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Melatonin for cardioprotection in ST elevation myocardial infarction: are we ready for the challenge?
  1. Alberto Dominguez-Rodriguez1,2,
  2. Pedro Abreu-Gonzalez3,
  3. Russel J Reiter4
  1. 1Department of Cardiology, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
  2. 2Facultad de Ciencias de la Salud, Universidad Europea de Canarias, La Orotava, Santa Cruz de Tenerife, Spain
  3. 3Departamento de Ciencias Médicas Básicas (Unidad de Fisiología), Universidad de La Laguna, Santa Cruz de Tenerife, Spain
  4. 4Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas, USA
  1. Correspondence to Dr Alberto Dominguez-Rodriguez, Department of Cardiology, Hospital Universitario de Canarias, Ofra s/n La Cuesta, Santa Cruz de Tenerife E-38320, Spain; adrvdg{at}

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Melatonin, an endocrine product of the pineal gland, is formed predominantly during the nighttime. Light has an inhibitory effect on pineal melatonin secretion. Pineal melatonin release is synchronised by this daily light-dark cycle via a multisynaptic pathway between the eyes and the pineal gland. Light stimulates the retina to modulate the activity of the suprachiasmatic nucleus, the master biological clock.1 The suprachiasmatic nucleus controls pineal melatonin synthesis and the concentrations of melatonin in the sera of healthy subjects, which reach values of 10−10 to 10−9 mol/L during the night, with much lower concentrations being present during the day. Many publications have shown that melatonin has an important role in a variety of cardiovascular pathophysiologic processes: the indoleamine has anti-inflammatory, antioxidant, antihypertensive, antithrombotic and antilipaemic properties1 (figure 1).

Figure 1

The properties of melatonin and the effects on multiple organs.

In their Heart manuscript, McMullan et al2 report their findings when analysing data from the Nurses's Health Study I (NHS I) and NHS II to investigate the independent association of nocturnal melatonin secretion with the incidence of myocardial infarction (MI). In accordance with the authors, the NHS I began in 1976, with 121 701 registered nurses aged 30–55 years returning an initial questionnaire; the NHS II began in 1989 with 116 430 female registered nurses. In the initial and subsequent biennial questionnaires, health status, medications, dietary intake and lifestyle factors, including smoking history, physical activity and sleeping patterns, were ascertained. In addition to completing questionnaires, blood and urine samples were provided by 18 743 women between 1999 and 2000 in NHS I and by 29 616 women between 1997 and 1999 in NHS II. Participants returned these samples which were stored until they were assayed. They identified 209 cases (146 women from NHS I and 63 women from NHS II) who had developed a confirmed diagnosis of MI through 2010. For each case, a control was selected from the risk set of similarly eligible participants who were free from MI at the time that the case was diagnosed. Controls were matched to cases.

The authors used multivariable models to control for factors included in the American College of Cardiology and American Heart Association Cardiovascular risk score plus circadian factors (sleep duration, recent exposure to rotating shift work, and self-reported snoring). With a very exhaustive statistical analysis, they identified that for every one unit lower in the sulfatoxymelatonin/creatinine ratio there was a significant increased risk of MI (OR 1.40, 95% CI 1.02 to 1.93), with an association that was strongly modified by the body mass index (p value for interaction=0.02). Therefore, in their interesting article, the authors demonstrated a prospective association between lower nocturnal melatonin secretion and increased incidence of MI that persisted after adjustment for established MI risk factors. From our view as clinicians, this paper can provide the basis for the design and rationale of randomised control trials investigating the effect of nocturnal melatonin supplementation in patients with established cardiovascular risk factors.

Ischaemic heart disease remains the leading cause of death and disability in Europe and worldwide. A major cause of morbidity and mortality in ischaemic heart disease patients is an acute ST elevation MI (STEMI), which despite prompt reperfusion by primary percutaneous coronary intervention (PCI) causes significant mortality and morbidity.3 Although myocardial reperfusion is essential to salvage the myocardium following a STEMI, the process of restoring coronary blood flow to the ischaemic tissue can, in itself, induce myocardial injury and cardiomyocyte death, a phenomenon which is known as ischaemia-reperfusion injury.4 The search for an effective therapy capable of targeting myocardial reperfusion injury and reducing MI size has been quite challenging, with a large number of failures to translate novel cardioprotective therapies into the clinical setting.4

Several studies have shown that humans with cardiovascular disease have noticeably lower nocturnal circulating melatonin concentrations than age-matched subjects without significant cardiovascular deterioration.5 Studies in animals have confirmed the ameliorative effects of melatonin on abnormal function and cardiac tissue destruction resulting from ischaemia reperfusion after the administration of pharmacologic doses of melatonin before ischaemia and/or during reperfusion.5 Currently there are two clinical trials (NCT00640094 and NCT01172171) underway to test the efficacy of melatonin in patients with acute coronary heart disease.

The utility of melatonin in STEMI patients has been of major interest for our group.6–8 The safety and efficacy of melatonin as an antioxidant and the participation of free radicals in mediating cardiac damage in STEMI patients have been the basis for the design and rationale of the MARIA trial (NCT00640094).6 The MARIA (Melatonin Adjunct in the acute myocaRdial Infarction treated with Angioplasty) trial is a study which randomised STEMI patients to melatonin (intravenous and intracoronary bolus) or placebo during primary PCI. The objective of this study has been to evaluate the safety, tolerability and efficacy of intravenous and intracoronary administration of melatonin as an adjunct therapy for the reduction of ischaemia reperfusion injury among patients who present with a first STEMI undergoing primary PCI. In our study, melatonin had an acceptable safety and tolerability profile. However, melatonin did not appear to exert a significant effect on myocardial infarct size measured by magnetic resonance imaging. Moreover, it may have a detrimental effect after STEMI, mainly because it might facilitate left ventricular remodelling.7 We speculate two possible mechanisms: (1) high doses of melatonin into the coronary circulation possibly lead to loss of cardioprotection as previously suggested in studies with other molecules;4 or (2) the median pain-to-balloon time was so long that it likely negated the benefits of melatonin.7

To date, no study has been undertaken to assess the optimal dose of melatonin for cardioprotection during myocardial reperfusion. It is important to note that those cardioprotective interventions that are effective only when present during the ischaemic period may act by reducing acute myocardial ischaemic injury. Limiting ischaemic injury is a very effective strategy to limit myocardial infarct size, but it may be difficult to apply in STEMI because it requires very early administration. An analysis post-hoc of the MARIA trial will be of interest to evaluate whether the treatment effect of melatonin therapy among patients with STEMI is influenced by the time to administration. The results of this analysis demonstrated that with a short ischaemic time (<2.5 hours) the infarct size was significantly smaller in the melatonin-treated individuals compared with placebo.

With this background, we are ready for the challenge of conducting a randomised clinical trial which will investigate the effect of melatonin on cardiac death and heart failure hospitalisation. EARLY MARIA (Melatonin as an Adjunct in patients with acute myocaRdial Infarction undergoing primary Angioplasty) will be an international, prospective, multicentre, randomised, double-blinded, placebo-controlled trial. The study will be designed to compare the efficacy and safety of melatonin versus placebo, in addition to revascularisation by primary PCI, in patients presenting with acute MI within 2.5 hours of symptom onset and initial TIMI (Thrombolysis In Myocardial Infarction) flow ≤1 in the culprit coronary artery. Patients will be randomised in a 1:1 fashion to intravenous infusion of melatonin or matching placebo performed in the minutes preceding PCI. The primary efficacy endpoint of EARLY MARIA will be a composite of 1-year all-cause mortality, rehospitalisation for heart failure or heart failure worsening during initial hospitalisation.

In this editorial we have tried to inform the medical community of our experience with the use of melatonin in patients with coronary heart disease. Given its low toxicity profile and high efficacy, melatonin should be tested more widely in the clinical setting.



  • Contributors AD-R, PA-G and RJR conceived and designed the commissioned Editorial.

  • Funding This editorial was supported by Institute Carlos III (ISCIII) (PI15/01260), General Branch Evaluation and Research Promotion, State Plan of Scientific and Technical Research and Innovation 2013–2016 and European Regional Development Fund Health—FEDER, which relates to the topic of this study.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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