Background: Small-scale studies have linked obesity (Ob) and metabolic ill-health with proarrhythmic repolarisation abnormalities. Whether these are observed at a population-scale, modulated by individuals’ genetics and confer higher risks of ventricular arrhythmias (VA) are not known. Methods and Results: Firstly, using the UK Biobank, the association between adiposity and QTc interval was assessed in participants with resting 12-lead ECG (n=23,683), and a polygenic risk score was developed to investigate any modulatory effect of genetics. Participants were also categorised into four phenotypes according to presence (+) or absence (-) of Ob, and if they were metabolically unhealthy (MU+) or not (MU-). QTc was positively associated with body mass index, body fat, waist:hip ratio, and hip and waist girths. Individuals’ genetics had no significant modulatory effect on QTc-prolonging effects of increasing adiposity. QTc was comparably longer in those with metabolic perturbation
without obesity (Ob-MU+) and obesity alone (Ob+MU-) compared to individuals with neither (Ob-MU-), and their co-existence (Ob+MU+) had an additive effect on QTc interval. Secondly, for 502,536 participants in the UK Biobank, odds ratios (OR) for ventricular arrhythmias (VA) were computed for the four clinical phenotypes above using their past medical records. Referenced to Ob-MU-, ORs for VA in Ob-MU+ males and females were 5.96 (95%CI: 4.70-7.55) and 5.10 (95%CI: 3.34-7.80), respectively. OR for Ob+MU+ were 6.99 (95%CI: 5.72-8.54) and 3.56 (95%CI: 2.66-4.77) in males and females, respectively. Conclusion: Adiposity and metabolic perturbation increase QTc to a similar degree, and their co-existence exerts an additive effect. These effects are not modulated by individuals’ genetics. Metabolic ill-health is associated with higher OR for VA than obesity.