The paradox of increased natriuretic hormones in congestive heart failure patients: Does the endocrine heart also fail in heart failure?

The normal heart secretes Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) from the atria, which counteract cardiac overload by stimulating renal natriuresis and lowering systemic blood pressure.1On a cellular level, the endocrine capacity of the atria is reflected by the presence of secretory granules for peptide storage, which almost 50 years ago gave the first clue to the discovery of the endocrine heart.2Cardiac natriuretic peptides are stored in secretory granules and secreted upon relevant stimuli such as stretch of the atrial myocytes.3When the function of the left ventricle deteriorates, however, the ventricular myocytes also begin to express the ANP and BNP genes and progressively become the major site of peptide secretion. This endocrine feature of ventricular peptide expression andsecretion has now proven its diagnostic and prognostic value in congestive heart failure patients. Cardiac conditions with impaired function of the left ventricle can be detected by measurement of the circulating concentrations of natriuretic peptides and their precursors.4–6The European Society of Cardiology has consequently included plasma measurement of cardiac natriuretic peptides as diagnostic markers of congestive heart failure, and the American Heart Association may soon be doing the same.7 The beneficial physiological effects mediated by the cardiac natriuretic hormones also have promising therapeutic advantages. Clearly, increased excretion of sodium and water, natriuresis, and lowering of blood pressure is often the therapeutic goal when treating cardiovascular disease. As the cardiac natriuretic hormones mediate these favourable effects, drugs enhancing this hormonal system have accordingly been developed. First, inhibiting their enzymatic degradation can prolong the effects of endogenous ANP and BNP peptides in blood. By inhibiting an endothelial membrane-bound endopeptidase, the degradation and thereby inactivation of ANP and BNP (and other important peptide hormones) are delayed and the hormones exert their beneficial effects for longer. Studies evaluating the clinical effect of such drugs are currently running, and so far these drugs may have a role in treating hypertension as well as congestive heart failure.8Another therapeutic strategy is to infuse the biologically active BNP peptide into congested heart failure patients.9The acute effects are highly encouraging, but as peptides unfortunately do not make good pills, the clinical use of these peptide-based drugs seems limited to intensive hospital treatment of severely decompensated heart failure patients.10 But why do the congested heart failure patients with highly increased plasma concentrations of potent natriuretic hormones then not display an increased renal excretion of sodium and water? With the marked ventricular upregulation of especially the BNP gene and subsequent high concentrations of proBNP-derived peptides in plasma, it seems only reasonable to expect increased natriuresis. Quite the opposite is, however, the everyday situation with congestive heart failure patients suffering from disabling congestion, sodium retention and oedema. Although congestive heart failure is a complex condition with activation and inhibition of both nervous and many hormonal systems, the paradoxical lack of ANP and BNP effects is still compelling. It is interesting that acute central blood volume expansion in patients with decompensated heart failure increase both the plasma concentrations of ANP and the reduced urinary sodium excretion rate.11However, the urinary excretion rate is first normalized during sustained treatment with an ACE inhibitor. One explanation for this endocrine paradox may just lie in the heart itself. Both ANP and BNP are synthesized as prohormones and require endoproteolytic maturation by cleavage to release the biologically active peptides (Fig. 1). Such cleavage takes place in the secretory granules and is mainly a feature of atrial peptide expression.3,12Indeed, a cardiac endoprotease named Corin was recently characterized in atrial myocytes13and also the well known prohormone convertase 1 (PC1/3) seems to be present in some myocytes.14The cardiac expression of these enzymes, being essential for hormone activation, may though differ between atrial and ventricular myocytes. As ventricular myocytes do not contain secretory granules and the storage capacity for maturating peptides is low, ventricular myocytes may not equally well process the precursors into the biologically active end products. In agreement with this suggestion, congestive heart failure patients have increased plasma concentrations of immunoreactive proBNP, and thisimmunoreactivity seems to consist also of a polypeptide corresponding to the unprocessed precursor.15,16 Schematic outline the BNP precursor, proBNP 1-108. Cleavage of the precursor gives rise to the molecularly identified and biologically active C-terminal BNP-32 (white bar). The theoretical complementary N-terminal fragment, proBNP 1-76, is also shown (black bar). Perhaps most captivating, the lack of natriuretic effect from ventricular proBNP in congestive heart failure patients could be a novel target for medical intervention. Advances in understanding of the cardiac posttranslational processing of proBNP could reveal novel ways to enhance hormone maturation in the failing heart. At present, the posttranslational maturation apparatus is still unexplored in ventricular myocytes. Characterization of the cardiac myocytes as truly endocrine cells rather than just ‘marker-secreting’ entities should be pursued more intensively, both from a cellular point of view as well as in clinical studies. Finally, a perhaps more conventional therapeutic approach to achieve plasma proBNP cleavage and BNP natriuretic effects could be enzymatic activation of the circulating proANP and proBNP. Like the well-established inhibition of both angiotensin-converting enzyme in plasma and the inhibition of neutral endopeptidase, it may be possible to activate an enzyme that can cleave endogenous proBNP to release the bioactive BNP hormone. In either way, amelioration of the congestion in congestive heart failure patients could be accomplished by activation of the all ready synthesized precursor peptides. We gratefully acknowledge the financial support of the Danish Heart Foundation.