Omega-3-fatty-acid eicosapentaenoic acid (EPA) associates with reduced QTc in patients with atrial fibrillation
M Allemann, P Lee, C Altomare, C Balbi, A Seeberger, E Pavlidou, S Aeschbacher, G G Camici, T F Luescher, N Rodondi, S Osswald, D Conen, M Kuehne, L Barile, J H BeerAbstract
Background
Atrial fibrillation (AF) is the most common cardiac arrhythmia, with incidence increasing with age, partly due to age-related cardiac fibrosis and structural remodeling. Omega-3 fatty acids (n-3 FAs) have anti-arrhythmic and cardioprotective properties as shown in experimental and clinical studies, although results remain inconsistent.
Methods
Red-blood-cell n3-FA levels were quantified as percentages of total n3-FAs in 2’415 patients enrolled in a Swiss, multicenter, cross-sectional cohort of atrial fibrillation patients. Linear logistic regression models were used to analyse associations of n3-FAs with QTc. Model 1 was adjusted for age and sex, and model 2 adjusted for demographic and clinical covariates. Restricted cubic splines were used to assess potential non-linear associations of continuous n3-FAs concentration and QTc intervals. Secondly, n3-FA were stratified into quartiles for further analysis. For the in vitro study, we treated hiPSC-derived cardiomyocytes with different doses of EPA and DHA. The QTc interval was measured using a Multielectrode array (MEA).
Results
In the cohort, 27% of patients were female and mean age was 73 years. In model 1, higher total n3-FA, EPA, and DHA levels were associated with shorter QTc intervals. In the fully adjusted linear regression model, only higher EPA levels were associated with a significantly shorter QTc interval per doubling of concentration (estimate: -3.20 ms, 95% CI -5.97 – -0.44, p=0.02) (Figure 1A). A significant overall trend toward shorter QTc across increasing EPA quartiles was observed (p for trend<0.01) (Figure 1B). Patients in the third quartile of EPA significantly associated with the shortest QTc intervals compared with those in the lowest quartile (estimate: -6.68 ms, 95% CI -10.92 – -2.44, p<0.01) (Figure 1C). Restricted cubic spline analyses confirmed a modest non-linear association between EPA and QTc, with the lowest predicted QTc at intermediate EPA concentrations (Figure 1D). Our preliminary in vitro study revealed a reduction in QTc with increasing EPA, the same trend was also observed for heart rate (Figure E).
Conclusion
Higher circulating EPA levels are associated with shorter QTc intervals in patients with AF with evidence of a u-shaped relationship. In vitro data support the hypothesis that n3-FA, particularly EPA, may beneficially modulate ventricular repolarization. Further studies are warranted to clarify the clinical relevance and mechanistic basis of EPA-mediated electrophysiological modulation in AF.