Metallomic Dysregulation and Cardiovascular Disease: Essential Trace Elements, Non-essential Metal Exposure, and...

Heart failure (HF) affects over 64 million people worldwide, with five-year mortality rates rivaling solid-organ malignancies. Despite advances in neurohormonal therapy, many patients continue to progress, suggesting additional pathophysiological drivers. Metallomic dysregulation-imbalance among essential trace elements combined with non-essential metal accumulation-engages pathways central to HF pathobiology, including oxidative stress, mitochondrial dysfunction, impaired calcium handling, and pro-fibrotic cascades. We conducted a systematic review compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement, searching PubMed/MEDLINE, Embase, Scopus, and Web of Science. Eligible studies enrolled adults who were assessed for at least one metal and reported a cardiac outcome. Risk of bias was evaluated using the Cochrane risk-of-bias tool for randomized trials (RoB 2) and the Newcastle-Ottawa Scale. Twenty-nine studies met the inclusion criteria-encompassing over 90,000 participants. Iron deficiency affected approximately 30-58% of patients with HF. In HF with reduced ejection fraction (HFrEF), intravenous ferric carboxymaltose improved Patient Global Assessment (odds ratio [OR] 2.51; 95% confidence interval [CI] 1.75-3.61) and reduced HF hospitalization (hazard ratio [HR] 0.39; 95% CI 0.19-0.82). Zinc, selenium, and magnesium deficiencies were associated with impaired antioxidant defenses, mitochondrial dysfunction, and susceptibility to arrhythmias. Among non-essential metals, cadmium showed the strongest prospective evidence for adverse cardiovascular outcomes, including HF risk and cardiac remodeling. Lead was associated with left ventricular hypertrophy and cardiovascular mortality, while arsenic was consistently linked to cardiovascular mortality. Evidence for mercury remained limited and inconsistent. Intravenous (IV) iron repletion in iron-deficient HFrEF is the only metallomic intervention with robust evidence. Remaining associations are hypothesis-generating. Adequately powered trials and Mendelian randomization studies are urgently needed. Registration number: PROSPERO CRD420261343598.