Electromechanical window negativity in genotyped long-QT syndrome patients: relation to arrhythmia risk

CLINICAL RESEARCH European Heart Journal (2015) 36, 179–186 doi:10.1093/eurheartj/ehu370 Arrhythmia/electrophysiology Electromechanical window negativity in genotyped long-QT syndrome patients: relation to arrhythmia risk 1 Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, The Netherlands; 2Department of Cardiology, Oslo University Hospital, Rikshospitalet and University of Oslo, Oslo, Norway; 3Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands; 4Department of Medicine, The Long QT Syndrome/Genetic Heart Rhythm Clinic, Rochester, MN, USA; 5Department of Pediatrics, The Long QT Syndrome/Genetic Heart Rhythm Clinic, Rochester, MN, USA; 6Department of Molecular Pharmacology and Experimental Therapeutics, The Long QT Syndrome/Genetic Heart Rhythm Clinic, Rochester, MN, USA; and 7The Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, USA Received 25 November 2013; revised 1 July 2014; accepted 12 August 2014; online publish-ahead-of-print 9 September 2014 See page 148 for the editorial comment on this article (doi:10.1093/eurheartj/ehu406) Aim Prolonged and dispersed left-ventricular (LV) contraction is present in patients with long-QT syndrome (LQTS). Electrical and mechanical abnormalities appear most pronounced in symptomatic individuals. We focus on the ‘electromechanical window’ (EMW; duration of LV-mechanical systole minus QT interval) in patients with genotyped LQTS. Profound EMW negativity heralds torsades de pointes in animal models of drug-induced LQTS. ..................................................................................................................................................................................... Methods We included 244 LQTS patients from three centres, of whom 97 had experienced arrhythmic events. Seventy-six matched healthy individuals served as controls. QT interval was subtracted from the duration of Q-onset to aorticand results valve closure (QAoC) midline assessed non-invasively by continuous-wave echocardiography, measured in the same beat. Electromechanical window was positive in controls but negative in LQTS patients (22 + 19 vs. 243 + 46 ms; P , 0.0001), being even more negative in symptomatic than event-free patients (267 + 42 vs. 227 + 41 ms; P , 0.0001). QT, QTc, and QAoC were longer in LQTS subjects (451 + 57, 465 + 50, and 408 + 37 ms, P , 0.0001). Electromechanical window was a better discriminator of patients with previous arrhythmic events than resting QTc (AUC 0.77 (95% CI, 0.71–0.83) and 0.71 (95% CI, 0.65–0.78); P ¼ 0.03). In multivariate analysis, EMW predicted arrhythmic events independently of QTc (odds ratio 1.25; 95% CI, 1.11–1.40; P ¼ 0.001). Adding EMW to QTc for risk assessment led to a net reclassification improvement of 13.3% (P ¼ 0.03). No EMW differences were found between the three major LQTS genotypes. ..................................................................................................................................................................................... Conclusions Patients with genotype-positive LQTS express EMW negativity, which is most pronounced in patients with documented arrhythmic events. ----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords Long-QT syndrome † Arrhythmia † Sudden death † Ion channels † Echocardiography Introduction The congenital long-QT syndromes (LQTS) are caused by mutations in genes encoding for cardiac ion-channel subunits or ion-channelassociated proteins. To date, at least 15 different genes have been causally implicated.1 Long-QT syndromes-related ion-channel defects predispose to cardiac action-potential prolongation and accentuate regional and temporal dispersion of repolarization. Genotype-specific pro-arrhythmic conditions can exacerbate repolarization dispersion and lead to the occurrence of * Corresponding author. Tel: +31 433875098, Fax: +31 433875104, Email: Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: . Rachel M.A. ter Bekke 1, Kristina H. Haugaa 2, Arthur van den Wijngaard 3, J. Martijn Bos 4,5,6,7, Michael J. Ackerman 4,5,6,7, Thor Edvardsen 2, and Paul G.A. Volders 1* 180 Methods This study was carried out in accordance with the ethical guidelines of the Declaration of Helsinki. Patients gave written informed consent for DNA diagnostics and echocardiographic research. IRB approval for the retrospective analysis of genotype and echocardiographic phenotype data was provided for the patients evaluated at Mayo Clinic. Study population In this case– control, multicentre study, 244 genotype-positive LQTS index cases and asymptomatic family members, and 76 healthy controls were included. A heterozygous KCNQ1 mutation was present in 107 individuals (LQT1), a KCNH2 mutation in 84 (LQT2), a SCN5A mutation in 41 (LQT3), a KCNE1 mutation in 8 (LQT5), a KCNE2 mutation in 1 (LQT6), and double heterozygous mutations (KCNQ1 + KCNH2) in 2 patients. The remaining patient was double heterozygote for KCNQ1 mutations with clinical features of Jervell and Lange– Nielsen syndrome (JLNS). Mutations were considered ‘pathogenic’ or ‘variants of uncertain significance’ (VUS) based on literature reports and molecular-genetic assessment. Class-3 VUS-positive patients were included after exclusion of other causative gene mutations. In all probands, the clinical diagnosis of LQTS was made using the Schwartz criteria.11 Arrhythmic events were scored as syncope, documented ventricular tachyarrhythmia (VT), aborted cardiac arrest, and/or sudden death. We included subjects older than 10 years. The use of antiarrhythmic drugs and history of implantable cardioverter defibrillator (ICD) or pacemaker implantation at the time of echocardiography were noted. If possible, EMW measurements were made prior to the initiation of antiarrhythmic therapy. The healthy control group is described in detail in Supplementary material online. Echocardiography Echocardiographic examinations were performed on a Vivid 7 (General Electric Healthcare, Horten, Norway) or IE33 system (Philips, Eindhoven, The Netherlands) and data were analysed by R.M.A.t.B. and K.H.H., blinded to the patient’s diagnosis. Electromechanical window calculation Continuous-wave Doppler images in the apical long-axis view assessing the aortic-valve flow and concurrent 3-lead ECG tracings were used for EMW calculations (Figure 1). We measured (i) the interval from QRS-onset to the aortic-valve closure midline [Q-onset to aortic-valve closure (QAoC) interval], (ii) QT interval in lead II, for the same beat. The EMW (ms) was calculated by subtracting QT from the QAoC interval. Q-onset to aortic-valve closure incorporates the LV– (...truncated)