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Early Repolarization is associated with Symptoms in Patients with Type 1 and Type 2 Long QT syndrome Zachary W.M. Laksman MD, Lorne J. Gula MD, Pradyot Saklani MD, Romain Cassagneau MD, Christian Steinberg MD, Susan Conacher MSc, Raymond Yee MD, Allan Skanes MD, Peter Leong-Sit MD, Jaimie Manlucu MD, George J. Klein MD, Andrew D. Krahn MD www.elsevier.com/locate/buildenv
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Cite this article as: Zachary W.M. Laksman MD, Lorne J. Gula MD, Pradyot Saklani MD, Romain Cassagneau MD, Christian Steinberg MD, Susan Conacher MSc, Raymond Yee MD, Allan Skanes MD, Peter Leong-Sit MD, Jaimie Manlucu MD, George J. Klein MD, Andrew D. Krahn MD, Early Repolarization is associated with Symptoms in Patients with Type 1 and Type 2 Long QT syndrome, Heart Rhythm, http://dx.doi.org/ 10.1016/j.hrthm.2014.05.027 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Early Repolarization is associated with Symptoms in Patients with Type 1 and Type 2 Long QT syndrome. Zachary W.M. Laksman MD, Lorne J. Gula MD, Pradyot Saklani MD, Romain Cassagneau MD, Christian Steinberg MD, Susan Conacher MSc., Raymond Yee MD , Allan Skanes MD, Peter Leong-Sit MD, Jaimie Manlucu MD, George J. Klein MD, Andrew D. Krahn MD
Address for correspondence: Dr. Andrew Krahn Arrhythmia Service 9th Floor, Gordon & Leslie Diamond Health Care Centre 2775 Laurel Street Vancouver, BC V5Z 1M9 Tel: 1-604-875-4111 Ext. 69821 Fax: 1-604-875-5504 Email: [email protected]
From the Division of Cardiology, University of Western Ontario, London, Ontario, Canada (ZWML, PS, RC, SC, RY, AS, PLS, JM. LJG, GJK); and the Division of Cardiology, University of British Columbia (CS, ADK), Vancouver, British Columbia, Canada Word Count Total: 4,824 Body Text: 2,739 Abstract: 250 Short Title: Early repolarization is associated with symptoms in LQTS The Authors reports no conflicts of interest
Abstract Background: Early repolarization (ER) is associated with an increased risk of death from cardiac causes. Recent evidence supports ER’s role as a modifier and/or predictor of risk in many cardiac conditions. Objectives: Determine the prevalence of ER amongst genotype positive patient with Long QT syndrome (LQTS) and evaluate its utility in predicting risk of symptoms. Methods: ER was defined as QRS slurring and/or notching associated with ≥1 mV QRS-ST junction (J-point) elevation in at least 2 contiguous leads, excluding the anterior precordial leads. The ECG with the most prominent ER was used for analysis. Major ER was defined as ≥ 2 mm J point elevation. Symptoms of LQTS included cardiac syncope, documented polymorphic ventricular tachycardia (VT) and resuscitated cardiac arrest. Results: One hundred and thirteen patients (mean age 41 ± 19, 63 female) were reviewed in whom 414 (mean 3.7 ± 1.5) ECGs were analyzed. Of these, there were 30 patients (27%) with a history of symptoms. Fifty patients (44%) had ER, and 19 patients (17%) had major ER. Patients with major ER were not different than patients without major ER with respect to age, sex, LQT type, longest QTc recorded, number of patients with QTc> 500 msec, or use of beta blockade. Univariate and independent predictors of symptom status included the presence of major ER, longest QTc recorded > 500 msec, and female sex. Conclusion: ER ≥ 2 mm was the strongest independent predictor of symptom status related to LQTS, along with female sex and QTc > 500 msec.
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Keywords: Long QT syndrome, Early Repolarization, risk stratification, syncope, arrhythmia Abbreviations: Early repolarization (ER), Long QT syndrome (LQTS), ventricular tachycardia (VT), implantable cardioverter defibrillators (ICDs), generalized estimating equation (GEE)
Introduction Early repolarization (ER) is a common electrocardiographic finding that is generally benign, with a prevalence of 5-13% in the general population(1, 2). Nonetheless, early repolarization in the inferior and lateral leads has been associated with vulnerability to ventricular fibrillation in independent case control studies (1, 3, 4), and in the general population (2). A rare, and at times familial form of early repolarization presents as a primary arrhythmogenic disorder (5, 6). More commonly, early repolarization appears to act as a cofactor or risk modifier as demonstrated in Brugada syndrome (7), coronary artery disease (8), acute coronary events (9), families with a history of sudden cardiac death (10), and in survivors of cardiac arrest with and without an established cause (11). Several studies of ER have tried to remove confounding repolarization abnormalities by screening ECGs and excluding patients with QT intervals that are outside the normal range, or when identified, treated ER and prolonged QT as independent variables (1, 2, 12). However, the impact or effect of ER as a cofactor in patients with Long QT Syndrome (LQTS) could be substantive in the search for
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explanations to the variability in penetrance and expressivity observed in LQT families (13, 14). We sought to determine the prevalence of ER in genetically positive LQT patients, and examine its association with symptoms of cardiac syncope, documented polymorphic ventricular tachycardia (VT) and resuscitated cardiac arrest.
Methods Patient Population: A review of patients followed in the London inherited arrhythmia clinic with genetically confirmed pathogenic mutations in the three most common LQTS genes, KCNQ1, KCNH2 and SCN5A, was undertaken. Probands underwent comprehensive direct sequencing of the complete KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in either a research laboratory or through a commercial laboratory, either PGx Health (New Haven, Conn) or GeneDx (Gaithersburg, MD), as previously described (15). Family members of probands with disease-causing mutations underwent family specific genetic screening only. Consecutive patients with genetic data from 1995 to 2013 were included in the analysis. One patient with Jervell and Lange-Nielsen syndrome was excluded from analysis. There were only 2 patients with pathogenic mutations in SCN5A, and they were excluded from the analysis as the small sample size was not felt to adequately represent this population. The protocol was approved by the Health Sciences Research Ethics Board of the University of Western Ontario
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Clinical Assessment: A retrospective chart review of clinic, device, and hospital-based charts was carried out. Patients were classified as symptomatic if they had a history of cardiac syncope, documented polymorphic VT, or a resuscitated cardiac arrest. Syncope was considered to be cardiac if it occurred suddenly with minimal prodrome and recovery was relatively rapid and complete (16). Appropriate shocks from implantable cardioverter defibrillators (ICDs) were recorded on the basis of the analysis of the treating physician as recorded in the chart.
ECG analysis: Serial 12-lead ECGs were interrogated by four cardiologists blinded to clinical data and the symptom status of the patient (PS, RC, ZL, CS). ECGs recorded within 24 h of cardiac resuscitation/defibrillation, during therapeutic hypothermia after cardiac arrest and while the patient was on intravenous inotropes were excluded. Patients with conduction left bundle branch block were excluded. Of note, ECGs recorded after symptomatic events were included in the data acquisition. QT interval measurements were made manually from the beginning of the QRS complex to the end of the T wave, as defined by the intersection of the tangent drawn at the maximum downslope of the T wave with the isoelectric T-P line (17). The mean QT interval of 3 consecutive QT interval measurements at a stable RR interval was used. The QT interval measurements were corrected for heart rate using Bazett’s correction formula (QTc = QT/√RR).
ER was defined as QRS slurring and/or notching associated with QRS-ST junction (Jpoint) elevation in at least 2 contiguous leads, excluding the anterior precordial
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leads (V1-V3) (1, 2, 18, 19). The ECG lead with the most prominent ER was used for analysis. J-wave elevation of ≥1 mV above baseline, associated with QRS slurring and/or notching in the inferior leads (II, III, aVF), lateral leads (I,aVL, and V5,V6), or both was classified as ER. When the J-wave amplitude was ≥ 0.2 mV (2mm), it was classified as major ER. ER patterns were recorded as inferior, lateral or inferolateral. ST segments were classified as horizontal, descending or rapidly ascending/upsloping (20). Terminal QRS notching and slurring was recorded (Figures 1 and 2). The interobserver variation was 0.83, and was calculated using a sample of ECGs read by all readers that accounted for 10% of the total number of ECGs interpreted. If a patient had more than 5 ECGs recorded, all ECGs available were screened for ER. If one or more of the ECGs demonstrated ER, they were included in the coding and subsequent statistical analyses. Only one ECG per day was recorded for each patient.
Statistics: Statistical analysis was performed by the authors (ZL and LJG) using SAS 9.2 (SAS Institute Inc., Cary, NC). P- values 500 msec and were more likely to have major ER (Table 1).
Early Repolarization ER was recorded in at least one ECG in 50 patients (44%). Amongst patients with ER pattern, 62% (31/50) had ECGs without ER. When comparing patients with vs. without ER pattern, there was no difference in the age, sex, LQT type, use of beta blockers, symptom status, longest QTc measured, and number of patients with at least one ECG demonstrating a QTc > 500 msec (Table 2). Of the 50 patients with ER, 15 were symptomatic (30%). There was no difference between symptomatic and
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asymptomatic patients with respect to ECG location of ER (inferior vs. lateral vs. inferolateral, Online Appendix Table 1). Only one of 9 patients with lateral ER had symptoms. There was no difference noted in ER morphology between symptomatic and asymptomatic patients. (Online Appendix Table 1). Terminal QRS slurring compared to terminal QRS notching was seen more often in symptomatic patients (p = 0.036). When comparing patients with minor ER to patients without ER (Table 3), there was no significant difference in the number of patients with a history of symptoms (p = 0.22), and there were significantly less females (p = 0.048).
Major Early Repolarization Major ER was present in 19 patients (17%). Amongst patients with major ER, 42% (8/19) had ECGs without ER pattern. Patients with major ER did not differ from patients without major ER with respect to sex, age, LQT type, use of beta blockers, length of follow-up, longest QTc recorded and number of patients with QTc> 500 msec (Table 4). Furthermore, significantly more patients with major ER were symptomatic compared to patients without major ER (58% vs. 20%, p = 0.001). Three of nineteen patients (16%) had persistent major ER, all of which had a history of symptoms, compared to 8 of 16 patients (50%) with intermittent ER having a history of symptoms (p = 0.11). When analyzing only the ECG with the greatest Jpoint elevation and the most recent ECG in patients without ER, there was a trend towards slower heart rates in patients with major ER compared to those without major ER (58 ± 11 bpm vs. 64 ± 11 bpm , p = 0.06, Online Appendix Table 2).
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Heritability There was no association between family pedigree and either symptom status or major ER. Only one family was identified with more than one family member demonstrating major ER (Online Appendix Figure 1). The intrafamily correlation coefficient for symptoms among families was 0.025, strongly indicating that results within families are no more consistent than results between families.
Predictors of symptoms Female gender, QTc > 500 msec, and major ER were assessed in a multivariable model. Major ER showed the strongest independent association with symptom status (OR 5.97, p = 0.009) followed by female gender (OR 5.21, p = 0.015), and QTc> 500 msec (OR 4.50, p = 0.0063) (table 5). Findings were similar with a multivariable analysis that included all variables with a univariate p value < 0.1 (Online Appendix Table 3).
Discussion ER may predict or predispose patients to a malignant course of ventricular arrhythmias and sudden cardiac death in rare families and in association with other cardiac entities (1, 3-5, 8-11, 21). These clinical observations may relate to a well developed cellular basis for the involvement of J point elevation in the initiation of ventricular fibrillation (21). In our cohort of gene positive LQT patients, ER ≥ 1 mm was common and was not associated with cardiac symptoms. Major ER, defined as ≥ 2 mm of J point elevation, was less common but associated with an increased risk
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of cardiac symptoms related to LQTS. ER was an independent predictor of symptom status along with other known risk factors including QTc > 500 msec, and female sex. Since the institution of beta blockade, mortality in patients with LQTS has declined significantly (14). There remains however a significant proportion of patients at risk of cardiac events (22). Multiple studies have identified QTc > 500 msec, female sex, and locus of causative mutation as predictors of outcome in patients with LQTS (23, 24). Our study lends support to the use of major ER as a clinically significant risk factor in gene positive LQT patients as it was able to predict cardiac symptom status independent of underlying sex or longest QTc recorded. While the majority of symptoms recorded were syncope and not sudden cardiac death, syncope remains the strongest predictor of future events (22, 23, 25). It is well recognized that not all mutations on the same gene produce the same phenotype or the same risk (13, 26, 27). Based on observations from large clinical registries, and with the support of cellular expression studies demonstrating plausible mechanistic pathways, patients can be further sub-genotyped in order to characterize risk and potentially tailor therapy (28). While rational and attractive, this pinpoint targeting has the potential to miss or obscure signals for which we do not yet have testable models with much phenotypic variability unaccounted for (13, 28). A notable example is the KCNQ1-A341V mutation, with 80% of carriers being symptomatic, >30% suffering cardiac arrest or sudden death, yet only demonstrates a modest reduction of IKs (29). To look for new pathways that act independently or as cofactors in disease expressivity, we chose to look at a heterogeneous groups of
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LQTS patients. ER in our study had independent predictive ability regardless of LQT type and did not appear to reside in any specific subtype. Figure 3 is portrayed as an illustrative example of the association of major ER and symptom status in a single family containing multiple genotype and phenotype positive members (other illustrative examples available in Figures 1 and 2 of the Online Appendix). Major ER was identified in the sole patient who was resuscitated from sudden cardiac arrest (ECG depicted in Figure 1 top), whereas other family members have remained asymptomatic. Our findings are in keeping with previously published data demonstrating ER in survivors of sudden cardiac arrest with and without an underlying diagnosis, including in patients with LQTS (11). While the mechanism of ER-related arrhythmogenesis remains unknown, it is generally felt to be related to regional repolarization variability as generalized ER would cause uniform shortening of the QT interval. To date, there has been no clear QT interval difference between individuals with ER and controls (30). From clinical and experimental evidence, it is believed that ER is a marker of increased dispersion of repolarization that can results from any number of imbalances related to sodium, calcium and potassium currents (21). This is a generally accepted model that unifies our understanding of molecular biology and genetics in the pathogenesis of arrhythmia and torsades de pointes in patients with LQTS. In a similar fashion to ER, dispersion and its prevention, can act locally to promote or inhibit reentry without effects on the surface QTc (31).
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It is plausible that the steep transmural action potential gradients that predispose patients with structurally normal hearts to ventricular fibrillation, might also contribute to arrhythmogenesis in patients with pre-existing repolarization abnormalities, and thus act as a cofactor, modifier or marker of risk in patients with LQTS. Interestingly, a study looking at patients with LQT3 demonstrated that almost half of patients developed ST elevation in the anterior precordial leads when challenged with sodium channel blockers, blurring the distinction between LQTS and J-wave syndromes including ER (32). This has been reported by others and labeled as a phenotypic overlap of LQT3 and Brugada syndrome (33). Furthermore, mutations in the KCNH2 domain amongst patients without SCN5A mutations have been shown to play a modulatory role in Brugada syndrome (34). The prevalence of ER in the general population can be as high as 13% and from 20% in non-competitive athletes up to 90% in elite athletes (30). ER in the inferior leads, and less commonly the lateral leads, as well as the degree of J-point elevation appear to predict increased risk(2). Our study demonstrates a higher than expected prevalence of ER, but is not out of keeping with previous studies of ER when we compare the number of patients with ER (44%) and major ER (17%) to other populations(7, 9). Also, when comparing our cohort to a control population of their gene negative first-degree relatives (N = 30), there was no difference in the prevalence of major ER (Online Appendix Table 4). The intermittent nature of ER has been described (11), and certainly the interpretation of a number of ECGs increased our sensitivity to detect intermittent ER. This was the case in 62% of all patients with ER (31/50), and 42% of patient with major ER (8/19), who had at
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least one ECG that was recorded as normal. Our study is also in agreement with previous studies that demonstrated incremental risk amongst patients with the greatest amount of ER, the vast majority of which had ER in the inferior and inferolateral leads(1, 2).
Limitations While we have identified an association of ER ≥ 2 mm with cardiac symptoms in patients with LQTS, we cannot infer causality. The majority of symptomatic episodes occurred prior to presentation to the inherited heart rhythm clinic and subsequent management, focused on beta-blockers for prevention. The number of end points limited our ability to include other factors in the GEE model known to put patients at increased risk in LQTS such as male patients with LQT1 < 14 years old, female patients with LQTS between 15 and 40 years old and in the post-partum period, as well as mutation specific risk factors. In addition, the analysis of differences in location and morphology of ER is underpowered. Finally, the study could not specifically assess the effect of ER on mortality. Nonetheless, ER ≥ 2 mm emerges as a major risk factor for symptom status in the most common genetic types of LQTS, as it has for other entities, and merits further assessment and validation.
Conclusions ER ≥ 2 mm was significantly more prevalent in patients with cardiac symptoms in patients with genetically confirmed LQTS. ER ≥ 2 mm remained independently
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predictive of symptom status when combined with the previously established risk factors of symptoms in LQTS of female sex and QTc > 500 msec.
Funding Sources: The study was supported by the Heart and Stroke Foundation of Ontario (T6730).
Disclosures: The authors had full access to the data and take full responsibility for its integrity. All authors have read and agreed to the manuscript as written. The authors have no conflicts of interest to declare.
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Table 1: Clinical and Electrocardiographic comparison between symptomatic and asymptomatic patients. Symptomatic N = 30
Asymptomatic N = 83
P value
24 (80%)
39 (47%)
0.002
Age, years
50 ± 22
38 ± 17
0.002
Follow-up, months
73 ± 49
81 ± 55
0.474
Beta blockers
28 (93%)
72 (87%)
0.402
KCNQ1
18 (60%)
52 (63%)
0.798
KCNH2
12 (40%)
31 (37%)
0.798
ER* (≥ 1 mm)
15 (50%)
35 (42%)
0.459
Major ER* (≥ 2 mm)
11 (37%)
8 (10%)
0.001
Longest QTc recorded, msec
494 ± 43
473 ± 37
0.012
Longest QTc recorded >500 msec
14 (47%)
18 (22%)
0.009
Female
*ER = Early Repolarization
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Table 2: Clinical and electrocardiographic comparison between patients with ER ≥ 1mm and patients without ER.
Female Age KCNQ1 KCNH2 Beta Blockers Symptoms Syncope Polymorphic VT† SCD‡ ICD§ Appropriate shock Longest QTc, msec Longest QTc > 500 msec
ER* N = 50 25 (50%) 38 ± 18 32 (64%) 18 (36%) 41 (82%) 15 (30%) 12 (24%) 3 (6%) 3 (6%) 4 (8%) 0 (0%) 473 ± 37 12 (24%)
No ER* N = 63 38 (60%) 43 ± 19 38 (60%) 25 (40%) 59 (94%) 15 (24%) 13 (21%) 6 (10%) 6 (10%) 5 (8%) 1 (2%) 483 ± 44 20 (32%)
P Value 0.273 0.223 0.689 0.689 0.025 0.459 0.669 0.492 0.492 0.990 0.343 0.236 0.364
*ER = early repolarization †polymorphic VT = polymorphic ventricular tachycardia, ‡SCD = sudden cardiac death, §ICD = implantable cardioverter defibrillator
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Table 3: Clinical and electrocardiographic comparison of patients with major ER (≥ 2mm), minor ER (≥ 1mm) and patients without major ER. Major ER* N = 19 13 (68%) 42 ± 20 14 (74%) 5 (26%) 19 (100%) 66 ± 44 11 (58%) 9 (47%) 3 (16%) 2 (11%) 2 (11%) 0 (0%) 474 ± 36 5 (26%)
Minor ER* N = 31 12 (39%) 36 ± 16 18 (58%) 13 (42%) 22 (71%) 84 ± 40 4 (13%) 3 (10%) 0 (0%) 1 (3%) 2 (6%) 0 (0%) 473 ± 10 7 (23%)
No ER* N = 63 Female 38 (60%) Age 42 ± 19 KCNQ1 38 (60%) KCNH2 25 (40%) Beta Blockers 59 (94%) Follow-up, months 80 ± 57 Symptoms 15 (24%) Syncope 13 (21%) Polymorphic VT† 6 (10%) SCD‡ 6 (10%) ICD§ 5 (8%) Appropriate shock 1 (2%) Longest QTc, ms 483 ± 44 Longest QTc >500 ms 20 (32%) *ER = early repolarization, †polymorphic VT = polymorphic ventricular tachycardia, ‡SCD = sudden cardiac death, §ICD = implantable cardioverter defibrillator
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Table 4: Clinical and electrocardiographic comparison of patients with major ER (≥ 2mm), and patients without major ER.
Female Age KCNQ1 KCNH2 Beta Blockers Follow-up, months Symptoms Syncope Polymorphic VT† SCD‡ ICD§ Appropriate shock Longest QTc, ms Longest QTc >500 ms
Major ER* N = 19 13 (68%) 42 ± 20 14 (74%) 5 (26%) 19 (100%) 66 ± 44 11 (58%) 9 (47%) 3 (16%) 2 (11%) 2 (11%) 0 (0%) 474 ± 36 5 (26%)
No Major ER* N = 94 50 (53%) 41 ± 19 56 (60%) 38 (40%) 81 (86%) 81 ± 55 19 (20%) 16 (17%) 6 (6%) 7 (7%) 7 (7%) 1 (1%) 479 ± 42 27 (29%)
P Value 0.223 0.812 0.248 0.248 0.098 0.266 0.001 0.004 0.167 0.651 0.661 0.572 0.549 0.832
*ER = early repolarization, †polymorphic VT = polymorphic ventricular tachycardia, ‡SCD = sudden cardiac death, §ICD = implantable cardioverter defibrillator
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Table 5: Multivariable model identifying independent risk factors for symptoms of LQTS.
Generalized Estimating Equation model* Odds Ratio
P value
Major Early Repolarization (≥ 2 mm)
5.97
0.0090
QTc > 500 msec
4.50
0.0063
Female
5.21
0.015
*Major ER, QTc>500 msec, and Female sex entered into generalized estimating equation.
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Figure 1 top. ECG example of ER with normal QTc in a17 year old male with LQT1 (KCNQ1, Arg231His, 692 G>A) who suffered a cardiac arrest at age 15. ECG demonstrates 2.3 mV rapidly ascending ER in the inferolateral leads with notched pattern. Note QTc = 420 msec. Family pedigree demonstrated in Figure 3. Figure 1 bottom. ECG example of ER with normal QTc in a 63 year old female with LQT1 (KCNQ1 Arg549Gln, 1781G>A) and a history of syncope prior to initiation of beta blockade. ECG demonstrates 2 mV horizontal ER in the inferior leads with slurred pattern.
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Figure 2 top. ECG example of ER with prolonged QTc in a 13 year old female with LQT1 (KCNQ1 Ala341Glu, 1022 C>A) who had a syncopal event prior to initiation of beta blockers. The ECG demonstrates 3 mV descending ER in the inferior leads with a slurred pattern. QTc = 503 msec. Figure 2 bottom. ECG example of ER with mildly prolonged QTc in a 44 year old man with LQT1 (KCNQ1 Tyr111Cys, 332 A>G) and a history of syncope prior to initiation of beta blockers. ECG demonstrates 2 mV upsloping ER in the inferior leads with a slurred pattern. QTc = 480 msec.
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Figure 3. Pedigree demonstrating association of major ER and symptom status in a family harboring a KCNQ1 mutation (KCNQ1, Arg231His, 692 G>A). Other ECG parameters listed in table. Index patient indicated by arrow. Genotype status for each patient listed in upper box as + = gene positive or - = gene negative, phenotype status for LQTS in each patient listed in lower box as + = phenotype positive, - = phenotype negative. *ID = patient identifier †ER = early repolarization.
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Early Repolarization is associated with Symptoms in Patients with Type 1 and Type 2 Long QT syndrome Zachary W.M. Laksman MD, Lorne J. Gula MD, Pradyot Saklani MD, Romain Cassagneau MD, Christian Steinberg MD, Susan Conacher MSc, Raymond Yee MD, Allan Skanes MD, Peter Leong-Sit MD, Jaimie Manlucu MD, George J. Klein MD, Andrew D. Krahn MD www.elsevier.com/locate/buildenv
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S1547-5271(14)00558-X http://dx.doi.org/10.1016/j.hrthm.2014.05.027 HRTHM5790
To appear in:
Heart Rhythm
Cite this article as: Zachary W.M. Laksman MD, Lorne J. Gula MD, Pradyot Saklani MD, Romain Cassagneau MD, Christian Steinberg MD, Susan Conacher MSc, Raymond Yee MD, Allan Skanes MD, Peter Leong-Sit MD, Jaimie Manlucu MD, George J. Klein MD, Andrew D. Krahn MD, Early Repolarization is associated with Symptoms in Patients with Type 1 and Type 2 Long QT syndrome, Heart Rhythm, http://dx.doi.org/ 10.1016/j.hrthm.2014.05.027 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Early Repolarization is associated with Symptoms in Patients with Type 1 and Type 2 Long QT syndrome. Zachary W.M. Laksman MD, Lorne J. Gula MD, Pradyot Saklani MD, Romain Cassagneau MD, Christian Steinberg MD, Susan Conacher MSc., Raymond Yee MD , Allan Skanes MD, Peter Leong-Sit MD, Jaimie Manlucu MD, George J. Klein MD, Andrew D. Krahn MD
Address for correspondence: Dr. Andrew Krahn Arrhythmia Service 9th Floor, Gordon & Leslie Diamond Health Care Centre 2775 Laurel Street Vancouver, BC V5Z 1M9 Tel: 1-604-875-4111 Ext. 69821 Fax: 1-604-875-5504 Email: [email protected]
From the Division of Cardiology, University of Western Ontario, London, Ontario, Canada (ZWML, PS, RC, SC, RY, AS, PLS, JM. LJG, GJK); and the Division of Cardiology, University of British Columbia (CS, ADK), Vancouver, British Columbia, Canada Word Count Total: 4,824 Body Text: 2,739 Abstract: 250 Short Title: Early repolarization is associated with symptoms in LQTS The Authors reports no conflicts of interest
Abstract Background: Early repolarization (ER) is associated with an increased risk of death from cardiac causes. Recent evidence supports ER’s role as a modifier and/or predictor of risk in many cardiac conditions. Objectives: Determine the prevalence of ER amongst genotype positive patient with Long QT syndrome (LQTS) and evaluate its utility in predicting risk of symptoms. Methods: ER was defined as QRS slurring and/or notching associated with ≥1 mV QRS-ST junction (J-point) elevation in at least 2 contiguous leads, excluding the anterior precordial leads. The ECG with the most prominent ER was used for analysis. Major ER was defined as ≥ 2 mm J point elevation. Symptoms of LQTS included cardiac syncope, documented polymorphic ventricular tachycardia (VT) and resuscitated cardiac arrest. Results: One hundred and thirteen patients (mean age 41 ± 19, 63 female) were reviewed in whom 414 (mean 3.7 ± 1.5) ECGs were analyzed. Of these, there were 30 patients (27%) with a history of symptoms. Fifty patients (44%) had ER, and 19 patients (17%) had major ER. Patients with major ER were not different than patients without major ER with respect to age, sex, LQT type, longest QTc recorded, number of patients with QTc> 500 msec, or use of beta blockade. Univariate and independent predictors of symptom status included the presence of major ER, longest QTc recorded > 500 msec, and female sex. Conclusion: ER ≥ 2 mm was the strongest independent predictor of symptom status related to LQTS, along with female sex and QTc > 500 msec.
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Keywords: Long QT syndrome, Early Repolarization, risk stratification, syncope, arrhythmia Abbreviations: Early repolarization (ER), Long QT syndrome (LQTS), ventricular tachycardia (VT), implantable cardioverter defibrillators (ICDs), generalized estimating equation (GEE)
Introduction Early repolarization (ER) is a common electrocardiographic finding that is generally benign, with a prevalence of 5-13% in the general population(1, 2). Nonetheless, early repolarization in the inferior and lateral leads has been associated with vulnerability to ventricular fibrillation in independent case control studies (1, 3, 4), and in the general population (2). A rare, and at times familial form of early repolarization presents as a primary arrhythmogenic disorder (5, 6). More commonly, early repolarization appears to act as a cofactor or risk modifier as demonstrated in Brugada syndrome (7), coronary artery disease (8), acute coronary events (9), families with a history of sudden cardiac death (10), and in survivors of cardiac arrest with and without an established cause (11). Several studies of ER have tried to remove confounding repolarization abnormalities by screening ECGs and excluding patients with QT intervals that are outside the normal range, or when identified, treated ER and prolonged QT as independent variables (1, 2, 12). However, the impact or effect of ER as a cofactor in patients with Long QT Syndrome (LQTS) could be substantive in the search for
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explanations to the variability in penetrance and expressivity observed in LQT families (13, 14). We sought to determine the prevalence of ER in genetically positive LQT patients, and examine its association with symptoms of cardiac syncope, documented polymorphic ventricular tachycardia (VT) and resuscitated cardiac arrest.
Methods Patient Population: A review of patients followed in the London inherited arrhythmia clinic with genetically confirmed pathogenic mutations in the three most common LQTS genes, KCNQ1, KCNH2 and SCN5A, was undertaken. Probands underwent comprehensive direct sequencing of the complete KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in either a research laboratory or through a commercial laboratory, either PGx Health (New Haven, Conn) or GeneDx (Gaithersburg, MD), as previously described (15). Family members of probands with disease-causing mutations underwent family specific genetic screening only. Consecutive patients with genetic data from 1995 to 2013 were included in the analysis. One patient with Jervell and Lange-Nielsen syndrome was excluded from analysis. There were only 2 patients with pathogenic mutations in SCN5A, and they were excluded from the analysis as the small sample size was not felt to adequately represent this population. The protocol was approved by the Health Sciences Research Ethics Board of the University of Western Ontario
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Clinical Assessment: A retrospective chart review of clinic, device, and hospital-based charts was carried out. Patients were classified as symptomatic if they had a history of cardiac syncope, documented polymorphic VT, or a resuscitated cardiac arrest. Syncope was considered to be cardiac if it occurred suddenly with minimal prodrome and recovery was relatively rapid and complete (16). Appropriate shocks from implantable cardioverter defibrillators (ICDs) were recorded on the basis of the analysis of the treating physician as recorded in the chart.
ECG analysis: Serial 12-lead ECGs were interrogated by four cardiologists blinded to clinical data and the symptom status of the patient (PS, RC, ZL, CS). ECGs recorded within 24 h of cardiac resuscitation/defibrillation, during therapeutic hypothermia after cardiac arrest and while the patient was on intravenous inotropes were excluded. Patients with conduction left bundle branch block were excluded. Of note, ECGs recorded after symptomatic events were included in the data acquisition. QT interval measurements were made manually from the beginning of the QRS complex to the end of the T wave, as defined by the intersection of the tangent drawn at the maximum downslope of the T wave with the isoelectric T-P line (17). The mean QT interval of 3 consecutive QT interval measurements at a stable RR interval was used. The QT interval measurements were corrected for heart rate using Bazett’s correction formula (QTc = QT/√RR).
ER was defined as QRS slurring and/or notching associated with QRS-ST junction (Jpoint) elevation in at least 2 contiguous leads, excluding the anterior precordial
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leads (V1-V3) (1, 2, 18, 19). The ECG lead with the most prominent ER was used for analysis. J-wave elevation of ≥1 mV above baseline, associated with QRS slurring and/or notching in the inferior leads (II, III, aVF), lateral leads (I,aVL, and V5,V6), or both was classified as ER. When the J-wave amplitude was ≥ 0.2 mV (2mm), it was classified as major ER. ER patterns were recorded as inferior, lateral or inferolateral. ST segments were classified as horizontal, descending or rapidly ascending/upsloping (20). Terminal QRS notching and slurring was recorded (Figures 1 and 2). The interobserver variation was 0.83, and was calculated using a sample of ECGs read by all readers that accounted for 10% of the total number of ECGs interpreted. If a patient had more than 5 ECGs recorded, all ECGs available were screened for ER. If one or more of the ECGs demonstrated ER, they were included in the coding and subsequent statistical analyses. Only one ECG per day was recorded for each patient.
Statistics: Statistical analysis was performed by the authors (ZL and LJG) using SAS 9.2 (SAS Institute Inc., Cary, NC). P- values 500 msec and were more likely to have major ER (Table 1).
Early Repolarization ER was recorded in at least one ECG in 50 patients (44%). Amongst patients with ER pattern, 62% (31/50) had ECGs without ER. When comparing patients with vs. without ER pattern, there was no difference in the age, sex, LQT type, use of beta blockers, symptom status, longest QTc measured, and number of patients with at least one ECG demonstrating a QTc > 500 msec (Table 2). Of the 50 patients with ER, 15 were symptomatic (30%). There was no difference between symptomatic and
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asymptomatic patients with respect to ECG location of ER (inferior vs. lateral vs. inferolateral, Online Appendix Table 1). Only one of 9 patients with lateral ER had symptoms. There was no difference noted in ER morphology between symptomatic and asymptomatic patients. (Online Appendix Table 1). Terminal QRS slurring compared to terminal QRS notching was seen more often in symptomatic patients (p = 0.036). When comparing patients with minor ER to patients without ER (Table 3), there was no significant difference in the number of patients with a history of symptoms (p = 0.22), and there were significantly less females (p = 0.048).
Major Early Repolarization Major ER was present in 19 patients (17%). Amongst patients with major ER, 42% (8/19) had ECGs without ER pattern. Patients with major ER did not differ from patients without major ER with respect to sex, age, LQT type, use of beta blockers, length of follow-up, longest QTc recorded and number of patients with QTc> 500 msec (Table 4). Furthermore, significantly more patients with major ER were symptomatic compared to patients without major ER (58% vs. 20%, p = 0.001). Three of nineteen patients (16%) had persistent major ER, all of which had a history of symptoms, compared to 8 of 16 patients (50%) with intermittent ER having a history of symptoms (p = 0.11). When analyzing only the ECG with the greatest Jpoint elevation and the most recent ECG in patients without ER, there was a trend towards slower heart rates in patients with major ER compared to those without major ER (58 ± 11 bpm vs. 64 ± 11 bpm , p = 0.06, Online Appendix Table 2).
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Heritability There was no association between family pedigree and either symptom status or major ER. Only one family was identified with more than one family member demonstrating major ER (Online Appendix Figure 1). The intrafamily correlation coefficient for symptoms among families was 0.025, strongly indicating that results within families are no more consistent than results between families.
Predictors of symptoms Female gender, QTc > 500 msec, and major ER were assessed in a multivariable model. Major ER showed the strongest independent association with symptom status (OR 5.97, p = 0.009) followed by female gender (OR 5.21, p = 0.015), and QTc> 500 msec (OR 4.50, p = 0.0063) (table 5). Findings were similar with a multivariable analysis that included all variables with a univariate p value < 0.1 (Online Appendix Table 3).
Discussion ER may predict or predispose patients to a malignant course of ventricular arrhythmias and sudden cardiac death in rare families and in association with other cardiac entities (1, 3-5, 8-11, 21). These clinical observations may relate to a well developed cellular basis for the involvement of J point elevation in the initiation of ventricular fibrillation (21). In our cohort of gene positive LQT patients, ER ≥ 1 mm was common and was not associated with cardiac symptoms. Major ER, defined as ≥ 2 mm of J point elevation, was less common but associated with an increased risk
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of cardiac symptoms related to LQTS. ER was an independent predictor of symptom status along with other known risk factors including QTc > 500 msec, and female sex. Since the institution of beta blockade, mortality in patients with LQTS has declined significantly (14). There remains however a significant proportion of patients at risk of cardiac events (22). Multiple studies have identified QTc > 500 msec, female sex, and locus of causative mutation as predictors of outcome in patients with LQTS (23, 24). Our study lends support to the use of major ER as a clinically significant risk factor in gene positive LQT patients as it was able to predict cardiac symptom status independent of underlying sex or longest QTc recorded. While the majority of symptoms recorded were syncope and not sudden cardiac death, syncope remains the strongest predictor of future events (22, 23, 25). It is well recognized that not all mutations on the same gene produce the same phenotype or the same risk (13, 26, 27). Based on observations from large clinical registries, and with the support of cellular expression studies demonstrating plausible mechanistic pathways, patients can be further sub-genotyped in order to characterize risk and potentially tailor therapy (28). While rational and attractive, this pinpoint targeting has the potential to miss or obscure signals for which we do not yet have testable models with much phenotypic variability unaccounted for (13, 28). A notable example is the KCNQ1-A341V mutation, with 80% of carriers being symptomatic, >30% suffering cardiac arrest or sudden death, yet only demonstrates a modest reduction of IKs (29). To look for new pathways that act independently or as cofactors in disease expressivity, we chose to look at a heterogeneous groups of
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LQTS patients. ER in our study had independent predictive ability regardless of LQT type and did not appear to reside in any specific subtype. Figure 3 is portrayed as an illustrative example of the association of major ER and symptom status in a single family containing multiple genotype and phenotype positive members (other illustrative examples available in Figures 1 and 2 of the Online Appendix). Major ER was identified in the sole patient who was resuscitated from sudden cardiac arrest (ECG depicted in Figure 1 top), whereas other family members have remained asymptomatic. Our findings are in keeping with previously published data demonstrating ER in survivors of sudden cardiac arrest with and without an underlying diagnosis, including in patients with LQTS (11). While the mechanism of ER-related arrhythmogenesis remains unknown, it is generally felt to be related to regional repolarization variability as generalized ER would cause uniform shortening of the QT interval. To date, there has been no clear QT interval difference between individuals with ER and controls (30). From clinical and experimental evidence, it is believed that ER is a marker of increased dispersion of repolarization that can results from any number of imbalances related to sodium, calcium and potassium currents (21). This is a generally accepted model that unifies our understanding of molecular biology and genetics in the pathogenesis of arrhythmia and torsades de pointes in patients with LQTS. In a similar fashion to ER, dispersion and its prevention, can act locally to promote or inhibit reentry without effects on the surface QTc (31).
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It is plausible that the steep transmural action potential gradients that predispose patients with structurally normal hearts to ventricular fibrillation, might also contribute to arrhythmogenesis in patients with pre-existing repolarization abnormalities, and thus act as a cofactor, modifier or marker of risk in patients with LQTS. Interestingly, a study looking at patients with LQT3 demonstrated that almost half of patients developed ST elevation in the anterior precordial leads when challenged with sodium channel blockers, blurring the distinction between LQTS and J-wave syndromes including ER (32). This has been reported by others and labeled as a phenotypic overlap of LQT3 and Brugada syndrome (33). Furthermore, mutations in the KCNH2 domain amongst patients without SCN5A mutations have been shown to play a modulatory role in Brugada syndrome (34). The prevalence of ER in the general population can be as high as 13% and from 20% in non-competitive athletes up to 90% in elite athletes (30). ER in the inferior leads, and less commonly the lateral leads, as well as the degree of J-point elevation appear to predict increased risk(2). Our study demonstrates a higher than expected prevalence of ER, but is not out of keeping with previous studies of ER when we compare the number of patients with ER (44%) and major ER (17%) to other populations(7, 9). Also, when comparing our cohort to a control population of their gene negative first-degree relatives (N = 30), there was no difference in the prevalence of major ER (Online Appendix Table 4). The intermittent nature of ER has been described (11), and certainly the interpretation of a number of ECGs increased our sensitivity to detect intermittent ER. This was the case in 62% of all patients with ER (31/50), and 42% of patient with major ER (8/19), who had at
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least one ECG that was recorded as normal. Our study is also in agreement with previous studies that demonstrated incremental risk amongst patients with the greatest amount of ER, the vast majority of which had ER in the inferior and inferolateral leads(1, 2).
Limitations While we have identified an association of ER ≥ 2 mm with cardiac symptoms in patients with LQTS, we cannot infer causality. The majority of symptomatic episodes occurred prior to presentation to the inherited heart rhythm clinic and subsequent management, focused on beta-blockers for prevention. The number of end points limited our ability to include other factors in the GEE model known to put patients at increased risk in LQTS such as male patients with LQT1 < 14 years old, female patients with LQTS between 15 and 40 years old and in the post-partum period, as well as mutation specific risk factors. In addition, the analysis of differences in location and morphology of ER is underpowered. Finally, the study could not specifically assess the effect of ER on mortality. Nonetheless, ER ≥ 2 mm emerges as a major risk factor for symptom status in the most common genetic types of LQTS, as it has for other entities, and merits further assessment and validation.
Conclusions ER ≥ 2 mm was significantly more prevalent in patients with cardiac symptoms in patients with genetically confirmed LQTS. ER ≥ 2 mm remained independently
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predictive of symptom status when combined with the previously established risk factors of symptoms in LQTS of female sex and QTc > 500 msec.
Funding Sources: The study was supported by the Heart and Stroke Foundation of Ontario (T6730).
Disclosures: The authors had full access to the data and take full responsibility for its integrity. All authors have read and agreed to the manuscript as written. The authors have no conflicts of interest to declare.
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Table 1: Clinical and Electrocardiographic comparison between symptomatic and asymptomatic patients. Symptomatic N = 30
Asymptomatic N = 83
P value
24 (80%)
39 (47%)
0.002
Age, years
50 ± 22
38 ± 17
0.002
Follow-up, months
73 ± 49
81 ± 55
0.474
Beta blockers
28 (93%)
72 (87%)
0.402
KCNQ1
18 (60%)
52 (63%)
0.798
KCNH2
12 (40%)
31 (37%)
0.798
ER* (≥ 1 mm)
15 (50%)
35 (42%)
0.459
Major ER* (≥ 2 mm)
11 (37%)
8 (10%)
0.001
Longest QTc recorded, msec
494 ± 43
473 ± 37
0.012
Longest QTc recorded >500 msec
14 (47%)
18 (22%)
0.009
Female
*ER = Early Repolarization
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Table 2: Clinical and electrocardiographic comparison between patients with ER ≥ 1mm and patients without ER.
Female Age KCNQ1 KCNH2 Beta Blockers Symptoms Syncope Polymorphic VT† SCD‡ ICD§ Appropriate shock Longest QTc, msec Longest QTc > 500 msec
ER* N = 50 25 (50%) 38 ± 18 32 (64%) 18 (36%) 41 (82%) 15 (30%) 12 (24%) 3 (6%) 3 (6%) 4 (8%) 0 (0%) 473 ± 37 12 (24%)
No ER* N = 63 38 (60%) 43 ± 19 38 (60%) 25 (40%) 59 (94%) 15 (24%) 13 (21%) 6 (10%) 6 (10%) 5 (8%) 1 (2%) 483 ± 44 20 (32%)
P Value 0.273 0.223 0.689 0.689 0.025 0.459 0.669 0.492 0.492 0.990 0.343 0.236 0.364
*ER = early repolarization †polymorphic VT = polymorphic ventricular tachycardia, ‡SCD = sudden cardiac death, §ICD = implantable cardioverter defibrillator
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Table 3: Clinical and electrocardiographic comparison of patients with major ER (≥ 2mm), minor ER (≥ 1mm) and patients without major ER. Major ER* N = 19 13 (68%) 42 ± 20 14 (74%) 5 (26%) 19 (100%) 66 ± 44 11 (58%) 9 (47%) 3 (16%) 2 (11%) 2 (11%) 0 (0%) 474 ± 36 5 (26%)
Minor ER* N = 31 12 (39%) 36 ± 16 18 (58%) 13 (42%) 22 (71%) 84 ± 40 4 (13%) 3 (10%) 0 (0%) 1 (3%) 2 (6%) 0 (0%) 473 ± 10 7 (23%)
No ER* N = 63 Female 38 (60%) Age 42 ± 19 KCNQ1 38 (60%) KCNH2 25 (40%) Beta Blockers 59 (94%) Follow-up, months 80 ± 57 Symptoms 15 (24%) Syncope 13 (21%) Polymorphic VT† 6 (10%) SCD‡ 6 (10%) ICD§ 5 (8%) Appropriate shock 1 (2%) Longest QTc, ms 483 ± 44 Longest QTc >500 ms 20 (32%) *ER = early repolarization, †polymorphic VT = polymorphic ventricular tachycardia, ‡SCD = sudden cardiac death, §ICD = implantable cardioverter defibrillator
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Table 4: Clinical and electrocardiographic comparison of patients with major ER (≥ 2mm), and patients without major ER.
Female Age KCNQ1 KCNH2 Beta Blockers Follow-up, months Symptoms Syncope Polymorphic VT† SCD‡ ICD§ Appropriate shock Longest QTc, ms Longest QTc >500 ms
Major ER* N = 19 13 (68%) 42 ± 20 14 (74%) 5 (26%) 19 (100%) 66 ± 44 11 (58%) 9 (47%) 3 (16%) 2 (11%) 2 (11%) 0 (0%) 474 ± 36 5 (26%)
No Major ER* N = 94 50 (53%) 41 ± 19 56 (60%) 38 (40%) 81 (86%) 81 ± 55 19 (20%) 16 (17%) 6 (6%) 7 (7%) 7 (7%) 1 (1%) 479 ± 42 27 (29%)
P Value 0.223 0.812 0.248 0.248 0.098 0.266 0.001 0.004 0.167 0.651 0.661 0.572 0.549 0.832
*ER = early repolarization, †polymorphic VT = polymorphic ventricular tachycardia, ‡SCD = sudden cardiac death, §ICD = implantable cardioverter defibrillator
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Table 5: Multivariable model identifying independent risk factors for symptoms of LQTS.
Generalized Estimating Equation model* Odds Ratio
P value
Major Early Repolarization (≥ 2 mm)
5.97
0.0090
QTc > 500 msec
4.50
0.0063
Female
5.21
0.015
*Major ER, QTc>500 msec, and Female sex entered into generalized estimating equation.
22
Figure 1 top. ECG example of ER with normal QTc in a17 year old male with LQT1 (KCNQ1, Arg231His, 692 G>A) who suffered a cardiac arrest at age 15. ECG demonstrates 2.3 mV rapidly ascending ER in the inferolateral leads with notched pattern. Note QTc = 420 msec. Family pedigree demonstrated in Figure 3. Figure 1 bottom. ECG example of ER with normal QTc in a 63 year old female with LQT1 (KCNQ1 Arg549Gln, 1781G>A) and a history of syncope prior to initiation of beta blockade. ECG demonstrates 2 mV horizontal ER in the inferior leads with slurred pattern.
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Figure 2 top. ECG example of ER with prolonged QTc in a 13 year old female with LQT1 (KCNQ1 Ala341Glu, 1022 C>A) who had a syncopal event prior to initiation of beta blockers. The ECG demonstrates 3 mV descending ER in the inferior leads with a slurred pattern. QTc = 503 msec. Figure 2 bottom. ECG example of ER with mildly prolonged QTc in a 44 year old man with LQT1 (KCNQ1 Tyr111Cys, 332 A>G) and a history of syncope prior to initiation of beta blockers. ECG demonstrates 2 mV upsloping ER in the inferior leads with a slurred pattern. QTc = 480 msec.
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Figure 3. Pedigree demonstrating association of major ER and symptom status in a family harboring a KCNQ1 mutation (KCNQ1, Arg231His, 692 G>A). Other ECG parameters listed in table. Index patient indicated by arrow. Genotype status for each patient listed in upper box as + = gene positive or - = gene negative, phenotype status for LQTS in each patient listed in lower box as + = phenotype positive, - = phenotype negative. *ID = patient identifier †ER = early repolarization.
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