Utility of Provocative Testing in the Diagnosis and Genotyping of Congenital Long QT Syndrome: A Systematic Review and Meta-Analysis

Background Diagnosis is particularly challenging in concealed or asymptomatic long QT syndrome (LQTS). Provocative testing, unmasking the characterization of LQTS, is a promising alternative method for the diagnosis of LQTS, but without uniform standards. Methods and Results A comprehensive search was conducted in PubMed, Embase, and the Cochrane Library through October 14, 2021. The fixed effects model was used to assess the effect of the provocative testing on QTc interval. A total of 22 studies with 1137 patients with LQTS were included. At baseline, QTc interval was 40 ms longer in patients with LQTS than in controls (mean difference [MD], 40.54 [95% CI, 37.43-43.65]; P<0.001). Compared with the control group, patients with LQTS had 28 ms longer Delta QTc upon standing (MD, 28.82 [95% CI, 23.05-34.58]; P<0.001), nearly 30 ms longer both at peak exercise (MD, 27.31 [95% CI, 21.51-33.11]; P<0.001) and recovery 4 to 5 minutes (MD, 29.85 [95% CI, 24.36-35.35]; P<0.001). With epinephrine infusion, QTc interval was prolonged both in controls and patients with QTS, most obviously in LQT1 (MD, 68.26 [95% CI, 58.91-77.60]; P<0.001) and LQT2 (MD, 60.17 [95% CI, 50.18-70.16]; P<0.001). Subgroup analysis showed QTc interval response to abrupt stand testing and exercise testing varied between LQT1, LQT2, and LQT3, named Type I, Type II, and Type III. Conclusions QTc trend Type I and Type III during abrupt stand testing and exercise testing can be used to propose a prospective evaluation of LQT1 and LQT3, respectively. Type II QTc trend combined epinephrine infusion testing could distinguish LQT2 from control. A preliminary diagnostic workflow was proposed but deserves further evaluation.