Reperfusion injury medical therapy

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Editors-In-Chief: Anjan K. Chakrabarti, M.D. [1]; C. Michael Gibson, M.S., M.D. [2]

Medical Therapy

Various proposed medical managements studied are:

• Therapeutic hypothermia
  • It has been shown in rats that neurons sometimes die completely 24 hours after the blood flow returns. Some claim that this delayed reaction is the result of the multiple inflammatory immune responses that occur during reperfusion. Such inflammatory reactions cause intracranial pressure, a pressure that leads to cell damage and cell death in some cases. Hypothermia has been shown to help reduce intracranial pressure and thus decrease the adverse effects of inflammatory immune responses during reperfusion. Besides that, reperfusion also increases free radical development. Hypothermia has also been shown to decrease the patient's development of deadly free radicals during reperfusion.  

• Hydrogen sulfide treatment
  • There are several preliminary studies in mice that seem to show that treatment with hydrogen sulfide ( H2S) could have a protective effect against reperfusion injury..

• Cyclosporine
  • In addition to its well-known immunosuppressive capabilities, the one-time administration of cyclosporine at the time of percutaneous coronary intervention (PCI) has been found to deliver a 40 percent reduction in infarct size in a small group proof of concept study of human patients with reperfusion injury published in The New England Journal of Medicine in 2008.
  • Cyclosporine has been confirmed in studies to inhibit the actions of cyclophilin D, a protein which is induced by excessive intracellular calcium flow to interact with other pore components and help open the MPT pore. Inhibiting cyclophilin D has been shown to prevent the opening of the MPT pore and protect the mitochondria and cellular energy production from excessive calcium inflows.
  • Reperfusion leads to biochemical imbalances within the cell that lead to cell death and increased infarct size. More specifically, calcium overload and excessive production of reactive oxygen species in the first few minutes after reperfusion set off a cascade of biochemical changes that result in the opening of the so-called mitochondrial permeability transition pore (MPT pore) in the mitochondrial membrane of cardiac cells.
  • The opening of the MPT pore leads to the inrush of water into the mitochondria, resulting in mitochondrial dysfunction and collapse. Upon collapse, the calcium is then released to overwhelm the next mitochondria in a cascading series of events that cause mitochondrial energy production supporting the cell to be reduced or stopped completely. The cessation of energy production results in cellular death. Protecting mitochondria is a viable cardio protective strategy.
  • Cyclosporine is currently in a phase II/III (adaptive) clinical study in Europe to determine its ability to ameliorate neuronal cellular damage in traumatic brain injury.

• TRO40303
  • TRO40303 is a new cardio protective compound that was shown to inhibit the MPT pore and reduce infarct size after ischemia-reperfusion.

• Stem cell therapy
  • Recent investigations suggest a possible beneficial effect of mesenchymal stem cells on heart and kidney reperfusion injury

• Superoxide dismutase
  • Superoxide dismutase is an important antioxidant enzyme that transforms superoxide anions to water and hydrogen peroxide. Recent work has demonstrated important therapeutic effects on pre-clinical models of reperfusion damage following an ischemic stroke .

• Metformin
  • A series of 2009 studies published in the Journal of Cardiovascular Pharmacology indicate that metformin may prevent injury to cardiac reperfusion by inhibiting Mitochondrial Complex I and opening up MPT pore and in rats.

• Cannabinoids
  • A research published in 2012 shows that the synthetic analog of phytocannabinoid tetrahydrocannabivarin (THCV), 8-Tetrahydrocannabivarin (THCV) and its 11-OH-8-THCV metabolite prevents hepatic ischemia / reperfusion injury by minimizing oxidative stress and inflammatory reactions through cannabinoid CB2 receptors, thereby lowering tissue damage and protective effects of inflammation. Pretreatment with a CB2 receptor antagonist, whereas a CB1 antagonist appeared to strengthen it, attenuated the defensive effects of somewhere else.
  • An earlier study published in 2011 found that cannabidiol (CBD) also protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signals and oxidative and nitrative stress response, resulting in cell death and tissue damage, but is independent of classic CB1 and CB2 receptors.

Therapies Associated with Limited Success

Pharmacotherapies that have either failed or that have met with limited success in improving clinical outcomes include:

1. Beta-blockade
2. GIK (glucose-insulin-potassium infusion) (Studied in the Glucose-Insulin-Potassium Infusion in Patients With Acute Myocardial Infarction Without Signs of Heart Failure: The Glucose-Insulin-Potassium Study (GIPS)-II and other older studies
3. Sodium-hydrogen exchange inhibitors such as cariporide (Studied in the GUARDIAN and EXPIDITION trials)
4. Adenosine (Studied in the AMISTAD I and AMISTAD II trials as well as the ATTACC trial ). It should be noted that at high doses in anterior ST elevation MIs, adenosine was effective in the AMISTAD trial. Likewise, intracoronary administration of adenosine prior to primary PCI has been associated with improved echocardiographic and clinical outcomes in one small study.
5. Calcium-channel blockers
6. Potassium–adenosine triphosphate channel openers
7. Antibodies directed against leukocyte adhesion molecules such as CD 18 (Studied in the LIMIT AMI trial )
8. Oxygen free radical scavengers/anti-oxidants, including Erythropoietin, estrogen, heme-oxygenase 1, and hypoxia induced factor-1 (HIF-1).
9. Pexelizumab, a humanized monoclonal antibody that binds the C5 component of complement (Studied in the Pexelizumab for Acute ST-Elevation Myocardial Infarction in Patients Undergoing Primary Percutaneous Coronary Intervention (APEX AMI) trial )
10. KAI-9803, a delta-protein kinase C inhibitor (Studied in the Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction trial or DELTA AMI trial).
11. Human atrial natriuretic peptide (Studied in the Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials.)
12. FX06, an anti-inflammatory fibrin derivative that competes with fibrin fragments for binding with the vascular endothelial molecule VE-cadherin which deters migration of leukocytes across the endothelial cell monolayer (studied in the F.I.R.E. trial (Efficacy of FX06 in the Prevention of Myocardial Reperfusion Injury)
13. Magnesium, which was evaluted by the Fourth International Study of Infarct Survival (ISIS-4) and the MAGIC trial.
14. Hypothermia
15. Hyperoxemia, the delivery of supersaturated oxygen after PCI (Studied in the AMIHOT II trial).
16. Bendavia studied in the EMBRACE STEMI trial

Therapies Associated with Improved Clinical Outcomes

Therapies that have been associated with improved clinical outcomes include:

1. Post conditioning (short repeated periods of vessel opening by repeatedly blowing the balloon up for short periods of time).
   • Mechanisms of protection include formation and release of several autacoids and cytokines, maintained acidosis during early repercussion, activation of protein kinases, and attenuation of opening of the mitochondrial permeability transition pore (MPTP)
   • One study in humans demonstrated an area under the curve (AUC) of creatine kinase (C) release over the first 3 days of reperfusion (as a surrogate for infarct size) was significantly reduced by 36% in the postconditioned versus control group
   • Infarct size reduction by PCI postconditioning persisted 6 months after AMI and resulted in a significant improvement in left ventricular (LV) function at 1 year
2. Inhibition of mitochondrial pore opening by cyclosporine.
   • Specifically, the study by Piot et al demonstrated that administration of cyclosporine at the time of reperfusion was associated with a reduction in infarct size
   • Infarct size was measured by the release of creatine kinase and delayed hyperenhancement on MRI
   • Patients with cardiac arrest, ventricular fibrillation, cardiogenic shock, stent thrombosis, previous acute myocardial infarction, or angina within 48 hours before infarction were not included in the study #*Occlusion of the culprit artery (TIMI flow 0) was part of the inclusion criteria.

Limitations to applying strategies that have demonstrated benefit in animal models is the fact that reperfusion therapy was administered prior to or at the time of reperfusion. In the management of STEMI patients, it is impossible to administer the agent before vessel occlusion (except during coronary artery bypass grafting). Given the time constraints and the goal of opening an occluded artery within 90 minutes, it is also difficult to administer experimental agents before reperfusion in STEMI.

There are several explanations for why trials of experimental agents have failed in this area:

1. The therapy was administered after reperfusion and after reperfusion injury had set in
2. The greatest benefit is observed in anterior ST elevation myocardial infarctions (as demonstrated in the AMISTAD study), and inclusion of non anterior locations minimizes the potential benefit
3. There are uninhibited redundant pathways mediating reperfusion injury
4. Inadequate dosing of the agent