PURPOSE: The incidence of acute myocardial infarctions (AMI) shows circadian variation typically peaking during morning hours with a decline at night. However, this variation does not occur in patients with diabetes mellitus (DM). The night's decline of AMI may be partially explained by melatonin-related platelet inhibition. Whether this effect is absent in diabetic patients is unknown. The aim was to study the effect of melatonin on in-vitro platelet aggregation in healthy individuals and patients with type 2 DM. METHODS: Platelet aggregation was measured in blood samples from healthy individuals (n = 15) and type 2 DM patients (n = 15) using multiple electrode aggregometry. Adenosine diphosphate (ADP), arachidonic acid (ASPI) and thrombin (TRAP) were used as agonists. Aggregability for each subject was tested after adding melatonin in two concentrations. RESULTS: In healthy individuals, melatonin inhibited platelet aggregation in both higher (10-5 M) and lower concentrations (10-9 M) induced by ADP, ASPI, and TRAP (p < 0.001, p = 0.002, p = 0.029, respectively). In DM patients, melatonin did not affect platelet aggregation in both concentrations induced by ADP, ASPI, and TRAP. Melatonin decreased platelet aggregation induced by ADP, ASPI, and TRAP significantly more in healthy individuals compared to patients with DM. (p = 0.005, p = 0.045 and p = 0.048, respectively). CONCLUSION: Platelet aggregation was inhibited by melatonin in healthy individuals. In-vitro antiplatelet effect of melatonin in type 2 DM patients is significantly attenuated.

3rd Department of Internal Medicine Faculty of Medicine Comenius University in Bratislava University Hospital Bratislava Bratislava Slovakia

Cardio Integra s r o Bratislava Slovakia

Department of Animal Physiology and Ethology Faculty of Natural Sciences Comenius University in Bratislava Bratislava Slovakia

Department of Complex Systems Institute of Computer Science Czech Academy of Sciences Prague 8 Czech Republic

Faculty of Medicine Comenius University in Bratislava Bratislava Slovakia

National Institute of Cardiovascular Diseases Bratislava Slovakia

Premedix Academy Medená 18 81102 Bratislava Slovakia

Slovak Medical University Bratislava Slovakia

Zobrazit více v PubMed

Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Fourth universal definition of myocardial infarction (2018) J Am Coll Cardiol. 2018;72(18):2231–2264. doi: 10.1016/j.jacc.2018.08.1038. PubMed DOI

Asano T, Mitsuhashi Y, Sachi M, Wakabayashi K, Yahagi K, Shinke T, et al. The impact of low diastolic blood pressure on 30-day mortality of patients with acute myocardial infarction. Eur Heart J. 2020 doi: 10.1093/ehjci/ehaa946.1652. DOI

Oecd . Mortality following acute myocardial infarction (AMI) Paris: OECD Publishing; 2017. Health at a Glance 2017: OECD indicators.

Mechanic OJ, Gavin M, Grossman SA (2022) Acute Myocardial Infarction. In: StatPearls. StatPearls Publishing, Copyright © 2022, StatPearls Publishing LLC.: Treasure Island (FL)

Jelic D, Mehmedbegovic Z, Milasinovic D, Dedovic V, Zobenica V, Zaharijev S, et al. P953Comparison of the original and updated ACTION risk scores for predicting in-hospital and one-year mortality in patients with acute myocardial infarction undergoing primary PCI. Eur Heart J. 2019 doi: 10.1093/eurheartj/ehz747.0547. DOI

Takeda N, Maemura K. Circadian clock and the onset of cardiovascular events. Hypertens Res. 2016;39(6):383–390. doi: 10.1038/hr.2016.9. PubMed DOI

Van Laake LW, Lüscher TF, Young ME. The circadian clock in cardiovascular regulation and disease: lessons from the Nobel Prize in Physiology or Medicine 2017. Eur Heart J. 2018;39(24):2326–2329. doi: 10.1093/eurheartj/ehx775. PubMed DOI PMC

Giles TD. Circadian rhythm of blood pressure and the relation to cardiovascular events. J Hypertens Suppl. 2006;24(2):S11–S16. doi: 10.1097/01.hjh.0000220098.12154.88. PubMed DOI

Scheer FA, Michelson AD, Frelinger AL, 3rd, Evoniuk H, Kelly EE, Mccarthy M, et al. The human endogenous circadian system causes greatest platelet activation during the biological morning independent of behaviors. PLoS One. 2011;6(9):e24549. doi: 10.1371/journal.pone.0024549. PubMed DOI PMC

Rana JS, Mukamal KJ, Morgan JP, Muller JE, Mittleman MA. Circadian variation in the onset of myocardial infarction: effect of duration of diabetes. Diabetes. 2003;52(6):1464–1468. doi: 10.2337/diabetes.52.6.1464. PubMed DOI

Stehle JH, Von Gall C, Korf HW. Melatonin: a clock-output, a clock-input. J Neuroendocrinol. 2003;15(4):383–389. doi: 10.1046/j.1365-2826.2003.01001.x. PubMed DOI

Liu C, Weaver DR, Jin X, Shearman LP, Pieschl RL, Gribkoff VK, et al. Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron. 1997;19(1):91–102. doi: 10.1016/s0896-6273(00)80350-5. PubMed DOI

Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, et al. Melatonin: pharmacology, functions and therapeutic benefits. Curr Neuropharmacol. 2017;15(3):434–443. doi: 10.2174/1570159x14666161228122115. PubMed DOI PMC

Feelisch M, Kolb-Bachofen V, Liu D, Lundberg JO, Revelo LP, Suschek CV, et al. Is sunlight good for our heart? Eur Heart J. 2010;31(9):1041–1045. doi: 10.1093/eurheartj/ehq069. PubMed DOI

Kostovski E, Dahm AE, Iversen N, Hjeltnes N, Østerud B, Sandset PM, et al. Melatonin stimulates release of tissue factor pathway inhibitor from the vascular endothelium. Blood Coagul Fibrinolysis. 2011;22(4):254–259. doi: 10.1097/MBC.0b013e3283442ce2. PubMed DOI

Dahm A, Osterud B, Hjeltnes N, Sandset PM, Iversen PO. Opposite circadian rhythms in melatonin and tissue factor pathway inhibitor type 1: does daylight affect coagulation? J Thromb Haemost. 2006;4(8):1840–1842. doi: 10.1111/j.1538-7836.2006.02048.x. PubMed DOI

Aydogan S, Yerer MB, Goktas A. Melatonin and nitric oxide. J Endocrinol Invest. 2006;29(3):281–287. doi: 10.1007/bf03345555. PubMed DOI

Del Zar MM, Martinuzzo M, Falcón C, Cardinali DP, Carreras LO, Vacas MI. Inhibition of human platelet aggregation and thromboxane-B2 production by melatonin: evidence for a diurnal variation. J Clin Endocrinol Metab. 1990;70(1):246–251. doi: 10.1210/jcem-70-1-246. PubMed DOI

Cardinali DP, Del Zar MM, Vacas MI. The effects of melatonin in human platelets. Acta Physiol Pharmacol Ther Latinoam. 1993;43(1–2):1–13. PubMed

Kornblihtt LI, Finocchiaro L, Molinas FC. Inhibitory effect of melatonin on platelet activation induced by collagen and arachidonic acid. J Pineal Res. 1993;14(4):184–191. doi: 10.1111/j.1600-079x.1993.tb00501.x. PubMed DOI

Sahna E, Parlakpinar H, Turkoz Y, Acet A. Protective effects of melatonin on myocardial ischemia/reperfusion induced infarct size and oxidative changes. Physiol Res. 2005;54(5):491–495. doi: 10.33549/physiolres.930664. PubMed DOI

Bekyarova G, Tancheva S, Hristova M. The effects of melatonin on burn-induced inflammatory responses and coagulation disorders in rats. Methods Find Exp Clin Pharmacol. 2010;32(5):299–303. doi: 10.1358/mf.2010.32.5.1437717. PubMed DOI

Tunali T, Sener G, Yarat A, Emekli N. Melatonin reduces oxidative damage to skin and normalizes blood coagulation in a rat model of thermal injury. Life Sci. 2005;76(11):1259–1265. doi: 10.1016/j.lfs.2004.08.024. PubMed DOI

Otamas A, Grant PJ, Ajjan RA. Diabetes and atherothrombosis: the circadian rhythm and role of melatonin in vascular protection. Diab Vasc Dis Res. 2020;17(3):1. doi: 10.1177/1479164120920582. PubMed DOI PMC

Patel R, Parmar N, Pramanik Palit S, Rathwa N, Ramachandran AV, Begum R. Diabetes mellitus and melatonin: where are we? Biochimie. 2022;202:2–14. doi: 10.1016/j.biochi.2022.01.001. PubMed DOI

Hikichi T, Tateda N, Miura T. Alteration of melatonin secretion in patients with type 2 diabetes and proliferative diabetic retinopathy. Clin Ophthalmol. 2011 doi: 10.2147/opth.s19559. PubMed DOI PMC

Peerschke EI, Castellone DD, Stroobants AK, Francis J. Reference range determination for whole-blood platelet aggregation using the Multiplate analyzer. Am J Clin Pathol. 2014;142(5):647–656. doi: 10.1309/ajcpp43seycbjlhj. PubMed DOI

Hsing AW, Meyer TE, Niwa S, Quraishi SM, Chu LW. Measuring serum melatonin in epidemiologic studies. Cancer Epidemiol Biomarkers Prev. 2010;19(4):932–937. doi: 10.1158/1055-9965.Epi-10-0004. PubMed DOI PMC

Carazo A, Hrubša M, Konečný L, Skořepa P, Paclíková M, Musil F, et al. Sex-related differences in platelet aggregation: a literature review supplemented with local data from a group of generally healthy individuals. Semin Thromb Hemost (EFirst) 2022 doi: 10.1055/s-0042-1756703. PubMed DOI

Friede KA, Infeld MM, Tan RS, Knickerbocker HJ, Myers RA, Dubois LG, et al. Influence of sex on platelet reactivity in response to aspirin. J Am Heart Assoc. 2020 doi: 10.1161/jaha.119.014726. PubMed DOI PMC

Le Blanc J, Lordkipanidzé M. Platelet function in aging. Front Cardiovasc Med. 2019 doi: 10.3389/fcvm.2019.00109. PubMed DOI PMC

Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT. Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol Cell Endocrinol. 2012;351(2):152–166. doi: 10.1016/j.mce.2012.01.004. PubMed DOI PMC

Hajam YA, Rai S. Melatonin supplementation revives diabetic induced biochemical, histological and hematological impairments in rats. Heliyon. 2020;6(4):e03770. doi: 10.1016/j.heliyon.2020.e03770. PubMed DOI PMC

Bougarne N, Weyers B, Desmet SJ, Deckers J, Ray DW, Staels B, et al. Molecular actions of PPARα in lipid metabolism and inflammation. Endocr Rev. 2018;39(5):760–802. doi: 10.1210/er.2018-00064. PubMed DOI

Paterniti I, Campolo M, Cordaro M, Impellizzeri D, Siracusa R, Crupi R, et al. PPAR-α modulates the anti-inflammatory effect of melatonin in the secondary events of spinal cord injury. Mol Neurobiol. 2017;54(8):5973–5987. doi: 10.1007/s12035-016-0131-9. PubMed DOI

Shao G, Tian Y, Wang H, Liu F, Xie G. Protective effects of melatonin on lipopolysaccharide-induced mastitis in mice. Int Immunopharmacol. 2015;29(2):263–268. doi: 10.1016/j.intimp.2015.11.011. PubMed DOI

Rhee YH, Ahn JC. Melatonin attenuated adipogenesis through reduction of the CCAAT/enhancer binding protein beta by regulating the glycogen synthase 3 beta in human mesenchymal stem cells. J Physiol Biochem. 2016;72(2):145–155. doi: 10.1007/s13105-015-0463-3. PubMed DOI

Muñoz-Gutiérrez C, Sepúlveda C, Caballero J, Palomo I, Fuentes E. Study of the interactions between edaglitazone and ciglitazone with PPARγ and their antiplatelet profile. Life Sci. 2017;186:59–65. doi: 10.1016/j.lfs.2017.07.031. PubMed DOI

Unsworth AJ, Kriek N, Bye AP, Naran K, Sage T, Flora GD, et al. PPARγ agonists negatively regulate αIIbβ3 integrin outside-in signaling and platelet function through up-regulation of protein kinase A activity. J Thromb Haemost. 2017;15(2):356–369. doi: 10.1111/jth.13578. PubMed DOI PMC

Zhou H, Li D, Zhu P, Hu S, Hu N, Ma S, et al. Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARγ/FUNDC1/mitophagy pathways. J Pineal Res. 2017 doi: 10.1111/jpi.12438. PubMed DOI

Wang Q, Imam MU, Yida Z, Wang F. Peroxisome proliferator-activated receptor gamma (PPARγ) as a target for concurrent management of diabetes and obesity-related cancer. Curr Pharm Des. 2017;23(25):3677–3688. doi: 10.2174/1381612823666170704125104. PubMed DOI

Dhananjay G, Averi AL, Navjot M, Mina P, Thomas LJ, Jack LL. Peroxisome proliferator-activated receptor γ (PPARγ) and its target genes are downstream effectors of foxo1 protein in islet β-cells: Mechanism of β-cell compensation and failure* *This work was supported, in whole or in part, by National Institutes of Health Grant DK56818 (to J. L. L.). This work was also supported by the American Diabetes Association (to M. P.). J Biol Chem. 2013;288(35):25440–25449. doi: 10.1074/jbc.M113.486852. PubMed DOI PMC

Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374(14):1321–1331. doi: 10.1056/NEJMoa1506930. PubMed DOI PMC

Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–2471. doi: 10.1056/NEJMoa072761. PubMed DOI

Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317(20):1237–1245. doi: 10.1056/nejm198711123172001. PubMed DOI

Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341(6):410–418. doi: 10.1056/nejm199908053410604. PubMed DOI

Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366(9500):1849–1861. doi: 10.1016/s0140-6736(05)67667-2. PubMed DOI

Ginsberg HN, Elam MB, Lovato LC, Crouse JR, 3rd, Leiter LA, Linz P, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563–1574. doi: 10.1056/NEJMoa1001282. PubMed DOI PMC