To the Editor:
It was with great interest that we read the recently published article by Ruiz-Meana et al1 regarding the pathophysiology of myocardial damage due to ischemia-reperfusion and new treatment options for acute myocardial infarction (AMI). The authors should be congratulated on their up-to-date information. However, we wanted to stress that there are experimental mechanistic data that establish a cause-effect relationship between the production of oxygen free radicals and their pathophysiological role as a possible treatment target for AMI.
When blood flow is restored in ischemic hearts, it produces oxygen-derived free radicals such as the superoxide anion, hydroxyl radicals, and hydrogen peroxide, which can damage cell membranes.2 The 3 principal mechanisms for damage by free radicals are lipid peroxidation, protein oxidation, and DNA breakage or alteration. Superoxide radicals can generate hydroxyl radicals by 2 methods. One involves the participation of nitric oxide through the formation of a compound named peroxynitrite, a toxic, unstable, and highly reactive compound causing lipid peroxidation and myocardial damage.2
Melatonin is an indolamine principally produced, with a circadian rhythm, by the pineal gland. It regulates various physiological and neuroendocrine functions through specific receptors or directly in subcellular organelles.
Their actions were initially described relative to the neuroendocrine-reproductive axis.3 However, numerous observations made at later dates have demonstrated its multiple immunomodulating functions, on both the cellular and humoural levels, and its antioxidant activity.4
Numerous clinical studies in humans have revealed a relationship between melatonin serum concentration and coronary artery disease.4 The observation that patients with coronary disease have low nocturnal melatonin levels and that concentrations in AMI patients is lower than in control subjects shows that this nocturnal drop in melatonin is at least partly due to its antioxidant effects, and particularly its ability to act as an interceptor of free radicals that are generated in the first hours of an AMI.5 However, it is unknown to date if this finding is a cause or effect of, or even a characteristic related to, diminished cardiovascular function.4 Two possible mechanisms have been described which could explain the antioxidant effects of melatonin in AMI patients: a) due to direct action as a free radical interceptor, detoxifying reactive forms of oxygen and nitrogen through non-enzymatic channels, which would result in the formation of another powerful antioxidant: N1-acetil-N2-formil-5-metoxiquinuramina; and b) by way of an indirect action mechanism through stimulation of various antioxidant enzymes and the stabilisation of membrane fluidity.6
Due to its antioxidant and anti-inflammatory properties, melatonin has been shown to have beneficial results and a significant protective effect in various experimental models of reperfusion injury.4 Experimental results have contributed solid evidence for considering melatonin to be one of the essential components of an organism's antioxidant defence system.4 The available scientific evidence has led our group to carry out a phase II clinical trial to demonstrate inhibition of reperfusion damage by administering melatonin to AMI patients immediately before percutaneous coronary intervention.7 Melatonin is an endogenous molecule with few side effects and a low monetary cost. Its lipophilic nature allows it to cross cell membranes with ease to reach cell compartments where oxygen-derived free radicals can be found.