Association of Ficolin-3 with Severity and Outcome of Chronic Heart Failure

Background
Inflammatory mechanisms involving complement activation has been shown to take part in the pathophysiology of congestive heart failure, but the initiating mechanisms are unknown. We hypothesized that the main initiator molecules of the lectin complement pathway mannose-binding lectin (MBL), ficolin-2 and ficolin-3 were related to disease severity and outcome in chronic heart failure.
Methods and Results
MBL, ficolin-2 and ficolin-3 plasma concentrations were determined in two consecutive cohorts comprising 190 patients from Hungary and 183 patients from Norway as well as controls. Disease severity and clinical parameters were determined at baseline, and all-cause mortality was registered after 5-years follow-up. In univariate analysis a low level of ficolin-3, but not that of MBL or ficolin-2, was significantly associated with advanced heart failure (New York Heart Association Class IV, p<0.001 for both cohorts) and showed inverse correlation with B- type natriuretic peptide (BNP) levels (r = −0.609, p<0.001 and r = −0.467, p<0.001, respectively). In multivariable Cox regression analysis, adjusted for age, gender and BNP, decreased plasma ficolin-3 was a significant predictor of mortality (HR 1.368, 95% CI 1.052–6.210; and HR 1.426, 95% CI 1.013–2.008, respectively). Low ficolin-3 levels were associated with increased complement activation product C3a and correspondingly decreased concentrations of complement factor C3.
Conclusions
This study provides evidence for an association of low ficolin-3 levels with advanced heart failure. Concordant results from two cohorts show that low levels of ficolin-3 are associated with advanced heart failure and outcome. The decrease of ficolin-3 was associated with increased complement activation.

研究背景
已有研究证实，涉及补体激活的炎症机制参与充血性心力衰竭的病理生理过程，但其起始触发机制尚未阐明。本研究假设：凝集素补体通路的主要起始分子——甘露聚糖结合凝集素（mannose-binding lectin, MBL）、纤维胶凝蛋白-2（ficolin-2）及纤维胶凝蛋白-3（ficolin-3）与慢性心力衰竭的疾病严重程度及预后密切相关。

方法与结果
本研究在两个连续入组的队列中检测受试者血浆中MBL、纤维胶凝蛋白-2及纤维胶凝蛋白-3的浓度：其中匈牙利队列纳入患者190例，挪威队列纳入患者183例，同时设置健康对照人群。于基线时评估疾病严重程度与临床参数，并对所有受试者开展为期5年的随访以记录全因死亡率。单因素分析结果显示，纤维胶凝蛋白-3水平降低（而非MBL或纤维胶凝蛋白-2）与晚期心力衰竭（纽约心脏协会心功能IV级）显著相关（两个队列的P值均<0.001），且与B型利钠肽（B-type natriuretic peptide, BNP）水平呈负相关（相关系数r分别为−0.609、−0.467，P值均<0.001）。在校正年龄、性别及BNP水平的多因素Cox回归分析中，血浆纤维胶凝蛋白-3水平降低是全因死亡率的显著预测因子（风险比HR分别为1.368，95%置信区间CI：1.052~6.210；以及1.426，95% CI：1.013~2.008）。此外，纤维胶凝蛋白-3水平降低与补体激活产物C3a水平升高及补体成分C3浓度相应降低显著相关。

研究结论
本研究证实低水平纤维胶凝蛋白-3与晚期心力衰竭存在关联。来自两个独立队列的一致性结果显示，纤维胶凝蛋白-3低水平与晚期心力衰竭及患者预后相关，且其水平降低与补体激活增强有关。