How Can We Evaluate Arrhythmic Risk in Children With Long QT Syndrome?

Long QT syndrome (LQTS) is characterized by QT interval prolongation and specific T-wave morphology on ECG, and is mainly caused by the mutations of genes associated with cardiac ion channels. LQTS is potentially lethal, and is clinically diagnosed by Bazett formula as corrected QT interval (QTc) ≥500 ms or as LQTS risk score ≥3.5 after excluding secondary causes, or genetically diagnosed through the identification of a pathogenic variant in LQTS-related genes regardless of the QTc interval.¹ Not all LQTS patients have phenotypic manifestation, and some exhibit borderline or nearly normal QTc interval on resting ECG (Figure).^2,3 To differentiate between suspected LQTS patients and normal subjects, prolonged QTc (≥480 ms) at 4 min after exercise stress testing is useful⁴ and is counted as score 1 in the LQTS risk score.⁵

Figure.

Schematic of diagnosis of congenital long QT syndrome (LQTS). Some of the QTc intervals at rest on the 12-lead ECG are nearly normal or borderline in genotype-positive LQTS patients. To diagnose borderline or concealed LQTS, Holter and exercise testing ECG may unmask the QT prolongation and can sometimes detect torsade de pointes (TdP). In addition to this clinical information, genetic and family segregation studies need to be performed.

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The QT interval is variable due to autonomic nerve activity, sex hormones, and some environmental factors. As such, the standard 12-lead ECG at rest does not always reflect the longest QT (QTc) interval. The 24-h Holter ECG, however, may record the longest QTc during the day, and can thus differentiate LQTS patients from normal subjects.⁶ A previous study revealed that the 24-h Holter ECG among genotyped LQTS (LQT1–3) showed a different circadian pattern of QTc that was particularly longer at night in LQT2 and LQT3, in contrast to the longer pattern in the daytime in LQT1.⁷ The QT/RR slope plotted by Holter ECG can differentiate the genotype of LQTS between LQT1 and LQT2.⁸ Furthermore, the mean corrected R-to-T peak interval by Holter ECG, reflecting an averaged repolarization length, may also manifest more clearly the clinical risk of LQTS compared with the QTc interval on 12-lead ECG at first visit.⁹ Therefore, Holter ECG may be useful in the diagnosis and risk stratification of LQTS. However, it remains unclear how often Holter ECG should be performed during follow-up, or what length QT (QTc) interval we should consider when investigating the risk of arrhythmic events in children or adolescent patients with LQTS.

In this issue of the Journal, Yoshinaga et al demonstrate the clinical usefulness of Holter ECG in both the diagnosis and risk stratification of pediatric LQTS patients who were screened by school-based ECG testing in Kagoshima, Japan.¹⁰ The authors manually measured the QT (QTc) interval recorded for 2 h at midnight, early morning, before noon, evening, and nighttime on Holter ECG. The beat-to-beat QTc was variable, more than 100 ms prolonged or abbreviated in a short period, probably due to autonomic nervous tone.¹¹ Next, they obtained the longest QTc at a rapidly increased heart rate for these same time periods. In comparing the clinical parameters between patients with and without cardiac events during follow-up, the maximum QTc on the standard 12-lead ECG was not associated with cardiac events; in contrast, the maximum QTc on Holter ECG was significantly associated with cardiac events.

For evaluation of the QT interval using Holter ECG, there are some limitations and concerns. Holter ECG in the near V1 or V5 leads sometimes under- or overestimate the QT interval compared with the respective leads in the standard 12-lead ECG.¹² Holter recording exhibits high specificity in predicting true prolonged QTc only during the longest RR intervals or low heart rates.¹³ Therefore, transient QTc prolongation on Holter ECG at increased heart rate in the general population sometimes causes overdiagnosis of LQTS.¹⁴ However, this study by Yoshinaga et al¹⁰ enrolled patients diagnosed with LQTS with a risk score ≥3.5, and the cutoff value predicting the events at the maximum QTc on Holter ECG was ≥590 ms, which looks like a longer period but had a significantly higher negative predictive value, 99.4%, for future events.

The authors conclude that the maximum QTc on Holter ECG was the only predictive parameter for cardiac events during follow-up. On the other hand, the general risk factors for LQTS patients, such as LQTS risk score, pathogenic variants, family history of LQTS, and QTc at resting ECG, were not associated with cardiac events. Because the population of this study was from a school-based ECG screening, which is common in Japan and useful for the early diagnosis of LQTS,¹⁵ few (2%) cardiac events were observed before diagnosis and there was a lower event rate (4%) during follow-up despite only 13% (27/207) of patients receiving β-blocker therapy. Moreover, among patients who underwent genetic testing, only 33% were identified as having pathogenic variants in LQTS genes, which is lower than previously reported.¹⁵ Thus, further investigations are necessary to predict arrhythmic risk using Holter ECG in “hospital-based” LQTS patients, members of a more genotype-positive and severe-phenotype group.

For analysis of Holter ECG in moderate to severe LQTS, both the QT (QTc) and the T-wave alternance, and spontaneous torsade de pointes (TdP) were also important. Recently, ≥7 days recordable ECG devices have become available and may catch the trigger of cardiac events. Furthermore, patients with a history of syncope with unknown cause would be better using an implantable loop-recorder for continuous monitoring. The maximum QTc on Holter ECG is not currently included in the risk score of LQTS; however, it might be useful to diagnose LQTS in patients in which the QT interval does not increase by exercise stress testing, particularly for patients with LQT2 or LQT3. Therefore, in the diagnosis and therapeutic strategy for LQTS, age, sex, clinical and genetic information, as well as the QT (QTc) interval from follow-up 12-lead and Holter ECG monitoring should be considered.

Disclosures

None.

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