Birner Christoph M, Ulucan Coskun, Fredersdorf Sabine, Rihm Munhie, Löwel Hannelore, Stritzke Jan, Schunkert Heribert, Hengstenberg Christian, Holmer Stephan, Riegger Günter, Luchner Andreas
Klinik und Poliklinik für Innere Medizin II, Klinikum der Universität Regensburg, 93042 Regensburg, Germany.
Cytokine. 2007 Nov;40(2):89-97. doi: 10.1016/j.cyto.2007.08.009. Epub 2007 Oct 24.
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+/-23pg/mL vs. CTRL 84+/-8, P<0.05) and IL-6 (2.7+/-0.1pg/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.
脑钠肽（BNP）和白细胞介素-6（IL-6）的激活是左心室（LV）功能障碍和充血性心力衰竭（CHF）的标志。为了评估临床和实验性心力衰竭中BNP和IL-6的相对激活情况，我们进行了一项人体研究，在一大组心肌梗死（MI）后慢性期的患者中测量血浆N末端脑钠肽原（NT-proBNP）和IL-6，以及一项动物研究，在快速心室起搏诱导的心力衰竭中评估BNP和IL-6的左心室基因表达。在人体研究中，通过非提取的酶联免疫分析法在845名受试者中测量NT-proBNP和IL-6（n = 468名MI后门诊患者，奥格斯堡莫妮卡MI登记处；377名无MI的兄弟姐妹，作为对照）。MI患者的NT-proBNP（295±23pg/mL vs. 对照组84±8，P<0.05）和IL-6（2.7±0.1pg/mL vs. 对照组2.1±0.1，P<0.05）均升高。在伴有CHF（与对照组相比均P<0.01）和LV功能障碍（射血分数<45%，与对照组相比均P<0.05）时，这些升高尤为明显。然而，回归分析显示NT-proBNP与多个心脏结构和功能参数（射血分数、左心室质量指数、MI病史、CHF症状；均P<0.05）显著相关，而IL-6仅与MI病史相关（P<0.001）。因此，与IL-6（分别为69%、53%和0.67）相比，NT-proBNP检测有症状LV功能障碍的MI患者具有更高的敏感性、特异性和ROC曲线下面积（分别为85%、88%和0.87）。在动物研究中，CHF时IL-6和BNP表达均显著升高（均P<0.05），但BNP的绝对激活程度要大得多。此外，BNP mRNA表达与LV功能的负相关（r = -0.74；P<0.001）比IL-6（r = -0.53；P = 0.001）更强，并且是LV功能障碍比IL-6更敏感和特异的分子标志物（敏感性91%，特异性100%，ROC曲线下面积0.94）（敏感性74%，特异性83%，ROC曲线下面积0.87）。我们的动物研究提供了证据，表明IL-6表达在心力衰竭中被激活，但程度明显低于BNP。BNP更强的表达以及与LV功能更好的相关性为NT-proBNP在临床LV功能障碍和心力衰竭中的诊断优势提供了分子基础。
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