A Potential Diagnostic Approach for Foetal Long-QT Syndrome, Developed and Validated in Children

Abstract

In patients with Long-QT Syndrome (LQTS), mechanical abnormalities have been described. Recognition of these abnormalities could potentially be used in the diagnosis of LQTS, especially in the foetus where an ECG is not available and DNA-analysis is invasive. We aimed to develop and validate a marker for these mechanical abnormalities in children and to test its feasibility in foetuses as a proof of principle. We measured the myocardial contraction duration using colour Tissue Doppler Imaging (cTDI) in 41 LQTS children and age- and gender-matched controls. Children were chosen to develop and validate the measurement of the myocardial contraction duration, due to the availability of a simultaneously recorded ECG. Feasibility of this measurement in foetuses was tested in an additional pilot study among seven LQTS foetuses and eight controls. LQTS children had a longer myocardial contraction duration compared to controls, while there was no statistical difference in heart rate. Measuring the myocardial contraction duration in children had a high inter- and intra-observer validity and reliably correlated with the QT-interval. There was an area under the curve (AUC) of 0.71, and the optimal cut-off value showed an especially high specificity in diagnosing LQTS. Measuring the myocardial contraction duration was possible in all foetuses and had a high inter- and intra-observer validity (ICC = 0.71 and ICC = 0.88, respectively). LQTS foetuses seemed to have a longer myocardial contraction duration compared to controls. Therefore, a prolonged contraction duration may be a potential marker for the prenatal diagnosis of LQTS in the future. Further studies are required to support the measurement of the myocardial contraction duration as a diagnostic approach for foetal LQTS.Electronic supplementary materialThe online version of this article (10.1007/s00246-018-1911-y) contains supplementary material, which is available to authorized users.

Left Ventricular Contraction Duration Is the Most Powerful Predictor of Cardiac Events in LQTS: A Systematic Review and Meta-Analysis

“…Of 1099 articles identified in the initial search, 545 were screened as potentially relevant. After careful assessment of 34 full articles, only 12 articles with a total 1041 patients, and 373 controls were finally included [ 2 , 4 , 5 , 7 , 8 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ] ( Figure S1 ).…”

“…Electrocardiographic indices were available from 10/12 studies analyzed in the meta-analysis [ 2 , 4 , 5 , 7 , 8 , 20 , 21 , 22 , 23 , 24 ]. Patients had a significantly prolonged QT C duration, with a weighted mean difference (WMD) 72.8 [95% CI 60.8 to 84.1, I 2 = 64%, p < 0.00001]); greater QT C dispersion, WMD 31.7 (95% CI 11.8 to 51.7, I 2 = 61%, p < 0.002); and prolonged RR interval, WMD 91.6 (95% CI 61.4 to 121.8, I 2 = 3%, p < 0.00001) compared to the controls ( Figure S2a–c ).…”

“…To assess LV mechanical abnormalities in LQTS patients, we measured four echocardiographic indices—CD, MD, QAoC, and EMW. Six of the twelve studies analyzed [ 2 , 5 , 18 , 21 , 23 , 24 ], unevenly measured these indices from a total of 716 LQTS patients. Compared to the controls, LQTS patients had prolonged CD, WMD 49.2 (95% CI 32.2 to 66.2, I 2 = 58%, p < 0.00001); higher MD, WMD 15.2 (95% CI 11.0 to 19.4, I 2 = 59%, p < 0.00001); prolonged QAoC, WMD 27.9 (95% CI 20.5 to 35.2, I 2 = 0%, p < 0.00001); and more negative EMW, WMD −62.5 (95% CI −66.4 to −58.5, I 2 = 0%, p < 0.00001) ( Figure 1 a–d).…”

“…The predictors of CEs were present in 5 papers with 203 patients with CEs vs. 289 without CEs [ 5 , 18 , 21 , 23 , 24 ]. To determine the best predictor of CEs in LQTS patients, we used a hierarchical summary ROC analysis, which proved that the contraction duration was the strongest index compared to EMW and QT C .…”

“…In contrast, diastolic function was compromised, as evidenced by lower E/A ratio, WMD −0.14 (95% CI −0.23 to −0.05, I 2 = 0%, p < 0.002); longer E deceleration time, WMD 43.40 (95% CI 19.6 to 67.2, I 2 = 67%, p < 0.0004); and prolonged isovolumic relaxation time (IVRT), WMD 7.12 (95% CI 0.71 to 13.52, I 2 = 57%, p < 0.03) in LQTS patients, compared to controls ( Figure S4a indices-CD, MD, QAoC, and EMW. Six of the twelve studies analyzed [2,5,18,21,23,24], unevenly measured these indices from a total of 716 LQTS patients. Compared to the controls, LQTS patients had prolonged CD, WMD 49.2 (95% CI 32.2 to 66.2, I 2 = 58%, p < 0.00001); higher MD, WMD 15.2 (95% CI 11.0 to 19.4, I 2 = 59%, p < 0.00001); prolonged QAoC, WMD 27.9 (95% CI 20.5 to 35.2, I 2 = 0%, p < 0.00001); and more negative EMW, WMD −62.5 (95% CI −66.4 to −58.5, I 2 = 0%, p < 0.00001) ( Figure 1a-d).…”