Low serum zinc levels and risk of incident atrial fibrillation/flutter: a multi-institutional study

Atrial fibrillation/flutter (AF) is increasingly prevalent, and identification of modifiable risk factors is a priority. Zinc deficiency (ZD) has been implicated in cardiovascular disease, but large-scale evidence linking ZD to incident AF remains limited.

We conducted a multi-institutional retrospective cohort study using the TriNetX Research Network, analyzing patients aged ≥40 years with documented serum zinc levels (index date) between 2010 and 2023. Patients were categorized as zinc-deficient (< 70 μg/dL, n = 61,732) or zinc-sufficient (70-120 μg/dL, n = 61,732) after 1:1 propensity score matching. The primary outcome was newly diagnosed AF within two years after the index date. The secondary outcomes included risks of pneumonia (positive control), ventricular fibrillation/flutter, and ischemic stroke. Outcome events were stratified into early and late onset, defined as those occurring within 1-6 months and 6-24 months, respectively.

ZD was associated with significantly increased AF risk during both the early (hazard ratios (HRs) 1.62, 95% confidence intervals (CIs) 1.39-1.90, p < 0.001) and late follow-up periods (HR 1.42, 95%CI 1.29-1.57, p < 0.001). A clear dose-response relationship was observed when comparing different levels of ZD to the control group. Severe ZD (< 50 μg/dL) conferred nearly two-fold higher late AF risk vs. controls (HR 2.04, 95% CI 1.67-2.49), while mild-to-moderate ZD (50-70 μg/dL) showed a modest but significant increase compared to controls (HR 1.26, 95% CI 1.14-1.41). The association between ZD and AF remained consistent across diverse patient subgroups and both pre-pandemic (2010-2019) and pandemic periods (2020-2023). The risks of pneumonia (early: HR 1.56; late: HR 1.40) and ischemic stroke (early: HR 1.19; late: HR 1.12) were also elevated in zinc-deficient patients, whereas ventricular fibrillation/flutter was not significantly associated with ZD.

ZD may serve as an important independent risk factor for incident AF, highlighting the potential value of incorporating zinc status into cardiovascular risk assessment and considering zinc supplementation as a cost-effective preventive strategy.