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

doi:10.1016/j.ahj.2009.03.007

American Heart Journal

Volume 157, Issue 6, June 2009, Pages 1035-1041

https://doi.org/10.1016/j.ahj.2009.03.007 Get rights and content

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.

Section snippets

Study patients and trial protocol

The design of the HORIZON-HF trial (www.clinicaltrials.gov identifier, NCT00616161) has been reported previously.¹⁸ Briefly, HORIZON-HF was a randomized, double-blind, placebo-controlled study designed to test the effects of short-term infusion of istaroxime on hemodynamics, echocardiography, neurohormones, renal function, and troponin release in patients hospitalized with AHFS and EF ≤35%. The study protocol was approved by site-specific independent institutional ethics committees and

Results

The baseline characteristics of the study patients (Table I) have previously been reported in detail.²⁴ At baseline, the study patients had hemodynamic evidence of AHFS, with elevated right atrial pressure, elevated PCWP, and decreased cardiac index (Table II). Echocardiography confirmed that the study cohort was made up of patients with LV enlargement and severe LV systolic dysfunction (mean EF 27% ± 7%). Most of the study patients also had concomitant LV diastolic dysfunction evidenced by

Discussion

Using tissue Doppler imaging and pressure-volume analysis, we have shown that istaroxime has a wide variety of beneficial effects on cardiac systolic and diastolic performance and appears to decreases LV diastolic stiffness compared to placebo. To our knowledge, this is the first randomized controlled trial in AHFS to use tissue Doppler imaging and pressure-volume parameters as outcomes.

Istaroxime, which allows for cytosolic calcium accumulation during systole (creating a positive inotropic

Disclosures

Dr Shah is supported by the American Society of Echocardiography Career Development Award, American Heart Association Scientist Development Grant, Northwestern Memorial Foundation Dixon Translational Research Award, and an Entilligence Young Investigators Award from Actelion (Allschwil, Switzerland). Dr Blair has no disclosures. Dr Gheorghiade reports receiving research grants from the National Institutes of Health, Otsuka (Tokyo, Japan), Sigma-Tau (Rome, Italy), Merck (Whitehouse Station, NJ),

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: Clinicaltrials.gov identifier: NCT00616161.

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Background

Methods

Results

Conclusions

Section snippets

Study patients and trial protocol

Results

Discussion

Disclosures

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