Sabbah Hani N, Imai Makoto, Cowart Doug, Amato Antonino, Carminati Paolo, Gheorghiade Mihai
Division of Cardiovascular Medicine, Department of Medicine, Henry Ford Health System, Detroit, Michigan 48202, USA.
Am J Cardiol. 2007 Jan 22;99(2A):41A-46A. doi: 10.1016/j.amjcard.2006.09.005. Epub 2006 Sep 18.
Currently available positive inotropic agents, such as dobutamine and milrinone, although needed as "rescue therapy" for patients with acute decompensated heart failure (ADHF), are not ideal drugs because of an inherent adverse side-effect profile. This study examined the hemodynamic effects of istaroxime, a novel agent with positive inotropic and lusitropic (luso-intropic) effects, under investigation for the treatment of ADHF. Studies were performed in 7 dogs with advanced heart failure (HF). Each dog received intravenous istaroxime or saline solution in random order 1 week apart in equal volume/volume escalating doses, with each dose maintained for 1 hour. Escalating istaroxime doses of 0.5, 1.0, 2.0, 3.0, and 5.0 microg/kg per min were used. Hemodynamic, ventriculographic, and 2-dimensional echocardiographic and Doppler indices of left ventricular (LV) systolic and diastolic function were made at baseline and at the end of each hour of each dose of istaroxime or saline solution used. Electrocardiographic results were monitored throughout the study for development of de novo arrhythmias. Results showed that saline solution had no effect on any hemodynamic, ventriculographic, echocardiographic, or Doppler indices of LV function. Compared with baseline, istaroxime had no effect on heart rate, with only a modest reduction of mean aortic pressure at high doses. Istaroxime decreased LV end-diastolic and end-systolic volumes and significantly increased LV ejection fraction in a dose-dependent manner from 0.25+/-0.01 to 0.42+/-0.02 at the highest dose (p<0.05), without increasing myocardial oxygen consumption (194+/-21 micromol/min at baseline to 144+/-20 micromol/min at the highest dose, p<0.05). In addition, istaroxime significantly reduced LV end-diastolic pressure and end-diastolic wall stress and increased deceleration time of early mitral inflow velocity. None of the doses administered were associated with the development of de novo arrhythmias. In dogs with advanced HF, istaroxime elicits potent positive luso-intropic effects. Unlike classic cyclic adenosine monophospate-dependent positive inotropic agents, istaroxime elicits its benefits without increasing myocardial oxygen consumption or heart rate. These results suggest that istaroxime may be a unique positive luso-inotropic agent for the treatment of patients with ADHF.
目前可用的正性肌力药物，如多巴酚丁胺和米力农，虽然作为急性失代偿性心力衰竭（ADHF）患者的“挽救疗法”是必需的，但由于其固有的不良副作用，并非理想药物。本研究考察了新型正性肌力和变时性（变时性）药物伊伐肟治疗ADHF时的血流动力学效应。研究在7只晚期心力衰竭（HF）犬身上进行。每只犬以随机顺序，每隔1周接受等体积/体积递增剂量的静脉注射伊伐肟或生理盐水，每个剂量维持1小时。使用的伊伐肟递增剂量为每分钟0.5、1.0、2.0、3.0和5.0微克/千克。在基线以及使用伊伐肟或生理盐水每个剂量的每小时末，记录左心室（LV）收缩和舒张功能的血流动力学、心室造影、二维超声心动图和多普勒指标。在整个研究过程中监测心电图结果，以观察新发心律失常的发生情况。结果显示，生理盐水对LV功能的任何血流动力学、心室造影、超声心动图或多普勒指标均无影响。与基线相比，伊伐肟对心率无影响，仅在高剂量时平均主动脉压有适度降低。伊伐肟以剂量依赖性方式降低LV舒张末期和收缩末期容积，并显著增加LV射血分数，最高剂量时从0.25±0.01增加到0.42±0.02（p<0.05），且不增加心肌耗氧量（基线时为194±21微摩尔/分钟，最高剂量时为144±20微摩尔/分钟，p<0.05）。此外，伊伐肟显著降低LV舒张末期压力和舒张末期壁应力，并增加二尖瓣早期血流速度的减速时间。所给予的任何剂量均与新发心律失常的发生无关。在晚期HF犬中，伊伐肟可产生强大的正性变时性效应。与经典的环磷酸腺苷依赖性正性肌力药物不同，伊伐肟在不增加心肌耗氧量或心率的情况下发挥其益处。这些结果表明，伊伐肟可能是治疗ADHF患者的一种独特的正性变时性药物。
