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Sacubitril/valsartan: beyond natriuretic peptides
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  • Published on:
    Author response to Siniorakis et al.
    • Jagdeep S.S. Singh, Cardiology Registrar / Honorary Clinical Research Fellow University of Dundee
    • Other Contributors:
      • Chim C. Lang, Consultant Cardiologist and Professor of Cardiology

    The authors thank Siniorakis et al. for highlighting the cardioprotective effect of enkephalins (ENK) as well as their potential role as biomarkers in post infarct heart failure (HF).[1] We had restricted our discussion around ENK and other vasoactive peptides to allow for a broader analysis of various concepts and also to comply with article length limitations. We note that the comments of Siniorakis et al. are consistent with the objective of our article, which is to highlight the potential role of other vasoactive pathways beyond that of the natriuretic peptide system when using sacubitril / valsartan in HF.[2] Indeed there is evidence to suggest that proenkephalin may be a prognostic indicator in acute heart failure.[3]

    1 Siniorakis E, Arapi S, Kaplanis I, et al. Cardioprotective effects of enkephalins and potential interference from neprilysin inhibitors. [Letter to Editor], Heart 2017.
    2 Singh JSS, Burrell LM, Cherif M, et al. Sacubitril/valsartan: beyond natriuretic peptides. Heart 2017.
    3 Ng LL, Squire IB, Jones DJ, et al. Proenkephalin, Renal Dysfunction, and Prognosis in Patients With Acute Heart Failure: A GREAT Network Study. J Am Coll Cardiol 2017;69:56-69.

    Conflict of Interest:
    None declared.
  • Published on:
    Cardioprotective effects of enkephalins and potential interference from neprilysin inhibitors
    • Eftychios E Siniorakis, Cardiologist Department of Cardiology, Sotiria Chest Diseases Hospital, Athens, Greece
    • Other Contributors:
      • Sophia M Arapi, Cardiologist
      • Ioannis K Kaplanis, Cardiologist
      • Vlassios N Pyrgakis, Cardiologist (Head of Department)
      • Sotiria J Limberi, Cardiologist (Head of Department)

    To the Editor, Singh et al¹ refer to cardiocirculatory effects of sacubitril/valsartan beyond those related to the activation of the natriuretic peptide system. Sacubitril, by inhibiting neprilysin (NEP), upregulates various vasoactive peptides, with enkephalins (ENK) performing a major role among them. It is not by chance that PARADIGM-HF trial, which established the novel NEP inhibitor, bestows NEP with the name ‘enkephalinase’, since the latter catalyzes the degradation of ENK. Singh et al¹ concentrate on the sacubitril-related augmentation of substance P, bradykinin and adrenomedullin, while they refrain from referring to ENK. ENK and proenkephalins, their precursors, are endogenous opioids, ligands to delta and kappa opioid receptors (ORs), which are abundant in the neural system as well as in the myocardium. The endogenous opioid system exerts a significant antinociceptive action in the heart, as we deduce by observations in animal and human models². An important field where ENK have already demonstrated their cardioprotective role, is reperfusion-related ischemia, with myocardial infarction, coronary artery by pass and angioplasty constituting the principal clinical equivalents in this setting³. In all the above mentioned conditions, ENK are overexpressed, both in the neural system and locally in the myocardium. ENK action during reperfusion ischaemia is exerted via various pathways. In detail, they increase intracellular Ca²+ levels, while, simultaneously, they ope...

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    Conflict of Interest:
    None declared.