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Syncope in Genotype-Negative Long QT Syndrome Family Members
Syncope in Genotype-Negative Long QT Syndrome Family Members Louise R.A. Olde Nordkamp, MDa, Martin H. Ruwald, MD, PhDb, Ilan Goldenberg, MDb, Wouter Wieling, MD, PhDc, Scott McNitt, MSb, Bronislava Polonsky, MSb, Arthur A.M. Wilde, MD, PhDa,*, Nynke van Dijk, MD, PhDd, and Arthur J. Moss, MDb Unaffected long-QT syndrome family members (FMs) frequently experience syncope. The aims of this study were to test the hypothesis that syncope events in FMs are benign events and to compare clinical characteristics, triggers eliciting the syncope events, and long-term outcomes between FMs and those with LQT1 or LQT2 mutations from the international Long QT Syndrome Registry. A total of 679 FMs, 864 LQT1 patients, and 782 LQT2 patients were included. Seventy-eight FMs (11%) experienced cardiovascular events. Almost all cardiovascular events were nonfatal syncope; only 1 FM, with an additional mitral valve prolapse, experienced aborted cardiac arrest during exercise. The mean age at first syncope in FMs was 17 years, and female FMs experienced syncope more frequently than male FMs (14% vs 9%, p [ 0.027). Syncope was more frequently triggered by exercise in LQT1 patients (43% in LQT1 patients vs 5% in FMs, p <0.001), while syncope triggered by a variety of other triggers was more frequent in FMs (54% in FMs vs 22% in LQT1 patients and 30% in LQT2 patients, p <0.001 for both). None of the FMs experienced aborted cardiac arrest or sudden cardiac death after the first syncopal episode. In conclusion, syncope is frequently present in FMs, and these syncopal events occurred more frequently in female than in male FMs, with an increased incidence in midadolescence. Triggers eliciting the syncopal events were different between FMs and patients with long-QT syndrome mutations. Hence, the type of trigger is useful in distinguishing between high- and low-risk syncope. These data indicate that FMs from families with LQTS have a benign form of syncope, most likely related to vasovagal syncope and not ventricular tachyarrhythmic syncope. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;-:-e-) Long-QT syndrome (LQTS) is an inherited arrhythmogenic disorder associated with an increased risk for ventricular arrhythmias leading to (arrhythmogenic) syncope and sudden cardiac death (SCD). Risk stratification studies have shown that a history of syncope is associated with a sixfold increased risk for subsequent aborted cardiac arrest (ACA) or SCD, and recurrent syncope episodes bear an even greater risk.1 Increased awareness of this risk has augmented the number of patients who receive implantable cardioverter-defibrillators (ICDs).2 In contrast, family members (FMs) who are genotype negative for a familyassociated LQTS mutation also experience a 15% rate of nonfatal syncope events but a near zero rate of lifethreatening events.3 These FMs with syncope might also be treated with ICDs on the basis of the presence of clinical symptoms in combination with their suspected familial sensitivity for SCD. However, in the general population, vasovagal syncope is extremely common, with a lifetime cumulative incidence of 1 syncopal episode in teenagers Departments of aCardiology, cInternal Medicine, and dGeneral Practice/ Family Medicine, Academic Medical Centre, Amsterdam, The Netherlands and bCardiology Division, University of Rochester Medical Centre, Rochester, New York. Manuscript received May 26, 2014; revised manuscript received and accepted July 9, 2014. See page 5 for disclosure information. *Corresponding author: Tel: þ31-20-5664503; fax: þ31-20-6971385. E-mail address: [email protected] (A.A.M. Wilde). 0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.07.044
up to 40% by the age of 21 years.4e7 Given the substantial complication rate of ICD implantations,8 adequate risk stratification is mandatory to distinguish whether a syncopal event was caused by a potentially lethal arrhythmia or whether the faint was a vasovagal episode occurring in an LQTS FM. We hypothesized that syncope events in FM are simple vasovagal syncope events, and we aimed to support this hypothesis by analyzing the characteristics of the syncope events. Methods The study population was drawn from subjects enrolled in the International Long QT Syndrome Registry9 who were genotype positive and had confirmed KCNQ1 (LQT1) or KCNH2 (LQT2) mutations. Patients were excluded if they had other LQTS-related mutations or if they had >1 mutation. First-, second-, third-, and fourth-degree genotypenegative FMs were (1) genotype-negative for a mutation in 1 of the LQTS-associated genes and (2) had corrected QT intervals 450 ms by Bazett’s formula.10 In particular, FMs of patients who had tested positive for LQTS-related mutations were excluded if they had not been tested for any gene or the test result was unknown. All subjects or their guardians provided informed consent for the genetic and clinical studies. Information on personal history, including cardiovascular events, defined as syncope (transient loss of consciousness due to cerebral hypoperfusion with abrupt onset and offset) www.ajconline.org
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Table 1 Demographic and clinical characteristics of family members and LQT1 and LQT2 patients Variable Female QTc (ms) Therapy Beta-blockers Left cardiac sympathetic denervation Pacemaker Implantable cardioverter-defibrillator Cardiovascular events Syncope Aborted cardiac arrest Sudden cardiac death Age at first syncope, mean (years) Recurrent syncope Total syncopal episodes Number of syncope, median
p-Value†
Family Members (N ¼ 695)
LQT1 Patients (N ¼ 864)
p-Value*
LQT2 Patients (N ¼ 782)
319 (46%) 393 16
488 (56%) 480 47
<0.001 NA
422 (54%) 481 54
0.002 NA
51 (7%) 0 (0%) 2 (0%) 3 (0%) 78 (11%) 77 (11%) 1 (0%) 0 (0%) 17.2 9.7 39 (6%) 176 2 (1e3)
400 (46%) 7 (1%) 18 (2%) 74 (9%) 302 (35%) 292 (34%) 24 (3%) 17 (2%) 13.1 8.4 179 (21%) 1022 2 (1e3.5)
<0.001 0.019 0.001 <0.001 NA
436 (56%) 12 (2) 62 (8) 120 (15%) 297 (38%) 278 (36%) 37 (5%) 27 (4%) 16.4 8.6 183 (23%) 932 2.5 (1e4)
<0.001 0.001 <0.001 <0.001 NA
0.001 <0.001 0.064
0.58 <0.001 0.002
In QTc values, family members had to have a QTc 450 ms. Cardiovascular events are compared using survival analysis in Figure 1. NA ¼ not applicable. * p-value calculated of LQT1 patients vs. family members. † p-value calculated of LQT2 patients vs. family members.
or ACA (requiring external defibrillation as part of the resuscitation or appropriate shock therapy in patients with ICDs) or LQTS-related SCD (abrupt in onset without evident cause, if witnessed, or death that was not explained by any other cause if it occurred in a nonwitnessed setting such as sleep), electrocardiography, and therapy was acquired at the time of enrollment. Clinical data were collected yearly on prospectively designed forms with information on medical therapy and the occurrence of LQTS-related cardiovascular events during long-term follow-up. Data regarding triggers for syncope were collected for each patient and FM as reported by the patient, if alive, by FMs, or by the primary care physician after the occurrence of an event. Additional information about the syncopal event was collected using a specific questionnaire and further corroborated by the study coordinators through the patients’ medical files and oral histories. Subsequently, the study specialists categorized each reported syncopal trigger into (1) exercise triggers, (2) arousal triggers, (3) syncope occurring during sleep or rest, and (4) other triggers.11 Clinical characteristics of the genotype-negative FMs and LQT1 and LQT2 patients were compared using chi-square or Fisher’s exact tests for categorical variables and Wilcoxon’s 2-sample test for continuous variables. The characteristics of the genotype-negative FMs were further compared by the occurrence of trigger-specific syncope using chi-square or Fisher’s exact tests for categorical variables and KruskalWallis tests for continuous variables. To assess the time to a first trigger-specific event by genotype (patients vs FMs) in LQT1 and LQT2, and to assess the independent contribution of gender to the first occurrence of other-trigger syncope events during follow-up, the Kaplan-Meier method was used, and significance was tested by using the log-rank test. Follow-up was censored at 40 years of age to avoid confounding by acquired cardiovascular disease. Multivariate Cox proportional-hazards regression models were used to evaluate the occurrence of trigger-specific syncopal events
by genotype. Prespecified covariates in the total population model included gender, age, corrected QT duration (500 ms), and medical therapy with b blockers. Betablocker therapy was assessed as a time-dependent covariate in the multivariate model. Results The study population consisted of 695 genotype-negative FMs, 864 LQT1 patients, and 782 LQT2 patients. Demographic and clinical characteristics of all study subjects are listed in Table 1. In general, LQT1 and LQT2 patients were more likely to be female and, as expected, were more frequently receiving therapy compared with FM. This notwithstanding, 51 FMs were also receiving therapy (b blockers n ¼ 51, pacemakers n ¼ 2, ICDs n ¼ 3). A total of 78 FMs (11%) experienced cardiovascular events. Almost all cardiovascular events in FMs were nonfatal syncope (n ¼ 77; Figure 1); only 1 FM experienced an ACA (Figure 1). This genotype-negative female FM with a familial LQT2 mutation experienced an ACA while playing volleyball at 14 years of age. She had a baseline corrected QT interval of 400 ms and had an additional mitral valve prolapse. In contrast, 302 LQT1 patients (35%) and 297 LQT2 patients (38%) experienced the primary end point of a first cardiovascular event (Table 1). ACA or SCD occurred in 41 LQT1 patients (4.7%) and 64 LQT2 patients (8.2%), and syncope was reported in 292 LQT1 patients (34%) and 278 LQT2 patients (36%). LQT1 patients were significantly younger than FMs when they experienced their first syncope events (13 vs 17 years, p <0.01). Female FMs experienced more syncopal events than men (14% vs 9%, p ¼ 0.027). Additionally, in female FMs, there was a distinct peak of first syncope events around 15 years. Only 1 FM was receiving a b blocker during a syncope event. Half of the FMs with syncope (n ¼ 39 [51%]) experienced 1 recurrent syncopal episode.
Arrhythmias and Conduction Disturbances/Triggers of Syncope in Long-QT Syndrome Families
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Figure 1. Kaplan-Meier curves of FMs versus LQT1 patients and LQT2 patients with the end point of syncope (A) and end point of ACA or shock (B).
Female FMs experienced a median of 1.5 (interquartile range 1 to 3), while the median number in male FMs was 2 (interquartile range 1 to 3). None of the FMs experienced ACA or SCD after the initial syncopal episode, while 28 LQT1 patients (10%) and 44 LQT2 patients (16%) did. The first syncopal event in FMs was triggered by exercise in 4 (5.2%), by arousal in 14 (18%), during sleep in 1 (1.3%), and by other triggers in 41 (53%) (Table 2). There was no difference in gender, age at first event, or degree of FM among the different types of triggers (Appendix A). In total, cardiovascular events (at any time) were triggered by exercise in 11 FMs (2%), by arousal in 19 FMs (3%), and by other triggers in 53 FMs (8%). Of 11 total exercise-triggered events, 4 (36%) occurred in FMs of LQT1 patients and 7 (64%) occurred in FMs of LQT2 patients (p ¼ 0.54). Of a total of 19 arousal-triggered events 8 (42%) occurred in
LQT1 FMs and 11 (58%) in LQT2 FMs (p ¼ 0.77). There was a significant difference in distribution of the triggers in FMs compared with LQTS patients (LQT1 patients vs FMs p <0.01, LQT2 patients vs FMs p <0.01; Figure 2). Syncope was significantly more frequently triggered by exercise in LQT1 patients and by arousal in LQT2 patients compared with FM (Table 2; extended specification in Appendix B). This was confirmed in multivariate analysis after adjustment for relevant covariates including gender and time-dependent b-blocker use, with a hazard ratio for exercise-triggered cardiovascular events of 12.5 (p <0.01) in LQT1 patients and for arousal-triggered events of 3.4 (p <0.01) in LQT2 patients. Syncope preceded by another known trigger (other triggered) was more frequent in FMs than in LQT1 and LQT2 patients (53% in FMs vs 22% in LQT1 patients and 30% in LQT2 patients, p <0.01 for both). This group
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Table 2 Specification of the triggers of first syncope events in family members and LQT1 and LQT 2 patients Variable Exercise Swimming Arousal Loud noise Rest or sleep Other Fever/illness, Substance abuse Menses Extreme heat/dehydration Unknown or missing information on trigger type
Family Members (N ¼ 77) 4 1 14 0 1 41 6 2 3 6 17
(5%) (1.3%) (18%) (0%) (1.3%) (53%) (7.7%) (2.6%) (3.8%) (7.5%) (22%)
LQT1 Patients (N ¼ 292) 126 46 35 2 1 64 10 2 2 2 66
(43%) (16%) (12%) (0.7%) (0%) (24%) (3%) (0.7%) (0.7%) (0.7%) (23%)
p-Value* <0.001 0.15 0.31 <0.001
0.92
LQT2 Patients (N ¼ 278) 19 0 57 34 23 86 13 0 2 8 93
(7%) (0%) (21%) (11%) (8%) (31%) (4.7%) (0%) (0.7%) (2.9%) (33%)
p-Value† 0.61 0.65 0.03 <0.001
0.056
* p-value calculated of LQT1 patients vs. family members. † p-value calculated of LQT2 patients vs. family members.
Figure 2. Distribution of triggers of syncope events in FMs, LQT1 patients, and LQT2 patients.
constituted a variety of triggers (Appendix B). Syncopal events triggered by extreme heat or dehydration or menses were more frequent in FMs. Kaplan-Meier analysis demonstrated a slight trend toward more other-triggered syncopal events in female than in male FMs (12% vs 9%, log-rank p ¼ 0.16; Figure 3). Additionally, similar to the syncope events of any trigger, there was a notable steep increase in incidence of other-triggered syncopal events in female FMs from the age of 12 years. Discussion In the international LQTS registry, 11% of the FMs experienced cardiovascular events. Almost all cardiovascular events were nonfatal syncope; only 1 FM experienced ACA during exercise. This patient additionally had mitral valve prolapse, a disorder that has been associated with lifethreatening arrhythmias.12 The lifetime cumulative incidence of benign syncopal events in FMs is relatively low compared with other studies performed in young subjects.7,13 The reason for the low frequency of syncopal events in FMs is not entirely clear. It is likely that most of the syncope in FMs relates to a vasovagal mechanism, and many of these overtly benign events may not have been included in the registry at
physicians’ discretion. Also, the total number of FMs and those with syncope are fewer than reported earlier by Barsheshet et al,3 probably because we excluded FMs who were not tested for a known familial mutation. Almost all FMs experienced their first syncope events as teenager or young adults. Additionally, female FMs were more likely to experience syncope, with a distinct peak of a first event during midadolescence. These data support our hypothesis that the syncope events in FMs are likely to involve a vasovagal mechanism. The findings regarding gender and age were even more prominent in other-triggered cardiovascular events, further implicating a vasovagal mechanism for these syncopal events. Other studies have consistently demonstrated that there is a difference in the incidence between female and male subjects4,13,14 and that there is a peak for the initial episode of syncope, predominantly in female patients, at the age of 15 years.4,13,15 Unfortunately, age and gender cannot be used to differentiate between cardiac and vasovagal syncope in LQTS patients, because LQTS symptoms are more frequent in female patients, and the age of first syncope event is similar in FMs and LQT2 patients. In contrast, LQT1 patients experienced their syncope events at a significantly younger age in childhood. This can potentially be explained by the fact that children perform more intensive physical activity, and most events in LQT1 patients occur during exercise. Distinguishing vasovagal syncope from other types of syncope by history taking can be difficult.16,17 Focus should be on the occurrence of prodromes and the presence of specific triggers that elicit the syncope episode.16 Although specific data on prodromes of the syncope event were missing in the LQTS registry, triggers were known in most patients. The distribution of triggers of the syncopal events was significantly different in FMs compared with LQT1 and LQT2 patients. As known from previous genotypephenotype studies,11,18,19 syncope triggered by exercise, especially swimming, was found to be highly predictive of syncopal events in LQT1 patients, and patients with LQT2 were more likely to have events during auditory stress, while events in FMs were never triggered by loud noise. Although emotional stress is also known to be a trigger for LQT2-related syncopal events, many FMs experienced
Arrhythmias and Conduction Disturbances/Triggers of Syncope in Long-QT Syndrome Families
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Figure 3. Kaplan-Meier of syncope by gender in other-triggered cardiovascular events in FMs.
syncopal events preceded by emotional stress as well. This could be well explained by the fact that syncope of vasovagal origin is often preceded by emotional stress such as pain or a blood-instrumentation-injection phobia.20 Hence, syncope during exercise and syncope triggered by loud noise are disease related and identify patients with high-risk events. In contrast, syncope triggered by a variety of other triggers often occurs in FMs. Especially syncope during extreme heat or dehydration and during menses were significantly more often reported in FMs. These triggers are well known for association with vasovagal syncope, underlining our hypothesis that these events in FM are benign vasovagal syncope events. The presence of othertriggered cardiovascular events might be caused by the presence of vasovagal syncope in LQTS patients, because the presence of LQTS does not exclude vasovagal events.21 Unfortunately, the data in the LQTS registry did not allow us to analyze the positions of the LQTS patients and FMs before the onset of syncope. Vasovagal events usually occur during standing (orthostatic stress), and cardiac syncope can occur in a supine position.22 A more thorough analysis with position and preceding prodromes should be done to diagnose syncope events in FMs more securely. In conclusion, syncope occurred in 11% of the FMs, and these events were likely to be of vasovagal origin, because the clinical characteristics of these syncopal events were similar to vasovagal syncope reported in previous research. These syncope events occurred mainly in female FMs during midadolescence. Syncope triggered by exercise and loud noise identified LQT1- and LQT2-related syncope, respectively. Syncope caused by other triggers (often typical vasovagal triggers) was more prevalent in FMs. Hence, the type of trigger may be used to distinguish between high- and low-risk syncope. These data suggest that genotypenegative FMs of LQTS patients most likely have benign vasovagal syncope because none of the FM experienced life-threatening events after the first syncope episode, and syncope was not a predictor of adverse outcomes in this population.
Disclosures Dr. Ruwald was funded by grants from The Danish Heart Foundation (12-04-R90-A3806-22701), Copenhagen, Denmark; The Lundbeckfonden (R108-A104415), Copenhagen, Denmark; and Arvid Nilssons Foundation, Copenhagen, Denmark. Dr. Wilde is a member of the Sorin Advisory Board. Dr. Goldenberg received research support from the Mirowski Foundation. Dr. Moss was supported in part by research grants HL-33843 and HL-51618 from the National Institutes of Health, Bethesda, Maryland, and by an unrestricted research grant from BioReference Laboratories, Inc., Elmwood Park, New Jersey. Supplementary Data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. amjcard.2014.07.044. 1. Liu J, Jons C, Moss A, McNitt S, Peterson D, Ming Q, Zareba W, Robinson JL, Kaufman ES, Locati E, Napolitano C, Priori SG, Schwartz PJ, Towbin JA, Vincent M, Zhang L, Goldenberg I. Risk factors for recurrent syncope and subsequent fatal or near-fatal events in children and adolescents with long QT syndrome. J Am Coll Cardiol 2011;57:941e950. 2. Schwartz PJ, Spazzolini C, Priori SG, Crotti L, Vicentini A, Landolina M, Gasparini M, Wilde AA, Knops RE, Denjoy I, Toivonen L, Monnig G, Al-Fayyadh M, Jordaens L, Borggrefe M, Holmgren C, Brugada P, De RL, Hohnloser SH, Brink PA. Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them? Data from the European long-QT syndrome implantable cardioverter-defibrillator (LQTS ICD) registry. Circulation 2010;122:1272e1282. 3. Barsheshet A, Moss AJ, McNitt S, Polonsky S, Lopes CM, Zareba W, Robinson JL, Ackerman MJ, Benhorin J, Kaufman ES, Towbin JA, Vincent GM, Qi M, Goldenberg I. Risk of syncope in family members who are genotype negative for a family-associated long QT syndrome mutation. Circ Cardiovasc Genet 2011;4:491e499. 4. Ganzeboom KS, Mairuhu G, Reitsma JB, Linzer M, Wieling W, van Dijk N. Lifetime cumulative incidence of syncope in the general population: a study of 549 Dutch subjects aged 35-60 years. J Cardiovasc Electrophysiol 2006;17:1172e1176.
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5. Olde Nordkamp LR, van Dijk N, Ganzeboom KS, Reitsma JB, Luitse JS, Dekker LR, Shen WK, Wieling W. Syncope prevalence in the ED compared to general practice and population: a strong selection process. Am J Emerg Med 2009;27:271e279. 6. Ruwald MH, Lock HM, Lamberts M, Vinther M, Torp-Pedersen C, Hansen J, Gislason GH. Unexplained syncope and diagnostic yield of tests in syncope according to the ICD-10 discharge diagnosis. J Clin Med Res 2013;5:441e450. 7. Serletis A, Rose S, Sheldon AG, Sheldon RS. Vasovagal syncope in medical students and their first-degree relatives. Eur Heart J 2006;27: 1965e1970. 8. Olde Nordkamp LR, Wilde AA, Tijssen JG, Knops RE, van Dessel PF, de Groot JR. The ICD for primary prevention in patients with inherited cardiac diseases: indications, use, and outcome: a comparison with secondary prevention. Circ Arrhythm Electrophysiol 2013;6:91e100. 9. Moss AJ, Schwartz PJ, Crampton RS, Locati E, Carleen E. The long QT syndrome: a prospective international study. Circulation 1985;71: 17e21. 10. Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920;7:353e370. 11. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, Denjoy I, Guicheney P, Breithardt G, Keating MT, Towbin JA, Beggs AH, Brink P, Wilde AA, Toivonen L, Zareba W, Robinson JL, Timothy KW, Corfield V, Wattanasirichaigoon D, Corbett C, Haverkamp W, Schulze-Bahr E, Lehmann MH, Schwartz K, Coumel P, Bloise R. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001;103:89e95. 12. Kligfield P, Levy D, Devereux RB, Savage DD. Arrhythmias and sudden death in mitral valve prolapse. Am Heart J 1987;113:1298e1307. 13. Ganzeboom KS, Colman N, Reitsma JB, Shen WK, Wieling W. Prevalence and triggers of syncope in medical students. Am J Cardiol 2003;91:1006e1008; A8.
14. Soteriades ES, Evans JC, Larson MG, Chen MH, Chen L, Benjamin EJ, Levy D. Incidence and prognosis of syncope. N Engl J Med 2002;347:878e885. 15. Sheldon RS, Sheldon AG, Connolly SJ, Morillo CA, Klingenheben T, Krahn AD, Koshman ML, Ritchie D. Age of first faint in patients with vasovagal syncope. J Cardiovasc Electrophysiol 2006;17:49e54. 16. Moya A, Sutton R, Ammirati F, Blanc JJ, Brignole M, Dahm JB, Deharo JC, Gajek J, Gjesdal K, Krahn A, Massin M, Pepi M, Pezawas T, Ruiz GR, Sarasin F, Ungar A, van Dijk JG, Walma EP, Wieling W. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J 2009;30:2631e2671. 17. van Dijk N, Boer KR, Colman N, Bakker A, Stam J, van Grieken JJ, Wilde AA, Linzer M, Reitsma JB, Wieling W. High diagnostic yield and accuracy of history, physical examination, and ECG in patients with transient loss of consciousness in FAST: the Fainting Assessment Study. J Cardiovasc Electrophysiol 2008;19:48e55. 18. Choi G, Kopplin LJ, Tester DJ, Will ML, Haglund CM, Ackerman MJ. Spectrum and frequency of cardiac channel defects in swimmingtriggered arrhythmia syndromes. Circulation 2004;110:2119e2124. 19. Wilde AA, Jongbloed RJ, Doevendans PA, Duren DR, Hauer RN, van Langen IM, van Tintelen JP, Smeets HJ, Meyer H, Geelen JL. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). J Am Coll Cardiol 1999;33:327e332. 20. Accurso V, Winnicki M, Shamsuzzaman AS, Wenzel A, Johnson AK, Somers VK. Predisposition to vasovagal syncope in subjects with blood/injury phobia. Circulation 2001;104:903e907. 21. Toft E, Aaroe J, Jensen BT, Christiansen M, Fog L, Thomsen PE, Kanters JK. Long QT syndrome patients may faint due to neurocardiogenic syncope. Europace 2003;5:367e370. 22. Colman N, Bakker A, Linzer M, Reitsma JB, Wieling W, Wilde AA. Value of history-taking in syncope patients: in whom to suspect long QT syndrome? Europace 2009;11:937e943.
up to 40% by the age of 21 years.4e7 Given the substantial complication rate of ICD implantations,8 adequate risk stratification is mandatory to distinguish whether a syncopal event was caused by a potentially lethal arrhythmia or whether the faint was a vasovagal episode occurring in an LQTS FM. We hypothesized that syncope events in FM are simple vasovagal syncope events, and we aimed to support this hypothesis by analyzing the characteristics of the syncope events. Methods The study population was drawn from subjects enrolled in the International Long QT Syndrome Registry9 who were genotype positive and had confirmed KCNQ1 (LQT1) or KCNH2 (LQT2) mutations. Patients were excluded if they had other LQTS-related mutations or if they had >1 mutation. First-, second-, third-, and fourth-degree genotypenegative FMs were (1) genotype-negative for a mutation in 1 of the LQTS-associated genes and (2) had corrected QT intervals 450 ms by Bazett’s formula.10 In particular, FMs of patients who had tested positive for LQTS-related mutations were excluded if they had not been tested for any gene or the test result was unknown. All subjects or their guardians provided informed consent for the genetic and clinical studies. Information on personal history, including cardiovascular events, defined as syncope (transient loss of consciousness due to cerebral hypoperfusion with abrupt onset and offset) www.ajconline.org
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Table 1 Demographic and clinical characteristics of family members and LQT1 and LQT2 patients Variable Female QTc (ms) Therapy Beta-blockers Left cardiac sympathetic denervation Pacemaker Implantable cardioverter-defibrillator Cardiovascular events Syncope Aborted cardiac arrest Sudden cardiac death Age at first syncope, mean (years) Recurrent syncope Total syncopal episodes Number of syncope, median
p-Value†
Family Members (N ¼ 695)
LQT1 Patients (N ¼ 864)
p-Value*
LQT2 Patients (N ¼ 782)
319 (46%) 393 16
488 (56%) 480 47
<0.001 NA
422 (54%) 481 54
0.002 NA
51 (7%) 0 (0%) 2 (0%) 3 (0%) 78 (11%) 77 (11%) 1 (0%) 0 (0%) 17.2 9.7 39 (6%) 176 2 (1e3)
400 (46%) 7 (1%) 18 (2%) 74 (9%) 302 (35%) 292 (34%) 24 (3%) 17 (2%) 13.1 8.4 179 (21%) 1022 2 (1e3.5)
<0.001 0.019 0.001 <0.001 NA
436 (56%) 12 (2) 62 (8) 120 (15%) 297 (38%) 278 (36%) 37 (5%) 27 (4%) 16.4 8.6 183 (23%) 932 2.5 (1e4)
<0.001 0.001 <0.001 <0.001 NA
0.001 <0.001 0.064
0.58 <0.001 0.002
In QTc values, family members had to have a QTc 450 ms. Cardiovascular events are compared using survival analysis in Figure 1. NA ¼ not applicable. * p-value calculated of LQT1 patients vs. family members. † p-value calculated of LQT2 patients vs. family members.
or ACA (requiring external defibrillation as part of the resuscitation or appropriate shock therapy in patients with ICDs) or LQTS-related SCD (abrupt in onset without evident cause, if witnessed, or death that was not explained by any other cause if it occurred in a nonwitnessed setting such as sleep), electrocardiography, and therapy was acquired at the time of enrollment. Clinical data were collected yearly on prospectively designed forms with information on medical therapy and the occurrence of LQTS-related cardiovascular events during long-term follow-up. Data regarding triggers for syncope were collected for each patient and FM as reported by the patient, if alive, by FMs, or by the primary care physician after the occurrence of an event. Additional information about the syncopal event was collected using a specific questionnaire and further corroborated by the study coordinators through the patients’ medical files and oral histories. Subsequently, the study specialists categorized each reported syncopal trigger into (1) exercise triggers, (2) arousal triggers, (3) syncope occurring during sleep or rest, and (4) other triggers.11 Clinical characteristics of the genotype-negative FMs and LQT1 and LQT2 patients were compared using chi-square or Fisher’s exact tests for categorical variables and Wilcoxon’s 2-sample test for continuous variables. The characteristics of the genotype-negative FMs were further compared by the occurrence of trigger-specific syncope using chi-square or Fisher’s exact tests for categorical variables and KruskalWallis tests for continuous variables. To assess the time to a first trigger-specific event by genotype (patients vs FMs) in LQT1 and LQT2, and to assess the independent contribution of gender to the first occurrence of other-trigger syncope events during follow-up, the Kaplan-Meier method was used, and significance was tested by using the log-rank test. Follow-up was censored at 40 years of age to avoid confounding by acquired cardiovascular disease. Multivariate Cox proportional-hazards regression models were used to evaluate the occurrence of trigger-specific syncopal events
by genotype. Prespecified covariates in the total population model included gender, age, corrected QT duration (500 ms), and medical therapy with b blockers. Betablocker therapy was assessed as a time-dependent covariate in the multivariate model. Results The study population consisted of 695 genotype-negative FMs, 864 LQT1 patients, and 782 LQT2 patients. Demographic and clinical characteristics of all study subjects are listed in Table 1. In general, LQT1 and LQT2 patients were more likely to be female and, as expected, were more frequently receiving therapy compared with FM. This notwithstanding, 51 FMs were also receiving therapy (b blockers n ¼ 51, pacemakers n ¼ 2, ICDs n ¼ 3). A total of 78 FMs (11%) experienced cardiovascular events. Almost all cardiovascular events in FMs were nonfatal syncope (n ¼ 77; Figure 1); only 1 FM experienced an ACA (Figure 1). This genotype-negative female FM with a familial LQT2 mutation experienced an ACA while playing volleyball at 14 years of age. She had a baseline corrected QT interval of 400 ms and had an additional mitral valve prolapse. In contrast, 302 LQT1 patients (35%) and 297 LQT2 patients (38%) experienced the primary end point of a first cardiovascular event (Table 1). ACA or SCD occurred in 41 LQT1 patients (4.7%) and 64 LQT2 patients (8.2%), and syncope was reported in 292 LQT1 patients (34%) and 278 LQT2 patients (36%). LQT1 patients were significantly younger than FMs when they experienced their first syncope events (13 vs 17 years, p <0.01). Female FMs experienced more syncopal events than men (14% vs 9%, p ¼ 0.027). Additionally, in female FMs, there was a distinct peak of first syncope events around 15 years. Only 1 FM was receiving a b blocker during a syncope event. Half of the FMs with syncope (n ¼ 39 [51%]) experienced 1 recurrent syncopal episode.
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Figure 1. Kaplan-Meier curves of FMs versus LQT1 patients and LQT2 patients with the end point of syncope (A) and end point of ACA or shock (B).
Female FMs experienced a median of 1.5 (interquartile range 1 to 3), while the median number in male FMs was 2 (interquartile range 1 to 3). None of the FMs experienced ACA or SCD after the initial syncopal episode, while 28 LQT1 patients (10%) and 44 LQT2 patients (16%) did. The first syncopal event in FMs was triggered by exercise in 4 (5.2%), by arousal in 14 (18%), during sleep in 1 (1.3%), and by other triggers in 41 (53%) (Table 2). There was no difference in gender, age at first event, or degree of FM among the different types of triggers (Appendix A). In total, cardiovascular events (at any time) were triggered by exercise in 11 FMs (2%), by arousal in 19 FMs (3%), and by other triggers in 53 FMs (8%). Of 11 total exercise-triggered events, 4 (36%) occurred in FMs of LQT1 patients and 7 (64%) occurred in FMs of LQT2 patients (p ¼ 0.54). Of a total of 19 arousal-triggered events 8 (42%) occurred in
LQT1 FMs and 11 (58%) in LQT2 FMs (p ¼ 0.77). There was a significant difference in distribution of the triggers in FMs compared with LQTS patients (LQT1 patients vs FMs p <0.01, LQT2 patients vs FMs p <0.01; Figure 2). Syncope was significantly more frequently triggered by exercise in LQT1 patients and by arousal in LQT2 patients compared with FM (Table 2; extended specification in Appendix B). This was confirmed in multivariate analysis after adjustment for relevant covariates including gender and time-dependent b-blocker use, with a hazard ratio for exercise-triggered cardiovascular events of 12.5 (p <0.01) in LQT1 patients and for arousal-triggered events of 3.4 (p <0.01) in LQT2 patients. Syncope preceded by another known trigger (other triggered) was more frequent in FMs than in LQT1 and LQT2 patients (53% in FMs vs 22% in LQT1 patients and 30% in LQT2 patients, p <0.01 for both). This group
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Table 2 Specification of the triggers of first syncope events in family members and LQT1 and LQT 2 patients Variable Exercise Swimming Arousal Loud noise Rest or sleep Other Fever/illness, Substance abuse Menses Extreme heat/dehydration Unknown or missing information on trigger type
Family Members (N ¼ 77) 4 1 14 0 1 41 6 2 3 6 17
(5%) (1.3%) (18%) (0%) (1.3%) (53%) (7.7%) (2.6%) (3.8%) (7.5%) (22%)
LQT1 Patients (N ¼ 292) 126 46 35 2 1 64 10 2 2 2 66
(43%) (16%) (12%) (0.7%) (0%) (24%) (3%) (0.7%) (0.7%) (0.7%) (23%)
p-Value* <0.001 0.15 0.31 <0.001
0.92
LQT2 Patients (N ¼ 278) 19 0 57 34 23 86 13 0 2 8 93
(7%) (0%) (21%) (11%) (8%) (31%) (4.7%) (0%) (0.7%) (2.9%) (33%)
p-Value† 0.61 0.65 0.03 <0.001
0.056
* p-value calculated of LQT1 patients vs. family members. † p-value calculated of LQT2 patients vs. family members.
Figure 2. Distribution of triggers of syncope events in FMs, LQT1 patients, and LQT2 patients.
constituted a variety of triggers (Appendix B). Syncopal events triggered by extreme heat or dehydration or menses were more frequent in FMs. Kaplan-Meier analysis demonstrated a slight trend toward more other-triggered syncopal events in female than in male FMs (12% vs 9%, log-rank p ¼ 0.16; Figure 3). Additionally, similar to the syncope events of any trigger, there was a notable steep increase in incidence of other-triggered syncopal events in female FMs from the age of 12 years. Discussion In the international LQTS registry, 11% of the FMs experienced cardiovascular events. Almost all cardiovascular events were nonfatal syncope; only 1 FM experienced ACA during exercise. This patient additionally had mitral valve prolapse, a disorder that has been associated with lifethreatening arrhythmias.12 The lifetime cumulative incidence of benign syncopal events in FMs is relatively low compared with other studies performed in young subjects.7,13 The reason for the low frequency of syncopal events in FMs is not entirely clear. It is likely that most of the syncope in FMs relates to a vasovagal mechanism, and many of these overtly benign events may not have been included in the registry at
physicians’ discretion. Also, the total number of FMs and those with syncope are fewer than reported earlier by Barsheshet et al,3 probably because we excluded FMs who were not tested for a known familial mutation. Almost all FMs experienced their first syncope events as teenager or young adults. Additionally, female FMs were more likely to experience syncope, with a distinct peak of a first event during midadolescence. These data support our hypothesis that the syncope events in FMs are likely to involve a vasovagal mechanism. The findings regarding gender and age were even more prominent in other-triggered cardiovascular events, further implicating a vasovagal mechanism for these syncopal events. Other studies have consistently demonstrated that there is a difference in the incidence between female and male subjects4,13,14 and that there is a peak for the initial episode of syncope, predominantly in female patients, at the age of 15 years.4,13,15 Unfortunately, age and gender cannot be used to differentiate between cardiac and vasovagal syncope in LQTS patients, because LQTS symptoms are more frequent in female patients, and the age of first syncope event is similar in FMs and LQT2 patients. In contrast, LQT1 patients experienced their syncope events at a significantly younger age in childhood. This can potentially be explained by the fact that children perform more intensive physical activity, and most events in LQT1 patients occur during exercise. Distinguishing vasovagal syncope from other types of syncope by history taking can be difficult.16,17 Focus should be on the occurrence of prodromes and the presence of specific triggers that elicit the syncope episode.16 Although specific data on prodromes of the syncope event were missing in the LQTS registry, triggers were known in most patients. The distribution of triggers of the syncopal events was significantly different in FMs compared with LQT1 and LQT2 patients. As known from previous genotypephenotype studies,11,18,19 syncope triggered by exercise, especially swimming, was found to be highly predictive of syncopal events in LQT1 patients, and patients with LQT2 were more likely to have events during auditory stress, while events in FMs were never triggered by loud noise. Although emotional stress is also known to be a trigger for LQT2-related syncopal events, many FMs experienced
Arrhythmias and Conduction Disturbances/Triggers of Syncope in Long-QT Syndrome Families
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Figure 3. Kaplan-Meier of syncope by gender in other-triggered cardiovascular events in FMs.
syncopal events preceded by emotional stress as well. This could be well explained by the fact that syncope of vasovagal origin is often preceded by emotional stress such as pain or a blood-instrumentation-injection phobia.20 Hence, syncope during exercise and syncope triggered by loud noise are disease related and identify patients with high-risk events. In contrast, syncope triggered by a variety of other triggers often occurs in FMs. Especially syncope during extreme heat or dehydration and during menses were significantly more often reported in FMs. These triggers are well known for association with vasovagal syncope, underlining our hypothesis that these events in FM are benign vasovagal syncope events. The presence of othertriggered cardiovascular events might be caused by the presence of vasovagal syncope in LQTS patients, because the presence of LQTS does not exclude vasovagal events.21 Unfortunately, the data in the LQTS registry did not allow us to analyze the positions of the LQTS patients and FMs before the onset of syncope. Vasovagal events usually occur during standing (orthostatic stress), and cardiac syncope can occur in a supine position.22 A more thorough analysis with position and preceding prodromes should be done to diagnose syncope events in FMs more securely. In conclusion, syncope occurred in 11% of the FMs, and these events were likely to be of vasovagal origin, because the clinical characteristics of these syncopal events were similar to vasovagal syncope reported in previous research. These syncope events occurred mainly in female FMs during midadolescence. Syncope triggered by exercise and loud noise identified LQT1- and LQT2-related syncope, respectively. Syncope caused by other triggers (often typical vasovagal triggers) was more prevalent in FMs. Hence, the type of trigger may be used to distinguish between high- and low-risk syncope. These data suggest that genotypenegative FMs of LQTS patients most likely have benign vasovagal syncope because none of the FM experienced life-threatening events after the first syncope episode, and syncope was not a predictor of adverse outcomes in this population.
Disclosures Dr. Ruwald was funded by grants from The Danish Heart Foundation (12-04-R90-A3806-22701), Copenhagen, Denmark; The Lundbeckfonden (R108-A104415), Copenhagen, Denmark; and Arvid Nilssons Foundation, Copenhagen, Denmark. Dr. Wilde is a member of the Sorin Advisory Board. Dr. Goldenberg received research support from the Mirowski Foundation. Dr. Moss was supported in part by research grants HL-33843 and HL-51618 from the National Institutes of Health, Bethesda, Maryland, and by an unrestricted research grant from BioReference Laboratories, Inc., Elmwood Park, New Jersey. Supplementary Data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. amjcard.2014.07.044. 1. Liu J, Jons C, Moss A, McNitt S, Peterson D, Ming Q, Zareba W, Robinson JL, Kaufman ES, Locati E, Napolitano C, Priori SG, Schwartz PJ, Towbin JA, Vincent M, Zhang L, Goldenberg I. Risk factors for recurrent syncope and subsequent fatal or near-fatal events in children and adolescents with long QT syndrome. J Am Coll Cardiol 2011;57:941e950. 2. Schwartz PJ, Spazzolini C, Priori SG, Crotti L, Vicentini A, Landolina M, Gasparini M, Wilde AA, Knops RE, Denjoy I, Toivonen L, Monnig G, Al-Fayyadh M, Jordaens L, Borggrefe M, Holmgren C, Brugada P, De RL, Hohnloser SH, Brink PA. Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them? Data from the European long-QT syndrome implantable cardioverter-defibrillator (LQTS ICD) registry. Circulation 2010;122:1272e1282. 3. Barsheshet A, Moss AJ, McNitt S, Polonsky S, Lopes CM, Zareba W, Robinson JL, Ackerman MJ, Benhorin J, Kaufman ES, Towbin JA, Vincent GM, Qi M, Goldenberg I. Risk of syncope in family members who are genotype negative for a family-associated long QT syndrome mutation. Circ Cardiovasc Genet 2011;4:491e499. 4. Ganzeboom KS, Mairuhu G, Reitsma JB, Linzer M, Wieling W, van Dijk N. Lifetime cumulative incidence of syncope in the general population: a study of 549 Dutch subjects aged 35-60 years. J Cardiovasc Electrophysiol 2006;17:1172e1176.
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