Hello Serguey;

To be honnest, the mode of action of sacubitril is not fully understood. I gave a presentation at the 4th meeting of the Heart Failure Association of the ESC last MAy, and the conclusion is we don't know. Neprilysin has 40+ targets with antagonistic effects. The cardioprotective effects could be and are most likely both direct and indirect. The restoration of better hemodynamics by vasodilation (e.g. natriuretic peptides, bradykinins...) is one of them, but is most likely indirect. Neprilysin inhibition has also metabolic effects (direct and indirect - see seferovitch et al in Lancet Diabetes and editorial)... So in conclusion, there are some beneficial effect but it remains unclear what does what. As I saud in my conclusion, you have a 20-50% increase in neprilysin targets with probable synergistic actions.

Sorry not to be able to give a better answer

Best

Thanks a lot for your answer. During HF-2017 Congress in Paris I've heard a lot of information about sacubitril, аnd as the president of HF society's Prof. Frank Ruschitzka said, I do not know what mechanism, but the drug works ... And my question is still open...  

Dear Sergey!

Thank a lot of your opinion regarding the metabolic effect of sacubitril. By that point, there is a large body of evidence regarding that recently used neprilysin inhibitors (racecodotril, candoxatrilat, ecadotril) and novel drugs (sacubitril) had similar effects on promoting natriuresis / wateruresis, increasing circulating NP levels and urinary excretion of atrial type of NP acting via several substrates, i.g. endothelin, vasopressin, bradykinin, etc. However, an effect of dual inhibiton including RAS blockade and nephrilysin on the clinical hard end points should be inevitablely addressed into trials' design (regardeless their innate molecular mechanisms affected) so no one can be opinionated that isolated sacubitril use may show comprehensive result on HF outcomes. Conceqquently, mechanism of sacubitril is probably interest in, but it is out of clinical confirmation. Maybe in the future, let's get a wait...

Medscape: Can't make it to Paris? Visit the virtual ENTRESTO® (sacubitril/valsartan) booth from the ESC-Heart Failure 2017 Congress

Frequently asked questions from health care professionals about ENTRESTO

Sacubitril blocks the breakdown of natriuretic peptides produced in the body. Natriuretic peptides help reduce both strain on the heart and blood pressure. They also protect the heart from developing fibrosis, or scar tissue, that occurs in heart failure.

My notes: 1) ...protect the heart from developing fibrosis - it is long time process, I thinks 6 and more month. 2) ...or scar tissue - maybe this medications influence on cardiomyocyte death or apoptosis...?!

To confirm cardioprotective property usually use two methods: 

1. Measurement of Troponin T and I 

2. Assessment of size and extent of scar or fibrosis by Late Gadolinium Enhancement by CMR

In recent article by M. Packer et all. confirmed differences in Troponin levels between sacubitril/valsartan and enalapril groups within 4 weeks and were sustained at 8 months, P

Mechanisms of action of novel therapeutics for heart failure.

The ARNi LCZ696 is split into the ARB valsartan and the neprilysin-inhibitor sacubitril. Valsartan abrogates signalling via the AT1 receptor, inhibiting deleterious effects mediated by Ang-II such as vasoconstriction, hypertrophy, and fibrosis in major cardiovascular organs. Sacubitril prevents breakdown of endogenous natriuretic peptides (ANP, BNP, and CNP), thereby augmenting their beneficial actions in cardiovascular disease. The overall effects of ARNi are vasodilatation, natriuresis, and diuresis, as well as inhibition of fibrosis and hypertrophy. Ularitide selectively targets NPR-A, whereas cenderitide activates both NPR-A and NPR-B. Both peptides increase intracellular cGMP, which in turn leads to inhibition of the renin–angiotensin–aldosterone system and attenuation of fibrosis, hypertrophy, and vasoconstriction. sGC activators such as cinaciguat, riociguat, and vericiguat augment the enzymatic activity of sGC (as do serelaxin and NRG-1, via NO), resulting in increased generation of cGMP, and beneficial cardiovascular effects through PKG activity. Upstream of Ang-II, aliskiren directly inhibits renin. Inotroptes include adrenoceptor agonists (dobutamine), PDE3 antagonists (enoximone, milrinone), calcium sensitizers (levosimendan), and a direct activator of cardiac myosin (omecamtiv mecarbil). Abbreviations: ACE, angiotensin-converting enzyme; ADRB1, β1-adrenergic receptor; Ang-I/II, angiotensin I/II; ANP, A-type natriuretic peptide; ARB, angiotensin-receptor blocker; ARNi, angiotensin receptor–neprilysin inhibitor; AT1, type-1 angiotensin II receptor; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide; ErbB2/4, receptor tyrosine-protein kinase erbB2/4; NO, nitric oxide; NOS, NO synthase; NPR-A/B, atrial natriuretic peptide receptor 1/2; NRG-1, neuregulin-1; PDE3, phosphodiesterase-3; pGC, plasma-membrane-bound guanylate cyclase; PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; RXFP1, relaxin receptor 1; sGC, soluble guanylate cyclase.

Article New medical therapies for heart failure

From article The Mechanism Of Action Of LCZ696:

Nevertheless, the precise mechanism by which LCZ696 reduces cardiovascular mortality in HF patients is uncertain.

https://www.cfrjournal.com/articles/mechanism-action-lcz696

Interesting data recently published about mechanisms of sacubitril.

The molecular mechanisms of Valsartan are strongly associated with the prevention of hypertrophy. In contrast, Sacubitril acts by preventing the breakdown of endogenous vasoactive peptides, including natriuretic peptides (ANP, BNP, and CNP), thereby limiting myocardial cell death. In the combination drug, molecular synergy may reverse or reduce left ventricular extracellular matrix remodeling (LVEMR), reduce cardiomyocyte cell death, and, via Valsartan, enhance the effects of Sacubitril. Remarkably, the molecular mechanisms of Sacubitril and Valsartan alone are not associated with LVEMR, and it is only their combination that activates these molecular processes.

https://www.nature.com/articles/s41540-017-0013-4

New information:

Sacubitril/Valsartan Attenuates Fibrosis and Improves Left Ventricular Function in a Rabbit Model of HFrEF. Circulation. 2017;136:A24021

Conference Paper Abstract 24021: Sacubitril/Valsartan Attenuates Fibrosis and...

I ask about protective property of SAC/VAL on I/R damage. This work give us answer...

Conclusion: Reperfusion therapy with SAC/VAL offers acute infarct-sparing benefits similar to VAL, however, LV function at 72h post MI is significantly preserved with SAC/VAL compared to VAL, which may indicate superior long-term benefits of SAC/VAL in prevention of MI-induced heart failure.

Please see:

Conference Paper Reperfusion Therapy With Sacubitril/Valsartan Attenuates Inf...

Francisco, good results, my congratulations!

Thanks Sergey! We will soon submit these results as a full text to a peer reviewed journal. I hope the Paradise-AMI clinical trial ongoing brings us new data regarding SAC-VAL cardioprotection in humans during acute STEMI phase

New data: post hoc secondary analysis of 8399 patients from the Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial.

In patients with heart failure with reduced ejection fraction, sacubitril/valsartan significantly improved nearly all KCCQ physical and social activities compared with enalapril, with the largest responses in household chores and sexual relationships. In addition to reduced likelihood of cardiovascular death, all-cause mortality, and heart failure hospitalization, sacubitril/valsartan may improve limitations in common activities in these patients.

Article Effects of Sacubitril/Valsartan on Physical and Social Activ...