Remote Ischemic Postconditioning Increases HIF-1α Plasma Levels and Improves Cardiac Markers After Cardiac Surgery

Study Overview
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Brief Summary
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Background. Cardiopulmonary bypass in on-pump cardiac surgery (OPCS) can have harmful effects by ischemia-reperfusion. No data about the effects of remote ischemic postconditioning (RIP) in hypoxia-inducible factor-1 alpha (HIF-1α) plasma level after OPCS. The aim of this study is evaluate the effects of RIP on postoperative HIF-1α plasma levels, cardiac markers and arterial oxygenation of patients after OPCS. Methods. Randomised controlled study in 70 patients undergoing OPCS: 35 patients receive RIP (RIP group) and 35 patients not (control group). Patients receive RIP on upper limb: 5 min of ischemia followed by 5 min of reperfusion (3 cycles) immediately after leaving on-pump. The primary outcome was to know the HIF-1α plasma levels after surgery in both groups: before starting surgery (T0) and after CPB period at 2 h (T1), 8 h (T2), 24 h (T3), 36 h (T4), 48 h (T5). Secondary outcomes included to measure the cardiac markers levels (Troponin T, CK-MB, CPK), arterial oxygenation (PaO2/FiO2) and others.

Detailed Description
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Cardiac surgery with cardiopulmonary bypass (CPB) is associated with ischemia-reperfusion (I-R) injury. Acute myocardial injury after cardiac surgery is associated with increased mortality and morbidity. In 1993, reported that brief circumflex artery occlusion reduces myocardial infarct size induced by a definitive occlusion of the left anterior descending artery, a phenomenon which has been named remote ischemic preconditioning (RIPC). This approach confers resistance to subsequent ischemic episodes in remote organs, possibly by transferring protective mediators through humoral, neuronal, and systemic mechanisms, however the mechanisms involved are not yet fully known. A recent study has found that cardioprotection induced by RIPC the mitochondria appear to be an important subcellular effector organelle. It has been reported that RIPC could be a potential protective approach for perioperative complications. Therefore, the effects on myocardial injury and clinical outcome in patients undergoing on-pump cardiac surgery (OPCS) are inconclusive. In the present study, we conducted a randomized clinical trial on patients undergoing OPCS by application of remote ischemic postconditioning (RIP), an alternative to remote ischemic preconditioning. RIP can be applied in different clinical situations, medical or surgical, when reperfusion is initiated and associated to acidosis, nitric oxide formation, mitochondrial permeability transition pore inhibition and reactive oxygen species generation. In the present study we have opted for remote postconditioning because we speculate a possible losses of plasmatic effectors during CPB procedures using polyvinylchloride (PVC) tubing. Since, when blood is exposed to the PVC surface the plasma proteins may be adsorbed. Also to minimize the bleeding or hemodilution effects on the potential protective plasmatic effectors levels during CPB. Tissue exposure to low O2 concentration starts a hypoxic response of the hypoxia-inducible factor 1 (HIF-1), a transcription factor heterodimer, consisting of an O2 regulated HIF-1α subunit and a constitutively expressed HIF-1β subunit that binds to the consensus sequence 5'-RCGTG-3', which is present near HIF-1-regulated genes. HIF-1α protein stability is upregulated in response to hypoxia. HIF-1α protein stability is negatively regulated by O2-dependent prolyl hydroxylation and is degraded under normoxia by prolyl hydroxylase. HIF-1α plays a critical role in the mammalian cells activating genes associate with angiogenesis, ischemia, energy metabolism and cell cycle. The aim of this study carried out in patients undergoing OPCS was the determination of the time course of HIF-1α plasma levels in response to RIP and the possible correlation between aortic cross-clamping time and HIF-1α plasma levels in both groups. HIF-1α role in remote ischemic conditioning (pre or post) is very little known. Therefore, we tested the hypothesis that RIP induces cardiac protection after OPCS and that this is associated to an increase of HIF-1α plasma levels.

Official Title
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Remote Ischemic Postconditioning Increases HIF-1α Plasma Levels and Improves Cardiac Markers After Cardiac Surgery: a Randomised Controlled Study

Conditions
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Ischemia-reperfusion Injury

Intervention / Treatment
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* Procedure: Remote ischemic post-conditioning (RIP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: elective cardiac surgery (coronary arteries and/or valve replacement) ASA physical status III or less Exclusion Criteria: pregnancy previous cardiac surgery myocardial infarction (< 6 weeks) renal failure severe chronic pulmonary disease.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 35 patients receive RIP on upper limb: 5 min of ischemia followed by 5 min of reperfusion (3 cycles) immediately after leaving on-pump. The primary outcome was to know the time course of HIF-1α plasma levels after surgery in both groups and compare the two groups at specific time points: before starting surgery (T0) and after CPB period at 2 h (T1), 8 h (T2), 24 h (T3), 36 h (T4), 48 h (T5). Secondary outcomes included to measure the cardiac markers levels (Troponin T, CK-MB, CPK), arterial oxygenation (PaO2:FiO2) and others.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control group<br>Patients do not receive remote ischemic post-conditioning (RIP) after cardiopulmonary bypass | |
| Experimental: RIP group<br>Patients receive remote ischemic post-conditioning (RIP) after cardiopulmonary bypass | Procedure: Remote ischemic post-conditioning (RIP)<br>* The limb RIP was applied after leaving of cardiopulmonary bypass and consisted of 3 cycles: 5 min of ischemia by a cuff-inflator on an arm and inflated to 200 mmHg, followed by 5 min deflated. The control group had during the same time a deflated cuff.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Study of time course of HIF-1α plasma levels (absorbance units) after on-pump cardiac surgery | Hipoxia induced factor 1 alpha (HIF-1α) is a transcriptional factor. Arterial blood samples were collected from the radial artery to evaluate the changes in HIF-1α plasma levels induced in patients undergoing on-pump cardiac surgery. Because we think that ischemic post-conditioning (RIP) can increase plasma HIF-1α plasma levels. | Before starting surgery, is the basal time (Time 0) | 
| Study of time course of HIF-1α plasma levels (absorbance units) after on-pump cardiac surgery | Hipoxia induced factor 1 alpha (HIF-1α) is a transcriptional factor. Arterial blood samples were collected from the radial artery to evaluate the changes in HIF-1α plasma levels induced in patients undergoing on-pump cardiac surgery. Because we think that ischemic post-conditioning (RIP) can increase plasma HIF-1α plasma levels. | 2 hours after cardiopulmonary bypass period (Time 1) | 
| Study of time course of HIF-1α plasma levels (absorbance units) after on-pump cardiac surgery | Hipoxia induced factor 1 alpha (HIF-1α) is a transcriptional factor. Arterial blood samples were collected from the radial artery to evaluate the changes in HIF-1α plasma levels induced in patients undergoing on-pump cardiac surgery. Because we think that ischemic post-conditioning (RIP) can increase plasma HIF-1α plasma levels. | 8 hours after cardiopulmonary bypass period (Time 2) | 
| Study of time course of HIF-1α plasma levels (absorbance units) after cardiac surgery | Hipoxia induced factor 1 alpha (HIF-1α) is a transcriptional factor. Arterial blood samples were collected from the radial artery to evaluate the changes in HIF-1α plasma levels induced in patients undergoing on-pump cardiac surgery. Because we think that ischemic post-conditioning (RIP) can increase plasma HIF-1α plasma levels. | 24 hours after cardiopulmonary bypass period (Time 3) | 
| Study of time course of HIF-1α plasma levels (absorbance units) after on-pump cardiac surgery | Hipoxia induced factor 1 alpha (HIF-1α) is a transcriptional factor. Arterial blood samples were collected from the radial artery to evaluate the changes in HIF-1α plasma levels induced in patients undergoing on-pump cardiac surgery. Because we think that ischemic post-conditioning (RIP) can increase plasma HIF-1α plasma levels. | 36 hours after cardiopulmonary bypass period (Time 4) | 
| Study of time course of HIF-1α plasma levels (absorbance units) after on-pump cardiac surgery | Hipoxia induced factor 1 alpha (HIF-1α) is a transcriptional factor. Arterial blood samples were collected from the radial artery to evaluate the changes in HIF-1α plasma levels induced in patients undergoing on-pump cardiac surgery. Because we think that ischemic post-conditioning (RIP) can increase plasma HIF-1α plasma levels. | 48 hours after cardiopulmonary bypass period (Time 5). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Study of time course of cardiac marker, Troponin T plasma levels (ng/l) | Troponin T (ng/l) plasma levels. Similar to HIF-1α measures were studied in six arterial blood samples, which were collected from a radial artery line at 6 specific time points (Time 0 to Time 5). | In summary, not repetitive (6 time points): after anesthetic induction, before starting surgery (Time 0) and after cardiopulmonary bypass period, at 2 hrs (Time 1), 8 hrs (Time 2), 24 hrs (Time 3), 36 hrs (T4), 48 hrs (Time 5). | 
| Study of time course of cardiac marker, creatine phospho-kinase (CPK) plasma levels (U/l) | Creatine phospho-kinase (CPK) plasma levels (U/l). Similar to HIF-1α measures were studied in six arterial blood samples, which were collected from a radial artery line at 6 specific time points (Time 0 to Time 5). | In summary, not repetitive (6 time points): after anesthetic induction, before starting surgery (Time 0) and after cardiopulmonary bypass period, at 2 hrs (Time 1), 8 hrs (Time 2), 24 hrs (Time 3), 36 hrs (T4), 48 hrs (Time 5). | 
| Study of time course of cardiac marker, creatine kinase-MB (CK-MB) plasma levels (ng/ml) | Creatine kinase-MB (CK-MB) plasma levels (ng/ml). Similar to HIF-1α measures were studied in six arterial blood samples, which were collected from a radial artery line at 6 specific time points (Time 0 to Time 5). | In summary, not repetitive (6 time points): after anesthetic induction, before starting surgery (Time 0) and after cardiopulmonary bypass period, at 2 hrs (Time 1), 8 hrs (Time 2), 24 hrs (Time 3), 36 hrs (T4), 48 hrs (Time 5). | 
| Study of time course of arterial oxygenation marker (PO2/FiO2), after on-pump cardiac surgery | Oxygenation marker (PO2/FiO2). Similar to HIF-1α measures were studied in six arterial blood samples, which were collected from a radial artery line at 6 specific time points (Time 0 to Time 5). | In summary, not repetitive (6 time points): after anesthetic induction, before starting surgery (Time 0) and after cardiopulmonary bypass period, at 2 hrs (Time 1), 8 hrs (Time 2), 24 hrs (Time 3), 36 hrs (T4), 48 hrs (Time 5). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIF-1α, on-pump cardiac surgery, Remote ischemic postconditioning, postoperative cardiac markers, cardiopulmonary bypass