Although other mechanisms cannot be ruled out, our data support the hypothesis that IL-18, by impacting SCN5A channel biophysics, may contribute to VT/SCD risk by impacting AP upstroke velocity, conduction velocity, and QT interval, highlighting the importance of multi-ion channel analyses that may inform the rational development of safer (reduced cardiotoxic effects), anti-arrhythmic monotherapy and polytherapy approaches for patients. Here, SCN5A is linked to Schnyder corneal dystrophy.