Kelland Nicholas F, Webb David J
Clinical Pharmacology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, 3rd Floor East Room E3.22, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
Exp Biol Med (Maywood). 2006 Jun;231(6):696-9.
Circulating plasma endothelin (ET)-1 concentrations are substantially elevated, and correlate with the hemodynamic severity and New York Heart Association (NYHA) class, in patients with chronic heart failure (CHF). In early preclinical studies involving different models of experimental heart failure, ET antagonists reduced cardiac pressures, increased cardiac output, and prolonged survival. ET receptor antagonists also impressively improved systemic and pulmonary hemodynamics in patients with CHF, without causing neurohormonal activation. However, recent clinical trials, including the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) and EARTH (Endothelin A Receptor Antagonist Trial in Heart Failure) studies, have shown neutral effects in terms of mortality and symptoms. This paper describes the possible reasons why benefit was not seen in these clinical studies, and suggests what lessons can be learnt from the way the studies were undertaken to apply to future studies.
在慢性心力衰竭（CHF）患者中，循环血浆内皮素（ET）-1浓度显著升高，且与血流动力学严重程度及纽约心脏协会（NYHA）心功能分级相关。在涉及不同实验性心力衰竭模型的早期临床前研究中，ET拮抗剂可降低心脏压力、增加心输出量并延长生存期。ET受体拮抗剂还显著改善了CHF患者的体循环和肺循环血流动力学，且不会引起神经激素激活。然而，包括ENABLE（内皮素拮抗剂波生坦降低心力衰竭心脏事件）和EARTH（心力衰竭中内皮素A受体拮抗剂试验）研究在内的近期临床试验，在死亡率和症状方面显示出中性效果。本文描述了这些临床研究未观察到获益的可能原因，并提出从这些研究的开展方式中可以吸取哪些教训以应用于未来研究。
