Effects of istaroxime on diastolic stiffness in acute heart failure syndromes: Results from the Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent: a Randomized Controlled Trial in Patients Hospitalized with Heart Failure (HORIZON-HF) trial

Background Istaroxime is a novel intravenous agent with inotropic and lusitropic properties related to inhibition of the Na + /K + adenosine triphosphatase and stimulation of sarcoplasmic reticulum calcium adenosine triphosphatase activity. We analyzed data from HORIZON-HF, a randomized, controlled trial evaluating the short-term effects of istaroxime in patients hospitalized with heart failure and left ventricular ejection fraction ≤35% to test the hypothesis that istaroxime improves diastolic stiffness in acute heart failure syndrome. Methods One hundred twenty patients were randomized 3:1 (istaroxime/placebo) to a continuous 6-hour infusion of 1 of 3 doses of istaroxime or placebo. All patients underwent pulmonary artery catheterization and comprehensive 2-dimensional/Doppler and tissue Doppler echocardiography at baseline and at the end of the 6-hour infusion. We quantified diastolic stiffness using pressure-volume analysis and tissue Doppler imaging of the lateral mitral annulus (E′). Results Baseline characteristics were similar among all groups, with mean age 55 ± 11 years, 88% men, left ventricular ejection fraction 27% ± 7%, systolic blood pressure (SBP) 116 ± 13 mm Hg, and pulmonary capillary wedge pressure (PCWP) 25 ± 5 mm Hg. Istaroxime administration resulted in an increase in E′ velocities, whereas there was a decrease in E′ in the placebo group ( P = .048 between groups). On pressure-volume analysis, istaroxime decreased end-diastolic elastance ( P = .0001). On multivariate analysis, increasing doses of istaroxime increased E′ velocity ( P = .043) and E-wave deceleration time ( P = .001), and decreased E/E′ ratio ( P = .047), after controlling for age, sex, baseline ejection fraction, change in PCWP, and change in SBP. Conclusions Istaroxime decreases PCWP, increases SBP, and decreases diastolic stiffness in patients with acute heart failure syndrome.