The evidence summarized here makes a powerful case for melatonin as a therapeutic agent in cardiovascular health, a potent, naturally occurring neuroendocrine hormone with impressive antioxidant and anti-inflammatory properties.

What stands out most is the breadth of its potential benefits: from protecting the heart muscle during a heart attack (I/R injury) to suppressing damage from chemotherapy (Doxorubicin-induced cardiotoxicity), and even helping regulate nocturnal blood pressure.

Clinical Bottom Line

This is a Narrative Review summarizing the extensive preclinical and early clinical evidence on the diverse cardioprotective effects of melatonin. The consensus is that melatonin, primarily due to its potent antioxidant and anti-inflammatory properties, shows significant therapeutic potential in various cardiovascular disorders, including heart attack recovery, drug-induced cardiotoxicity, hypertension, atherosclerosis, and heart failure. While numerous animal and human studies confirm its cardioprotective activity, the authors stress that melatonin is inexpensive and non-toxic, and therefore, more extensive and well-planned clinical trials are required to definitively confirm these benefits in humans and address inconsistencies in dosage and mode of administration.

Results in Context

Melatonin’s Cardioprotective Mechanisms

Melatonin, a neuroendocrine hormone produced by the pineal gland, functions as an antioxidant (via direct free radical scavenging and upregulating antioxidant enzymes) and exerts its effects through G-protein coupled receptors (MT1 and MT2) as well as nuclear receptors (RZR and ROR$\alpha$). Its beneficial effects include:

• Anti-oxidant and anti-inflammatory activity.

• Modulation of the circadian rhythm and sleep-wake cycle.

• Protection against the death of cardiac muscle in response to ischemia-reperfusion (IR) injury in rodents.

• Suppression of heart damage mediated by pharmacologic drugs.

• Prevention of heart muscle hypertrophy, which may lessen the development of heart failure.

Evidence Across Cardiovascular Conditions

• Drug-Induced Cardiotoxicity: Melatonin has shown significant protective effects against damage caused by chemotherapeutic drugs like Doxorubicin (Dox). It achieves this by reducing oxidative stress and apoptosis and maintaining levels of proteins like Yes-associated protein (YAP) and activating the AMPK/PGC1$\alpha$ pathway.

• Ischemia-Reperfusion Injury (I/R): Melatonin serves as a protective agent, diminishing the risk of reperfusion injury after myocardial infarction. Its action involves preserving mitochondrial function, activating pathways like cGMP-PKGI$\alpha$ and JAK2/STAT3, and inhibiting the destructive effects of mitochondrial fission and necroptosis.

• Hypertension: It has been shown to reduce nocturnal blood pressure in patients with hypertension and regulate heart rate. In vitro and animal studies suggest it acts by lowering vasoconstrictive agents (Angiotensin II and Endothelin) and elevating vasodilators (Nitric Oxide/eNOS).

• Atherosclerosis: Melatonin suppresses the progression of atherosclerosis by activating the Nrf2/ROS/NLRP3 axis, improving endothelial function, and increasing plaque stability through the HGF/c-Met and ROR$\alpha$ pathways.

• Cardiac Arrhythmia: It reduces the rate and severity of ventricular tachycardia (VT) and ventricular fibrillation (VF) following IR injury, potentially by regulating oxidative stress and restoring the normal distribution of connexin-43.

Assertive Critical Appraisal

Certainty of Evidence (GRADE Framework)

This is a Narrative Review, not a Systematic Review or Meta-Analysis. Therefore, it does not provide an overall certainty of evidence rating (GRADE).

Critical Appraisal of Source Material:

• Strength: The review is comprehensive, covering numerous mechanistic studies (molecular targets, signaling pathways) and a wide range of cardiovascular pathologies, which is excellent for hypothesis generation and understanding potential action pathways. The inclusion of tables summarizing specific animal model data (dosage, duration, effects) is highly valuable.

• Weakness (for Clinical Translation): The vast majority of the supportive evidence cited is derived from preclinical (animal) and in vitro studies. Findings from animal models, especially in acute settings, do not always translate to effective clinical therapies in humans, particularly in complex, chronic diseases like human CVD.

• Need for Context: The authors acknowledge that some clinical trials have reported inconsistencies regarding the cardioprotective effects of melatonin. They rightly suggest that previous failures may be due to using young, healthy animals that lack the comorbidities typical of human patients, and they explicitly call for more well-planned clinical trials. The current evidence base is strong for “proof of concept” but insufficient for broad clinical implementation beyond specific, smaller niches like nocturnal hypertension in certain patient populations.

Research Objective

The objective of this review was to summarize the most established benefits of melatonin in the cardiovascular system with a focus on its molecular mechanisms of action, and to discuss current clinical trials using melatonin in heart disease.

Study Design

Type: Narrative Review.

Search Strategy & Selection Criteria: The paper is a narrative review, meaning the process for literature search and study selection is generally not systematic or fully transparent, unlike a systematic review.

Setting and Participants: The review summarizes findings from numerous primary research studies across various models, including in vitro cell culture experiments, in vivo animal models (rats, mice, rabbits, hamsters), and some human clinical trials, focusing on cardiovascular disease (CVD).

Bibliographic Data

Title: Evidence for the Benefits of Melatonin in Cardiovascular Disease

Authors: Mohammad Tobeiha, Ameneh Jafari, Sara Fadaei, Seyed Mohammad Ali Mirazimi, Fatemeh Dashti, Atefeh Amiri, Haroon Khan, Zatollah Asemi, Russel J. Reiter, Michael R. Hamblin and Hamed Mirzaei

Journal: Frontiers in Cardiovascular Medicine

Year: 2022

DOI: 10.3389/fcvm.2022.888319

Mandatory Disclaimer: This AI-generated analysis is for informational and research purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of a qualified health provider with any questions you may have regarding a medical condition.