“Letter to the Editor of Elsevier,” is as published by The National Center for Biotechnology Information (NCIS).

Letter to the Editor of Elsevier

Melatonin, coronavirus, cardiovascular disease, and the geriatric emergency: let’s use everything we have! 

To the Editor, 

We read with interest the joint document of the Section on Geriatric Cardiology of the Spanish Society of Cardiology related to the geriatric emergency and coronavirus infectious disease-19 (COVID-19).1 Based on data published by the Spanish Ministry of Health, up to May 24, 2020, 235 772 confirmed cases of COVID-19 had been diagnosed in Spain, of which 86% of the deceased were older than 70 years.2 We would like to make some important points about melatonin, elderly patients, and COVID-19. 

Excellent reviews have noted that melatonin has significant beneficial effects against ischemia-reperfusion injury, myocardial chronic intermittent hypoxia injury, pulmonary hypertension, hypertension, valvular heart diseases, vascular diseases, and lipid metabolism.3,4 Melatonin is synthesized from tryptophan in the pineal gland and by almost all the organs of the body, since its production is associated with mitochondria. It is noteworthy that high levels of melatonin play positive roles in health and aging.3 Melatonin, a well-known chronobiotic, is also a promising adjunct drug for viral infections due to its anti-inflammatory, antiapopto- tic, immunomodulatory, and powerful antioxidant properties. Melatonin binds to M1 and M2 receptors that can be found in the retinae and in the brain, as well as in the heart, gut, lymphocytes, and liver.3 

Melatonin levels change during the life span. Nocturnal melatonin levels are highest in young children, approximately 325 pg/mL and then decline gradually with age. For example, levels are between 50 and 55pg/mL in 15 to 50-year-olds, approximately 27 pg/mL in 50 to 70-year-olds and approximately 15 pg/mL in persons > 70 years.3 COVID-19 infection attacks the melatonin synthetic pathway resulting in reduced melatonin levels at a time when melatonin is most needed. This often leads to altered immune responses, specifically, with the overreaction of the innate immune response. The uncontrolled innate immune response promotes a massive inflammatory reaction and causes irreversible tissue damage and mortality.5,6 Our group recently published a review on how the various medical comorbidities (diabetes mellitus, hypertension, obesity, and cardiovascular disease) can affect the melatonergic pathway and its relationship with COVID-19. In addition, we suggest melatonin doses for treatment and prophylactic use.6 

When a vaccine is developed, it may not be as effective in elderly patients. A limited immune response to vaccines has been previously reported in older patients due to immunosenescence.7 Thus, adjuvant therapy to enhance vaccine efficacy in the elderly is urgently needed amidst the COVID-19 crisis and melatonin may be a suitable candidate.6 Melatonin is an inexpensive product with scalable production. It has a long shelf life, the simplest mode of transportation, and can be self-administered orally in remote areas. 

G Model REC-101346; No. of Pages 2 

Rev Esp Cardiol. 2020;xx(x):xxx–xxx 

Under normal circumstances, the conclusion of this Letter to the Editor would be to initiate elderly prophylactic prospective clinical studies dividing patients into case-control groups with one group receiving the standard of care alone, and the other group receiving the standard of care supplemented with melatonin. Let’s assume that we conduct exactly this type of study and then conclude that melatonin reduces rates of hospitalization and the incidence of irreversible postinfection complications. Under the current COVID-19 crisis, there is a serious ethical problem with this otherwise correct approach. Because melatonin is known as a safe, inexpensive, readily-available over-the-counter product, how could we justify its nonuse to millions of people not benefitting from it at the time of a deadly crisis?8 Therefore, we propose to immediately inform physicians, nurses, health care providers, and the general public of the potential benefits of melatonin in COVID-19 patients. 

Acknowledgements 

The authors report no financial interests relevant to the research contained in this manuscript. This research was funded by Fundacio ́n Canaria Instituto de Investigacio ́n Sanitaria de Canarias (FIISC) (PIFUN11/18) 

Alberto Domınguez-Rodrıguez,a,b,c,* Russel J. Reiter,d Pedro Abreu-Gonza ́lez,e and Paul E. Marik,f

aDepartamento de Cardiologı ́a, Hospital Universitario de Canarias San Cristo ́bal de La Laguna, Santa Cruz de Tenerife, Spain

bFacultad de Ciencias de la Salud, Universidad Europea de Canarias, La Orotava, Santa Cruz de Tenerife, Spain

cCentro de Investigacio ́n Biome ́dica en Red Enfermedades Cardiovaculares, CIBERCV, Madrid, Spain

dDepartment of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, Texas, United States

eDepartamento de Fisiologı ́a, Facultad de Medicina, Universidad de La Laguna, San Cristo ́bal de La Laguna, Santa Cruz de Tenerife, Spain

fDivision of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, Virginia, United States 

* Corresponding author: E-mail address: adrvdg@hotmail.com (A. Domınguez-Rodrıguez). 

REFERENCES 

1. Bonanad C, Garcıa-Blas S, Tarazona-Santabalbina FJ, et al. Coronavirus: la emergencia geria ́ trica de 2020. Documento conjunto de la Seccio ́ n de Cardiologıa Geria ́trica de la Sociedad Espan ̃ola de Cardiologıa y la Sociedad Espan ̃ola de Geriatrıa y Gerontologıa. Rev Esp Cardiol. 2020. http://dx.doi.org/10.1016/j.recesp. 2020.03.027.
2. Ministerio de Sanidad. Gobierno de Espan ̃a. Actualizacio ́ n n.8 115. Enfermedad por el coronavirus (COVID-19). 24.05.2020. Situacio ́ n en Espan ̃a. Available at: https:// www.mscbs.gob.es/profesionales/saludPublica/ccayes/alertasActual/nCov-China/ documentos/Actualizacion_115_COVID-19.pdf. Consulted 2 Jun 2020.
3. Reiter RJ, Ma Q, Sharma R. Melatonin in Mitochondria: Mitigating Clear and Present Dangers. Physiology (Bethesda). 2020;35:86–95.
4. Opie LH, Lecour S. Melatonin has multiorgan effects. Eur Heart J Cardiovasc Pharmacother. 2016;2:258-265.
5. Reiter RJ, Sharma R, Ma Q, Dominquez-Rodriguez A, Marik PE, Abreu-Gonzalez P. Melatonin Inhibits COVID-19-induced Cytokine Storm by Reversing Aerobic Glycolysis in Immune Cells: A Mechanistic AnalysisMed Drug Discov. 2020;6:100044.
6. Reiter RJ, Abreu-Gonzalez P, Marik PE, Dominguez-Rodriguez A. Therapeutic algorithm for the use of melatonin in patients with COVID-19. Front Med. 2020;7:226. 
7. Chen WH, Kozlovsky BF, Effros RB, Grubeck-Loebenstein B, Edelman R, Sztein MB. Vaccination in the elderly: an immunological perspective. Trends Immunol. 2009;30:351–359.
8. 8. Shneider A, Kudriavtsev A, Vakhrusheva A. Can melatonin reduce the severity of COVID-19 pandemic? IntRev Immunol. 2020. http://dx.doi.org/10.1080/08830185. 2020.1756284.

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SEE RELATED CONTENT:
https://doi.org/10.1016/j.rec.2020.05.001
https://doi.org/10.1016/j.rec.2020.06.005
1885-5857/ C 2020 Sociedad Espan ̃ola de Cardiologıa. Published by Elsevier Espan ̃a, S.L.U. All rights reserved. 

Article Source: Domınguez-Rodrıguez A, et al. Melatonin, coronavirus, cardiovascular disease, and the geriatric emergency: let’s use everything we have! Rev Esp Cardiol. 2020. https://doi.org/10.1016/j.rec.2020.06.005 

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Letter to the Editor of Elsevier, is as published by The National Center for Biotechnology Information (NCIS). For more information on Melatonin research visit melatoninfacts.org.