The Effect of Melatonin on Ischemia-reperfusion Injury Following Acute Myocardial Infarction

Purpose The purpose of this Ph.D study is to examine the antioxidative effect of melatonin in relation to ischemia-reperfusion injury.

The investigators wish to examine to which extend melatonin administered to patients undergoing primary PCI for acute myocardial infarction will reduce the damage of the myocardium caused by ischemia-reperfusion injury and thereby hopefully improve the clinical outcome.

Theory and hypotheses Because there is strong evidence that free radicals contribute to post-ischemic injury, antioxidant enzyme therapy could potentially be extremely effective in reducing the cellular damage. In reality, however, the usefulness of this therapy is limited by a number of factors, in particular the ability of the antioxidants to penetrate the cell membrane and to scavenge free radicals in situ. Fortunately, this limitation can, in part, be addressed with the use of melatonin, a potent indirect and direct free radical scavenger that easily diffuses through the cell membrane to exert its antioxidant effects in all compartments of the cell. Indeed, in contrast to the partial of distribution of other antioxidants, such as vitamin C or E, the melatonin distributes it readily in all subcellular compartments owing to its double-solubility in both, aqueous and in lipid environment. Several recent publications present evidence that the newly discovered antioxidant melatonin has significant protective actions against the cardiac damage such as occurs during ischemia-reperfusion injury.

Primary hypothesis: Melatonin given to patients undergoing PCI can reduce the myocardial damage sustained by ischemia-reperfusion.

Inclusion:

• Adults who are able to give informed consent
• 1 significant coronary occlusion (>2mm) with TIMI 0-1 expected to undergo PCI.
• ECG criteria: The occlusion must be ECG-verified with new ST-elevations ≥ 0.2 mV in V2-V3 and/or ≥ 0.1 in the other leads or with a new onset left bundle branch block.
• Having onset of symptoms of qualifying AMI and undergo PCI within 6 hours.
• If the patients do not fulfill the ECG inclusion criteria they can still be included if the primary PCI reveals an acute coronary occlusion (>2mm) with TIMI 0-1.

Exclusion: Patients with prior myocardial infarction, more than one significant occlusion, prehospital thrombolysis, known history of renal failure, history of autoimmune diseases, pregnancy, fertile women or breastfeeding, severe concurrent illness with reduced short-term prognosis, pacemaker, claustrophobia, cardiogenic shock, metals in the body, atrial fibrillation, BMI ≥ 40.

Intervention: The STEMI patient with 1 significant occlusion undergoing PCI less than 6 hours from onset of symptoms will be randomized to intracoronary injection of either melatonin or placebo(saline). The melatonin or placebo will be given as a bolus of 10 ml in relation to PCI, as soon as the occlusion is removed. Immediately after the bolus is given, a solution of 490 ml of either placebo (saline) or 0,1 mg/ml melatonin (49 mg melatonin)will be given intravenously over 6 hours (80 ml/hour).

Primary end point: MRI of the heart at day 4 (+/- 1 day) after the PCI procedure to determine myocardial salvage index.

Secondary end point:

• To determine whether melatonin treatment reduces infarct size as determined by the concentration of high sensitive TnT or high-sensitive TnI and Creatinin Kinase Myocardial Band (CK-MB)(area under the curve) in the blood, measured daily for the first 4 days after AMI.
• the concentration of plasma melatonin after PCI
• the concentration of oxidative markers 24 hours after PCI

Clinical events occurring within the first 90 days after surgery; death, sustained ventricular arrhythmias, resuscitation from cardiac arrest, cardiogenic shock, heart failure, major bleedings, stroke, need for revascularization, recurrent ischemia, re-infarctions and re-hospitalization.

Design: Randomized, double-blind, placebo-controlled interventional study.

Method: Patients who meet the criteria of inclusion will be randomized to intra-coronary injection plus intravenous infusion of melatonin or placebo. The bolus will be given just after the opening of the vessel (TIMI ≥ 2) . Hs-Troponin T/I and CK-MB will be measured in a blood sample taken 1 hour, 6 hours, 24 hours, 48 hours, 72 hours and 96 hours after the PCI procedure. At day 4 after PCI, the patients will undergo MRI of the heart focusing on infarct size and area at risk.

Patient number: Statistical power analysis shows that with a type 1 error of 5% and a type 2 error of 20%, mean at 9,63 and the SD with MRI of 0,16, one should be able to detect a difference in infarct size of 25% between the two groups, when including 2x17 patients in each group. The investigators are including 2x 20 patients.

Safety: The experiments are considered to be of no risk or discomfort for the patients. Both the intervention group and the placebo group are operated by current clinical guidelines.