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

Background Electromechanical (EM) coupling heterogeneity is significant in long QT syndrome (LQTS), particularly in symptomatic patients; EM window (EMW) has been proposed as an indicator of interaction and a better predictor of arrhythmia than QTc. Hypothesis To investigate the dynamic response of EMW to exercise in LQTS and its predictive value of arrhythmia. 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 recovery. 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.

Background: Electromechanical (EM) coupling heterogeneity is significant in long QT syndrome (LQTS), particularly in symptomatic patients; EM window (EMW) has been proposed as an indicator of interaction and a better predictor of arrhythmia than QTc.
Hypothesis: To investigate the dynamic response of EMW to exercise in LQTS and its predictive value of arrhythmia.
Methods: Forty-seven LQTS carriers (45 AE 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 recovery.
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 AE 22 vs 17 AE 5 ms, P < 0.0001).
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.

K E Y W O R D S
arrhythmia, electromechanical window, exercise echocardiography, long QT syndrome 1 | INTRODUCTION Ventricular tachyarrhythmias, syncope, and even sudden death are of concern in inherited long QT syndrome. 1,2 Balancing between potential risks, side effects of aggressive management, and life style changes remains a challenge. 3 LQTS mutations-related cardiac ion channels defects result in prolonged action potential and increased spatiotemporal dispersion of myocardial repolarization, which predispose to arrhythmia and adverse cardiac events. 4,5 Identifying patients at risk of arrhythmia is often difficult, particularly among those without previous symptoms and with normal or borderline QTc. 6,7 Moreover, efforts to optimize individual risk stratification using only electrocardiogram (ECG) parameters of heterogeneity have given conflicting results, 7 thus highlighting the importance of associated mechanical left ventricular (LV) dysfunction. [8][9][10][11][12][13][14][15][16][17] Electromechanical (EM) coupling heterogeneity has also been shown in health but appears significantly more pronounced in LQTS. [14][15][16][17] Noninvasive cardiac EM window (EMW) has been proposed as an indicator of such EM coupling disturbances. 16,17 EMW corresponds to the time difference between the end of electrical systole (QT interval) and the completion of mechanical systole (onset of aortic valve closure), which is positive in healthy individuals. 17 Significantly negative EMW has been shown to precede ventricular tachyarrhythmias in drug-induced LQT. 18,19 Similar findings have been shown in genotype-positive LQTS patients, particularly those with arrhythmia. 17,19 Finally, sympathetic stimulation has been shown to provoke arrhythmia in LQTS 21 and to worsen the negativity of EMW. 22,23 We, therefore, aimed to assess the dynamic response of EMW to exercise in LQTS in general and according to its genotype (LQT1 or LQT2), in an attempt to identify carriers at risk of major arrhythmic events.

| Study population
Both patients and controls were followed up at the cardiology department of Umeå University Hospital. Molecular analyses of LQTS genotype were performed at the Umeå Department of Clinical Genetics following the current clinical practices for molecular genetic diagnostics. 24 Individuals with coronary heart disease and those at high risk for atherosclerosis were excluded. Patients were divided into symptomatic and asymptomatic based on documented history of cardiac events (syncope, cardiac arrest, ventricular tachyarrhythmia), according to the patients' hospital clinical notes. Ongoing therapy with B-blockers (BB) was recorded. ECG and echocardiography parameters were obtained and analyzed by two independent investigators blinded to genotype and clinical details.
The study protocol complied with the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Regional Ethical Review Board (Umeå University). All participating subjects had given informed consent to take part.

| Exercise echocardiography protocol
All participants underwent a semi-supine (slightly left lateral tilt) bicycle exercise echocardiography using General Electric-GE ergometer (model 900, Ergoline GmbH, Bitz, Germany) with an increasing workload of 10 W every 2 minutes. Measurements were made at: (a) rest, prior to the exercise, (b) peak exercise (PE), achieving 85% of the maximum predicted heart rate for age, and (c) 4 minutes into recovery.

| Echocardiography
The echocardiographic examination was performed in the semi-supine position using a Vivid 7 echocardiograph (GE, Horten, Norway) equipped with an adult 1.5-4.3 MHz phased array transducer. We acquired images as consecutive loops from the standard apical fourchamber and parasternal long-and short-axis views at the end of each exercise stage. All recordings were made with a superimposed ECG (Lead II). Left ventricular ejection fraction (LV EF) was estimated using Simpson's biplane method. 25 Aortic valve velocity was obtained using pulsed wave Doppler technique from the apical five-chamber view with the sample volume placed at the aortic valve level. 26 The aortic valve closure time (QAoC) was measured with respect to the onset of QRS complex. The EMW was calculated by subtracting the QT interval from the QAoC (12, Supporting Information Figure SS1). Offline analyses were made using a commercially available software system (EchoPAC, version 8.0.1; GE, Waukesha, Wisconsin).

| EMW measurements reproducibility
A good inter-observer agreement was found for EMW measurements at 0.97 and intraobserver agreement was 0.98.

| Population characteristics
The study population included 47 LQTS mutation carriers (36 LQT1 and 11 LQT2) who were compared with 35 healthy controls matched for age

| QT, QTc, and QAoC intervals
Patients had significantly longer QT, QTc, and QAoC intervals than controls, at rest, PE and recovery phase (P < 0.01 for all, Table 1). The QTc interval lengthened at PE in patients but shortened in controls (Δ +10 AE 9 vs −5.5 AE 3.8%, P < 0.0001). It also remained significantly longer at recovery with respect to baseline in patients but reached baseline values in controls (Δ +6.2 AE 5 vs 0.007 AE 2%, P < 0.0001).

| Electromechanical window
The EMW was negative in patients at all three phases in contrast to controls in whom it was and remained positive (P = 0.0001, Table 1 and Figure SS2) throughout exercise and recovery. It became more negative at PE in patients but did not change in controls (Δ −45 AE 34 vs 1.1 AE 8%, P < 0.001). Patient's EMW was more negative at recovery than baseline, but again remained unchanged in controls (Δ −23 AE 44 vs 0.9 AE 8%, P = 0.005).

| EMW and cardiac events
There were no differences between symptomatic and asymptomatic patients in age, gender or genotype. QT and QTc intervals were longer in symptomatic compared with asymptomatic patients at rest, PE and during recovery (P ≤ 0.03 for both, Table 2). QAoC interval was also longer in symptomatic patients at PE and at recovery (P ≤ 0.03 for both, Table 2). The EMW was more negative in symptomatic patients at rest and worsened further at PE and recovery (P ≤ 0.02 for all phases, Table 3 and Figure SS3).

| Relationship between QTc and EMW
EMW correlated with QTc (r = −0.63, P < 0.0001). Symptomatic and asymptomatic patients had a more negative EMW for the same QTc value than controls. Symptomatic patients had more negative slope (P = 0.04, Figure SS4).

| EMW and high-risk patients
On the ROC analysis, EMW was stronger than QTc in discriminating symptomatic from asymptomatic patients at all three exercise phases (  (Table 3).    (Table 5 and Figure S5). Data interpretation: Spatiotemporal EM heterogeneity is exaggerated in inherited LQTS 10,27,28 with increased dispersion of myocardial repolarization during exercise and recovery preceding arrhythmias. 6,20 Mechanical heterogeneity, reflected by prolonged myocardial contraction and increased regional and transmural mechanical dispersion, is known to be more pronounced in symptomatic LQTS. 4,15,16,29 These EM coupling disturbances have been shown in the form of reversed (negative) EMW with mechanical  to that in controls, in whom a parallel and analogous EM shortening occurs. 30 As such, repolarization continues after completion of mechanical systole resulting in prolonged action potential duration and myocardial Ca 2+ overload during diastole. 10 These may generate early and late potentials, induce mechanical postsystolic contraction and predispose to tachyarrhythmias. 19,20,31 The association of EMW negativity with arrhythmia has been shown in animal models of drug-induced LQTS arrhythmia. 10 These findings may reflect the different response to adrenergic stimulation triggers between the two genotypes. 34 In LQT2, genetic mutations are responsible for the malfunction of the rapidly activating component of the delayed rectifier potassium current (I Kr ), which mainly controls repolarization at rest. 35 However, in LQT1, defects in the slowly activating delayed rectifier potassium current (I Ks ), affect the repolarization process during exercise. 10,35 The result is inadequate action potential shortening, manifested as prolonged QT interval, which combined with the mechanical effects (increased myocardial inotropy and lucinotropy) of adrenergic stimulation at PE, may explain the different EMW response between the two groups. 36,37 These findings may also explain the variations we noted in the predictive value of EMW in the three phases of exercise in the two genotype groups. Peak EMW was stronger for LQTI patients as opposed to the rest and recovery EMW in the LQT2 group. However, these results need to be seen with caution as the number of patients is small and cannot be generalized.

| DISCUSSION
Clinical implications: Our study showed that EMW negativity at all three phases of exercise was more pronounced in the symptomatic LQTS patients. B-blockers appeared to decrease the extent of EMW negativity at PE in LQTS. EMW is easy to assess and independently predicted previous arrhythmic events with higher sensitivity and specificity than QTc. Measuring EMW response to exercise increased the accuracy of stress echocardiography in identifying patients at risk of arrhythmias, thus may play a role in guiding towards optimum management.
Study limitations: Our study includes a modest number of patients and our results need to be reproduced in a larger cohort of patients with and without arrhythmic events and in relation to genotype. Limitations in defining the end of T wave may arise especially due to motion artifacts from exercise. Our proposed accuracy of EMW in predicting arrhythmia is based on the documented history we have in patients records rather than symptoms developing during exercise, except two patients in whom the exercise test has to be prematurely terminated due to signs of arrhythmia. PE heart rate was below the age predicted in controls and patients, with no significant difference between groups. While lack of fitness could be the explanation for low achieved heart rate in controls, it could also be the effect of B blockers which attenuated the heart rate rise in patients. The lack of difference between groups supports our potential explanations.

| CONCLUSION
Cardiac EMW measurements correlate with QT interval, and reflect significantly reversed LV end systolic EM relationship in LQTS patients. These disturbances are worsened during exercise and early recovery and seem to be associated with previous arrhythmias. While EMW negativity is worse in symptomatic patients, it is less pronounced in those treated with B-blockers. Thus, incorporating EMW assessment in the routine assessment of LQTS patients may help better stratification and symptom interpretation, even if only in some.

CONFLICT OF INTEREST
No conflicts of interest.