Derivation and Validation of a Simple Exercise-Based Algorithm for Prediction of Genetic Testing in Relatives of LQTS Probands

• Published in: Circulation (New York, N.Y.) Vol. 124; no. 20; pp. 2187 - 2194
• Main Authors: Sy, Raymond W., van der Werf, Christian, Chattha, Ishvinder S., Chockalingam, Priya, Adler, Arnon, Healey, Jeffrey S., Perrin, Mark, Gollob, Michael H., Skanes, Allan C., Yee, Raymond, Gula, Lorne J., Leong-Sit, Peter, Viskin, Sami, Klein, George J., Wilde, Arthur A., Krahn, Andrew D.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 15.11.2011
• Subjects: Adolescent; Adult; Algorithms; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Child; Cohort Studies; Coronary heart disease; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Exercise - physiology; Exercise Test - methods; Exercise Test - standards; Female; Genetic Testing - methods; Genetic Testing - standards; Heart; Heart Rate - physiology; Humans; Long QT Syndrome - diagnosis; Long QT Syndrome - genetics; Long QT Syndrome - physiopathology; Male; Medical sciences; Middle Aged; Predictive Value of Tests; Young Adult; Physical exercise; QT interval; Cardiovascular disease; Diagnosis; exercise test; genetic testing
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.111.028258

Genetic testing can diagnose long-QT syndrome (LQTS) in asymptomatic relatives of patients with an identified mutation; however, it is costly and subject to availability. The accuracy of a simple algorithm that incorporates resting and exercise ECG parameters for screening LQTS in asymptomatic relatives was evaluated, with genetic testing as the gold standard. Asymptomatic first-degree relatives of genetically characterized probands were recruited from 5 centers. QT intervals were measured at rest, during exercise, and during recovery. Receiver operating characteristics were used to establish optimal cutoffs. An algorithm for identifying LQTS carriers was developed in a derivation cohort and validated in an independent cohort. The derivation cohort consisted of 69 relatives (28 with LQT1, 20 with LQT2, and 21 noncarriers). Mean age was 35±18 years, and resting corrected QT interval (QTc) was 466±39 ms. Abnormal resting QTc (females ≥480 ms; males ≥470 ms) was 100% specific for gene carrier status, but was observed in only 48% of patients; however, mutations were observed in 68% and 42% of patients with a borderline or normal resting QTc, respectively. Among these patients, 4-minute recovery QTc ≥445 ms correctly restratified 22 of 25 patients as having LQTS and 19 of 21 patients as being noncarriers. The combination of resting and 4-minute recovery QTc in a screening algorithm yielded a sensitivity of 0.94 and specificity of 0.90 for detecting LQTS carriers. When applied to the validation cohort (n=152; 58 with LQT1, 61 with LQT2, and 33 noncarriers; QTc=443±47 ms), sensitivity was 0.92 and specificity was 0.82. A simple algorithm that incorporates resting and exercise-recovery QTc is useful in identifying LQTS in asymptomatic relatives.