Belperio John, Horwich Tamara, Abraham William T, Fonarow Gregg C, Gorcsan John, Bersohn Malcolm M, Singh Jagmeet P, Sonel Ali, Lee Li-Yin, Halilovic Jasmina, Kadish Alan, Shalaby Alaa A
David Geffen School of Medicine, University of California, Los Angeles, California.
Ohio State University, Columbus, Ohio.
Am J Cardiol. 2016 Feb 15;117(4):617-625. doi: 10.1016/j.amjcard.2015.11.049. Epub 2015 Dec 8.
Expression of different cytokines and growth factors after myocardial injury has been associated with fibroplasia and dilatation versus reverse remodeling and myocardial repair. Specifically, the proinflammatory/fibrotic mediators: interleukin (IL)-6, epidermal growth factor, and fibroblast growth factor (FGF)-2 cause fibroplasia, whereas reparative cytokines including: IL-1α, IL-1β, IL-4, and IL-13 can limit fibrosis. In appropriate patients, cardiac resynchronization therapy (CRT) reverses cardiomyopathy and improves outcome. However, a significant proportion will not respond to this therapy. We conducted this study to assess the association of proinflammatory/fibrotic and/or reparative immune response mediators at baseline with outcome after CRT. In the multicenter RISK study, plasma samples were collected prospectively before CRT implantation. Plasma IL-6, epidermal growth factor, FGF-2, IL-1α, IL-1β, IL-4, and IL-13 were evaluated by Luminex technology. The primary outcome was predefined as freedom from heart failure hospitalization or death and a decrease in echocardiographic end-systolic volume of >15% at 12 months. To determine associations with the outcome, multivariate logistic regression models including baseline clinical characteristics and the specific cytokines and growth factors were constructed. On multivariate analysis of 257 patients, detectable reparative cytokine IL-13 was significantly associated with the primary outcome (odds ratio 3.79; 95% CI 2.10 to 6.82, p <0.0001). In contrast, detectable proinflammatory/fibrotic growth factor FGF-2 was negatively associated (odds ratio 0.31; 95% CI, 0.14 to 0.68; p = 0.004). In conclusion, in CRT recipients, baseline levels of inflammatory mediators affecting cardiac fibrosis versus repair were associated with subsequent clinical outcome.
心肌损伤后不同细胞因子和生长因子的表达与纤维增生、心脏扩张以及逆向重构和心肌修复有关。具体而言，促炎/纤维化介质：白细胞介素（IL）-6、表皮生长因子和成纤维细胞生长因子（FGF）-2会导致纤维增生，而包括IL-1α、IL-1β、IL-4和IL-13在内的修复性细胞因子可限制纤维化。在合适的患者中，心脏再同步治疗（CRT）可逆转心肌病并改善预后。然而，相当一部分患者对这种治疗无反应。我们开展这项研究以评估基线时促炎/纤维化和/或修复性免疫反应介质与CRT治疗后预后的关联。在多中心RISK研究中，在CRT植入前前瞻性收集血浆样本。采用Luminex技术评估血浆中的IL-6、表皮生长因子、FGF-2、IL-1α、IL-1β、IL-4和IL-13。主要结局预先定义为12个月时无心力衰竭住院或死亡，且超声心动图测量的收缩末期容积减少>15%。为确定与结局的关联，构建了包括基线临床特征以及特定细胞因子和生长因子的多变量逻辑回归模型。对257例患者进行多变量分析时，可检测到的修复性细胞因子IL-13与主要结局显著相关（比值比3.79；95%置信区间2.10至6.82，p<0.0001）。相比之下，可检测到的促炎/纤维化生长因子FGF-2与主要结局呈负相关（比值比0.31；95%置信区间0.14至0.68；p=0.004）。总之，在接受CRT治疗的患者中，影响心脏纤维化与修复的炎症介质基线水平与随后的临床结局相关。
