Renin–Angiotensin Blockade Combined With Natriuretic Peptide System Augmentation

Abstract

Cardiovascular diseases in general and heart failure (HF) in particular are major contributors to death and morbidity in the Western world, where they are also recognized as important drivers of healthcare expenditure. The health and economic burden of these disorders is projected to increase with the aging of populations around the world.1–3 On the basis of accumulating evidence that chronic overactivity of the renin–angiotensin–aldosterone system (RAAS) plays a fundamental role in HF pathophysiology, drugs inhibiting key components of the RAAS have become a cornerstone of contemporary cardiovascular drug therapy.4–6 For example, angiotensin-converting enzyme inhibitors (ACEi) reduce biosynthesis of angiotensin-II (Ang-II), 1 of the strongest vasoconstrictors, prohypertrophic and profibrotic hormones in man. Moreover, ACEi may prevent proteolysis of bradykinin, thus enhancing bradykinin-mediated vasodilatory effects that may counteract the profound vasoconstriction seen in patients with HF.7 Excessive levels of Ang-II have been implicated in many cardiovascular diseases, and in addition to ACEi, the detrimental actions of Ang-II can be abrogated by direct angiotensin-receptor blockers (ARB). However, despite encouraging results from many clinical trials, ACEi- and ARBs-based pharmacotherapy is still far from optimal. ACEi may lose their efficacy over time because of redundant Ang-II–generating pathways and the so-called aldosterone escape,8 whereas conventional ARBs do not possess the bradykinin-enhancing properties of ACEi and are considered less effective in HF compared with ACEi.4,5 The natriuretic peptides (NPs), consisting of atrial NP (ANP), B-type NP (BNP), C-type NP (CNP), and urodilatin, are predominantly generated by the heart, vasculature, kidney, and central nervous system in response to wall stress and number of other stimuli. Importantly the NPs, particularly ANP and BNP, represent the body’s own blood pressure (BP)–lowering system. Besides promoting vasodilation, NPs counteract pathological growth, fibrosis, and dysfunction of heart, kidneys, brain, and the vasculature. Current NP-augmenting strategies include …