 2022
Further, within the ARNI, valsartan is partnered with another active chemical that promotes other beneficial effects, sacubitril. Sacubitril is classified as a prodrug that is activated by blood proteins called esterases [12]. The activated metabolite of sacubitril is then able to inhibit the enzyme, neprilysin [12]. Neprilysin is a neutral endopeptidase located on the surface of the cells where this enzyme can degrade natriuretic peptides, bradykinin and adrenomedullin [13]. Neprilysin also breaks down angiotensin II, so blocking neprilysin leads to an increase in angiotensin II [3]. Therefore, valsartan is added to counteract this increase. By inhibiting neprilysin activity, sacubitril indirectly increases brain natriuretic peptide (BNP), and the vasodilators, bradykinin and adrenomedullin [12]. BNP is the main endocrine peptide in the pathophysiology of heart failure [13]. BNP is created and processed and made in the cardiac muscle cells of the ventricles [13]. Once released, the peptide causes dilation in the arteries and veins, increased excretion of sodium and chloride, followed by increased excretion of water; thus, reducing the blood volume [13]. This is completed by BNP binding to the natriuretic peptide receptor A: upon binding, an increase in the levels of the secondary messenger cyclic guanosine monophosphate carries out the previously explained diuretic effect [13]. To conclude, sacubitril provides benefits in treating heart failure by increasing BNP and reducing the volume of blood required for the heart to pump.
Sacubitril and valsartan protect from experimental myocardial infarction by ameliorating oxidative damage in Wistar rats
Published in Clinical and Experimental Hypertension, 2019
Mohd Imran, Md Quamrul Hassan, Md Sayeed Akhtar, Obaid Rahman, M. Akhtar, Abul Kalam Najmi
Neprilysin is a neutral endopeptidase, degrades vasoactive peptides and their inhibition prevents neurohormonal activation, vascular tone, cardiac fibrosis and sodium retention (10–12). Encountering these endopeptidases, counteracts sodium retention, vasoconstriction and cardiac remodeling (13). Sacubitril(SAC) is a prodrug which is converted into the well-tolerated neprilysin inhibitor, LBQ657 (14). Concurrent inhibitions of neprilysin and angiotensin II receptors were considered to offer the clinical cardioprotection in the range of cardiovascular diseases, including hypertension and heart failure. Angiotensin receptors blockers (ARBs) including VAL have a lower risk of angioedema than Angiotensin-converting enzymes (ACE) inhibitors, probably because of their neutral effect on metallopeptidases involved in bradykinin breakdown (15). SAC/valsartan (VAL) is first-in-class neprilysin/angiotensin II receptor inhibitors for the treatment of chronic heart failure. These drug combinations have been studied for HF with preserved ejection fraction (HFpEF) as well as heart failure with reduced ejection fraction (HFrEF) (14,16). SAC/VAL represents a promising new treatment option for patients with HFrEF. Ongoing studies will continue to refine the role of this agent in clinical practice (17).
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