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Thromboembolic episodes related to atrial arrhythmias in adults with transposition of great arteries Wan, Darryl; Tsui, Clara; Grewal, Jasmine; Kiess, Marla; Barlow, Amanda; Human, Derek; Krahn, Andrew; Chakrabarti, Santabhanu Aug 7, 2017

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RESEARCH ARTICLE Open AccessThromboembolic episodearrhythmias in adults withmBackground Atrial arrhythmias (including Intra-atrial Reentrantuality of life,death [2–4].mias involverative cardiacnd has beenh stroke andJournal ofCongenital CardiologyWan et al. Journal of Congenital Cardiology  (2017) 1:6 DOI 10.1186/s40949-017-0009-3Paul’s Hospital-University of British Columbia, Suite 211-1033 Davie St,Vancouver, BC V6E 1M7, Canadaheart failure, especially with increasing age [6–8]. Inaddition to the known thromboembolic risk associated* Correspondence: SChakrabarti@providencehealth.bc.ca1Division of Cardiology, University of British Columbia, Vancouver, Canada2Heart Rhythm Services, Department of Medicine, Division of Cardiology, St.in adults under the age of 55, it is increasingly recog-nized to occur at a younger age in adults with congenitalheart disease (ACHD).bidity and mortality associated with poor qincreased thromboembolic risk, and suddenThe majority of cases with atrial arrhythpatients who have undergone prior repasurgery [5]. AF is a growing concern ashown to have important associations witAtrial fibrillation (AF) is the most common atrialarrhythmia in the general population, estimated to occurat a prevalence of 0.95% [1]. Although AF is uncommonTachycardia: IART, Atrial Flutter: AFL, Focal AtrialTachycardia: FAT, and AF) are a common sequelae inthe ACHD population, accounting for significant mor-AbstractBackground: Atrial arrhythmias (AA) are common in adults with congenital heart disease (ACHD). AlthoughIntra-atrial Reentrant Tachycardia (IART) is well described in ACHD, Atrial Fibrillation (AF) is uncommon, butincreasingly recognized. Patients with Transposition of the Great Arteries (TGA) and congenitally corrected-TGA(CC-TGA) have a high burden of AA at a relatively young age. However, long-term data of AA and associatedthromboembolic risk are lacking in these patients. The prevalence, associated clinical factors, andcomplications of AA in a longitudinal TGA cohort was studied.Methods: A retrospective cohort study of all TGA patients from a single tertiary care centre was conducted.Data regarding documented atrial arrhythmias, thromboembolic events, and factors associated with thromboembolismwere extracted and analyzed. Mean values and standard deviations were calculated for normally distributed continuousvariables. When frequencies and means were compared, the chi-squared test and student t-test were used, respectively.Results: One-hundred twenty-five patients with TGA (76 TGA, 49 CC-TGA) were followed for a mean of 20.8 ± 13.2 years.AF was confirmed in 20% (n = 25) and there were 5 (20%) thromboembolic complications within the AF population. AFwas associated with an annual thromboembolic event rate of 2.7%/year (stroke/transient ischemic attack 1.7%, systemicembolism 1.0%).Conclusion: AF is relatively common in the TGA ACHD population in long-term follow up. Although annualrisk of thromboembolism is low in this young group of patients, life-time cumulative risk is potentially high.TGA patients should be screened actively for AF and appropriate anticoagulation therapy initiated. It is unclear ifestablished risk prediction scores in other non-valvular AF populations may be applicable to this cohort.Keywords: Atrial fibrillation, Congenital heart disease, Atrial arrhythmiagreat arteriesDarryl Wan1, Clara Tsui1, Jasmine Grewal1, Marla Kiess1, Aand Santabhanu Chakrabarti1,2*© The Author(s). 2017 Open Access This articInternational License (http://creativecommonsreproduction in any medium, provided you gthe Creative Commons license, and indicate if(http://creativecommons.org/publicdomain/zes related to atrialtransposition ofanda Barlow1, Derek Human1, Andrew Krahn1le is distributed under the terms of the Creative Commons Attribution 4.0.org/licenses/by/4.0/), which permits unrestricted use, distribution, andive appropriate credit to the original author(s) and the source, provide a link tochanges were made. The Creative Commons Public Domain Dedication waiverro/1.0/) applies to the data made available in this article, unless otherwise stated.with AF, ACHD patients face a host of unique issues andcomplications related to their specific cardiac lesions [2].We investigated the prevalence and risk factors associ-ated with development of AF and thromboembolic riskassociated with AF, AFL or IART in a consecutive obser-vational cohort of CC-TGA and post-atrial switch TGApatients.MethodsOur Adult Congenital Heart Disease Clinic is the desig-nated single advanced care provider for all provincialpatients with ACHD, in a single payer public health caresystem situated in Vancouver, British Columbia, Canada.This study was a single centre, retrospective observa-tional cohort of all adults ≥18 years with TGA (TGAwith atrial switch and CC-TGA) seen in the Adult Con-the chi-squared test and student t-test were used, respect-ively. For all analyses, two-tailed P-values <0.05 were con-sidered statistically significant. Thromboembolic riskprediction was modeled using the CHADS-VASc risk fac-tors, but specific scores were not calculated. InstitutionalResearch and Ethics Board approval was obtained prior toinitiation of the study.ResultsOne hundred twenty five patients with TGA (TGA withatrial switch and CC-TGA) were identified and datafrom 123 patients were used for analysis. Seventy-fivesubjects (61%) had TGA and 48 had CC-TGA (39%).The mean age of the TGA patients was 34.5 (±7.6) years,while the average age of the CC-TGA patients was 45.4Wan et al. Journal of Congenital Cardiology  (2017) 1:6 Page 2 of 6genital Heart Disease Clinic. Examination of case chartswas conducted based on data extracted from the clinicdatabase. Information recorded included basic demo-graphic information, cardiac procedures, arrhythmia onelectrocardiogram (rhythm strip or standard 12-leadECG) thromboembolic events, co-morbidities and con-current medical treatment.One hundred twenty five TGA patients were identifiedfrom the ACHD database. Two patients were excludeddue to incomplete follow up data after migration out ofprovince. The thromboembolic outcomes were definedas clinically adjudicated with imaging confirmation whenavailable. Arrhythmia diagnosis was as adjudicated bythe treating cardiologist with confirmation from ECG/Holter and electrophysiology studies (Fig. 1).Descriptive statistics for nominal data were expressedin absolute numbers and percentages. Mean values andSDs were calculated for normally distributed continuousvariables. When frequencies and means were compared,Fig. 1 Flow diagram showing selection of suitable patients for inclusion in(±18.3) yrs. Males were predominant in the study popu-lation, accounting for 70/123 (57%). The mean follow upduration was 20.8 (±13.2) years (Table 1).Atrial Fibrillation was identified in 25 patients(20.3%), in whom 20 had paroxysmal AF and 5 hadpermanent AF at last contact. The onset of AF wasfirst documented at age 37.2 ± 11.2 years, with latestfollow-up at 46.8 ± 12.5 years. The majority weremales (17/25, 68%). AF was associated with previousoccurrence of IART, ventricular tachycardia and re-quirement of implantable cardiac defibrillator(p = 0.01), but not associated with age, sex, previousheart surgeries, heart failure, NYHA functional class,or requirement of pacemaker.Five subjects had cerebrovascular accidents after theonset of AF (stroke: n = 3, TIA: n = 2). There were 1.7CVA events per 100 patient years of follow-up after on-set of AF. Systemic thromboembolism (n = 3) risk was1% per year after onset of AF.study- 1 complication 1 bilateral PE with infarctionWan et al. Journal of Congenital Cardiology  (2017) 1:6 Page 3 of 6Table 1 Demographic information for patients included in studyTGA CC-TGATotal number 75 48Average age 34.5 (±7.6) 45.4 (±18.3)Male 40 (53%) 30 (62%)SurgeriesMustard procedure 64 (85) 0Senning procedure 11 (15) 0DevicesPacemaker 20 (26%) 20 (41%)ICD 5 (6%) 5 (10%)Biventricular pacing 1 (1.3%) 0Mechanical valve 0 5 (10%)MedicationsLasix 3 (4%) 11 (23%)Beta blocker 22 (29%) 17 (35%)ACE inhibitor 20 (27%) 25 (52%)Digoxin 1 (1.3%) 7 (15%)Warfarin 7 (9.3%) 13 (27%)Stroke and transient ischemic attack (TIA)Thirteen patients with AF had stroke/TIA. However,six occurred during childhood. These were associatedwith surgery (n = 3), deemed idiopathic (n = 2) ordue to possible intrauterine insult (n = 1). Hence,these were excluded from further analysis. In six ofthe remaining seven patients (7/123, 5.6%), TIA/stroke was confirmed on brain CT or MRI. Theremaining patient had clinical TIA without radio-logical confirmation. The average age of presentationwas 38.1 (range 25–50 years). The details of atrial ar-rhythmias and thromboembolic findings are describedin Table 2.There was a significant preponderance of male sexin the thromboembolic event group (6/7, p < 0.05)and presence of AF (5/7, p = 0.038). Most subjects(4/5, 80%) had paroxysmal AF, while only one subjecthad persistent AF. No patient with IART had stroke.TGA patients with heart failure requiring diuretictherapy were also more likely to have stroke/TIA thanthose who were not (p = 0.03). Incidence of diabetes,hypertension and peripheral vascular disease were notsignificantly different in the stroke/TIA populationversus the rest of the study population.ASA 9 (12%) 11 (23%)Systemic RV systolic functionMild dysfunction 41 (55%) 26 (54%)Moderate dysfunction 24 (32%) 9 (19%)Severe dysfunction 5 (7%) 8 (17%)post-op MustardOther: 1 renal infarctHeart failure: 1Heart failure: 1Atrial fibrillationpersistent2 patientsTIA: 0Stroke: 03 patientsTIA: 1Stroke 1- Stroke and TIA in the samepatientHeart failure: 1Atrial flutterparoxysmal15 (20%)TIA: 0Stroke: 2- 1 peri-operativeMustardOther: 1 femoral arteryclaudication4 (8%)TIA: 0Stroke: 0Other: 1 thrombosedprosthetic AV and left poplitealthrombosis in same patientAtrial flutterpersistent1No thrombosis1No thrombosisEctopic atrialtachycardia16(21%) 6 (12.5%)Table 2 Summary of all thromboembolic events in TGA andCC-TGA cohortsTGA CC-TGAAtrial fibrillationparoxysmal10 patients (13%)TIA: 0Stroke: 6- 1 peri-operativeMustard10 patients (21%)TIA: 2Stroke: 1- 1 during VSD repairOther:Systemic thromboembolismIn this group, apart from the cerebral thromboembolicepisodes, three other subjects had systemic emboliccomplications (3/123, 2.4%), two had AF, and the otherhad IART.One male patient with TGA and AF (documented bypacemaker electrogram) had a renal infarction at age24 years but no CVA. Another 26-year-old with paroxys-mal AFL developed popliteal artery thrombosis on abackground of a history of mechanical aortic valvethrombus. The third patient was a 59-year-old male withCC-TGA and paroxysmal AF who had acute coronarysyndrome from a presumed coronary embolism but nor-mal coronary angiogram; he had multiple strokes 2 yearslater. Only one patient with thromboembolism had abaffle leak.Relationship between AF and IART/FATFourteen subjects with AF (14/20, 70%) had previousIART that was documented by ECG or Holter. This issignificantly higher than the ones who did not have AF(23/103, 22.3%, p < 0.01).Thirty seven patients (37/123, 30%) of the group haddocumented IART while 13% (n = 22) patients had FAT.Six AF (24%, 6/25) patients had documented FAT beforedeveloping AF in follow up.AVRT/AVNRT 1 2Wan et al. Journal of Congenital Cardiology  (2017) 1:6 Page 4 of 6Follow upThe average follow up duration was 20.6 ± 13.2 years.There were seven deaths (5.6%) One patient underwentcardiac transplant. Three patients in the AF group died(versus 4 in the non-AF group, p = 0.14).DiscussionThis study reports the factors associated with AF and itscomplications in TGA with atrial switch and CC-TGA.Although the sample size is small, the relatively long fol-low up in a single tertiary care facility provides somemeaningful insight into the situation. In our small co-hort, AF was found in 20% of patients and was associ-ated with a 2.7% annual thromboembolic event rate.In the general population, AF is an established risk fac-tor for thromboembolic stroke [7], significant morbidityand a 40–90% overall increase in mortality during long-term follow up [6, 8, 9]. While there may be similarities inAF affecting the general and ACHD population, thesegroups are inherently different in their co-morbidities,arrhythmia substrate, and presentation. With techno-logical advances in arrhythmia detection, the true preva-lence of atrial arrhythmias may be underestimated by thisstudy. In addition to occurring at higher rates, AF alsoseems to have presented at a much younger age in our co-hort. This is consistent with other studies showing rela-tively young age at development of AF in patients withACHD [10]. Risk stratification systems such as CHADS2[11] and CHADS-VASc [12] have been validated for usein non-valvular AF in the general population, but may notapply to ACHD.It is very challenging to aggregate all ACHD into a sin-gle pathophysiological process in order to understandAF meaningfully. Therefore, we chose the TGA group asthese patients have similar physiology with regards tosusceptibility from atrial arrhythmia substrate and sig-nificant systemic ventricular dysfunction. The TGApatients who underwent atrial switch procedure are nowin their third and fourth decades of life [2]. These pa-tients are also experiencing the complications associatedwith systemic right ventricular dysfunction and areuniquely positioned as a study population in this regard.The atrial switch procedure for TGA in the 1960sdramatically improved survival in that group [13–15].However, long-term follow up care revealed growingproblems in this population including systemic ven-tricular failure, valve regurgitation, and significant latearrhythmias [16–18]. In 2000, Oechslin et al. [16] de-scribed late atrial flutter or atrial fibrillation as a re-sult of systemic ventricular dilatation and dysfunction,contributing as risk factors for death. Furthermore,Gatzoulis et al. [17] reported that sustained atrial flut-ter/fibrillation was found in 19.6% of their 51 adultTGA patients post-Mustard procedure.In TGA, extensive atrial scar substrate may potentiallylead to IART/FAT but it is unclear how this may progressto AF. Atrial dilatation may be a factor in CC-TGA butthere is sparse evidence to validate this as a clinical risk.Furthermore, this is unlikely in TGA post-atrial switchprocedure due to relatively poor distensibility of the baffleanatomy. AF was diagnosed in 20% of these patients.There were significant overlaps, but in the clinical context,it may be very challenging to differentiate between IARTand FAT without intracardiac electrophysiological ma-noeuvres, especially with suboptimal P-waves on surfaceelectrograms. The prevalence of AF in our study popula-tion is similar to previous experience with TGA but higherthan the 11 to 15% prevalence of atrial arrhythmia in thegeneral CHD population [19–21].IART is well described in TGA but the significant riskof developing AF in the long term has not been reportedpreviously. Due the high prevalence of AF in the TGAgroup, routine care should include active screening foratrial arrhythmias in this group of patients. By beginningearly surveillance and active screening, prophylactictherapy can be initiated to reduce TE risk.The risk of developing AF is high in AFL patients andtherefore active monitoring is required.The incidence of stroke is approximately 1% in thegeneral population, increasing to up to 8% in the elderly[1]. Cerebrovascular accidents (CVA) are also respon-sible for a major contribution to morbidity in the youngCHD population, despite the absence of traditional car-diovascular risk factors. A 2010 study by Hoffmann et al.demonstrated 10 to 100 times increased risk of CVA inthe CHD population when compared to aged matchedhealthy controls in the general population [22].Our data suggests an 8% prevalence of thromboembolicevents in long term follow up, excluding pediatric/peripro-cedural events. This is currently under-recognized andlikely to worsen with further follow up. The EuroHeartstudy showed a 6% prevalence of CVA but it is unclear ifperi-procedural or previous events had been excluded [21].Our data also demonstrates that males had significantlymore thromboembolic episodes in the non-valvular AFpopulation. The incidence of diabetes, hypertension andperipheral vascular disease is quite small in this youngpopulation. There was no association with diabetes, hyper-tension or peripheral vascular disease in our study, but inview of very limited numbers, the significance of this isuncertain. Heart failure predisposed to thromboembolicepisodes risk in our group of patients. The medianCHADS2 score in this population was 0, and hence notpredictive of thromboembolic risk.With continued follow up, this group of patients withTGA in adulthood will continue to experience worsen-ing of late complications and place a growing burden onexisting limited healthcare resources [19]. Even thoughthose variables have not been included in data analysis.Wan et al. Journal of Congenital Cardiology  (2017) 1:6 Page 5 of 6Moreover, the event rates for AF and thromboemboliccomplications are low, which precludes prediction ofany solid risk scoring system. This emphasizes the cru-cial need for prospective data collection from multiplecentres in the future to address these questions moreeffectively.Finally, our findings may not be generalized to theACHD cohort as a whole because comorbidities such asintracardiac shunt, erythrocytosis, cyanosis or mechan-stroke/TIAs are relatively rare, they often leave se-quelae which may add significantly to the diseaseburden in the ACHD population. The risk ofthromboembolic episodes in our study may seemlow. However, in this population with a relativelyyoung mean age of 38 years at last follow-up, thisfigure is significantly higher than in an otherwisehealthy general population.LimitationsThis study has several limitations, mostly from thoseassociated with any retrospective analysis spanningover decades. The end points are clinical and mayhave been underestimated. For example, TIA or otherembolic events cannot be excluded, as minor episodesmay be overlooked by the patients, not be recordedby caregivers, or captured in a different hospital. However,our centre is the only tertiary centre in our province andhas dependable follow up including regular telephoneinterviews with the Clinic Nursing team. Outcome defini-tions may have varied between the clinicians but this isunlikely, considering this is a single centre.We acknowledge that the post-atrial switch procedureTGA and CC-TGA clinical profiles are different but theywere included together because of the systemic RVwhich has high risk of systolic dysfunction and is aknown risk factor for stroke in the non valvular AFpopulation. We have therefore presented the data separ-ately in these 2 groups.In view of the small number of end points, meaningfulprediction scores or trends using logistic regression werenot possible and points towards the need for multicentrecollaborative research in the future to have further insightinto this problem. Alternatively, a central database forACHD patients would be a useful adjunct to provide ad-equate numbers for meaningful statistical analysis and riskprediction.Clinical parameters such as systemic ventricular ejec-tion fraction, atrioventricular valvular regurgitation, andmedications are dynamic and very likely to change overlong term follow up in complex ACHD patients, henceical valves independently affect stroke and thrombo-embolic risk.ConclusionAF is common in the TGA (TGA post atrial switch andCC-TGA) ACHD population in long term follow up. AFstarts at a relatively young age and is often preceded byother atrial arrhythmias (IART/FAT). AF is associatedwith a risk of thromboembolic stroke (annual risk 1.7%)and systemic thromboembolism (annual risk 1%) total-ling an overall 2.7% risk annually after onset of AF. Malesex and heart failure requiring diuretic use were associ-ated with increased incidence of stroke/TIA.TGA patients with non-AF atrial arrhythmias shouldbe screened actively for AF and treated accordingly.Further multicentre, prospective studies are required forCVA and TE risk stratification in ACHD patients.AbbreviationsACHD: Adults with congenital heart disease; AF: Atrial fibrillation; AFL: Atrialflutter; CC-TGA: Congenitally corrected transposition of the great arteries;CVA: Cerebrovascular accident; FAT: Focal atrial tachycardia; IART: Intra-atrialre-entrant tachycardia; RV: Right ventricle; TE: Thromboembolism;TGA: Transposition of the great arteries; TIA: Transient ischemic attackAcknowledgementsNot applicableFundingNo funding was provided.Availability of data and materialsNot applicableAuthors’ contributionsAll authors contributed equally to the creation of this manuscript. DW: Datacollection, drafting article. CT: Critical revision of article. JG: Critical revision ofarticle. MK: Critical revision of article. AB: Critical revision of article. DH: Criticalrevision of article. AK: Critical revision of article. SC: Concept/design, dataanalysis/interpretation, approval of article. All authors read and approved thefinal manuscript.Ethics approval and consent to participateRetrospective patient chart data was used for this study. Institutional Researchand Ethics Board approval was obtained prior to initiation of the study.Consent for publicationNot applicableCompeting interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Received: 22 June 2016 Accepted: 21 July 2017References1. Go AS, Hylek EM, Phillips KA, Henault LE, Selby JV, Singer DE. 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