Left Ventricular Contraction Duration Is the Most Powerful Predictor of Cardiac Events in LQTS: A Systematic Review and Meta-Analysis

Background: Long-QT syndrome (LQTS) is primarily an electrical disorder characterized by a prolonged myocardial action potential. The delay in cardiac repolarization leads to electromechanical (EM) abnormalities, which adds a diagnostic value for LQTS. Prolonged left ventricular (LV) contraction was identified as a potential risk for arrhythmia. The aim of this meta-analysis was to assess the best predictor of all EM parameters for cardiac events (CEs) in LQTS patients. Methods: We systematically searched all electronic databases up to March 2020, to select studies that assessed the relationship between echocardiographic indices—contraction duration (CD), mechanical dispersion (MD), QRS onset to peak systolic strain (QAoC), and the EM window (EMW); and electrical indices— corrected QT interval (QTC), QTC dispersion, RR interval in relation to CEs in LQTS. This meta-analysis included a total of 1041 patients and 373 controls recruited from 12 studies. Results: The meta-analysis showed that LQTS patients had electrical and mechanical abnormalities as compared to controls—QTC, WMD 72.8; QTC dispersion, WMD 31.7; RR interval, WMD 91.5; CD, WMD 49.2; MD, WMD 15.9; QAoC, WMD 27.8; and EMW, WMD −62.4. These mechanical abnormalities were more profound in symptomatic compared to asymptomatic patients in whom disturbances were already manifest, compared to controls. A CD ≥430 ms had a summary sensitivity (SS) of 71%, specificity of 84%, and diagnostic odds ratio (DOR) >19.5 in predicting CEs. EMW and QTC had a lower accuracy. Conclusions: LQTS is associated with pronounced EM abnormalities, particularly prolonged LV myocardial CD, which is profound in symptomatic patients. These findings highlight the significant role of EM indices like CD in managing LQTS patients.


Introduction
Almost three decades have passed since M-mode echocardiography confirmed that Long-QT syndrome (LQTS) is associated with electromechanical (EM) abnormalities [1]. In the past, LQTS was characterized purely as an electrical abnormality of the myocardium that results in cardiac action potential (AP) prolongation. LQTS patients with mechanical dysfunction have impairments in both systolic and diastolic functions, as a result of prolonged QT C [2]. The prolonged QT duration in LQTS increases the susceptibility for exacerbated heterogeneity in repolarization between myocardial

Quality Assessment
Assessment of risk of bias in the cohort studies was evaluated by the same investigators, using the Newcastle-Ottawa Scale (NOS). Three domains were evaluated with the following items: (A) Selection-(1) representativeness of the exposed cohort, (2) selection of the non-exposed cohort, (3) ascertainment of exposure and (4) demonstration that outcome of interest was not present at start of study. (B). Comparability of exposed and non-exposed. and (C) Exposure-(1) assessment of outcome, (2) follow-up long enough for outcomes to occur, and (3) adequacy of the follow-up of cohorts. The risk of bias in each study was judged to be "good", "fair", or "poor" [13].

Statistical Analysis
The meta-analysis was conducted using statistical analysis, performed using the RevMan (Review Manager (RevMan) Version 5.1, The Cochrane Collaboration, Copenhagen, Denmark), with two-tailed p < 0.05 considered to be significant. Relative risk (RR) ratios with 95% confidence interval (CI) are presented as summary statistics, whereas for continuous variables, weighted mean differences (WMD) and 95% CI were used. The baseline characteristics are reported as median and range. Mean and standard deviation (SD) values were estimated using the method described by Hozo et al. [14]. Analysis is presented in forest plots, the standard way for illustrating the results of individual studies and meta-analysis. To evaluate the relationship between LV EM abnormalities and CEs, we performed hierarchical summary receiver operating characteristic (ROC) analysis using the Rutter and Gatsonis model [15]. Summary sensitivity and specificity with 95% CI for individual studies based on true positive (TP), true negative (TN), false positive (FP), and false negative (FN) were computed using the diagnostic random-effects model [16]. Summary point from the hierarchical ROC analysis was then used to calculate the positive likelihood ratio (LR+), negative likelihood ratio (LR-), positive predictive value (PPV), negative predictive value (NPV), and diagnostic odds ratio (DOR). In studies that did not provide optimal cutoffs, we created the ROC curve and identified the optimal cutoff as the point on the ROC curve closest to 0.1 on the x-y coordinate. The RevMan was used for statistical analysis including graphic presentations of forest plots of sensitivity and specificity, as well as hierarchical summary ROC curves.
Heterogeneity between studies was assessed using Cochrane Q test and I 2 index. As a guide, I 2 < 25% indicated low, 25-50% moderate, and >50% high heterogeneity [17]. To assess the additive (between-study) component of variance, the reduced maximum likelihood method (tau 2 ) incorporated the occurrence of residual heterogeneity into the analysis [8]. Publication bias was assessed using visual inspections of funnel plots and Egger's test.

Electrical and Mechanical Predictors of Cardiac Events in LQTS Patients
The predictors of CEs were present in 5 papers with 203 patients with CEs vs. 289 without CEs [20,21,[24][25][26]. To determine the best predictor of CEs in LQTS patients, we used a hierarchical summary ROC analysis, which proved that the contraction duration was the strongest index compared to EMW and QTC. A cutoff of CD ≥ 430 ms predicted CE with a summary sensitivity of 71%, a summary specificity of 84%, accuracy of 83%, and a higher DOR > 19.5; EMW = −59 ms, with a summary sensitivity of 82%, summary specificity of 56%, accuracy of 67%, and a DOR > 7.47; and QTC ≥ 460 ms with a summary sensitivity of 53%, summary specificity of 73%, accuracy of 68%, and DOR > 4.14 ( Figure 4, Table S2).

Electrical and Mechanical Predictors of Cardiac Events in LQTS Patients
The predictors of CEs were present in 5 papers with 203 patients with CEs vs. 289 without CEs [5,18,21,23,24]. To determine the best predictor of CEs in LQTS patients, we used a hierarchical summary ROC analysis, which proved that the contraction duration was the strongest index compared to EMW and QT C . A cutoff of CD ≥ 430 ms predicted CE with a summary sensitivity of 71%, a summary specificity of 84%, accuracy of 83%, and a higher DOR > 19.5; EMW = −59 ms, with a summary sensitivity of 82%, summary specificity of 56%, accuracy of 67%, and a DOR > 7.47; and QT C ≥ 460 ms with a summary sensitivity of 53%, summary specificity of 73%, accuracy of 68%, and DOR > 4.14 ( Figure 4, Table S2). QTc: corrected QT interval.

Risk of Bias Assessment
Most cohorts had good quality, where approximately 20% had fair quality. There was also no evidence for publication bias, as evaluated by the Egger's test.

Discussion
Findings: The findings of this meta-analysis could be summarized as follows-(1) LQTS patients had significant cardiac electromechanical abnormalities, irrespective of their genotype, LQT1 and LQT2, compared to control; (2) LQTS patients had preserved LVEF but reduced global longitudinal strain and compromised LV diastolic function; (3) mechanical abnormalities were worse in symptomatic compared to asymptomatic patients; (4) asymptomatic patients themselves had

Risk of Bias Assessment
Most cohorts had good quality, where approximately 20% had fair quality. There was also no evidence for publication bias, as evaluated by the Egger's test.

Discussion
Findings: The findings of this meta-analysis could be summarized as follows-(1) LQTS patients had significant cardiac electromechanical abnormalities, irrespective of their genotype, LQT1 and LQT2, compared to control; (2) LQTS patients had preserved LVEF but reduced global longitudinal strain and compromised LV diastolic function; (3) mechanical abnormalities were worse in symptomatic compared to asymptomatic patients; (4) asymptomatic patients themselves had pronounced mechanical abnormalities compared to controls; and (5) a cutoff of CD ≥ 430 ms was more accurate in predicting cardiac events in LQTS patients compared to EMW = −47 ms and QT C duration ≥ 460 ms.
Data Interpretation: LQTS was characterized as a pure electrical disorder for more than six decades [25], which limited our understanding of the underlying potential mechanisms of the disease in symptomatic patients. Over the last four decades, cardiac imaging techniques rapidly developed, with high precision in measuring cardiac cycle events in milliseconds. Doppler echocardiography was at the forefront of these advancements. Even the earliest generation of echocardiographic devices could report LV mechanical dysfunction associated with conduction abnormalities, e.g., left bundle branch block, as described by Edler [26]. Recently, echocardiographic speckle tracking technology was developed to assess myocardial deformation [27,28].
The aim of this meta-analysis was to ascertain LV mechanical abnormalities in LQTS, with an emphasis on symptomatic patients, to identify the strongest cardiac index that predicted occurrence of cardiac events. Despite a normal LV size and ejection fraction, the GLS, which reflects subendocardial function, was significantly reduced, a result that was consistent with previous findings [2]. The subendocardial layer might, therefore, have a selective role in LQTS pathophysiology, since it encompasses the purkinje fiber conduction system. Such disturbances have their clear impact on LV diastolic function, as we and others [29,30] previously showed in patients with coronary artery disease and heart failure, and preserved ejection fraction (HFpEF) [31]. Furthermore, our analysis showed that LV CD was significantly prolonged and EMW was abnormally negative, especially in symptomatic patients. However, CD was the strongest predictor of clinical events, even when compared with the conventionally reported prolonged QT C in LQTS patients. These findings were closely interrelated, in a similar manner, to electromechanical disturbances in other conditions [32]. Increased CD prolonged the isovolumic relaxation time (IVRT) and delayed mitral valve opening, the product of which yielded a negative EMW, which resulted in a lowered E/A ratio (as reported) [2,9,33]. Consequently, early (E) diastolic LV filling volume was reduced, and so was the stroke volume and cardiac output, which might be ameliorated by beta blockers in symptomatic LQTS patients [34]. In addition, the relationship between electrical dysfunction and mechanical abnormalities were reported in other conditions like heart failure, cardiac resynchronization therapy (CRT), absent septal q wave, myocardial infarction, etc. [35][36][37][38][39][40] A possible explanation for this mechanism was that low stroke volumes might provoke arrhythmias in LQTS patients. Similar abnormalities exist in asymptomatic LQTS patients; however, with a severity less enough to cause symptoms. Additionally, the nature and extent of these abnormalities did not seem to be different between LQT1 and LQT2 subtypes.
Mechanical and Molecular Mechanisms: Mechanical dysfunction proved to be a pivotal marker for risk stratification in LQTS patients. From a pathophysiological perspective, the QT C might not be an accurate index for measuring the risk of CE in LQTS patients compared to CD. The difference could be ascribed to the ability of the echocardiogram to encompass both high temporal and spatial resolutions, compared to a standard 12-lead ECG that only provides a measure of cardiac electric activity with high temporal resolution. Echocardiograms have a spatial resolution of more than 100 µm and a temporal resolution greater than 600 frames/s [41,42]. Different configurations like M-mode imaging has a high temporal resolution (>1000 frames s−1) [43], which allows for the visualization of rapid valve and ventricular wall movements. The standard 12-lead ECG, however, has a low resolution, compared to the echocardiogram [44]. The benefit of accounting for spatial resolution with cardiac indices is the ability to detect abnormalities in longitudinal and circumferential fibers of the ventricular wall. The sub-endocardium mainly consists of longitudinal fibers, oriented to 80 • with respect to the circumferential fibers, which are condensed heavily in the basal and mid-cavity region [45,46]. The delay in electrical conduction between longitudinal and circumferential layers might generate an accentuated lag in depolarization and hence contraction in LQTS patients. Studies showed that CD is longer in longitudinal compared to circumferential fibers, resulting in a significant transmural mechanical dispersion in symptomatic patients [18]. This effect might be attributed to the presence of subendocardial Purkinje fibers, which have a significantly longer AP duration compared to the mid-myocardium [3]. De Ferrari et al. showed that prolonged CD in LQTS patients could be abolished by verapamil, suggesting a role played by L-type calcium current in the EM abnormalities [10]. Calcium, the excitation-contraction coupling ion, can both underlie electrical and mechanical disturbances. Due to a decrease in repolarization reserve in LQTS, the depolarization reserve prevails during the late phases of the action potential, which are specifically mediated by calcium ions. This compensatory mechanism might explain the preserved LVEF in LQTS patients, despite the presence of systolic and diastolic dysfunction. The depolarization wave mediated by calcium release in the myocardium of LQTS patients can differ, depending on the spatial region, yielding spatio-temporal heterogeneity within the wall of the myocardium [47]. Symptomatic patients might have a CD that exceeds that of aortic valve closure, signifying delayed contraction, despite the normal onset of ventricular diastole [47].
Clinical implications: LQTS is not a simple electrical abnormality but is associated with significant mechanical and electromechanical disturbances. These abnormalities have a profound impact on the overall cardiac performance in the form of compromised stroke volume, which could be an underlying trigger for arrhythmias. Left ventricular prolonged CD is the strongest predictor of clinical events in LQTS. Thus, it must be routinely measured in patients, even in the absence of symptoms. Adopting this suggestion could play an important role in optimum clinical management of LQTS patients.
Study Limitations: In this meta-analysis, little attention was given to EM abnormalities in genotype-specific LQTS patients, LQT1 and LQT2, due to the scarcity of the data. Our results showed that there were no differences between LQT1 and LQT2 patients with respect to the electrocardiographic and echocardiographic indices analyzed. The QT C was shown to be inadequate in risk stratification in LQTS mutation carriers older than 40 years old [48]. LQTS genotypic differences ultimately determine a patient's propensity to experience arrhythmic episodes during different physiological states, such as rest or exercise [49]. This factor might be another potential reason why we could not differentiate between latent EM abnormalities, since there is a lack of data on the effects of exercise, sleep, or other physiological/environmental triggers on EM parameters in LQT1 and LQT2 patients. Despite including the 12 studies included in this meta-analysis, a large variety existed in the parameters measured between studies; thus, only 2-4 studies were used in the calculation of the electro-mechanical parameters analyzed. Another potential limitation was the fact that we did not perform the electrocardiographic or echocardiographic measurements; however, we trust the analysis made by the authors of the 12 studies included in this meta-analysis. Likewise, we relied on the published data based on the statistics undertaken by the individual authors of those studies.

Conclusions
These findings seem to highlight that LQTS is associated with pronounced electromechanical abnormalities, particularly the prolonged LV myocardial contraction duration, which is profound in symptomatic patients, irrespective of their type. These findings highlight the significant role of such measurements, particularly LV contraction duration, in managing LQTS patients.