Head-to-head comparison of BNP and IL-6 as markers of clinical and experimental heart failure: Superiority of BNP

Activation of BNP and IL-6 are hallmarks of left ventricular (LV) dysfunction and congestive heart failure (CHF). To assess the relative activation of BNP and IL-6 in clinical and experimental heart failure, we performed a human study in which plasma N-terminal proBNP (NT-proBNP) and IL-6 were measured in a large group of patients in the chronic phase after myocardial infarction (MI) and an animal study in which LV gene expression of BNP and IL-6 was assessed in rapid ventricular pacing-induced heart failure. In the human study, NT-proBNP and IL-6 were measured by non-extracted, enzyme-linked immunoassay in 845 subjects (n = 468 outpatients after MI, MONICA MI register Augsburg; and 377 siblings without MI, control). NT-proBNP (295 ± 23 pg/mL vs. CTRL 84 ± 8, P < 0.05) and IL-6 (2.7 ± 0.1 pg/mL vs. CTRL 2.1 ± 0.1, P < 0.05) were both elevated in subjects with MI. These increases were particularly pronounced in the presence of concomitant CHF (both P < 0.01 vs. CTRL) and LV dysfunction (EF < 45%, both P < 0.05 vs. CTRL). However, NT-proBNP was significantly correlated with several cardiac structural and functional parameters (EF, LVMI, history of MI, CHF symptoms; all P < 0.05) upon regression analysis whereas IL-6 was only correlated with history of MI (P < 0.001). Accordingly, MI subjects with symptomatic LV dysfunction were detected by NT-proBNP with a greater sensitivity, specificity, and ROC-area (85%, 88%, and 0.87, respectively) as compared to IL-6 (69%, 53%, and 0.67, respectively). In the animal study, IL-6 and BNP expression were both significantly elevated in CHF (both P < 0.05) but with a much greater absolute activation of BNP. In addition, BNP mRNA expression displayed a stronger inverse correlation with LV function (r = −0.74; P < 0.001) than IL-6 (r = −0.53; P = 0.001) and was a markedly more sensitive and specific molecular marker of LV dysfunction (sensitivity 91%, specificity 100%, ROC-area 0.94) than IL-6 (sensitivity 74%, specificity 83%, ROC-area 0.87). Our animal study provides evidence that IL-6 expression is activated in heart failure but to a significantly lesser degree than that of BNP. Both the stronger expression of BNP and the better correlation with LV function provide the molecular basis for a diagnostic superiority of NT-proBNP in clinical LV dysfunction and heart failure.