Sleep Medications Containing Melatonin can Potentially Induce Ventricular Arrhythmias in Structurally Normal Hearts: A 2-Patient Report

Vries, Lennart J. de; Géczy, Tamás; Szili-Török, Tamás

doi:10.1097/fjc.0000000000000515

Cited by 13 publications

(15 citation statements)

References 14 publications

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“…Several safety studies showed the lack of severe side effects of melatonin during chronic and sustained administration [ 243 – 245 ]. Regarding arrhythmias, one report of two patients suffering frequent premature ventricular contractions claimed that arrhythmic events resolved after stopping melatonin 1 mg as their sleeping pills [ 246 ]. On the other hand, several studies validated the melatonin safety profile during long periods of supervised side effect evaluation.…”

Section: Melatonin As a Potential Antiarrhythmic Treatment In Aginmentioning

confidence: 99%

Melatonin to Rescue the Aged Heart: Antiarrhythmic and Antioxidant Benefits

Segovia-Roldán

Diez

Pueyo

2021

Oxidative Medicine and Cellular Longevity

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Aging comes with gradual loss of functions that increase the vulnerability to disease, senescence, and death. The mechanisms underlying these processes are linked to a prolonged imbalance between damage and repair. Damaging mechanisms include oxidative stress, mitochondrial dysfunction, chronodisruption, inflammation, and telomere attrition, as well as genetic and epigenetic alterations. Several endogenous tissue repairing mechanisms also decrease. These alterations associated with aging affect the entire organism. The most devastating manifestations involve the cardiovascular system and may lead to lethal cardiac arrhythmias. Together with structural remodeling, electrophysiological and intercellular communication alterations during aging predispose to arrhythmic events. Despite the knowledge on repairing mechanisms in the cardiovascular system, effective antiaging strategies able to reduce the risk of arrhythmias are still missing. Melatonin is a promising therapeutic candidate due to its pleiotropic actions. This indoleamine regulates chronobiology and endocrine physiology. Of relevance, melatonin is an antiaging, antioxidant, antiapoptotic, antiarrhythmic, immunomodulatory, and antiproliferative molecule. This review focuses on the protective effects of melatonin on age-induced cardiac functional and structural alterations, potentially becoming a new fountain of youth for the heart.

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Section: Melatonin As a Potential Antiarrhythmic Treatment In Aginmentioning

confidence: 99%

Melatonin to Rescue the Aged Heart: Antiarrhythmic and Antioxidant Benefits

Segovia-Roldán

Diez

Pueyo

2021

Oxidative Medicine and Cellular Longevity

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“…A putative antiarrhythmic effect of melatonin has been implicated to occur in preclinical studies by reducing sympathetic tone [26] and its antioxidant activity [27]. In the meantime, a clinical case report suggests that melatonin can potentially induce ventricular arrhythmias [28]. Therefore, the ultimate proarrhythmic vs. antiarrhythmic effect of melatonin awaits to be further clarified in translational studies [28].…”

Section: Clinical Trials With Melatonin In Heart Diseasesmentioning

confidence: 99%

“…In the meantime, a clinical case report suggests that melatonin can potentially induce ventricular arrhythmias [28]. Therefore, the ultimate proarrhythmic vs. antiarrhythmic effect of melatonin awaits to be further clarified in translational studies [28].…”

Section: Clinical Trials With Melatonin In Heart Diseasesmentioning

confidence: 99%

Cardioprotective Melatonin: Translating from Proof-of-Concept Studies to Therapeutic Use

Baltatu

Senar²,

Campos

et al. 2019

IJMS

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In this review we summarized the actual clinical data for a cardioprotective therapeutic role of melatonin, listed melatonin and its agonists in different stages of development, and evaluated the melatonin cardiovascular target tractability and prediction using machine learning on ChEMBL. To date, most clinical trials investigating a cardioprotective therapeutic role of melatonin are in phase 2a. Selective melatonin receptor agonists Tasimelteon, Ramelteon, and combined melatonergic-serotonin Agomelatine, and other agonists with registered structures in CHEMBL were not yet investigated as cardioprotective or cardiovascular drugs. As drug-able for these therapeutic targets, melatonin receptor agonists have the benefit over melatonin of well-characterized pharmacologic profiles and extensive safety data. Recent reports of the X-ray crystal structures of MT1 and MT2 receptors shall lead to the development of highly selective melatonin receptor agonists. Predictive models using machine learning could help to identify cardiovascular targets for melatonin. Selecting ChEMBL scores > 4.5 in cardiovascular assays, and melatonin scores > 4, we obtained 284 records from 162 cardiovascular assays carried out with 80 molecules with predicted or measured melatonin activity. Melatonin activities (agonistic or antagonistic) found in these experimental cardiovascular assays and models include arrhythmias, coronary and large vessel contractility, and hypertension. Preclinical proof-of-concept and early clinical studies (phase 2a) suggest a cardioprotective benefit from melatonin in various heart diseases. However, larger phase 3 randomized interventional studies are necessary to establish melatonin and its agonists’ actions as cardioprotective therapeutic agents.

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“…Thus, sudden death during sleep in patients with RYR2 variants may be due to episodes triggered by increased sympathetic activity comparable to exercise or emotional stress. Contrastingly, specific RYR2 variants may exhibit properties that increase their sensitivity to other sleep related triggers like rises in hormones such as melatonin which has been shown to induce ventricular arrythmias (20,21). Importantly in a recent prospective study of sudden cardiac death the majority of deaths occurred during sleep (22) and CPVT should be considered as a potential cause in this setting.…”

Section: Discussionmentioning

confidence: 99%

Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships

et al. 2020

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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is predominantly caused by heterozygous missense variants in the cardiac ryanodine receptor, RYR2. However, many RYR2 missense variants are classified as variants of uncertain significance (VUS). We systematically reevaluated all RYR2 variants in healthy individuals and those with CPVT or arrhythmia using the 2015 American College of Medical Genomics guidelines. RYR2 variants were identified by the NW Genomic Laboratory Hub, from the published literature and databases of sequence variants. Each variant was assessed based on minor allele frequencies, in silico prediction tools and appraisal of functional studies and classified according to the ACMG-AMP guidelines. Phenotype data was collated where available. Of the 326 identified RYR2 missense variants, 55 (16.9%), previously disease-associated variants were reclassified as benign. Application of the gnomAD database of >140,000 controls allowed reclassification of 11 variants more than the ExAC database. CPVTassociated RYR2 variants clustered predominantly between amino acid positions 3949-4332 and 4867-4967 as well as the RyR and IP3R homology associated and ion transport domains (P < 0.005). CPVT-associated RYR2 variants occurred at more conserved amino acid positions compared to controls, and variants associated with sudden death had higher conservation scores (P < 0.005). There were five potentially pathogenic RYR2 variants associated with sudden death during sleep which were located almost exclusively in the C-terminus of the protein. In conclusion, control sequence databases facilitate reclassification of RYR2 variants but the majority remain as VUS. Notably, pathogenic variants in RYR2 are associated with death in sleep.

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Sleep Medications Containing Melatonin can Potentially Induce Ventricular Arrhythmias in Structurally Normal Hearts: A 2-Patient Report

Cited by 13 publications

References 14 publications

Melatonin to Rescue the Aged Heart: Antiarrhythmic and Antioxidant Benefits

Melatonin to Rescue the Aged Heart: Antiarrhythmic and Antioxidant Benefits

Cardioprotective Melatonin: Translating from Proof-of-Concept Studies to Therapeutic Use

Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships

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