Fichtlscherer S, Rössig L, Breuer S, Vasa M, Dimmeler S, Zeiher A M
Department of Internal Medicine IV, Division of Cardiology, Johann W. Goethe-University Frankfurt, Germany.
Circulation. 2001 Dec 18;104(25):3023-5. doi: 10.1161/hc5001.101749.
Anti-tumor necrosis factor (TNF)-alpha therapy with etanercept, a recombinant TNF receptor that binds to and functionally inactivates TNF-alpha, was shown to improve the functional status of patients with congestive heart failure (CHF). Because administration of TNF-alpha has been shown experimentally to depress endothelium-dependent relaxation, we hypothesized that TNF-alpha antagonism with etanercept might improve the depressed systemic endothelial vasodilator function, which importantly contributes to increased peripheral vascular resistance in patients with advanced CHF.
Endothelium-dependent (acetylcholine, ACH; 10 to 50 microgram/min) and endothelium-independent (sodium nitroprusside, SNP; 2 to 8 microgram/min) forearm blood flow (FBF) responses were measured by venous occlusion plethysmography in 13 patients with documented CHF (New York Heart Association class III) before, 6 hours after, and 7 days after subcutaneous injection of a single dose of 25 mg etanercept. Maximum ACH-induced FBF increased significantly from 6.9+/-1.0 to 13.0+/-1.6 mL/min per 100 mL of forearm tissue (P<0.05) 6 hours after administration of etanercept and returned to 7.0+/-1.1 mL/min per 100 mL of forearm tissue after 7 days (P=NS), whereas SNP-induced FBF responses were not significantly affected. In contrast, FBF responses were not altered in control CHF patients, who did not receive etanercept (n=5). Etanercept-induced increases in ACH-mediated FBF were closely correlated with baseline TNF-alpha serum levels (r=0.66; P<0.02).
The administration of etanercept profoundly improves systemic endothelial vasodilator capacity in patients with advanced heart failure, suggesting an important role of inflammatory mediators for impaired endothelial vasoreactivity in CHF. Improvement of systemic endothelial function might importantly contribute to the beneficial effects of etanercept on the functional status of patients with CHF.
用依那西普进行抗肿瘤坏死因子（TNF）-α治疗，依那西普是一种重组TNF受体，可与TNF-α结合并使其功能失活，已证明该治疗可改善充血性心力衰竭（CHF）患者的功能状态。因为实验表明给予TNF-α会抑制内皮依赖性舒张，我们推测用依那西普拮抗TNF-α可能会改善受损的全身内皮血管舒张功能，这在晚期CHF患者外周血管阻力增加中起重要作用。
通过静脉阻塞体积描记法测量13例确诊为CHF（纽约心脏协会III级）患者在皮下注射单剂量25mg依那西普之前、之后6小时和7天后的内皮依赖性（乙酰胆碱，ACH；10至50μg/分钟）和内皮非依赖性（硝普钠，SNP；2至8μg/分钟）前臂血流量（FBF）反应。依那西普给药6小时后，最大ACH诱导的FBF从每100mL前臂组织6.9±1.0显著增加至13.0±1.6mL/分钟（P<0.05），7天后恢复至每100mL前臂组织7.0±1.1mL/分钟（P=无显著性差异），而SNP诱导的FBF反应未受到显著影响。相比之下，未接受依那西普的对照CHF患者（n=5）的FBF反应未改变。依那西普诱导的ACH介导的FBF增加与基线TNF-α血清水平密切相关（r=0.66；P<0.02）。
给予依那西普可显著改善晚期心力衰竭患者的全身内皮血管舒张能力，提示炎症介质在CHF内皮血管反应性受损中起重要作用。全身内皮功能的改善可能对依那西普对CHF患者功能状态的有益作用起重要作用。
