Table 2.

Clinical studies on melatonin’s efficacy in ischemia-reperfusion injury. Coronary artery bypass graft (CABG), acute myocardial infarction, (AMI), nuclear factor erythroid 2-related factor (Nrf2), ST-elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI), creatine kinase-MB (CK-MB), high sensitive troponin-T (hs-TnT), left ventricular ejection fraction (LVEF), heart ratio (HR), cardiac troponin I (cTn-I), myocardial ischemia/reperfusion (MI/R), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricle (LV), malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), N-acetyl cysteine (NAC).

Clinical Studies
Study Model	Sample Size	Melatonin Administration	Reperfusion Medical Strategies	Major Findings			Interpretation
				Lv Function/Hemodynamic Parameters	Infarct Size	Biomarkers
Elective CABG None with AMI [39].	30	Before bedtime, orally 10 mg of melatonin 1 month before the procedure	CABG	-	-	↑ Melatonin ↑ Nrf2	Melatonin, through the Nrf2 pathway, may have a key role in the potentiation of antioxidant defense and mitigation of cellular damages caused by CABG surgery.
Elective surgery for abdominal aortic aneurysm [43].	50	Intraoperatively and intravenously 50 mg melatonin over 2 h; and orally 10 mg of melatonin throughout the first 3 nights after the procedure	CABG	-	-	↓ Troponin-I	Clinical cardiac morbidity, troponin I levels, the frequency of ST-segment deviations, and the incidence of myocardial ischemia were reduced following the procedure.
Patients with STEMI [44].	40	The night following PCI melatonin 3 mg was orally given and maintained daily in the hospital	PCI	-	-	↓ CK-MB hs-TnT	There is no impact. The length of the trial, the sample size, and the low doses of melatonin used were all limitations.
Ischemic heart disease patients undergoing elective CABG [45].	45	From the fifth day before surgery, a low dosage melatonin therapy group (10 mg/day) and a high dosage melatonin treatment group (20 mg/day) were used	CABG	↑ LVEF ↓ HR	-	↓ cTn-I ↓ Interleukin-1β ↓ Inducible nitric oxide synthase ↓ Caspase-3 enzymes.	Melatonin reduced oxidative stress, inflammation, and apoptosis in ischemic heart disease patients following CABG, decreasing MI/R injury.
ST-elevation myocardial infarction patients [46].	146	An intravenous bolus of 51.7 μmol melatonin was given 60 min before reperfusion, followed by an intracoronary bolus of 8.6 μmol (total 14 mg) melatonin at the start of reperfusion.	Primary PCI	LVEDV LVESV Total LV mass	↓ Infarct size with symptoms starting 136 ± 23 min later Infarct size with symptoms starting between 196 ± 19 min and 249 ± 41 min later	-	In STEMI individuals, early melatonin treatment decreased infarct size.
ST-elevation myocardial infarction patients [47].	48	0.1 mg/mL melatonin intracoronary and 0.1 mg/mL melatonin intravenous injection (total 50 mg)	Primary PCI	LVEDV LVESV LVEF	Infarct size	hs-TnT, CK-MB	Melatonin did not affect LV function or clinical outcomes in STEMI patients.
Elective CABG [48].	88	Melatonin 5 mg given orally (3 times beginning from 24 h before the procedure and a single dose [15 mg] 1 h before the surgery)	CABG	-	-	↓ Troponin I ↓ Lactate ↓ MDA ↓ TNF-α	NAC and melatonin are powerful antioxidants that have almost equal effectiveness in decreasing CABG-related heart damage and oxidative stress at the doses used in the study.