Characterization of the non-linear rate-dependency of QT interval in humans

Abstract

Aims: Repolarization has rate-dependent and rate-independent components. A function considering such components separately was validated in canine Purkinje fibres and applied to the QT/RR relation in humans.

Methods and results: Action potential duration (APD) was measured in Purkinje fibres during steady-state pacing at different cycle lengths (CL) and after prolonged quiescence (APD(0)). The APD/CL relationship was expressed by this function: APD=APD(max)(*)CL(S)/(CL(50)(S)+CL(S)), where APD(max) (APD extrapolated at infinite CL) is a rate-independent measure of repolarization, CL(50) (CL at which 50% of APD(max) is achieved) and S evaluates the rate dependency of APD. The same function was used to fit the QT/RR relation in 46 normal subjects (20 males, 26 females) and in 7 amiodarone-treated subjects undergoing a bicycle stress test. RR and QT (V(5)) were measured at the end of each load step; QT(c) (Bazett's formula) was obtained at rest. The APD/CL and QT/RR relations were equally well expressed by the function with high correlation coefficients (R>or=0.90). In Purkinje fibres, APD(max) was 461+/-37 ms, CL(50) was 394+/-54 ms and S was 0.98+/-0.11. APD(max) and APD(0) correlated (R=0.96) and were similar. The corresponding values in humans were: QT(max) 432+/-63 ms, RR(50) 345+/-60 ms and S 2.6+/-0.8. While QT(c) and QT(max) were longer in females, RR(50) and S were similar between genders. Amiodarone increased QT(c), QT(max) and RR(50) and decreased S. In QT(max) and QT(c) distributions generated by pooling data from treated and untreated subjects, 86% of treated subjects were correctly identified by QT(max) and 28% by QT(c).

Conclusions: Canine and human repolarization showed a saturating dependency on cycle length, described by the proposed function. Gender and amiodarone independently affected QT(max), RR(50) and S: therefore they might reflect specific ionic mechanisms. Finally, QT(max) identified drug-induced repolarization abnormalities in individual subjects better than QT(c).