Exercise worsening of electromechanical disturbances: A predictor of arrhythmia in long QT syndrome.

Received: 12 August 2018 Revised: 29 October 2018 Accepted: 6 December 2018 DOI: 10.1002/clc.23132 CLINICAL INVESTIGATIONS Exercise worsening of electromechanical disturbances: A predictor of arrhythmia in long QT syndrome Dafni Charisopoulou1,2 | George Koulaouzidis1,3 | Annika Rydberg4 | Henein Y. Michael1,5,6 1 Institute of Public Health and Clinical Medicine, Umea University, Umea, Sweden Background: Electromechanical (EM) coupling heterogeneity is significant in long QT syndrome 2 (LQTS), particularly in symptomatic patients; EM window (EMW) has been proposed as an indi- Department of Paediatric Cardiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK 3 Department of Cardiology, Mid Yorkshire Hospitals NHS Trust, Wakefield, UK Hypothesis: To investigate the dynamic response of EMW to exercise in LQTS and its predictive value of arrhythmia. 4 Department of Clinical Sciences, Paediatrics, Umea University, Umea, Sweden 5 Molecular and Clinical Sciences Research Institute, St George University London, London, UK 6 cator of interaction and a better predictor of arrhythmia than QTc. Methods: Forty-seven LQTS carriers (45  15 years, 20 with arrhythmic events), and 35 controls underwent exercise echocardiogram. EMW was measured as the time difference between aortic valve closure on Doppler and the end of QT interval on the superimposed electrocardiogram (ECG). Measurements were obtained at rest, peak exercise (PE) and 4 minutes into Brunel University, Middlesex, UK recovery. Correspondence Dr Dafni Charisopoulou, Paediatric Cardiology Department, Leeds General Infirmary, Leeds, LS1 3EX, UK. Email: Results: Patients did not differ in age, gender, heart rate, or left ventricular ejection fraction but had a negative resting EMW compared with controls (−42  22 vs 17  5 ms, P < 0.0001). EMW became more negative at PE (−89  43 vs 16  7 ms, P = 0.0001) and recovery (−65  39 vs 16  6 ms, P = 0.001) in patients, particularly the symptomatic, but remained unchanged in controls. PE EMW was a stronger predictor of arrhythmic events than QTc (AUC:0.765 vs 0.569, P < 0.001). B-blockers did not affect EMW at rest but was less negative at PE (BB: −66  21 vs no-BB: −113  25 ms, P < 0.001). LQT1 patients had worse PE EMW negativity than LQT2. Conclusion: LQTS patients have significantly negative EMW, which worsens with exercise. These changes are more pronounced in patients with documented arrhythmic events and decrease with B-blocker therapy. Thus, EMW assessment during exercise may help improve risk stratification and management of LQTS patients. KEYWORDS arrhythmia, electromechanical window, exercise echocardiography, long QT syndrome 1 | I N T RO D UC T I O N arrhythmia is often difficult, particularly among those without previous symptoms and with normal or borderline QTc.6,7 Moreover, efforts to Ventricular tachyarrhythmias, syncope, and even sudden death are of optimize individual risk stratification using only electrocardiogram (ECG) concern in inherited long QT syndrome.1,2 Balancing between potential parameters of heterogeneity have given conflicting results,7 thus risks, side effects of aggressive management, and life style changes highlighting the importance of associated mechanical left ventricular remains a challenge.3 LQTS mutations-related cardiac ion channels (LV) dysfunction.8–17 Electromechanical (EM) coupling heterogeneity defects result in prolonged action potential and increased spatiotempo- has also been shown in health but appears significantly more pro- ral dispersion of myocardial repolarization, which predispose to arrhyth- nounced in LQTS.14–17 Noninvasive cardiac EM window (EMW) has 4,5 mia and adverse cardiac events. Identifying patients at risk of been proposed as an indicator of such EM coupling disturbances.16,17 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2018 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc. Clinical Cardiology. 2019;42:235–240. wileyonlinelibrary.com/journal/clc 235 236 CHARISOPOULOU ET AL. EMW corresponds to the time difference between the end of elec- equipped with an adult 1.5-4.3 MHz phased array transducer. We trical systole (QT interval) and the completion of mechanical systole acquired images as consecutive loops from the standard apical four- (onset of aortic valve closure), which is positive in healthy individuals.17 chamber and parasternal long- and short-axis views at the end of each Significantly negative EMW has been shown to precede ventricular exercise stage. All recordings were made with a superimposed ECG 18,19 Similar findings have been (Lead II). Left ventricular ejection fraction (LV EF) was estimated using shown in genotype-positive LQTS patients, particularly those with Simpson's biplane method.25 Aortic valve velocity was obtained using tachyarrhythmias in drug-induced LQT. 17,19 arrhythmia. Finally, sympathetic stimulation has been shown to pro- pulsed wave Doppler technique from the apical five-chamber view 22,23 with the sample volume placed at the aortic valve level.26 The aortic We, therefore, aimed to assess the dynamic response of EMW to exer- valve closure time (QAoC) was measured with respect to the onset of cise in LQTS in general and according to its genotype (LQT1 or LQT2), QRS complex. The EMW was calculated by subtracting the QT inter- in an attempt to identify carriers at risk of major arrhythmic events. val from the QAoC (12, Supporting Information Figure SS1). Offline 21 voke arrhythmia in LQTS and to worsen the negativity of EMW. analyses were made using a commercially available software system (EchoPAC, version 8.0.1; GE, Waukesha, Wisconsin). 2 | METHODS 2.5 | Statistical analysis 2.1 | Study population For the statistical analysis, we used the Statistical Package of Social Both patients and controls were followed up at the cardiology depart- Science (SPSS) for windows (version 13.0; SPSS Inc, Chicago, Illinois). ment of Umeå University Hospital. Molecular analyses of LQTS genotype We expressed continuous variables as mean  SD and categorical were performed at the Umeå Department of Clinical Genetics following variables as absolute number and percentage (%). Groups were com- the current clinical practices for molecular genetic diagnostics.24 Individ- pared with Student t test for normally distributed variables and with uals with coronary heart disease and those at high risk for atherosclerosis Mann-Whitney U-test if variables were not normally distributed. One- were excluded. Patients were divided into symptomatic and asymptom- way analysis of variance was used for multiple comparisons. Pearson's atic based on documented history of cardiac events (syncope, cardiac test was used to test correlations. The sensitivity and (...truncated)