Hildemann Steven K, Schulz Christian, Fraccarollo Daniela, Schöpp Corinna, Flierl Ulrike, Wissel Kerstin, Pelisek Jaroslav, Massberg Steffen, Bauersachs Johann, Schäfer Andreas
Prof. Dr. Andreas Schäfer, Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany, Tel.: +49 511 532 5240, Fax: +49 511 532 8244, E-mail:
Thromb Haemost. 2014 Apr 1;111(4):725-35. doi: 10.1160/TH13-08-0640. Epub 2013 Dec 12.
Endothelial dysfunction and enhanced platelet reactivity in congestive heart failure (CHF) contribute to poor prognosis. CHF patients display an impaired responsiveness to clopidogrel. Fractalkine activates platelets and elevated plasma levels of this chemokine are a feature of CHF. We here addressed the interrelation of fractalkine, platelet reactivity and clopidogrel efficacy in humans and rats with CHF. Fractalkine serum levels determined by ELISA were increased in CHF patients (CHF: 1548 ± 650 pg/ml;
968 ± 575 pg/ml, p<0.01) and following CHF induction in rats (CHF: 1509 ± 753 pg/ml; Sham: 1181 ± 275 pg/ml, p<0.05). Expression of fractalkine and its receptor CX3CR1 was enhanced in aortas of CHF rats as determined by immunofluorescence microscopy and molecular analysis. Fractalkine significantly aggravated endothelial dysfunction and augmented P-selectin expression on platelets from CHF rats. Platelet surface expression of CX3CR1 was increased in CHF rats, who displayed an impaired response to clopidogrel (platelet reactivity to ADP: CHF 30 ± 22%; Sham: 8 ± 5%, p<0.05). Similarly in humans with CHF, elevated fractalkine levels were accompanied by reduced clopidogrel responsiveness. Patients with high on-clopidogrel treatment platelet P2Y12 reactivity displayed higher fractalkine levels (1525 ± 487 pg/ml) than those with sufficient clopidogrel response (684 ± 315 pg/ml, p<0.01). In conclusion, in CHF fractalkine was increased on the endothelium and in blood serum, and platelet surface-expression of CX3CR1 was enhanced. Fractalkine diminished endothelial function beyond the impairment already observed in CHF and was associated with a reduced responsiveness to the platelet inhibitor clopidogrel. These findings may indicate a novel pathophysiological mechanism contributing to impaired clopidogrel responsiveness in CHF.
充血性心力衰竭（CHF）中的内皮功能障碍和血小板反应性增强会导致预后不良。CHF患者对氯吡格雷的反应性受损。趋化因子激活血小板，这种趋化因子的血浆水平升高是CHF的一个特征。我们在此探讨了趋化因子、血小板反应性和氯吡格雷疗效在CHF患者和大鼠中的相互关系。通过ELISA测定的趋化因子血清水平在CHF患者中升高（CHF：1548±650 pg/ml；对照组：968±575 pg/ml，p<0.01），在大鼠诱导CHF后也升高（CHF：1509±753 pg/ml；假手术组：1181±275 pg/ml，p<0.05）。通过免疫荧光显微镜和分子分析确定，趋化因子及其受体CX3CR1在CHF大鼠主动脉中的表达增强。趋化因子显著加重了CHF大鼠的内皮功能障碍，并增加了血小板上P-选择素的表达。CHF大鼠血小板表面CX3CR1的表达增加，这些大鼠对氯吡格雷的反应受损（血小板对ADP的反应性：CHF 30±22%；假手术组：8±5%，p<0.05）。同样，在CHF患者中，趋化因子水平升高伴随着氯吡格雷反应性降低。接受氯吡格雷治疗的血小板P2Y12反应性高的患者趋化因子水平（1525±487 pg/ml）高于氯吡格雷反应充分者（684±315 pg/ml，p<0.01）。总之，在CHF中，内皮和血清中的趋化因子增加，血小板表面CX3CR1的表达增强。趋化因子使内皮功能障碍超过了CHF中已观察到的损害，并与血小板抑制剂氯吡格雷的反应性降低有关。这些发现可能表明一种导致CHF中氯吡格雷反应性受损的新的病理生理机制。
