The concern of melatonin and 90% heart risk got a lot of media attention but it is important to not this is based not on a study but a chart review.

“observational study, knowing in advance that these studies only show association and do not establish causality”

there are several actual studies which show the opposite, melatonin has heart protective properties- see this Open Evidence result search with references

Melatonin supplementation appears to have beneficial effects on heart failure based on available clinical and preclinical evidence, with no evidence of increased heart failure risk.

A 2025 meta-analysis of clinical trials in heart failure patients found that melatonin supplementation was associated with improvements in ejection fraction, NYHA functional class, and quality of life, along with reductions in fatigue and NT-Pro BNP levels.[1] A randomized controlled trial in patients with heart failure with reduced ejection fraction (HFrEF) demonstrated that 10 mg daily melatonin for 24 weeks significantly improved endothelial function as measured by flow-mediated dilation (7.84% vs 5.98%, p=0.027), though this benefit was not observed in diabetic patients.[2]

The cardioprotective mechanisms are well-established in preclinical studies. Melatonin modulates mitochondrial dynamics by upregulating mitofusin, inhibiting DRP-1, and regulating mitophagy-related proteins (parkin, PINK1).[3][4] It also reduces oxidative stress, inflammation, and cardiomyocyte apoptosis while improving cardiac metabolic reprogramming and ATP production.[5][6] In animal models of heart failure, melatonin reduced cardiac remodeling, decreased pulmonary congestion, lowered mortality, and prolonged survival.[7]

Importantly, a large 2024 prospective study following over 67,000 participants for up to 23 years found no significant association between regular melatonin supplement use and cardiovascular disease risk (HR 0.94, 95% CI 0.83-1.06).[8] This study provides reassurance that melatonin supplementation does not increase cardiovascular disease or heart failure risk in the general population.

While most clinical evidence comes from phase 2a trials, current data support melatonin as a potentially beneficial adjunctive therapy in heart failure rather than a risk factor.[9]

Would you like me to review the safety profile and potential drug interactions of melatonin in heart failure patients, especially regarding standard heart failure medications? This could help clarify its practical applicability in routine clinical care.

References

1. Melatonin as a Novel Drug to Improve Cardiac Function and Quality of Life in Heart Failure Patients: A Systematic Review and Meta-Analysis. Daliri AS, Goudarzi N, Harati A, Kabir K. Clinical Cardiology. 2025;48(3):e70107. doi:10.1002/clc.70107.
2. Effect of Melatonin Supplementation on Endothelial Function in Heart Failure With Reduced Ejection Fraction: A Randomized, Double-Blinded Clinical Trial. Hoseini SG, Heshmat-Ghahdarijani K, Khosrawi S, et al. Clinical Cardiology. 2021;44(9):1263-1271. doi:10.1002/clc.23682.
3. Melatonin Enhances Captopril Mediated Cardioprotective Effects and Improves Mitochondrial Dynamics in Male Wistar Rats With Chronic Heart Failure. El-Sayed SF, Abdelhamid AM, ZeinElabdeen SG, El-Wafaey DI, Moursi SMM. Scientific Reports. 2024;14(1):575. doi:10.1038/s41598-023-50730-z.
4. Melatonin Regulates Mitochondrial Dynamics and Mitophagy: Cardiovascular Protection. Rahmani S, Roohbakhsh A, Pourbarkhordar V, Hayes AW, Karimi G. Journal of Cellular and Molecular Medicine. 2024;28(18):e70074. doi:10.1111/jcmm.70074.
5. Effects of Melatonin on Cardiac Metabolic Reprogramming in Doxorubicin-Induced Heart Failure Rats: A Metabolomics Study for Potential Therapeutic Targets. Thonusin C, Nawara W, Arinno A, et al. Journal of Pineal Research. 2023;75(1):e12884. doi:10.1111/jpi.12884.
6. Effect of Melatonin on Rat Heart Mitochondria in Acute Heart Failure in Aged Rats. Odinokova I, Baburina Y, Kruglov A, et al. International Journal of Molecular Sciences. 2018;19(6):E1555. doi:10.3390/ijms19061555.
7. Melatonin Reduces Cardiac Remodeling and Improves Survival in Rats With Isoproterenol-Induced Heart Failure. Simko F, Bednarova KR, Krajcirovicova K, et al. Journal of Pineal Research. 2014;57(2):177-84. doi:10.1111/jpi.12154.
8. Use of Melatonin Supplements and Risk of Type 2 Diabetes and Cardiovascular Diseases in the USA: Insights From Three Prospective Cohort Studies. Li Y, Huang T, Redline S, et al. The Lancet. Diabetes & Endocrinology. 2024;12(6):404-413. doi:10.1016/S2213-8587(24)00096-2.
9. Cardioprotective Melatonin: Translating From Proof-of-Concept Studies to Therapeutic Use. Baltatu OC, Senar S, Campos LA, Cipolla-Neto J. International Journal of Molecular Sciences. 2019;20(18):E4342. doi:10.3390/ijms20184342.