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

Pediatric Cardiology (2018) 39:1413–1422 https://doi.org/10.1007/s00246-018-1911-y ORIGINAL ARTICLE A Potential Diagnostic Approach for Foetal Long-QT Syndrome, Developed and Validated in Children Arja Suzanne Vink1,2 · Irene M. Kuipers2 · Rianne H. A. C. M. De Bruin‑Bon1 · Arthur A. M. Wilde1 · Nico A. Blom2,3 · Sally‑Ann B. Clur2 Received: 3 January 2018 / Accepted: 11 May 2018 / Published online: 22 May 2018 © The Author(s) 2018 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. Keywords Paediatrics · Echocardiography · Electrocardiogram (ECG) · Long-QT syndrome · Foetus Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00246-018-1911-y) contains supplementary material, which is available to authorized users. * Arja Suzanne Vink 1 Heart Centre, Department of Cardiology, Academic Medical Centre, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, The Netherlands 2 Department of Paediatric Cardiology, Emma Children’s Hospital, Academic Medical Centre, Amsterdam, The Netherlands 3 Department of Paediatric Cardiology, Willem‑Alexander Children’s Hospital, University Medical Centre Leiden, Leiden, The Netherlands Congenital Long-QT syndrome (LQTS) in an inherited cardiac repolarization disorder, with a predisposition to malignant ventricular arrhythmias, that can precipitate syncope, sudden cardiac arrest or sudden cardiac death [1]. The degree of impairment and dispersion of repolarization have been considered to play a role in the occurrence of these ventricular arrhythmias [2]. Although, patients with LQTS have a normal left ventricular function, several studies have shown mechanical abnormalities in the contraction and relaxation pattern in adult LQTS patients using M-Mode echocardiography,[3–5] continuous-wave Doppler images,[6] colour Tissue Doppler Imaging (cTDI) [7, 8] and Speckle Tracking [9–11]. One study has found mechanical dysfunction in children with the use of MRI [12]. These abnormalities were almost absent in healthy individuals, but prevalent among LQTS patients whereas in symptomatic 13 Vol.:(0123456789) 1414 patients this was even more frequent, suggesting their potential value in the diagnosis and risk stratification in LQTS. The use of the presence of mechanical abnormalities in the risk stratification for malignant cardiac arrhythmias in adult and paediatric LQTS patients is perhaps more promising than its use in diagnosing LQTS, since most LQTS patients can be diagnosed based on a high clinical suspicion using electrocardiographic features, clinical and family history or in the presence of a confirmed pathogenic mutation [13]. Diagnosing LQTS prenatally is however challenging due to the lack of an accurate and comprehensible electrocardiogram (ECG), [14] the scarcity of foetal magnetocardiography, [15–18] and the invasiveness of DNA-analysis with a risk of miscarriage [19]. To date, foetal arrhythmias are diagnosed by echocardiography providing accurate information about the atrial and ventricular contractions that indirectly reflect the P-wave and QRS-complex [20]. Unfortunately echocardiography cannot assess a derivative of the QT-interval. However, diagnosing LQTS before birth is relevant as it is a cause of sudden infant death and sudden unexplained intrauterine death [14, 21, 22]. In addition, when LQTS is diagnosed during foetal life there are important clinical consequences [14]. For instance, maternal QT-prolonging drugs frequently used during pregnancy and childbirth must be withheld, even if the mother does not suffer from LQTS. Furthermore, in case of foetal arrhythmias, some antiarrhythmic drugs that are usually given are contraindicated if the foetus has LQTS, e.g. amiodarone [23–25]. Lastly, a sinus bradycardia, 2:1 atrioventricular conduction or reduced beat to beat variability in the foetus can be attributed to the LQTS phenotype [26] instead of foetal distress. Hence, an accurate prenatal diagnosis of LQTS can avoid potentially unnecessary preterm deliveries or emergency caesarean sections for incorrectly presumed foetal distress. Haugaa et al. [8] used a combination of cTDI and a simultaneously recorded ECG to evaluate the mechanical abnormalities in adult LQTS patients, and found a prolonged myocardial contraction duration in these patients. As cTDI has proven to be feasible in foetuses, has already been used in the evaluation of foetal cardiac function in various pregnancy complications,[27–29] and has been shown to be reliable in the measurement of foetal time intervals,[30] it could potentially be used for the measurement of the myocardial contraction duration prenatally. However, this measurement then needs to be made in the absence of an ECG. This study had three aims: Firstly, to assess the diagnostic value of measuring the myocardial contraction duration by measuring it in children and correlating it to the QT-interval on the ECG. Children were chosen due to the availability of a simultaneously recorded ECG. Secondly, we aimed to develop a technique for the measurement of the myocardial contraction duration without the need for a simultaneously recorded ECG in children and to test its diagnostic value. 13 Pediatric Cardio (...truncated)