Peripheral Resistance to Atrial Natriuretic Peptide in Patients with Idiopathic Dilated Cardiomyopathy

Abstract

Atrial natriuretic peptide (ANP) has been suggested to play an important role in asymptomatic left ventricular dysfunction, preserving cardiorenal homeostasis through the maintenance of the sodium balance and the inhibition of the detrimental effects of the neurohormonal vasoconstrictor system. The current study was designed to investigate whether differences in the renewal and distribution of ANP may play a role in the pathogenesis and evolution of heart failure in idiopathic dilated cardiomyopathy (IDC). A tracer method was used to study ANP kinetics in the steady-state condition in 10 normal subjects and in 13 patients with IDC with different degrees of hemodynamic dysfunction at variable sodium intakes. [125I]-labeled ANP was bolus injected and high-pressure liquid chromatography (HPLC) was used to purify the labeled hormone in venous plasma samples collected up to 50 min after injection. The main ANP kinetic parameters were then derived from the disappearance curve of the labeled hormone. Patients with IDC showed a gradual reduction in the total distribution volume (on average from 20.5 ± 4.51/m2 to 12.2 ± 7.21/m2, p < 0.0279) with the progression of disease, mainly due to a contraction of the peripheral distribution spaces in the early phases of the disease and to a reduction in both the initial distribution volume and the peripheral spaces in the late phases of the disease. Moreover, the ANP production rate, which was in the normal range (120.0 ± 104.7 ng/ min/m2) in the early stages (99.8 ± 52.3ng/min/m2), greatly (more then three times, p < 0.0055) increased in patients with more severe myocardial involvement (378.9 ± 189.1 ng/min/m2). Different relationships between the metabolic clearance rate (MCR) values and daily sodium excretion were observed in patients (r = 0.837, p < 0.0001) and controls (r = 0.962, p < 0.0001). The significantly (p < 0.02) different linear regression coefficients (slopes) indicate that, on average, for each millimole rise in sodium excretion, the ANP MCR increased by 17ml/min/m2 in the patients, that is, there was an increase of about twofold with respect to the controls. Our study demonstrates a markedly altered peripheral distribution and degradation of ANP in patients with IDC, even those in the early phase of the disease (NYHA class I and II), who have plasma levels in the normal range. This alteration of ANP metabolism indicates the presence of a peripheral resistance to hormone effects and also suggests disturbed renal handling of sodium in patients with IDC and asymptomatic left ventricular dysfunction.