The purpose of this study is to determine the minimum effective dose of Istaroxime, in patients requiring hospitalization for deterioration of chronic heart failure and left ventricular systolic dysfunction. This goal will be reached by comparing the hemodynamic effect of three different doses of the drug versus placebo. Efficacy will be measured as a change in Pulmonary Capillary Wedge Pressure from pre-infusion to the last assessment at six hours intravenous infusion.Secondary objectives will be to evaluate safety, tolerability and efficacy on other main hemodynamic parameters, echocardiographic and echo-doppler measurements, plus preliminary pharmacokinetics of the drug.

Congestive heart failure is one of the most common cardiovascular conditions and it is presently reaching epidemic proportions. The prevalence of chronic heart failure has risen specifically as a result of the increased longevity and longer survival after myocardial infarction. In 2003, over one million hospitalization with a primary diagnosis of heart failure occurred in the United States of America, and a similar number has been reported in Europe, too. At present, approximately 5 million Americans are estimated to suffer of this syndrome and the number is expected to continue to increase with the increase and aging of the population. Despite advances in treatment, the mortality remains high in U.S.A. as in Europe, with nearly three hundred thousands patients dying of CHF as the primary or contributory cause each year.

The total number of hospital admissions approaches 3 million yearly when HF is listed as a primary or secondary diagnosis. Although these patients have a relatively low mortality during the hospitalization (less than 4%), the readmission rates within 60 days of discharge range from 20 to 30% and mortality within 60 days of discharge is 5 - 10%.

The primary aim of acute treatment of worsening CHF is to alleviate the symptoms of congestion and edema, improve the hemodynamic profile, and preserve renal function without causing myocardial injury. Improved hemodynamics usually results in relief of primary symptoms like dyspnea and edema and in a consequent improved sense of wellbeing and mental status. The improvement in hemodynamics may persist after the pharmacological interventions used in the acute phase are withdrawn.

The need in this setting is to decrease the filling pressures (RA pressure and PCWP), increase cardiac output, without increasing the heart rate and inducing/worsening atrial or ventricular arrhythmias. In addition, the agent should improve diastolic function, modulate the exaggerated neurohormonal responses to CHF and preserve/protect the viable but non contractile myocardium (e.g.: the hibernated myocardium). The agent should also facilitate the earlier start of life-saving therapies (e.g. beta - blockers).Pre-clinical data on Istaroxime show that this drug increases contractility without increasing heart rate and oxygen consumption; furthermore it is improving diastolic dysfunction and it not causing vasodilatation.

Inclusion Criteria:

• Signing of a written informed consent form.
• Male or female patients aged between 18 and 85 years.
• Negative pregnancy test at screening, for women of childbearing potential.
• Body weight less or equal to 100 kg.
• Blood pressure not more than SAP=150 or DAP=90 mmHg.
• Heart rate in the range of 60-110 bpm
• Adequate Echo window available.
• Hospital admission to a monitored bed with a primary diagnosis of worsening of heart failure and LV Ejection Fraction less or equal to 35% documented by 2D-Echocardiogram, or radionuclide angiography or LV angiogram within 6 months prior to screening or at hospitalization.
• the clinical condition of the patient are stabilized within 48 hours from hospitalization and do not require continuous iv drug treatments
• no need for additional new oral treatments or any intravenous treatment administration over the following 8 hours is foreseen

Randomisation period inclusion criteria:

• Any residual sign of heart failure (e.g.: Jugular Venous Distension, and/or Rales and/or Peripheral Oedema) associated with a PCWP more or equal to 20 mmHg,
• The last three consecutive determinations of PCWP, obtained during the stabilization period, have to be in a maximum range of variability of 10%.

Exclusion Criteria:

• Ongoing treatment with oral or intravenous inotropes and/or inodilators.
• Patient treated with digoxin within the last week, can be randomised if the plasma concentration of digoxin are tested before randomisation and its value will be less than 0.5 ng/ml.
• Intermittent inotropes administration within 2 weeks.
• Symptoms of Heart Failure at randomization e.g.: dyspnoea
• Systolic blood pressure < 90 mmHg.
• Atrial fibrillation within 2 weeks.
• Left Ventricular Bundle Branch Block
• Cardiogenic shock or mechanical ventilation.
• Creatinine level > 3.0 mg/dl or requiring dialysis treatment.
• Left ventricular failure primarily from uncorrected obstructive valvular disease, hypertrophic obstructive cardiomyopathy, restrictive/obstructive cardiomyopathy, uncorrected thyroid disease, known acute myocarditis, known amyloid cardiomyopathy.
• Artificial heart valve.
• Electrical device implanted (ICD, CRT)
• Evidence of acute coronary syndrome within 3 months.
• History of stroke or transient ischemic attack in the 6 months prior to screening.
• History of sustained ventricular tachycardia.
• Coronary by-pass grafting or PTCA within the last 30 days
• INR > 1.5.
• Status post successful cardiac resuscitation.
• Serum K < 3.5 mEq/l or > 5.3 mEq/l just prior to treatment.
• ALT, AST > 3 times the upper normal limit just prior to treatment.
• Hemoglobin < 10 g/dl (either gender) just prior to treatment.
• Other clinically significant laboratory or medical conditions, which in the opinion of the Investigator make the patient unsuitable for evaluation in the study.
• Anticipated survival of less than 2 months for concomitant diseases.