Myocardial Ischemia
Conditions
Keywords
carboxyhemoglobin, neutrophil, reactive oxygen species, reperfusion injury
Brief summary
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.
Interventions
DRUGHeme arginate 3mg/kg
DRUGHeme arginate 1mg/kg
DRUGPlacebo
Sponsors
National Bank of Austria
Orphan Medical
Martin Andreas, M.D.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Heme Oxygenase-1 (HO-1) Messenger Ribonucleic Acid (mRNA) Levels (Atrial Tissue) | intraoperative | 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. |
| Myocardial HO-1 mRNA Levels (Ventricular Tissue Before Aortic Cross-clamping) | intraoperative | 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. |
| Myocardial HO-1 mRNA Levels (Ventricular Tissue After Aortic Cross-clamping) | intraoperative | 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. |
| Myocardial HO-1 Protein Concentrations (Atrial Tissue) | intraoperative | 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. |
| Myocardial HO-1 Protein Concentrations (Ventricular Tissue Before Aortic Cross-clamping) | intraoperative | 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. |
| Myocardial HO-1 Protein Concentrations (Ventricular Tissue After Aortic Cross-clamping) | intraoperative | 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. |
Countries
Austria
Participant flow
Recruitment details
Patients who were scheduled for elective surgical aortic valve replacement were assessed for eligibility after hospitalization at the Medical University of Vienna.
Pre-assignment details
A total of 31 patients signed the informed consent to participate in the study. Of them, 27 patients were assigned to a group and 4 patients (3 patients for organizational reasons and 1 patient for other reasons) were excluded from the study prior to assignment to a group.
Participants by arm
| Arm | Count |
|---|---|
| Heme Arginate (High Dose) 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. | 9 |
| Heme Arginate (Low Dose) 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. | 10 |
| Placebo 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. | 8 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | organizational reasons | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Heme Arginate (Low Dose) | Placebo | Heme Arginate (High Dose) |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 21 Participants | 9 Participants | 5 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 1 Participants | 3 Participants | 2 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — | — |
| Region of Enrollment Austria | 27 participants | 10 participants | 8 participants | 9 participants |
| Sex: Female, Male Female | 16 Participants | 5 Participants | 5 Participants | 6 Participants |
| Sex: Female, Male Male | 11 Participants | 5 Participants | 3 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 10 | 0 / 8 |
| other Total, other adverse events | 1 / 9 | 5 / 10 | 4 / 8 |
| serious Total, serious adverse events | 2 / 9 | 0 / 10 | 1 / 8 |
Outcome results
Primary
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.
Time frame: intraoperative
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Heme Arginate (High Dose) | Heme Oxygenase-1 (HO-1) Messenger Ribonucleic Acid (mRNA) Levels (Atrial Tissue) | 392.7 arbitrary units | Standard Deviation 195.7 |
| Heme Arginate (Low Dose) | Heme Oxygenase-1 (HO-1) Messenger Ribonucleic Acid (mRNA) Levels (Atrial Tissue) | 229.8 arbitrary units | Standard Deviation 173.1 |
| Placebo | Heme Oxygenase-1 (HO-1) Messenger Ribonucleic Acid (mRNA) Levels (Atrial Tissue) | 10.8 arbitrary units | Standard Deviation 8.8 |
p-value: =0.001ANOVA
Primary
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.
Time frame: intraoperative
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Heme Arginate (High Dose) | Myocardial HO-1 mRNA Levels (Ventricular Tissue After Aortic Cross-clamping) | 219.4 arbitrary units | Standard Deviation 162.8 |
| Heme Arginate (Low Dose) | Myocardial HO-1 mRNA Levels (Ventricular Tissue After Aortic Cross-clamping) | 108.1 arbitrary units | Standard Deviation 73.2 |
| Placebo | Myocardial HO-1 mRNA Levels (Ventricular Tissue After Aortic Cross-clamping) | 8.3 arbitrary units | Standard Deviation 5.4 |
p-value: =0.002ANOVA
Primary
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.
Time frame: intraoperative
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Heme Arginate (High Dose) | Myocardial HO-1 mRNA Levels (Ventricular Tissue Before Aortic Cross-clamping) | 203.6 arbitrary units | Standard Deviation 148.7 |
| Heme Arginate (Low Dose) | Myocardial HO-1 mRNA Levels (Ventricular Tissue Before Aortic Cross-clamping) | 88.6 arbitrary units | Standard Deviation 49.1 |
| Placebo | Myocardial HO-1 mRNA Levels (Ventricular Tissue Before Aortic Cross-clamping) | 7.9 arbitrary units | Standard Deviation 5 |
p-value: =0.002ANOVA
Primary
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.
Time frame: intraoperative
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Heme Arginate (High Dose) | Myocardial HO-1 Protein Concentrations (Atrial Tissue) | 29022 pixels under the curve | Standard Deviation 8583 |
| Heme Arginate (Low Dose) | Myocardial HO-1 Protein Concentrations (Atrial Tissue) | 28585 pixels under the curve | Standard Deviation 10692 |
| Placebo | Myocardial HO-1 Protein Concentrations (Atrial Tissue) | 8401 pixels under the curve | Standard Deviation 3889 |
p-value: <0.001ANOVA
Primary
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.
Time frame: intraoperative
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Heme Arginate (High Dose) | Myocardial HO-1 Protein Concentrations (Ventricular Tissue After Aortic Cross-clamping) | 17062 pixels under the curve | Standard Deviation 18164 |
| Heme Arginate (Low Dose) | Myocardial HO-1 Protein Concentrations (Ventricular Tissue After Aortic Cross-clamping) | 11277 pixels under the curve | Standard Deviation 3918 |
| Placebo | Myocardial HO-1 Protein Concentrations (Ventricular Tissue After Aortic Cross-clamping) | 12037 pixels under the curve | Standard Deviation 10962 |
p-value: =0.696ANOVA
Primary
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.
Time frame: intraoperative
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Heme Arginate (High Dose) | Myocardial HO-1 Protein Concentrations (Ventricular Tissue Before Aortic Cross-clamping) | 13752 pixels under the curve | Standard Deviation 8069 |
| Heme Arginate (Low Dose) | Myocardial HO-1 Protein Concentrations (Ventricular Tissue Before Aortic Cross-clamping) | 10534 pixels under the curve | Standard Deviation 4686 |
| Placebo | Myocardial HO-1 Protein Concentrations (Ventricular Tissue Before Aortic Cross-clamping) | 6842 pixels under the curve | Standard Deviation 4343 |
p-value: =0.138ANOVA