Role of endogenous endothelin in chronic heart failure - Effect of long-term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodeling
Role of endogenous endothelin in chronic heart failure - Effect of long-term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodeling
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DOI：
10.1161/01.cir.96.6.1976
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发表时间：
1997-09-16
期刊：
影响因子：
37.8
通讯作者：
Thuillez, C
中科院分区：
文献类型：
--
作者：
Mulder, P;Richard, V;Thuillez, C
背景：慢性心力衰竭（CHF）患者血浆血管收缩肽内皮素（ET）水平升高，ET水平是CHF患者死亡率的主要预测因子。因此，ET可能在CHF中起有害作用。本研究的目的是评估慢性治疗的效果与ET受体拮抗剂波生坦在大鼠模型的CHF。方法和结果大鼠进行冠状动脉结扎和治疗2或9个月的安慰剂或波生坦（30或100 mg.kg（-1）.d（-1））。波生坦100 mg.kg（-1）显著增加生存率（9个月后：未治疗，47%;波生坦，65%; P < .01）。在整个9个月的治疗期间，波生坦显著降低了动脉压和心率。治疗2个月或9个月后，ET拮抗剂降低了中心静脉压和左心室（LV）舒张末期压以及血浆儿茶酚胺、尿cGMP和LV心室胶原密度。波生坦还减少了LV扩张（在2个月时通过离体压力/容积关系的变化证明）。2个月后进行的超声心动图研究表明，ET拮抗剂减少肥厚和增加非梗死左心室壁的收缩力。较低剂量的波生坦（30 mg.kg（-1））对血流动力学或结构无明显影响，对存活率也无影响。结论：在CHF大鼠模型中，ET拮抗剂长期治疗可显著增加存活率。这种存活率的增加与前负荷和后负荷的降低、心输出量的增加以及LV肥大、LV扩张和心脏纤维化的减少有关。因此，用ET拮抗剂如波生坦长期治疗可能对人CHF有益，并可能增加这种疾病的长期生存率。
Background Plasma levels of the vasoconstrictor peptide endothelin (ET) are increased in chronic heart failure (CHF), and ET levels are a major predictor of mortality in this disease. Thus, ET may play a deleterious role in CHF. The purpose of this study was to assess the effects of chronic treatment with the ET receptor antagonist bosentan in a rat model of CHF.Methods and Results Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg.kg(-1).d(-1)). Bosentan 100 mg.kg(-1) markedly increased survival (after 9 months: untreated, 47%; bosentan, 65%; P < .01). Throughout the 9-month treatment period, bosentan significantly reduced arterial pressure and heart rate. After 2 or 9 months of treatment, the ET antagonist reduced central venous pressure and left ventricular (LV) end-diastolic pressure as well as plasma catecholamines, urinary cGMP, and LV ventricular collagen density. Bosentan also reduced LV dilatation (evidenced at 2 months by a shift in the pressure/volume relationship ex vivo). Echocardiographic studies performed after 2 months showed that the ET antagonist reduced hypertrophy and increased contractility of the noninfarcted LV wall. The lower dose of bosentan (30 mg.kg(-1)), which had no major hemodynamic or structural effects, also had no effect on survival.Conclusions Long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival is associated with decreases in both preload and afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.