Comprehensive T wave morphology assessment in a randomized clinical study of dofetilide,quinidine,ranolazine,and verapamil

Background: congenital long qt syndrome type 2 (abnormal herg potassium channel) patients can develop flat,asymmetric,and notched t waves. similar observations have been made with a limited number of herg-blocking drugs. however,it is not known how additional calcium or late sodium block,that can decrease torsade risk,affects t wave morphology. methods and results: twenty-two healthy subjects received a single dose of a pure herg blocker (dofetilide) and 3 drugs that also block calcium or sodium (quinidine,ranolazine,and verapamil) as part of a 5-period,placebo-controlled cross-over trial. at predose and 15 time-points post-dose,ecgs and plasma drug concentration were assessed. patch clamp experiments were performed to assess block of herg,calcium (l-type) and late sodium currents for each drug. pure herg block (dofetilide) and strong herg block with lesser calcium and late sodium block (quinidine) caused substantial t wave morphology changes (p<0.001). strong late sodium current and herg block (ranolazine) still caused t wave morphology changes (p<0.01). strong calcium and herg block (verapamil) did not cause t wave morphology changes. at equivalent qtc prolongation,multichannel blockers (quinidine and ranolazine) caused equal or greater t wave morphology changes compared with pure herg block (dofetilide). conclusions: t wave morphology changes are directly related to amount of herg block; however,with quinidine and ranolazine,multichannel block did not prevent t wave morphology changes. a combined approach of assessing multiple ion channels,along with ecg intervals and t wave morphology may provide the greatest insight into drug-ion channel interactions and torsade de pointes risk. © 2015 the authors. published on behalf of the american heart association,inc.