Syncope in Genotype-Negative Long QT Syndrome Family Members
2014; Elsevier BV; Volume: 114; Issue: 8 Linguagem: Inglês
10.1016/j.amjcard.2014.07.044
ISSN1879-1913
AutoresLouise R.A. Olde Nordkamp, Martin H. Ruwald, Ilan Goldenberg, Wouter Wieling, Scott McNitt, Bronislava Polonsky, Arthur A.M. Wilde, Nynke van Dijk, Arthur J. Moss,
Tópico(s)Cardiac Arrhythmias and Treatments
Resumo•Syncope occurred in 11% of family members of patients with LQTS.•These syncope events occurred mainly in female family members during midadolescence.•None of the family members had life-threatening events after the syncope episodes.•These data suggest that family members most likely have benign vasovagal syncope. 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. 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 1 mutation. First-, second-, third-, and fourth-degree genotype-negative 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.10Bazett H.C. An analysis of the time-relations of electrocardiograms.Heart. 1920; 7: 353-370Google Scholar 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) 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.11Schwartz P.J. Priori S.G. Spazzolini C. Moss A.J. Vincent G.M. Napolitano C. Denjoy I. Guicheney P. Breithardt G. Keating M.T. Towbin J.A. Beggs A.H. Brink P. Wilde A.A. Toivonen L. Zareba W. Robinson J.L. Timothy K.W. Corfield V. Wattanasirichaigoon D. Corbett C. Haverkamp W. Schulze-Bahr E. Lehmann M.H. Schwartz K. Coumel P. Bloise R. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.Circulation. 2001; 103: 89-95Crossref PubMed Scopus (1447) Google ScholarClinical 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 Kruskal-Wallis 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 β blockers. Beta-blocker therapy was assessed as a time-dependent covariate in the multivariate model.ResultsThe 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 (β blockers n = 51, pacemakers n = 2, ICDs n = 3).Table 1Demographic and clinical characteristics of family members and LQT1 and LQT2 patientsVariableFamily Members (N = 695)LQT1 Patients (N = 864)p-Value∗p-value calculated of LQT1 patients vs. family members.LQT2 Patients (N = 782)p-Value†p-value calculated of LQT2 patients vs. family members.Female319 (46%)488 (56%)<0.001422 (54%)0.002QTc (ms)393 ± 16480 ± 47NA481 ± 54NATherapy Beta-blockers51 (7%)400 (46%)<0.001436 (56%)<0.001 Left cardiac sympathetic denervation0 (0%)7 (1%)0.01912 (2)0.001 Pacemaker2 (0%)18 (2%)0.00162 (8)<0.001 Implantable cardioverter-defibrillator3 (0%)74 (9%)<0.001120 (15%)<0.001Cardiovascular events78 (11%)302 (35%)NA297 (38%)NA Syncope77 (11%)292 (34%)278 (36%) Aborted cardiac arrest1 (0%)24 (3%)37 (5%) Sudden cardiac death0 (0%)17 (2%)27 (4%)Age at first syncope, mean (years)17.2 ± 9.713.1 ± 8.40.00116.4 ± 8.60.58Recurrent syncope39 (6%)179 (21%)<0.001183 (23%)<0.001Total syncopal episodes1761022932Number of syncope, median2 (1–3)2 (1–3.5)0.0642.5 (1–4)0.002In QTc values, family members had to have a QTc ≤ 450 ms. Cardiovascular events are compared using survival analysis in Figure 1.NA = not applicable.∗ p-value calculated of LQT1 patients vs. family members.† p-value calculated of LQT2 patients vs. family members. Open table in a new tab A total of 78 FMs (11%) experienced cardiovascular events. Almost all cardiovascular events in FMs were nonfatal syncope (n = 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 = 0.027). Additionally, in female FMs, there was a distinct peak of first syncope events around 15 years. Only 1 FM was receiving a β blocker during a syncope event. Half of the FMs with syncope (n = 39 [51%]) experienced ≥1 recurrent syncopal episode. 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 = 0.54). Of a total of 19 arousal-triggered events 8 (42%) occurred in LQT1 FMs and 11 (58%) in LQT2 FMs (p = 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 β-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 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 = 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.Table 2Specification of the triggers of first syncope events in family members and LQT1 and LQT 2 patientsVariableFamily Members (N = 77)LQT1 Patients (N = 292)p-Value∗p-value calculated of LQT1 patients vs. family members.LQT2 Patients (N = 278)p-Value†p-value calculated of LQT2 patients vs. family members.Exercise4 (5%)126 (43%)<0.00119 (7%)0.61 Swimming1 (1.3%)46 (16%)0 (0%)Arousal14 (18%)35 (12%)0.1557 (21%)0.65 Loud noise0 (0%)2 (0.7%)34 (11%)Rest or sleep1 (1.3%)1 (0%)0.3123 (8%)0.03Other41 (53%)64 (24%)<0.00186 (31%)<0.001 Fever/illness,6 (7.7%)10 (3%)13 (4.7%) Substance abuse2 (2.6%)2 (0.7%)0 (0%) Menses3 (3.8%)2 (0.7%)2 (0.7%) Extreme heat/dehydration6 (7.5%)2 (0.7%)8 (2.9%)Unknown or missing information on trigger type17 (22%)66 (23%)0.9293 (33%)0.056∗ p-value calculated of LQT1 patients vs. family members.† p-value calculated of LQT2 patients vs. family members. Open table in a new tab Figure 2Distribution of triggers of syncope events in FMs, LQT1 patients, and LQT2 patients.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Kaplan-Meier of syncope by gender in other-triggered cardiovascular events in FMs.View Large Image Figure ViewerDownload Hi-res image Download (PPT)DiscussionIn 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 life-threatening arrhythmias.12Kligfield P. Levy D. Devereux R.B. Savage D.D. Arrhythmias and sudden death in mitral valve prolapse.Am Heart J. 1987; 113: 1298-1307Abstract Full Text PDF PubMed Scopus (142) Google ScholarThe lifetime cumulative incidence of benign syncopal events in FMs is relatively low compared with other studies performed in young subjects.7Serletis A. Rose S. Sheldon A.G. Sheldon R.S. Vasovagal syncope in medical students and their first-degree relatives.Eur Heart J. 2006; 27: 1965-1970Crossref PubMed Scopus (170) Google Scholar, 13Ganzeboom K.S. Colman N. Reitsma J.B. Shen W.K. Wieling W. Prevalence and triggers of syncope in medical students.Am J Cardiol. 2003; 91 (A8): 1006-1008Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar 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,3Barsheshet A. Moss A.J. McNitt S. Polonsky S. Lopes C.M. Zareba W. Robinson J.L. Ackerman M.J. Benhorin J. Kaufman E.S. Towbin J.A. Vincent G.M. 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: 491-499Crossref PubMed Scopus (8) Google Scholar 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 subjects4Ganzeboom K.S. Mairuhu G. Reitsma J.B. 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: 1172-1176Crossref PubMed Scopus (258) Google Scholar, 13Ganzeboom K.S. Colman N. Reitsma J.B. Shen W.K. Wieling W. Prevalence and triggers of syncope in medical students.Am J Cardiol. 2003; 91 (A8): 1006-1008Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar, 14Soteriades E.S. Evans J.C. Larson M.G. Chen M.H. Chen L. Benjamin E.J. Levy D. Incidence and prognosis of syncope.N Engl J Med. 2002; 347: 878-885Crossref PubMed Scopus (997) Google Scholar and that there is a peak for the initial episode of syncope, predominantly in female patients, at the age of 15 years.4Ganzeboom K.S. Mairuhu G. Reitsma J.B. 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: 1172-1176Crossref PubMed Scopus (258) Google Scholar, 13Ganzeboom K.S. Colman N. Reitsma J.B. Shen W.K. Wieling W. Prevalence and triggers of syncope in medical students.Am J Cardiol. 2003; 91 (A8): 1006-1008Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar, 15Sheldon R.S. Sheldon A.G. Connolly S.J. Morillo C.A. Klingenheben T. Krahn A.D. Koshman M.L. Ritchie D. Age of first faint in patients with vasovagal syncope.J Cardiovasc Electrophysiol. 2006; 17: 49-54Crossref PubMed Scopus (106) Google Scholar 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.16Moya A. Sutton R. Ammirati F. Blanc J.J. Brignole M. Dahm J.B. Deharo J.C. Gajek J. Gjesdal K. Krahn A. Massin M. Pepi M. Pezawas T. Ruiz G.R. Sarasin F. Ungar A. van Dijk J.G. Walma E.P. Wieling W. Guidelines for the diagnosis and management of syncope (version 2009).Eur Heart J. 2009; 30: 2631-2671Crossref PubMed Scopus (22) Google Scholar, 17van Dijk N. Boer K.R. Colman N. Bakker A. Stam J. van Grieken J.J. Wilde A.A. Linzer M. Reitsma J.B. 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: 48-55Crossref PubMed Scopus (1) Google Scholar Focus should be on the occurrence of prodromes and the presence of specific triggers that elicit the syncope episode.16Moya A. Sutton R. Ammirati F. Blanc J.J. Brignole M. Dahm J.B. Deharo J.C. Gajek J. Gjesdal K. Krahn A. Massin M. Pepi M. Pezawas T. Ruiz G.R. Sarasin F. Ungar A. van Dijk J.G. Walma E.P. Wieling W. Guidelines for the diagnosis and management of syncope (version 2009).Eur Heart J. 2009; 30: 2631-2671Crossref PubMed Scopus (22) Google Scholar 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 genotype-phenotype studies,11Schwartz P.J. Priori S.G. Spazzolini C. Moss A.J. Vincent G.M. Napolitano C. Denjoy I. Guicheney P. Breithardt G. Keating M.T. Towbin J.A. Beggs A.H. Brink P. Wilde A.A. Toivonen L. Zareba W. Robinson J.L. Timothy K.W. Corfield V. Wattanasirichaigoon D. Corbett C. Haverkamp W. Schulze-Bahr E. Lehmann M.H. Schwartz K. Coumel P. Bloise R. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.Circulation. 2001; 103: 89-95Crossref PubMed Scopus (1447) Google Scholar, 18Choi G. Kopplin L.J. Tester D.J. Will M.L. Haglund C.M. Ackerman M.J. Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes.Circulation. 2004; 110: 2119-2124Crossref PubMed Scopus (200) Google Scholar, 19Wilde A.A. Jongbloed R.J. Doevendans P.A. Duren D.R. Hauer R.N. van Langen I.M. van Tintelen J.P. Smeets H.J. Meyer H. Geelen J.L. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1).J Am Coll Cardiol. 1999; 33: 327-332Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar 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 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.20Accurso V. Winnicki M. Shamsuzzaman A.S. Wenzel A. Johnson A.K. Somers V.K. Predisposition to vasovagal syncope in subjects with blood/injury phobia.Circulation. 2001; 104: 903-907Crossref PubMed Scopus (73) Google Scholar 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 other-triggered cardiovascular events might be caused by the presence of vasovagal syncope in LQTS patients, because the presence of LQTS does not exclude vasovagal events.21Toft E. Aaroe J. Jensen B.T. Christiansen M. Fog L. Thomsen P.E. Kanters J.K. Long QT syndrome patients may faint due to neurocardiogenic syncope.Europace. 2003; 5: 367-370Crossref PubMed Scopus (18) Google ScholarUnfortunately, 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.22Colman N. Bakker A. Linzer M. Reitsma J.B. Wieling W. Wilde A.A. Value of history-taking in syncope patients: in whom to suspect long QT syndrome?.Europace. 2009; 11: 937-943Crossref PubMed Scopus (60) Google Scholar 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 genotype-negative 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.DisclosuresDr. 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, Maryla
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