Hemodynamic properties of a new-generation positive luso-inotropic agent for the acute treatment of advanced heart failure.

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.

A phase 1-2 dose-escalating study evaluating the safety and tolerability of istaroxime and specific effects on electrocardiographic and hemodynamic parameters in patients with chronic heart failure with reduced systolic function.

Istaroxime (PST2744) is a luso-inotrope that stimulates the sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a without chronotropic effects. Additionally, it has beneficial effects on myocardial energetics. This phase 1-2 clinical trial in patients with chronic stable heart failure (HF) is the first evaluation of istaroxime in humans. Three cohorts of 6 patients each were exposed to 4 sequentially increasing 1-hour infusions with a random placebo. Doses were 0.005-5.0 micro/kg per min. Safety and hemodynamics were evaluated by impedance cardiography, digital Holter recorder, and electrocardiography. Pharmacokinetic data were obtained for 1 hour during treatment and for 6 hours after dosing. The mean age was 53+/-7 years, and the mean left ventricular ejection fraction was 0.27+/-0.08. Impedance cardiography demonstrated enhanced contractility as measured by the acceleration index, left cardiac work index, cardiac index, and pulse pressure at doses>or=1 micro/kg per min, with evidence of activity at doses of 0.5 micro/kg per min. Istaroxime shortened QTc. After infusion, the hemodynamic effect rapidly dissipated over 1-2 hours. Istaroxime was pharmacologically active and well tolerated at doses up to 3.33 micro/kg per min. Side effects were related to gastrointestinal symptoms and injection site pain at higher doses, which dissipated within minutes after the infusion ended. Ventricular ectopy was not altered. This study suggests that istaroxime is potentially useful in the treatment of HF and may offer a unique treatment for systolic and/or diastolic dysfunction. Additional studies are under way to further define its utility in acute HF.