Mutation-Specific Cardiac Risk Assessment in LQT3

Long QT type 3 (LQT3) is a common form of LQT syndrome caused by mutations in the cardiac sodium channel. These mutations lead to an increase in the cardiac sodium current during the late phases of the cardiac action potential (AP), leading to cardiac arrhythmias. We attempted to predict mutation-specific cardiac event risk for LQT3 mutations using a combination of in vitro and in silico risk assessment. For that, we first characterized, using patch clamp, eight common mutations associated with LQT3. Using our data as an input to a cardiomyocyte computer model, we predicted action potential duration (APD) and early after-depolarization (EAD) susceptibility for these mutants, at different heart rates. Our risk predictions correlated well to the cardiac event risk observed in patients with these mutations. Second, we measured the effect of the late sodium blocker ranolazine for each of the mutants tested. We used the model to predict drug treatment efficacy. Interestingly, ranolazine showed mutation-specific effects, with some mutations showing strongly shortened APDs and decreased predicted risk, while little effect was observed in other mutants. Most importantly, for one of the mutations assessed, risk was predicted to be increased, despite shortening of APD. Thus, our results suggest that drug treatment efficacy is mutation-specific. In summary, our results show that mutation-specific in silico models may be an important new tool for clinical risk assessment in LQT3.