Alterations in metabolic clearance of atrial natriuretic peptides in heart failure: how do they relate to the resistance to atrial natriuretic peptides?

Deficiencies in activity of the atrial natriuretic peptide (ANP) system may be able to explain the disturbed electrolyte and fluid homeostasis occurring in chronic heart failure. Generally, in studies concerning the possible pathophysiologic role of ANP in heart failure, only the circulating levels of the hormone were measured. It has been shown, however, that plasma ANP levels exhibit marked variability attributable to the pulsatory pattern of secretion and to its very short plasma half-life. An evaluation of the main turnover parameters might represent a significant improvement in the assessment of the functioning of the overall ANP system. By using a tracer method, which does not alter the steady-state condition, a disturbed peripheral metabolism of ANP and a resistance to its biologic effects was demonstrated in patients with idiopathic dilated cardiomyopathy, even in those in the asymptomatic phase of the disease, showing ANP circulating levels, atrial pressure and volume, and cardiac index within the normal range. The altered degradation and distribution of ANP in patients with heart failure were demonstrated by a great increase in metabolic clearance (on average, 2.5-fold), production (on average, 6-fold), or both, and by a progressive reduction in the distribution spaces of the hormone when compared with normal subjects at the same sodium intake. The ratio between ANP disposal and the daily excretion of sodium (equal to the sodium intake in subjects at a strictly controlled sodium balance) may give a good index of the biologic activity (natriuresis) of the ANP system. Preliminary studies suggest that an index of biologic activity of the ANP system may be a useful tool for the comparison of the efficacy of different therapeutic strategies in heart failure. Indeed, after a 2-month treatment with an angiotensin-converting enzyme inhibitor, this index was returned to within the normal range, suggesting that the drug was able to "normalize" the peripheral distribution and degradation of the hormone in these patients. Although future studies in a large series of patients will be useful to assess this important issue, the setup of accurate methods able to evaluate the presence and degree of resistance to biologic activity of ANP may be a useful tool in the follow-up evaluation of patients with heart failure, and may pave the way for further progress in the knowledge of more general physiologic and pathophysiologic mechanisms of this important clinical condition.