Effect of melatonin on heart failure: design for a double‐blinded randomized clinical trial

Abstract

Aims Current studies indicate that melatonin can counteract renin-angiotensin-aldosterone system and sympathetic over activity in heart failure (HF) and might have a protective and repairing effect on cardiovascular injuries, skeletal muscle weakness, and metabolic abnormalities, which are common pathological processes in patients with HF. The MeHR trial (Melatonin for Heart Failure with Reduced Ejection Fraction) aims to evaluate the effect of oral melatonin on myocardial, skeletal muscle, and metabolic dysfunctions in HF, which leads to lower quality of life and increased morbidity and mortality in these patients. Methods and results This is a double-blind randomized clinical trial with two parallel arms of 1:1 allocation, which recruits 90 outpatients with HF with reduced ejection fraction. Participants receive 10 mg tablets of melatonin or placebo for 24 weeks. The primary outcomes are changes in echocardiographic indexes of HF and serum levels of N terminal pro brain natriuretic peptide. Secondary outcome is a composite clinical endpoint score including all-cause mortality, hospitalization for HF, and change in the quality of life during the study. Other outcomes are the evaluation of melatonin attributable adverse effects, flow-mediated vasodilation, skeletal muscle mass, exercise capacity, and serum markers of inflammation, oxidative stress, and metabolism. Statistical analysis will include simple unadjusted analyses for the detection of differences between groups and changes in outcomes and also a generalized linear mixed model to explore potential associations between outcomes and participant characteristics. Conclusions The results of this comprehensive study might elucidate the safety of oral melatonin in patients with HF and provide some evidence on its effectiveness as an adjunctive therapy to enhance the well-being of these patients.

Short-term melatonin supplementation decreases oxidative stress but does not affect left ventricular structure and function in myxomatous mitral valve degenerative dogs

“…This finding does, however, appear to support the hypothesis that melatonin has a cardioprotective effect in cardiac physiology based on its demonstrated antioxidant properties. The present study is in concordance with many previous studies which have reported the cardioprotective effect of melatonin on heart failure in human and animal models as well as in in vitro studies [48,54,59,60]. The predominant antioxidant mechanisms of melatonin include direct free radical scavenging of oxygen-based free radicals and related free radical species, stimulation of antioxidative enzymes, increased mitochondrial efficiency of oxidative phosphorylation, reduced electron leakage and augmentation of the efficiency of other antioxidants [61].…”

Effect of melatonin supplementation on endothelial function in heart failure with reduced ejection fraction: A randomized, double‐blinded clinical trial

“…We conducted a unicenter phase II prospective randomized double‐blinded placebo‐controlled clinical trial with two parallel arms of 1:1 allocation on patients with HFrEF (Melatonin in Heart failure with Reduced ejection fraction: MeHR trial) between January 2019 and August 2020. This trial's rationale and design are thoroughly described elsewhere, 11 and the protocol has been registered in http://clinicaltrials.gov (NCT03894683). The trial has been approved by the Ethical Committee of Isfahan University of Medical Sciences (IUMS) (IR.MUI.MED.REC.1397.067).…”

“…Patients with HFrEF were recruited from outpatient clinics of Chamran cardiology hospital, the referral cardiology center in Isfahan, Iran. Participants' eligibility criteria are fully explained before 11 . Briefly, stable patients over 18 years with a documented diagnosis of HFrEF and on optimum medication according to the 2016 European Society of Cardiology (ESC) guidelines were enrolled.…”

“…Participants' eligibility criteria are fully explained before. 11 Briefly, stable patients over 18 years with a documented diagnosis of HFrEF and on optimum medication according to the 2016 European Society of Cardiology (ESC) guidelines were enrolled. No sex or HF type (ischemic or non‐ischemic) restriction was imposed.…”

Endoplasmic Reticulum-Mitochondria Contacts: A Potential Therapy Target for Cardiovascular Remodeling-Associated Diseases

“…In brief, this finding highlights the role of melatonin, which may be considered as an ideal agent for the targeted therapy of septic cardiomyopathy via modulating mitochondrial homeostasis and ER function. An attempt at therapy in a randomized placebo-controlled phase II trial (NCT 03894683) is currently ongoing to determine the effect of melatonin on cardiovascular and muscle mass and function in patients with CHF ( Sadeghi et al, 2020 ). Another randomized, placebo-controlled trial (NCT 01172171), which was designed to determine whether administration of melatonin reduces infarct size in patients with acute myocardial infarction, is proceeding ( Dominguez-Rodriguez et al, 2007 ).…”