Sex Differences and Utility of Treadmill Testing in Long-QT Syndrome

Area of Science:

• Cardiology
• Genetics
• Electrocardiography

Background:

• Diagnosing congenital long-QT syndrome (LQTS) is challenging due to ambiguous phenotypes and normal-to-borderline resting QT intervals.
• A previously developed 3-step algorithm using exercise-induced corrected QT interval (QTc) changes aids LQTS diagnosis and subtype prediction.

Purpose of the Study:

• To evaluate the diagnostic and predictive utility of the 3-step QT exercise algorithm in a broader LQTS population with milder phenotypes.
• To establish sex-specific QTc cutoffs beyond resting values for improved diagnostic accuracy.

Main Methods:

• Analysis of exercise treadmill tests (Bruce protocol) in 208 LQTS variant carriers (KCNQ1, KCNH2) and 215 controls.
• Receiver operating characteristic (ROC) curve analysis to determine optimal QTc cutoffs during different exercise and recovery phases.
• Evaluation of diagnostic performance across sexes for carrier status and LQTS subtype differentiation.

Main Results:

• A significant proportion of LQTS carriers (78% males, 74% females) presented with normal-to-borderline resting QTc.
• The 4-minute recovery QTc showed the highest predictive value for carrier status (AUC 0.90 females, 0.82 males), with optimal cutoffs of 450 ms (females) and 440 ms (males).
• The 1-minute recovery QTc distinguished LQTS1 from LQTS2 in females (AUC 0.82), while peak exercise QTc was marginally better for males (AUC 0.71).

Conclusions:

• The 3-step QT exercise algorithm is a validated and reliable tool for diagnosing LQTS in populations with ambiguous phenotypes.
• The algorithm provides a simple method for identifying LQTS carriers and predicting major genotype subtypes using sex-specific QTc cutoffs.