KINETIC-STUDY OF ATRIAL-NATRIURETIC-PEPTIDE IN PATIENTS WITH IDIOPATHIC DILATED CARDIOMYOPATHY - EVIDENCE FOR RESISTANCE TO BIOLOGIC EFFECTS OF THE HORMONE EVEN IN PATIENTS WITH MILD MYOCARDIAL INVOLVEMENT

Atrial natriuretic peptide (ANP) kinetics was studied in 12 patients w ith idiopathic dilated cardiomyopathy at different sodium excretion (3 0-175 mmol/day) and variable degrees of hemodynamic dysfunction [New Y ork Heart Association (NYHA) class range I-III] to investigate whether differences in renewal and distribution of this hormone (as compared with those of a control group) play a role in pathogenesis and evoluti on of heart failure. [I-125]Labeled ANP was injected as a bolus, and a highperformance liquid chromatography (HPLC) procedure was used to pu rify the labeled hormone in venous plasma samples collected for less t han or equal to 50 min after injection; the main ANP kinetic parameter s were then derived from the disappearance curve of the labeled hormon e. As in controls, a positive linear regression between ANP metabolic clearance rate (MCR, ml/min/m(2)) values and daily urinary excretion o f sodium (NaUE, mmol/day) was noted in patients. The different linear regression coefficients between normal subjects (MCR = 365 +/- 8.08 Na UE, r = 0.986, p < 0.0001) and patients (MCR = 497 + 18.5 NaUE, r = 0. 867, p = 0.001) indicate that in patients a higher peptide clearance r ate is needed to obtain the same biologic effect (sodium excretion) an d suggest that resistance to biologic effects of the hormone exists in patients at an early stage of disease (NYHA class I). When the effici ency of the ANP system in excreting sodium was expressed as the ratio of NaUE to ANP production rate (PR = MCR x ANP plasma concentration, m u g/day/m(2)) patients showed significantly lower values (p = 0.0126) than normal volunteers, thus confirming resistance to the hormone effe cts. Significantly lower values for ANP total distribution volume (16. 5 +/- 8.4 L/m(2)), mean residence time in the sampling space (4.04 +/- 1.14 min), mean residence time in the body (7.25 +/- 2.13 min), and f ewer recycles through the initial (sampling) space (0.27 +/- 0.16) wer e noted in patients, indicating an altered mechanism regulating distri bution of the hormone. The positive correlations between ANP MCR (L/mi n/m(2)) values and cardiac index (CI, L/min/m(2)) (MCR = - 1.24 + 1.17 CI, r = 0.689, p = 0.0092) and between initial distribution volume (I DV, L/m(2)) and CI (IDV = - 11.2 + 6.85 CI, r = 0.730, p = 0.0046) in all patients indicate that hemodynamic factors contribute to the progr essive reduction in MCR and IDV values throughout the progression of m yocardial involvement. Moreover, the high significant positive correla tion between MCR/CI ratio (i.e., ANP total body extraction) and NaUE ( MCR/CI = 0.28 + 0.0049 NaUE, r = 0.904, p < 0.0001, n 13) indicate tha t disturbed regulation of receptor (and degradation sites) plays a rol e in evolution of heart failure.