Validation of a Demography-Based Adaptive QTc Formula using Pediatric and Adult Datasets Acquired from Humans and Guinea Pigs

Abstract

IntroductionA variety of QT rate-correction (QTc) formulae have been utilized for both clinical and research purposes. However, these formulae are not universally effective, likely due to significant influences of demographic diversity on the QT-HR relationship. To address this limitation, we proposed an adaptive QTc (QTcAd) formula that adjusts to subject demographics (i.e., age). Further, we compared the efficacy and accuracy of the QTcAd formula to other widely used alternatives. MethodUsing age as a demographic parameter, we tested the QTcAd formula across diverse age groups with different heart rates (HR) in both humans and guinea pigs. Utilizing retrospective human (n=1360) and guinea pig electrocardiogram (ECG) data from in-vivo (n=55) and ex-vivo (n=66) settings, we evaluated the formulas effectiveness. Linear regression fit parameters of HR-QTc (slope and R{superscript 2}) were utilized for performance assessment. To evaluate the accuracy of the predicted QTc, we acquired epicardial electrical and optical voltage data from Langendorff-perfused guinea pig hearts. ResultsIn both human subjects and guinea pigs, the QTcAd formula consistently outperformed other formulae across all age groups. For instance, in a 20-year-old human group (n=300), the QTcAd formula successfully nullified the inverse HR-QT relationship (R{superscript 2}=5.1E-09, slope=-3.5E-05), while the Bazett formula (QTcB) failed to achieve comparable effectiveness (R{superscript 2}= 0.20, slope=0.91). Moreover, the QTcAd formula exhibited better accuracy than the age-specific Benatar formula (QTcBe), which overcorrected QTc (1-week human QT: 263.8{+/-}14.8 ms, QTcAd: 263.8{+/-}7.3 ms, p=0.62; QTcBe: 422.5{+/-}7.3 ms, p<0.0001). The optically measured pseudo-QT interval (143{+/-}22.5 ms, n=44) was better approximated by QTcAd (180.6{+/-}17.0 ms) compared to all other formulae. Furthermore, we demonstrated that the QTcAd formula was not inferior to individual-specific QTc formulae. ConclusionThe demography-based QTcAd formula showed superior performance across human and guinea pig age groups, which may enhance the efficacy of QTc for cardiovascular disease diagnosis, risk stratification, and drug safety testing. What is knownCorrected QT (QTc) is a well-known ECG biomarker for cardiovascular disease risk stratification and drug safety testing. Various QT rate-correction formulae have been developed, but these formulae do not perform consistently across diverse datasets (e.g., sex, age, disease, species). What the study addsWe introduce a novel QTc formula (QTcAd) that adapts to demographic variability, as the parameters can be modified based on the characteristics of the study population. The formula (QTcAd = QT + (|m|*(HR-HRmean)) - includes the absolute slope (m) of the linear regression of QT and heart rate (HR) and the mean HR of the population (HRmean) as population characteristics parametersUsing datasets from both pediatric and adult human subjects and an animal model, we demonstrate that the QTcAd formula is more effective at eliminating the QT-HR inverse relationship, as compared to other commonly used correction formulae.