Neurohormonal activation in severe heart failure: Relations to patient death and the effect of treatment with flosequinan
Neurohormonal activation in severe heart failure: Relations to patient death and the effect of treatment with flosequinan
复制标题
DOI：
10.1016/s0002-8703(00)90035-8
复制
发表时间：
2000-04-01
影响因子：
4.8
通讯作者：
Packer, M
中科院分区：
文献类型：
--
作者：
Moe, GW;Rouleau, JL;Packer, M
背景氟喹喃是一种直接作用的血管扩张剂，可发挥有益的血流动力学作用，并提高心力衰竭患者的运动耐量。然而，一项多中心试验表明，长期服用氟喹喃与死亡率增加有关。为了探讨神经激素激活对这种不良结果的可能作用，我们进行了一项子研究，以检查已知对心力衰竭有预后影响的3种神经激素系统的血浆水平。方法在20个参与的加拿大中心，在基线和随机分组后1个月配对血浆样本，用于测量N-末端心房钠尿肽（N-ANP），血管紧张素II，234例患者获得去甲肾上腺素（114例接受氟喹喃治疗，120例接受安慰剂治疗）。结果氟喹喃治疗与血浆N-ANP水平中位数下降相关（基线时为2139 pmol/L，1个月时为1625 pmol/L [P = .0001]），血浆血管紧张素II水平不变（40至50 pmol/L [P = .2700]），血浆去甲肾上腺素水平适度升高（391至439 pg/mL [P = .002]）。这些变化在安慰剂组中未观察到。基线变量的多变量分析显示，血浆去甲肾上腺素水平预测患者的死亡，而结合基线和1个月变量的分析表明，血浆N-ANP水平预测患者的死亡。此外，在氟喹喃组中，仅在存活者中观察到血浆N-ANP水平显著下降。多变量分析的基线和1个月的数据，血浆去甲肾上腺素水平的增加并没有预测与使用flosquinan的心率增加，这表明2种影响可能是介导的单独mechanism.Conclusions我们的研究结果表明，在严重的心力衰竭患者，基线去甲肾上腺素水平前饮食死亡。Flosquinan通过超越其有益的血液动力学效应的机制增加这些患者的血浆去甲肾上腺素水平和心率。我们的研究强化了这样一个概念，即药物的直接作用可能比血流动力学效应对这些患者的预后有更深远的影响。
Background Flosequinan is a direct-acting vasodilator that exerts beneficial hemodynamic effects and improves the exercise tolerance of patients with heart failure. However, a multicenter trial has demonstrated that long-term administration of flosequinan is associated with increased mortality rate. To explore a possible role of neurohormonal activation on this adverse outcome, we conducted a substudy to examine the plasma levels of 3 neurohormonal systems known to have prognostic implications in heart failure.Methods At 20 participating Canadian centers, paired plasma samples at baseline and 1 month after randomization for the measurement of N-terminal atrial natriuretic peptide (N-ANP), angiotensin Ii, and norepinephrine were obtained in 234 patients (114 receiving flosequinan and 120 receiving placebo).Results Treatment with flosequinan was associated with a decline in median plasma N-ANP levels (2139 pmol/L at base line to 1625 pmol/L at 1 month [P = .0001]), unchanged plasma angiotensin II levels (40 to 50 pmol/L [P = .2700]), and a modest increase in plasma norepinephrine levels (391 to 439 pg/mL [P = .002]). These changes were riot observed in the placebo group. Multivariate analysis of baseline variables revealed that plasma norepinephrine level predicted patients' death whereas analysis incorporating both baseline and 1-month variables indicated that plasma N-ANP level predicted patients' death. Furthermore, in the flosequinan group, a significant decline in plasma N-ANP level was observed in the survivors only. On multivariate analysis of baseline and 1-month data, the increase in plasma norepinephrine level did not predict the increase in heart rate associated with the use of flosequinan, suggesting that the 2 effects might be mediated by separate mechanisms.Conclusions Results of our study demonstrate that in patients with severe heart failure, baseline norepinephrine level pre diets death. Flosequinan increases plasma norepinephrine level and heart rate in these patients through mechanisms that override its beneficial hemodynamic effects. Our study reinforces the concept that the direct actions of a pharmacologic agent may have a more profound impact on the prognosis of these patients than the hemodynamic effects.