Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: A simple algorithm that incorporates resting and exercise-recovery QTc is useful in identifying LQTS in asymptomatic relatives.

Repolarization dynamics during exercise discriminate between LQT1 and LQT2 genotypes.

UNLABELLED: Genotype and Exercise in LQTS. BACKGROUND: Repolarization dynamics during exercise in patients with long-QT Syndrome (LQTS) may be influenced by various factors such as a patient's genotype. We sought to systematically characterize the repolarization dynamics during exercise in patients with LQTS with a particular focus on the influence of genotype. METHODS: Three groups of patients were studied on the basis of clinical status and genotype: LQT1, LQT2, and normal controls. Twenty-five age- and gender-matched patients were selected for each group. The QTc was measured during bicycle exercise testing and its dynamics were compared between the 3 groups. RESULTS: The degree of QTc prolongation during exercise was greater in LQTS patients (LQT1 80 ± 47 ms, LQT2 64 ± 41 ms, Control 46 ± 20 ms, P = 0.02), with significant differences between LQT1 and LQT2 patients observed at heart rates ≥ 60% of the predicted maximum (P < 0.05). LQT1 patients demonstrated progressive or persistent QTc prolongation at higher heart rates, whereas LQT2 patients demonstrated maximum QTc prolongation at submaximal heart rates (50% of the predicted maximum) with subsequent QTc correction toward baseline values at higher heart rates. Importantly, these observations were consistent regardless of age, gender, or exercise type in subgroup analyses. CONCLUSIONS: Reduced repolarization reserve in LQTS is genotype and heart rate specific.

Utility of the recovery electrocardiogram after exercise: a novel indicator for the diagnosis and genotyping of long QT syndrome?

BACKGROUND: Exercise testing has shown modest utility in the ability to diagnose and genotype long QT syndrome (LQTS). Although numerous small studies have shown a genotype-specific repolarization response to exercise, the repolarization responses during recovery from exercise have received less focus. OBJECTIVE: The purpose of this study was to characterize genotype-specific QT responses during recovery from exercise and to determine its potential as a diagnostic and genotyping tool. METHODS: Seventy-five patients were age and sex matched into three groups (n = 25): LQT1, LQT2, and unaffected controls based on Schwartz score and genetic testing results. Each group underwent upright burst and gradual bicycle exercise testing while being monitored by 12-lead electrocardiogram. RESULTS: LQT1 patients had significantly longer corrected QT (QTc) than LQT2 intervals during early recovery (P <.01). Control subjects showed little variation in QTc throughout the recovery period, maintaining a QTc within normal limits. Each group showed a distinct pattern of QTc adaptation during recovery. LQT1 patients began the recovery period at a QTc of 492 +/- 11 ms, after which the QTc decreased by 33 +/- 11 ms during recovery. Conversely, the LQT2 patients began recovery at its lowest mean QTc of 420 +/- 10 ms, which increased by 40 +/- 16 ms. At the end of recovery, a QTc cut-off value of 445 ms distinguished 92% of LQTS patients from unaffected controls, while a start-of-recovery QTc cut-off of 460 ms correctly identified genotype in 80% of LQT1 and 92% of LQT2 patients. CONCLUSIONS: Genotype-specific differences exist in QT recovery after exercise. These differences can help to identify LQTS patients and distinguish LQT1 from LQT2 genotypes.