The Effects of Intravenous Heme Arginate on Heme Oxygenase-1 Expression (HO-1) and Oxidative Stress in the Human Heart

Study Overview
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Brief Summary
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Ischemia reperfusion injury may be attenuated by HO-1 induction. Our previous data confirmed strong HO-1 induction in peripheral blood cells following heme arginate infusion in healthy humans. Furthermore, we could demonstrate the amelioration of experimental ischemia reperfusion injury in the calf musculature by heme arginate in healthy subjects as measured by functional MRI. Therefore, we propose that HO-1 induction in the human heart may be a suitable target to mitigate cardiac ischemia-reperfusion injury. The HO-1 induction will be assessed in a clinical trial by myocardial biopsy prior to and after aortic cross-clamping in subjects with or without preceding heme arginate treatment in two different dosages. The HO-1 expression will also be measured in the clinical trials in peripheral blood mononuclear cells. As additional outcome, levels of myoglobin, creatine-kinase and troponin T and reactive oxygen species will be measured in plasma according to standard laboratory procedures.

Official Title
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Pilot Trial: The Effects of Intravenous Heme Arginate on HO-1 Expression and Oxidative Stress in the Human Heart

Conditions
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Myocardial Ischemia

Intervention / Treatment
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* Drug: Heme arginate 3mg/kg
* Drug: Heme arginate 1mg/kg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Signed informed consent Men and women aged between 40 and 85 years (inclusive) Body mass index < 35 kg/m2 Ability to communicate well with the investigator in the local language and to understand and comply with the requirements of the study Exclusion criteria (any of the following): Known hypersensitivity to the study drug or any excipients of the drug formulation Treatment with another investigational drug within 3 weeks prior to screening History or clinical evidence of any disease and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism or excretion of the study drug Severe renal failure (glomerula filtration rate < 30 ml/min) Moderately or severe impaired left ventricular function (ejection fraction < 40%) Moderately or severe impaired right ventricular function Systolic pulmonary pressure > 45 mmHg Acute or recent (<7 days) myocardial infarction Child bearing potential

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Heme arginate (high dose)<br>24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump. | Drug: Heme arginate 3mg/kg<br> <br> * Other names: Normosang;|
| Experimental: Heme arginate (low dose)<br>24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump. | Drug: Heme arginate 1mg/kg<br> <br> * Other names: Normosang;|
| Placebo Comparator: Placebo<br>24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution. | Drug: Placebo<br> <br> * Other names: 0.9% sodium chloride solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heme Oxygenase-1 (HO-1) Messenger Ribonucleic Acid (mRNA) Levels (Atrial Tissue) | The right atrial appendage was clamped and cut for cannulation before cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling. | intraoperative | 
| Myocardial HO-1 mRNA Levels (Ventricular Tissue Before Aortic Cross-clamping) | A small biopsy was taken from the right ventricular free wall directly before aortic cross-clamping. The tissue samples were snap-frozen in the operating theater after sampling. | intraoperative | 
| Myocardial HO-1 mRNA Levels (Ventricular Tissue After Aortic Cross-clamping) | A small biopsy was taken from the right ventricular free wall after aortic clamp release before weaning from cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling. | intraoperative | 
| Myocardial HO-1 Protein Concentrations (Atrial Tissue) | The right atrial appendage was clamped and cut for cannulation before cardiopulmonary bypass.The tissue samples were snap-frozen. Western blot analysis was performed. The amount of HO-1 protein (quantified as pixels under the curve) was evaluated. | intraoperative | 
| Myocardial HO-1 Protein Concentrations (Ventricular Tissue Before Aortic Cross-clamping) | A small biopsy was taken from the right ventricular free wall directly before aortic cross-clamping. The tissue samples were snap-frozen. Western blot analysis was performed. The amount of HO-1 protein (quantified as pixels under the curve) was evaluated. | intraoperative | 
| Myocardial HO-1 Protein Concentrations (Ventricular Tissue After Aortic Cross-clamping) | A small biopsy was taken from the right ventricular free wall after aortic clamp release before weaning from cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling. Western blot analysis was performed. The amount of HO-1 protein (quantified as pixels under the curve) was evaluated. | intraoperative | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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carboxyhemoglobin, neutrophil, reactive oxygen species, reperfusion injury