Current thinking views the progression of
heart failure as the result of sustained activation of
vasoconstrictor neurohormones. In this model, the sustained synthesis of
vasoconstrictor neurohormones leads to
disease progression through alterations in cardiomyocyte structure and function, which affects myocardial contractility, cardiac metabolism, and cellular growth. Ultimately, these events induce irreversible adverse
ventricular remodeling through myocyte cell loss and progressive myocardial
fibrosis. In the past decade, several landmark clinical trials tested the neurohormonal hypothesis, by targeting the activation of both the beta-
adrenergic and the
renin-
angiotensin-
aldosterone systems. Although the observed decrease in mortality using this strategy in
heart failure populations was encouraging, morbidity and mortality levels remained elevated, and it has now been shown that several other humoral interactions are at play and potentially deserve antagonizing, or in the case of
vasodilator neurohormones, deserve stimulation. It is known a family of
vasodilator neurohormones - the
natriuretic peptides - that have natriuretic, vasodilatory, and antiproliferative effects, endogenously inhibit the renin-angiotensin system. These
peptides are degraded primarily by a
neutral endopeptidase (NEP), an endothelial cell-surface
zinc metallopeptidase, which shares a similar structure and catalytic site with the
angiotensin converting enzyme (ACE). NEPs have broad substrate specificity, encompassing
atrial natriuretic peptide,
brain natriuretic peptide, and
C-type natriuretic peptide, but also
bradykinin and
adrenomedullin. The recognition that ACE and NEP
enzymes had related structures, led to the design and development of a class of molecules with a dual inhibitory effect on ACE and NEP, referred to as
vasopeptidase inhibitors. Preliminary clinical trials in
heart failure with
vasopeptidase inhibitors have become available and show promising results. Thus, the combined inhibition of ACE and NEP, by attenuating excessive vasoconstriction and enhancing
vasodilator substances, holds promise as a valuable option in
heart failure treatment for the near future.