Kourea Kallirrhoe, Parissis John T, Farmakis Dimitrios, Panou Fotios, Paraskevaidis Ioannis, Venetsanou Koula, Filippatos Gerasimos, Kremastinos Dimitrios Th
Second Department of Cardiology and Heart Failure Unit, University of Athens Medical School, Attikon University Hospital, Athens, Greece.
Atherosclerosis. 2008 Jul;199(1):215-21. doi: 10.1016/j.atherosclerosis.2007.09.039. Epub 2007 Nov 7.
Pro-inflammatory cytokine over-expression may be implicated to the pathogenesis of anemia in chronic heart failure (CHF) through the suppression of bone marrow erythropoiesis. Erythropoietin administration has anti-inflammatory and anti-apoptotic properties in experimental CHF models and improves exercise capacity in anemic CHF patients. The present study investigates the effects of recombinant human erythropoietin analogue darbepoetin-alpha on circulating pro-inflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with CHF and anemia. Forty-one CHF patients (NYHA class: II-III; left ventricular (LV) ejection fraction (EF) <40%; hemoglobin <12.5g/dl; serum creatinine <2.5mg/dl) were randomized to receive either 3-month darbepoietin-* at 1.5 microg/kg every 20 days plus iron orally (n=21) or placebo plus iron orally (n=20). LV systolic function, plasma B-type natriuretic peptide (BNP), inflammatory markers (TNF-, IL-6, CRP), anti-inflammatory cytokine IL-10, endothelial adhesion molecules (soluble ICAM-1 and VCAM-1) and soluble apoptosis mediators (soluble Fas, soluble Fas ligand), and 6-min walking distance were assessed at baseline and 3 months post-treatment. In darbepoetin- treated patients, plasma BNP (451 (62-2770) from 802 (476-4440) pg/ml, p=0.002), IL-6 (6.5+/-4.7 from 10.5+/-7.8 pg/ml, p=0.013) and soluble Fas ligand (53.2+/-16.6 from 59.2+/-17.9 pg/ml, p=0.023) decreased significantly, while LVEF (32+/-6 from 26+/-6%, p<0.001), hemoglobin (12.8+/-1.4 from 10.9+/-1.0 g/dl, p<0.001) and 6-min walked distance (274+/-97 from 201+/-113m, p<0.01) increased significantly. No significant changes were observed in the placebo arm, except for a worsening in 6-min walked distance (p=0.044). In conclusion, darbepoetin-alpha reduces circulating pro-inflammatory cytokine IL-6 and apoptotic mediator soluble Fas ligand in CHF patients with anemia, with a parallel improvement of cardiac performance and exercise capacity.
促炎细胞因子的过度表达可能通过抑制骨髓红细胞生成而与慢性心力衰竭（CHF）贫血的发病机制有关。在实验性CHF模型中，促红细胞生成素给药具有抗炎和抗凋亡特性，并可改善贫血CHF患者的运动能力。本研究调查了重组人促红细胞生成素类似物α-达贝泊汀对CHF合并贫血患者循环促炎细胞因子和可溶性Fas/可溶性Fas配体系统的影响。41例CHF患者（纽约心脏协会心功能分级：II-III级；左心室（LV）射血分数（EF）<40%；血红蛋白<12.5g/dl；血清肌酐<2.5mg/dl）被随机分为两组，一组每20天接受1.5μg/kg的α-达贝泊汀治疗3个月并口服铁剂（n=21），另一组接受安慰剂并口服铁剂（n=20）。在基线和治疗后3个月评估左室收缩功能、血浆B型利钠肽（BNP）、炎症标志物（TNF-α、IL-6、CRP）、抗炎细胞因子IL-10、内皮黏附分子（可溶性ICAM-1和VCAM-1）和可溶性凋亡介质（可溶性Fas、可溶性Fas配体），以及6分钟步行距离。在接受α-达贝泊汀治疗的患者中，血浆BNP（从802（476-4440）pg/ml降至451（62-2770）pg/ml，p=0.002）、IL-6（从10.5±7.8pg/ml降至6.5±4.7pg/ml，p=0.013）和可溶性Fas配体（从59.2±17.9pg/ml降至53.2±16.6pg/ml，p=0.023）显著降低，而左室射血分数（从26±6%升至32±6%，p<0.001）、血红蛋白（从10.9±1.0g/dl升至12.8±1.4g/dl，p<0.001）和6分钟步行距离（从201±113m增至274±97m，p<0.01）显著增加。在安慰剂组中未观察到显著变化，除了6分钟步行距离恶化（p=0.044）。总之，α-达贝泊汀可降低CHF合并贫血患者循环中的促炎细胞因子IL-6和凋亡介质可溶性Fas配体，同时改善心脏功能和运动能力。
