Congestive Heart Failure

Circulating levels of ANP and BNP and the amino-terminal fragments NT-proANP and NT-proBNP of their prohormones (proANP and proBNP) are elevated in CHF. The concentrations are related to the severity of symptoms (36,152,153), the degree of LV dysfunction (154), and cardiac filling pressures (4,35,155). Very high circulating levels can be found in patients with severe, untreated CHF (156) or during episodes of acute decompensation (157). Both systolic and diastolic impairment of the left ventricle can result in elevated circulating natriuretic peptide levels (158,159). However, circulating levels of these peptides are elevated even in mildly symptomatic or asymptomatic patients with LV impairment (155,160,161).

Stretching of the atrial and failing ventricular myocardium secondary to volume overload is a potent stimulus for ANP and BNP gene expression and release and probably outweighs the influence of other modulating factors of natriuretic peptide production (34,60,62). Several other mechanisms also contribute to elevated circulating levels of natriuretic peptides in heart failure. Cardiac hypertrophy per se is a potent stimulus for ANP and BNP production (64). The increased muscle mass associated with LV hypertrophy will also contribute to increased production and subsequent elevation of plasma natriuretic peptides. In patients with an old myocardial infarction, secretion of BNP is much greater from the infarcted region than from the noninfarcted region, suggesting that regional ventricular wall stretch caused by the old infarct strongly stimulates secretion of BNP (162). Vasoconstrictor neurohormones stimulate natriuretic peptide production. Renal impairment, a condition commonly associated with cardiac impairment, will result in decreased clearance of natriuretic peptides (163).

Natriuretic peptides have beneficial actions in heart failure. The natriuretic, diuretic, and vasodilatory effects tend to decrease cardiac preload and afterload. In addition, inhibition of the renin-angiotensin system and SNS will act synergistically with the direct hemodynamic and renal effects. The significance ofthe inhibitory actions ofthe natriuretic peptide system on the renin-angiotensin system is illustrated by the effect of NPR-A blockade. In a canine experimental model ofearly LV dysfunction, NPR-A blockade with the receptor antagonist HS-142-1 resulted in sodium retention, augmented renin release, increased aldosterone production, and accelerated progression to overt heart failure (148, 164). Bilateral atrial appendectomies had a similar effect (164). In an experimental model of canine heart failure, coinfusion of BNP and furosemide resulted in a more profound diuretic and natriuretic response than furosemide alone (165). Moreover, during coinfusion, glomerular filtration was increased while renal function was preserved and aldosterone activation was inhibited. As mentioned in Table 7, BNP and NPR-A receptor gene knockout (KO) models are associated with cardiac fibrosis (134) and hypertension, cardiac hypertrophy, and sudden death (135), respectively. These findings are suggestive ofan important role for natriuretic peptides for the maintenance of cardiovascular homeostasis.

Based on theoretical considerations and observations made in experimental models, drugs that increase circulating levels of natriuretic peptides have been developed for use in human heart failure. Two strategies have reached late-stage clinical development: administration of exogenous recombinant BNP (nesiritide) and potentiation of endogenous effects of natriuretic peptides by inhibition ofNEP (166). Nesiritide infusion has beneficial effects in human heart failure, including a dose-dependent decrease in pulmonary capillary wedge pressure, improved cardiac index, and augmented urinary flow (167-169). Subcutaneous administration of BNP has also been shown to represent an efficacious strategy in human heart failure (170).

Combined NEP inhibition and ACE inhibition by vasopeptidase inhibitors such as omapatrilat result in greater hemodynamic and renal effects than with selective inhibition of either of these enzymes (166). In early studies in heart failure, omapatrilat caused a dose-dependent reduction in BP and pulmonary capillary wedge pressure, improvement in cardiac output, and lowering ofcirculating norepinephrine concentrations (171). These beneficial effects did not, however, translate into reduced survival in a large-scale phase III clinical trial (172).

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