The clinical diagnosis of long-QT syndrome (LQTS) remains challenging when ECG abnormalities are borderline or intermittent. Despite issues with access, cost, and heterogeneity of LQTS mutations, genetic testing remains the diagnostic gold standard for diagnosis of LQTS. We sought to develop a provocative testing strategy to unmask the LQTS phenotype and relate this to the results of genetic testing.
Methods and Results—
From 1995 to 2008, 159 consecutive patients with suspected LQTS underwent provocative testing that consisted of a modified Bruce protocol treadmill exercise test, with ECGs recorded supine at rest, immediately on standing, and at 1-minute intervals during exercise, at peak exercise, and at 1-minute intervals during the recovery phase. Similar testing was carried out on a stationary bike in a gradual and burst exercise fashion. LQTS was confirmed with genotyping in all 95 affected LQTS patients and excluded with negative family screening in 64 control subjects. Patients were studied before and after initiation of β-blockers. Of 159 patients, 50 had an LQT1 mutation and 45 had an LQT2 mutation. In the LQTS group, 44.3% of patients had a normal-to-borderline resting QTc interval. LQTS patients exhibited a greater prolongation in QTc with postural change than unaffected patients (LQT1: 40 ms [IQR, 42]; LQT2: 35 ms [IQR, 46]; and LQTS-negative: 21 ms [IQR, 37];
=0.029). During exercise, LQT1 patients had marked QTc prolongation compared with LQT2 and LQTS-negative patients (LQT1: 65 ms , LQT2: 3 ms , LQTS negative: 5 ms ;
<0.0001). QT hysteresis was more pronounced in patients with LQT2 mutations compared with LQT1 and LQT-negative patients (LQT2: 40 ms , LQT1: 15 ms ; LQTS-negative: 20 ms ;
<0.001). β-Blockade normalized the QTc changes seen with standing and QT hysteresis.
The presence and genotype of LQTS can be predicted by a combination of postural and exercise changes in the QT/RR relationship. β-Blockade normalized these changes. Routine exercise testing is useful in predicting and directing genetic testing in LQTS.