Gemmati Donato, Federici Federica, Campo Gianluca, Tognazzo Silvia, Serino Maria L, De Mattei Monica, Valgimigli Marco, Malagutti Patrizia, Guardigli Gabriele, Ferraresi Paolo, Bernardi Francesco, Ferrari Roberto, Scapoli Gian L, Catozzi Linda
Center Study Haemostasis and Thrombosis, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Ferrara, Italy.
Mol Med. 2007 Jan-Feb;13(1-2):112-20. doi: 10.2119/2006-00049.Gemmati.
It has been demonstrated recently that coagulation factor XIII (FXIII) plays an extraordinary role in myocardial healing after infarction, improving survival in a mouse model. Common FXIII gene variants (i.e. FXIIIA-V34L and FXIIIB-H95R) significantly influence the molecular activity. To evaluate whether there is a relationship between the two FXIII gene variants and survival in patients after myocardial infarction (MI), V34L and H95R were PCR-genotyped in a cohort of 560 MI cases and follow-up was monitored. Cases with ST-segment elevation MI (STEMI) were 416 (74.3%) and 374 of these were treated with primary percutaneous coronary intervention (PCI) (89.9%). The remaining 144 patients showed non-ST-segment elevation MI (NSTEMI) at enrollment. The combined endpoint was the occurrence of death, re-infarction, and heart failure. Kaplan-Meier analysis at one year yielded an overall rate for adverse events of 24.5% with a lower incidence in the L34-carriers (28.8% vs 17.1%; log-rank, P = 0.00025), similar to that of the 416 STEMI (23.8%) being (28.0% and 16.9%; VV34- and L34-carriers respectively; log-rank, P = 0.001). Primary PCI-group had a slight lower incidence (22.9%) of adverse events (26.8% and 17.1%; VV34- and L34-carriers respectively; log-rank, P = 0.009). During hospitalization, 506 patients received PCI (374 primary PCI and 132 elective PCI). Significance was conserved also in the overall PCI-group (28.6% and 17.8%; VV34- and L34-carriers respectively; log-rank, P = 0.001). Similar findings were observed at 30 days follow-up. Cases carrying both FXIII variants had improved survival rate (log-rank, P = 0.019). On the other hand, minor bleeding complications were found increased in L34-carriers (P = 0.0001) whereas major bleeding complications were not. Finally, more direct evidence on the role of FXIII molecule on survival might come from the fact that despite significant FXIII antigen reductions observed in cases after MI, regardless the FXIII genotype considered, L34-carriers kept almost normal FXIII activity (VV34- vs L34-carriers; P < 0.001). We conclude that FXIII L34-allele improves survival after MI in all the groups analyzed, possibly through its higher activity associated with assumable positive effects on myocardial healing and recovered functions. Genetically determined higher FXIII activity might influence post-MI outcome. This paves the way for using FXIII molecules to improve myocardial healing, recovery of functions, and survival after infarction.
最近有研究表明，凝血因子 XIII（FXIII）在心肌梗死后的心肌愈合过程中发挥着特殊作用，可提高小鼠模型的存活率。常见的 FXIII 基因变异（即 FXIIIA-V34L 和 FXIIIB-H95R）会显著影响分子活性。为评估这两种 FXIII 基因变异与心肌梗死（MI）患者存活率之间是否存在关联，对 560 例 MI 病例进行了 V34L 和 H95R 的 PCR 基因分型，并进行了随访监测。ST 段抬高型心肌梗死（STEMI）病例有 416 例（74.3%），其中 374 例接受了直接经皮冠状动脉介入治疗（PCI）（89.9%）。其余 144 例患者在入组时表现为非 ST 段抬高型心肌梗死（NSTEMI）。联合终点为死亡、再梗死和心力衰竭的发生。一年时的 Kaplan-Meier 分析显示，不良事件的总体发生率为 24.5%，L34 携带者的发生率较低（28.8%对 17.1%；对数秩检验，P = 0.00025），与 416 例 STEMI 患者的情况相似（23.8%）（分别为 VV34 和 L34 携带者，28.0%和 16.9%；对数秩检验，P = 0.001）。直接 PCI 组的不良事件发生率略低（22.9%）（分别为 VV34 和 L34 携带者，26.8%和 17.1%；对数秩检验，P = 0.009）。住院期间，506 例患者接受了 PCI（374 例直接 PCI 和 132 例择期 PCI）。在总体 PCI 组中也观察到了显著性差异（分别为 VV34 和 L34 携带者，28.6%和 17.8%；对数秩检验，P = 0.001）。在 30 天随访时观察到了类似的结果。携带两种 FXIII 变异的病例存活率有所提高（对数秩检验，P = 0.019）。另一方面，发现 L34 携带者的轻微出血并发症增加（P = 0.0001），而严重出血并发症则没有。最后，关于 FXIII 分子对存活率作用的更直接证据可能来自于以下事实：尽管在 MI 病例中观察到 FXIII 抗原显著降低，但无论考虑何种 FXIII 基因型，L34 携带者的 FXIII 活性几乎保持正常（VV34 与 L34 携带者相比；P < 0.001）。我们得出结论，FXIII L34 等位基因在所有分析的组中均能提高 MI 后的存活率，可能是通过其较高的活性以及对心肌愈合和功能恢复的假定积极作用。基因决定的较高 FXIII 活性可能会影响 MI 后的结局。这为使用 FXIII 分子改善心肌愈合、功能恢复和梗死后存活率铺平了道路。
