The global prevalence of atrial fibrillation/flutter (AF) is steadily rising and poses an increasing public health challenge. A nationwide study from Denmark reported a cumulative prevalence of AF of 3.0% (1), while global estimates indicated an AF prevalence of 0.51% in 2017, with projections suggesting a potential 60% increase by 2050 (2). AF not only increases the risk of stroke and heart failure but also contributes to cognitive decline, physical disability, and reduced quality of life, particularly among older adults (3, 4). Moreover, AF imposes a substantial healthcare burden, with significantly higher hospitalization rates and annual medical costs, up to $27,896 more per patient than those without AF (5, 6). Although traditional risk factors, such as hypertension, diabetes, heart failure, and aging, are well-established contributors to AF (7), they do not fully explain its growing incidence. Recent studies have identified a wider range of modifiable risk factors, including obesity, smoking, alcohol consumption, physical inactivity, and obstructive sleep apnea, all of which contribute significantly to atrial remodeling and the development of AF (7–9). As the global population age and AF prevalence continue to rise, there is an urgent need to shift attention toward AF prevention through early identification and management of potential risk factors.

Zinc, an essential trace element, functions as a cofactor for more than 300 enzymes and is vital for numerous physiological processes (10). Within the cardiovascular system, zinc has been implicated in the pathophysiology of heart failure, vascular calcification, and myocardial infarction (11). Additionally, zinc has emerged as a potential modulator of cardiac rhythm owing to its critical role in maintaining cellular homeostasis (12). Several small-scale studies have reported the potential association between zinc deficiency and development of AF. For instance, lower zinc levels have been linked to a higher incidence of postoperative AF in patients undergoing coronary artery bypass grafting (13). Similarly, research conducted on elderly patients admitted to medical intensive care units reported a significant association between low zinc concentration and the occurrence of AF (14). However, these studies provide limited evidence regarding the role of zinc deficiency in the development of new-onset AF, largely due to the small sample sizes and inherent limitations of the study design. Given the growing clinical burden of AF and the biological plausibility of zinc involvement, we conducted a large-scale investigation to evaluate whether zinc deficiency is an independent risk factor for incident AF.

This large-scale, multi-institutional study provides evidence that zinc deficiency is a significant and independent risk factor for developing AF. Our analysis of over 123,000 matched patients demonstrated that individuals with serum zinc levels below 70 μg/dL exhibited a 62% increased risk of incident AF during the early follow-up period and a sustained 42% elevated risk throughout the extended observation phase. A clear dose-response relationship was observed when comparing different levels of ZD to the control group. Severe ZD conferred nearly two-fold higher late AF risk vs. controls (HR 2.04), while mild-to-moderate ZD showed a modest but significant increase compared to controls (HR 1.26). These associations remained robust across diverse patient populations and different healthcare environments, including the pre-pandemic and pandemic periods, suggesting that the relationship reflects genuine biological mechanisms rather than confounding factors related to healthcare delivery patterns.

The link between zinc deficiency and AF may be explained by multiple interconnected biological pathways that influence both cardiac electrical activity and structural remodeling. Zinc serves as a cofactor for over 300 enzymes involved in cellular metabolism, protein synthesis, and antioxidant defense systems. In cardiac tissues, zinc deficiency disrupts calcium homeostasis by impairing calcium-handling proteins, leading to altered excitation-contraction coupling and increased susceptibility to triggered arrhythmias (29, 30). This mineral also plays a crucial role in maintaining cellular membrane stability through its involvement in phospholipid metabolism and membrane-bound enzyme function (31, 32). Furthermore, zinc deficiency promotes oxidative stress by reducing the activity of zinc-dependent antioxidant enzymes such as superoxide dismutase (31, 33). This oxidative environment facilitates atrial remodeling through fibroblast activation, collagen deposition, and inflammatory cascade activation (34). The resulting structural changes create a substrate for reentrant arrhythmias by altering the conduction velocity and refractoriness patterns. Additionally, zinc deficiency affects ion channel function, particularly potassium and sodium channels, which are critical for maintaining normal cardiac rhythm (12, 35), thereby creating an electrophysiological milieu conducive to arrhythmia initiation and maintenance.

Previous meta-analyses reported inconsistent associations between serum zinc and cardiovascular outcomes (36, 37). Chu et al. (36) found largely null associations overall, with inverse serum zinc relationships limited to high-risk subgroups, while Hashemian et al. (37) reported supportive evidence mainly from case–control studies, with inconsistent results across prospective cohorts. Subsequent studies focused on advanced cardiovascular disease and mortality-related endpoints rather than arrhythmia incidence (38, 39). Consequently, prior literature often included patients with structural heart disease or prevalent AF, limiting inference on zinc status and incident arrhythmia risk. In contrast, the present study uniquely examined incident AF as the primary outcome, using strict exclusion of pre-existing AF, comprehensive propensity score matching, and dose–response modeling. These methodological features enhance temporal inference compared with prior cross-sectional or mortality-based studies (36, 37). Clinically, our findings suggest that zinc deficiency may represent a modifiable risk factor for atrial arrhythmogenesis, and serum zinc assessment could help identify individuals who may benefit from targeted nutritional evaluation or supplementation trials.

This study is the first large-scale investigation to establish zinc deficiency as an independent risk factor for incident AF. A key strength of our analysis lies in the assessment of new-onset AF within a clearly defined follow-up window, enabling time-sequenced evaluation and enhancing the validity of causal inference. We found that zinc deficiency was associated with a significantly increased risk of developing AF, with HRs of 1.62 for early-stage and 1.42 for late-stage onset. Our findings not only extend the clinical relevance of zinc beyond heart failure and myocardial infarction (40–42), but also underscore the importance of incorporating micronutrient evaluation into cardiovascular risk stratification. The temporal pattern of the risk revealed important clinical insights. The higher early stage risk suggests an acute vulnerability period where zinc deficiency may trigger arrhythmia through immediate metabolic disruption, while sustained late-stage elevation may indicate chronic structural remodeling effects. This dual-phase pattern has not been previously described for micronutrient deficiencies in the development of arrhythmia.

Interestingly, while AF risk increased substantially, the corresponding ischemic stroke elevation was mild (12–19%). This disparity may be explained by the temporal relationship between new-onset AF and subsequent thromboembolic events. The development of ischemic stroke following incident AF typically requires time for atrial thrombus formation and embolization to occur, particularly in patients who may not have received immediate anticoagulation therapy. Given our relatively short follow-up period of 2 years, this timeframe may be insufficient to capture the full stroke risk associated with zinc deficiency-induced AF. The mild stroke elevation observed in our study likely reflects the early phase of this pathophysiological process, where the arrhythmogenic effects of zinc deficiency are immediately apparent, but the downstream thromboembolic consequences have not yet been fully manifested. This temporal delay underscores the importance of early recognition and management of zinc deficiency as a modifiable risk factor, potentially preventing both arrhythmia development and subsequent stroke complications with long-term follow-up.

Because our study period encompassed the COVID-19 pandemic, and zinc homeostasis has been implicated in COVID-19 susceptibility and disease severity (43, 44), we specifically addressed this potential confounding by performing stratified sensitivity analyses across pre-pandemic (2010–2019) and pandemic (2020–2023) periods. The association between zinc deficiency and incident AF remained consistent in both periods, indicating that our findings were unlikely to be driven by pandemic-related healthcare disruptions or infection-related biases. These results support a stable biological relationship between zinc deficiency and atrial arrhythmogenesis independent of COVID-19–related effects.

Regarding the clinical implications of our findings, healthcare providers may consider incorporating serum zinc assessment into cardiovascular risk evaluation, particularly for patients with established AF risk factors or unexplained palpitations. The dose-response relationship observed in our study suggests that even mild zinc deficiency warrants attention, as it still conferred a 26% increased risk of late-stage AF. From a therapeutic perspective, zinc supplementation represents a potentially cost-effective intervention for AF prevention. However, the optimal dosing, duration, and target population for zinc supplementation require careful investigation in randomized controlled trials. Clinicians should also be aware that zinc deficiency often coexists with other nutritional deficiencies and comorbid conditions, suggesting that comprehensive nutritional assessment and management are necessary.

The inclusion of pneumonia risk as a positive control outcome provided crucial biological validation of our primary findings. Pneumonia risk showed substantial elevation in zinc-deficient patients during both the early (HR 1.56) and late stages (HR 1.40), closely paralleling the AF pattern. This observation strongly supports the biological plausibility of our cardiovascular findings, as the role of zinc in immune function is well established (45). The established effectiveness of zinc even as a direct anti-infective, as in treatment of conditions such as cutaneous leishmaniasis (46), provides further credence to the validity of its association with infection-related outcomes, such as pneumonia, in our cohort. Parallel patterns between pneumonia and AF risks further establish our confidence that observed associations reflect real biologic relationships.

The absence of increased ventricular fibrillation/flutter risk in zinc-deficient patients provides important insights into the specificity of the arrhythmogenic effects of zinc. This finding suggests that zinc deficiency preferentially affects atrial electrophysiology rather than ventricular electrophysiology. This specificity has clinical relevance, as it indicates that zinc deficiency may represent a targeted risk factor for supraventricular rather than life-threatening ventricular arrhythmias. This observation also supports the biological plausibility of our findings by demonstrating that the association is not simply due to increased overall arrhythmia surveillance or detection bias in zinc-deficient patients. Instead, it points to specific pathophysiological mechanisms that primarily affect the atrial substrate and conduction properties.

Several limitations must be acknowledged when interpreting our findings. First, despite extensive adjustment and demonstration of a dose–response relationship, this observational study cannot establish causality. Residual confounding from unmeasured lifestyle or nutritional factors may persist. Important factors such as overall dietary quality, intake of other micronutrients (e.g., magnesium or potassium), socioeconomic status, physical activity, alcohol consumption patterns, smoking intensity, and underlying chronic inflammatory states were not fully captured and may influence both zinc status and AF risk. Second, the TriNetX database may not capture all relevant confounding variables, particularly subclinical conditions that could influence both zinc status and arrhythmia risk. For example, reverse causality remains possible, whereby subclinical or undiagnosed AF, or shared underlying conditions such as systemic inflammation or heart failure, could contribute to reduced zinc levels rather than zinc deficiency preceding AF development. Third, the definition of zinc deficiency may not represent the optimal cut-off point for cardiovascular risk stratification. Our dose–response analyses across graded deficiency levels demonstrated progressively increasing AF risk, suggesting that cardiovascular risk varies continuously with zinc status and is not dependent on a single threshold. Future prospective studies are required to define the optimal zinc cut-off for AF risk stratification. Fourth, serum zinc levels are influenced by acute-phase responses, infection, circadian variation, and recent dietary intake. Therefore, reliance on a single zinc measurement may not accurately reflect an individual's long-term zinc status or tissue-level deficiency and may result in exposure misclassification (e.g., transient reductions or unrecognized chronic deficiency). Although such non-differential misclassification would be expected to bias the observed associations toward the null, it remains an important limitation of the present study. Fifth, our analysis focused on diagnosed AF episodes, potentially missing asymptomatic or undetected cases, which could lead to underestimation of the true association. Finally, selection bias is also possible because study participants were drawn from individuals who received medical evaluation and serum zinc testing, who may differ systematically from healthier community populations. Furthermore, confounding by indication cannot be excluded, as the clinical rationale for zinc testing was unavailable and may have been influenced by suspected malnutrition or higher baseline cardiovascular risk. Accordingly, our findings indicate association rather than causation, and prospective interventional studies are required to confirm any preventive effect of zinc supplementation on AF.

Our analysis of over 123,000 patients demonstrates an association between zinc deficiency and increased risk of incident AF, with a clear dose–response pattern across deficiency severity. These findings support the potential clinical value of serum zinc assessment in AF risk evaluation. However, causality cannot be established, and randomized controlled trials are required to determine whether zinc supplementation can effectively prevent AF and define optimal treatment strategies.