Long QT syndrome, a purely electrical disease? Not anymore

EDITORIAL European Heart Journal (2009) 30, 253–255 doi:10.1093/eurheartj/ehn587 Long QT syndrome, a purely electrical disease? Not anymore Gaetano M. De Ferrari 1 and Peter J. Schwartz 1,2,3,4* 1 Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 2Section of Cardiology, Department of Lung, Blood and Heart, University of Pavia, Pavia, Italy; Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy; and 4Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research, Department of Medicine, University of Cape Town, South Africa 3 Online publish-ahead-of-print 16 January 2009 This editorial refers to ‘Left ventricular mechanical dispersion by tissue Doppler imaging: a novel approach for identifying high risk individuals with long QT syndrome’†, by K.H. Haugaa et al. on page 330 The identification in 1995–1996 of the three major genes for the long QT syndrome (LQTS) has opened up the molecular era for arrhythmogenic disorders and has led to the frequent use of the term ‘channelopathies’ to define several diseases characterized by a high potential for life-threatening arrhythmias and by being caused by mutations on genes encoding ion channels involved in the control of the action potential.1 Another concept, developed in parallel, was that of ‘primary electrical diseases’ which is now regularly applied to disorders such as LQTS, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, and others.2,3 ‘Primary electrical diseases’ soon became equivalent to ‘purely electrical diseases’ and the consensus still is that in these diseases there are no mechanical dysfunctions. As far as LQTS is concerned, the idea that this was a purely electrical disease in an otherwise completely normal heart has been around since the early days. When in 19914 and 19945 we attempted to challenge this concept, the cardiological community gave us the cold shoulder. Now, the tide may have turned. Kristina Hermann Haugaa, with the group led by Jan Amlie in Oslo, reports an interesting study that evaluated myocardial contraction duration by tissue Doppler imaging (TDI) in 73 patients with genetically confirmed LQTS.6 The group included nine subjects affected by the Jervell and Lange-Nielsen (JLN) syndrome7,8 and 40 controls. Approximately half of the single mutation LQTS patients (RW-LQTS) and all JLN patients had a history of cardiac events (arrhythmias, syncope, or cardiac arrest). As expected, RW-LQTS patients had longer QT intervals compared with controls, and JLN patients had longer QT intervals compared with both controls and RW-LQTS patients. The duration of myocardial contraction was measured in the basal septal segment and defined as the time from the start of the R wave on ECG to the definitive zero-crossing of the decreasing velocity slope. The duration of contraction of the basal segment was assessed in all six traditional left ventricular wall positions and the standard deviation of these six values was calculated as an index of mechanical dispersion of contraction. A longer contraction duration was found between RW-LQTS patients and controls and, within LQTS patients, between those with and those without a previous cardiac event. Dispersion of contraction was also more pronounced in RW-LQTS patients with cardiac events compared with asymptomatic patients. When we reported in 1991 the presence of an unsuspected abnormality in left ventricular contraction in 23 of 42 LQTS patients, we developed two quantitative indexes to quantify this phenomenon more efficiently.4 The most evident abnormality was the presence of a very slow contraction phase before rapid relaxation that appeared either as a plateau or as a double-peaked contraction. Subsequently, calcium channel blockade by intravenous verapamil was shown to normalize completely even the most severe patterns of abnormality such as those with a doublepeak morphology.5 Despite our pointing out that the contraction abnormality and, particularly, the double-peak morphology were the first clinical features found to be strongly associated with a history of syncope or cardiac arrest, these two reports were received with scepticism, more or less dismissed, and essentially ignored. Seven years of silence passed until, in 1998, Nakayama, working in the group led by Tohru Ohe in Okayama, confirmed the presence of a phase of slow contraction (plateau) before rapid relaxation in patients with LQTS.9 They digitized two-dimensional short axis images performed at the basal and middle level of the left ventricle and reconstructed M mode echocardiograms in the corresponding 12 segments. They found that LQTS patients spent, on average, twice the amount of time in the plateau late systolic phase of contraction and that this plateau time, although abnormally prolonged in the whole left ventricle, was significantly more variable within the 12 analysed segments in LQTS patients The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. * Corresponding author. Tel: þ 39 0382 503567, Fax: þ 39 0382 503002. Email: † doi:10.1093/eurheartj/ehn466 Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: . 254 compared with controls, suggesting the presence of a dispersion in the contraction abnormality. This good study apparently did not particularly impress the cardiological community which continued to ignore this aspect of LQTS. In 2003, Savoye et al. first employed TDI to assess wall motion and myocardial velocities in LQTS.10 They compared 14 control subjects with 10 patients with ‘mild’ LQTS; their average QTc was 454 ms—not very prolonged. Myocardial velocities were measured in the basal and mid-segments of the septal, lateral, inferior, and anterior wall. They found results almost identical to ours.4 Not even this study, employing a novel and more powerful technique, has been able to shake the general view that LQTS is a purely electrical disease. The present Norwegian study6 on a large group of genetically confirmed LQTS patients will hopefully force the cardiological community to accept the reality that LQTS is not a purely electrical disease. TDI has been validated as a method to quantify regional myocardial function11 as it allows more reliable regional measurements. While M mode echocardiography assessed radial wall thickness and movement,4,5,9 TDI, using apical views, assesses longitudinal myocardial velocities. Once it has been established that the contraction abnormalities in LQTS patients do exist, the main practical question for the clinician is whether the contraction abnormality may contribute to a better risk assessment and what is the best way to quantify the abnormality for prognostic purposes. Current risk stratification in LQTS is largely based on previo (...truncated)