IMMUNOREACTIVE AMINO-TERMINAL PRO-BRAIN NATRIURETIC PEPTIDE (NT-PROBNP) - A NEW MARKER OF CARDIAC IMPAIRMENT

OBJECTIVE Human brain natriuretic peptide-32 (BNP) (i.e. proBNP(77-108 )), the mature form of BNP and secreted predominantly by the cardiac v entricle, is formed from a high molecular weight precursor, proBNP(1-1 08). We have recently identified the aminoterminal form proBNP(1-76) ( NT-proBNP) in human plasma but its source, metabolism and production i n circulatory disorders are unknown. We have investigated the relation ship between immunoreactive (IR) NT-proBNP and BNP-32 in normal and hy pertensive subjects and in patients with cardiac impairment, as well a s the regional plasma concentrations in patients undergoing routine ca rdiac catheterization. DESIGN AND PATIENTS Plasma hormone measurements were made in 26 normal subjects, 20 subjects with untreated mild hype rtension and 111 treated patients with a history of coronary heart dis ease and documented cardiac impairment (left ventricular ejection frac tion (LVEF) < 45% (mean 29%); 25 NYHA Class 1, 65 Class II and 21 Clas s III). Regional blood sampling from the femoral artery, femoral vein, renal vein and coronary sinus was undertaken in 14 patients presentin g for left and right cardiac catheterization studies in the course of standard investigation for a range of cardiac disorders. MEASUREMENTS Plasma samples were assayed for IR NT-proBNP and IR BNP-32 (and atrial natriuretic peptide (ANP) in the regional blood samples). In the pati ents with cardiac impairment, LVEF was determined by gated radionuclid e ventriculography, exercise capacity was measured using a modified Na ughton multistage protocol and creatinine clearance was calculated fro m plasma creatinine, age and weight. In the regional study, extraction ratios across the kidney and lower limb (and step-ups across the hear t) were calculated from plasma peptide concentrations. RESULTS in norm al subjects mean IR NT-proBNP levels (10.8 +/- 1.3 pmol/L) were simila r to levels of IR BNP-32 (9.7 +/- 0.5 pmol/L). In hypertensive patient s the levels of IR NT-proBNP and IR BNP-32 tended to be higher than bu t were not significantly different from normal subjects. Both IR NT-pr oBNP and IR BNP-32 were raised in NYHA Classes I, II and III compared with normals (P < 0.001 for all) with higher levels of both BNP forms seen with increasing cardiac impairment. The levels of IR NT-proBNP we re greater than IR BNP-32 in all NYHA Classes (P < 0.001) for all). Ov erall, the levels of IR NT-proBNP (129 +/- 12 pmol/L) were 4-fold high er than concomitant BNP-32 levels (29 +/- 2 pmol/L). Multivariate anal ysis showed that LVEF, exercise test time and creatinine clearance wer e independent predictors of IR NT-proBNP. In all study groups, the lev els of IR NT-proBNP and IR BNP-32 levels were highly correlated. Regio nal plasma sampling showed similar step-ups in IR NT-proBNP and IR BNP -32 levels across the heart, together with similar extraction of both BNP forms across the kidney and lower limb. For both BNP forms, these changes across tissues were significantly less than for ANP. CONCLUSIO NS Plasma levels of immunoreactive amino terminal-proBNP are raised in cardiac impairment, including NYHA Class I, and rise with increasing cardiac decompensation. Metabolism and tissue uptake of immunoreactive amino terminal-proBNP and immunoreactive BNP-32 appear similar. In ca rdiac impairment the proportional and absolute increment above normal levels of the aminoterminal BNP peptide exceeds that for BNP-32 and su ggest that amino terminal-proBNP may be a more discerning marker of ea rly cardiac dysfunction than BNP-32.