Incidence and outcome of arrhythmias and electrical disease in patients with Trisomy 18

Patients with Trisomy 18 have a high incidence of cardiac anomalies and are associated with early death. Because of early mortality, electrical system disease and arrhythmia has been difficult to delineate and the incidence remain unknown. We sought to describe the association and clinical outcomes of electrical system disease and cardiac tachy‐arrhythmias in patients with Trisomy 18. This was a retrospective, single institutional study. All patients with Trisomy 18 were included in the study. Patient characteristics, congenital heart disease (CHD), conduction system and clinical tachy‐arrhythmia data were collected on all patients. Outcomes including cardiac surgical interventions, electrical system interventions and death were collected until the time of study. Patients with tachy‐arrhythmias/electrical system involvement were compared to those without to identify potential associated variables. A total of 54 patients with Trisomy 18 were included in analysis. The majority of patients was female and had associated CHD. AV nodal conduction system abnormalities with either first or second degree AV block were common (15%) as was QTc prolongation (37%). Tachy‐arrhythmias were common with 22% of patients having at least one form of tachy‐arrhythmia and associated with concomitant conduction system disease (p = 0.002). Tachy‐arrhythmias were typically treatable with monitoring or medication with eventual resolution without need for procedural intervention. Although early death was common, there were no causes of death associated with tachy‐arrhythmia or conduction system disease. In conclusion, patients with Trisomy 18 have a high incidence of conduction system abnormalities and burden of clinical tachy‐arrhythmias. Although frequent, electrical system disease did not affect patient outcome or difficultly of care delivery.

Patients with Trisomy 18 have a high incidence of congenital anomalies and are associated with early death in the neonatal and newborn periods.Amongst the common anomalies, patients with Trisomy 18 have a high incidence of various forms congenital heart disease (CHD) ranging from mild to severe in complexity.In the recent past, patients with Trisomy 18 were most frequently offered palliative care secondary to expectedly poor outcomes and often lack of potential therapy (Janvier et al., 2016).Cardiac surgery was rarely offered, and when performed, was typically in patients with mild disease or palliative in nature.In the more recent era, advances in care have allowed sub-populations of patients with Trisomy 18 to have improved survival which has led to a change in philosophy around cardiac care.
CHD repair in other patient populations with complex extra-cardiac disease is now routinely offered if the associated extra-cardiac anomalies are not prohibitive to reasonable chances of survival (Carvajal et al., 2020).Some tertiary pediatric institutions are now offering surgical intervention to patients with Trisomy 18 though despite our recent improvements, this population has continued to demonstrate worse outcomes compared to similar cardiac lesions without associated Trisomy 18 (Cooper et al., 2019;Domingo et al., 2019;Kosiv et al., 2017;Ma et al., 2019).
With the evolution of improved extra-cardiac care, increasing frequency of cardiac surgical intervention and longer life span, the associated frequency and outcomes of conduction system disease and cardiac arrhythmias in this population becomes increasingly important though no data exists on the overall incidence, treatment strategies or management outcomes in this complex population.In this study, we seek to determine the incidence of conduction system disease and cardiac arrhythmia in patients with Trisomy 18 at a large quaternary children's hospital.In addition, we describe arrhythmic therapies including medical antiarrhythmic therapy, electrical cardioversion and other arrhythmic interventions.

| METHODS
This is a single intuitional, retrospective study of patients with Trisomy 18 with a primary focus on conduction system involvement and tachy-arrhythmic disease.The study was conducted with permission from the institutional review board (IRB# 2022-0436).Patients were identified from electronic medical records from January 2010 until January of 2022.Patient demographic and cardiac data were obtain from electronic records including patient sex, pulmonary hypertension status, need for cardiac catheterization and congenital heart disease status.Electrophysiology specific data was obtained including data on ECG, ambulatory monitoring and inpatient telemetry when available.

| Electrophysiologic data
ECG variables were obtained including P-R interval, QRS duration and QTc intervals.Conduction system involvement including first and second degree heart block and repolarization abnormalities were noted.The corrected QT interval (QTc) was collected and QTc prolongation was dichotomized with a QTc > 440 ms as abnormal.Bazett's formula was used for all QTc calculations (QTc = QT/√RR).ECG and hospital records were used to collect arrhythmia data and tachyarrhythmias were categorized as atrial arrhythmia (premature atrial contractions (PAC), atrial flutter or atrial ectopy), junctional tachycardia, ventricular arrhythmias and supra-ventricular tachycardia (SVT).
Ventricular arrhythmias were classified as premature ventricular contractions (PVCs), nonsustained ventricular tachycardia (4 consecutive ventricular beats to <30 s) and sustained ventricular tachycardia (VT) (≥30 s of consecutive ventricular tachycardia).Data on antiarrhythmic use was collected including medication type and duration of usage.

| Outcome data
Clinical outcomes were collected including cardiac surgical repair, electrical cardioversion, development of cardiac dysfunction and death.Patient age at the time of study was defined as the time from birth to the last clinic/hospital follow up or death.Cause of death was evaluated and as associated with cardiac tachy-arrhythmia/ conduction system disease or not.Duration of clinical tachyarrhythmia and duration of anti-arrhythmia treatments were collected.
Duration of clinical tachy-arrhythmia was defined as the time from first notation of arrhythmia until last arrhythmia.In patients with antiarrhythmic use, duration of clinical arrhythmia was included until the time of medication cessation.

| Statistical design
The results of the study are primarily descriptive in nature.Descriptive statistical analysis was performed using median (range) for continuous variables including all time variables and QTc duration.Percentage was used to denote nominal variables.Patients with and without tachy-arrhythmia or conduction system disease were compared to determine values associated with arrhythmia.Categorical values were compared using Fisher's exact and continuous variables were compared using t-testing.

| RESULTS
A total of 54 patients with Trisomy 18 were included in this analysis.
There was a female predominance (67%) and the majority of patients had associated CHD (93%) (Table 1).CHD lesions are as follows: Polyvavlular disease with or without additional ventricular septal defect in 20 patients, ventricular septal defect with or without valvar disease in 37, aortic arch anomalies in 5, tetralogy of Fallot in 3, double outlet right ventricle in 2, atrio-ventricular canal defect in 1 patient, single ventricle anatomy in 1 and d-transposition of the great arteries (d-TGA) in 1.The median age at the time of the study was 16 (0-304) months.The need for cardiac surgical repair was common and 28% of patients had cardiac surgical palliation.Surgical repair consisted of ventricular septal defect repair in 11 patients (4 with ligation of pulmonary ductus arteriosus, 3 with repair of atrial septal defect, 1 with tricuspid valve annuloplasty, 1 with RVOT muscle bundle resection), tetralogy of Fallot repair in 2, double outlet right ventricle repair in 1 and isolated pulmonary ductus arteriosus ligation in 1.In total 9 patients underwent cardiac catheterization, 2 with intervention (1 aortic stenting, 1 pulmonary ductus arteriosus occlusion).Tachyarrhythmias were seen frequently and any tachy-arrhythmia was noted in 22% of patients within this cohort.Ventricular arrhythmias were most common accounting for 50% of arrhythmias and seen in 11% of the total cohort (Figure 1).Within the ventricular arrhythmia category, PVCs were most common (5%) followed by sustained VT (4%).NSVT was seen in two patients.One patient had isolated events of non-sustained VT and one of the patients with PVCs also had episodes of NSVT.

| Conduction system
Of the cohort, 89% (48/54) had one or more electrocardiograms for review.In those with an ECG, the majority of patients had some ECG abnormality (92%).Conduction system abnormalities were common.
For the cohort, 15% of patients had AV nodal conduction abnormalities including 13% with first degree AV block and 2% with Mobitz

| Outcomes
For the sub-cohort of patients with tachy-arrhythmia, 75% (9/12) patients had resolution of their arrhythmia and three patients had ongoing arrhythmia or were currently on anti-arrhythmic therapy at the time of the study.For the 9 patients with resolution of clinical tachy-arrhythmia, the median duration of arrhythmia was 5.2 (0.03-28) months.In patients requiring anti-arrhythmic medications, treatment was ongoing in 2 patients and discontinued without further arrhythmia in 3.In those with completed therapy, antiarrhythmic medication was used for 11-546 days.No patient had noted antiarrhythmic medication toxicity and all medical therapies were felt to adequately suppress arrhythmia during treatment.Death was common in the cohort and 37% of patients had died at the time of the study at a median age of 2.7 months (0.2-304).No patient died as a result of their conduction system disease, tachy-arrhythmia or arrhythmia treatment and no arrhythmia was felt to limit nonarrhythmia care leading to their death.

| DISCUSSION
The care of patients with complex genetic syndromes, particularly those with early lethality, is complicated and can lead to difficulties and obtaining sufficient knowledge about associated electrical disease.In patients with Trisomy 18, patient complexity and early mortality has led to a paucity of data with regards to electrical disease and arrhythmia knowledge that has become increasingly important as the care of the population advances and evolves.The data in this study demonstrated several key electrical characteristics in the Trisomy 18 population.First, there is frequent conduction system involvement in the Trisomy 18 population, typical mild AV nodal disease and QTc prolongation.Second, tachy-arrhythmias were common and often associated with conduction system disease.While electrical issues were common, during this early time point, these abnormalities were typically manageable and did not impact early patient survival.
While basic cardiac structural phenotyping has been well described in patients with Trisomy 18, cardiac disease outside of structural anomalies has been poorly defined.The combined comorbidities of CHD and extra-cardiac anomalies associated with the disease have resulted in poor early outcomes making electrical phenotyping difficult and often not relevant in clinical care.With the evolution of care in this population an understanding of electrical disease is of growing importance.Abnormalities of the conduction system in this cohort were common.AV nodal conduction disease was seen in 15% and primarily first degree AV block.Although mild AV nodal abnormality was common in this cohort, it did not play a role in patient outcome and no patient required temporary or permanent pacing.Similarly, AV nodal involvement did not appear to be associated with cardiac surgical intervention and was seen in patients with and without surgical palliation.While there are a number of genetic and CHD phenotypes in which AV nodal disease can be rapidly progressive and early intervention is prudent, this was not the case in this cohort during infancy (Groh et al., 2022;Joosten et al., 2021;Vacca et al., 2014).Whether this mild conduction system disease is Trisomy 18 patient cohort with tachyarrhythmia and arrhythmia type.Patients with conduction system disease not included.SVT, supraventricular tachycardia; VT, ventricular tachycardia.*One patient had nonsustained VT and additional premature ventricular contractions.
progressive and more important at older ages is yet to be determined and longer term assessment is needed.
Similar to AV nodal abnormalities, electrical repolarization involvement in the form of mild to moderate QTc prolongation was seen in 37% of the population.A similar phenomenon has been seen in other conditions such as Rhett's Syndrome and its link to QT prolongation (Crosson et al., 2017;Ellaway et al., 1999).While less is understood about the impact of QT involvement in these genetic syndromes than with genetic long QT syndrome, there has yet to be reports of significant arrhythmic events such as Torsade's de Pointes in these populations.Additionally, the use of beta blocker has not been studied and is not currently recommended as standard of care.
Based on this small cohort, it would be premature to make recommendations and additional long term phenotyping of older and larger populations will be needed to determine whether QTc prolongation is an additive risk in older populations.
Of potentially greater clinical significance, tachy-arrhythmias were seen frequently including 22% of the cohort.Similar to AV nodal disease, these arrhythmias were not associated directly with history of cardiac surgery and were also seen in surgery naïve patients (Ringel et al., 1984;Tateno et al., 2003).While frequent, tachycardia often required no treatment, such as with isolated atrial or ventricular ectopy, or was able to be routinely managed with anti-arrhythmic medications in patients with more sustained tachycardia.Tachy-arrhythmias are not uncommon in patients with CHD and given the high incidence of CHD in the Trisomy 18 population, the driving factor underlying the frequency is not distinguishable.
While this may represent an underlying link to the genetic abnormality itself, many patients had additional CHD lesions with ventricular or atrial level shunting.The resultant myocardial stretch and increased chamber pressure maybe an additional arrhythmic driver.
Of interest, there was a particularly high incidence of ventricular arrhythmia both with isolated ventricular ectopy as well as sustained ventricular tachycardia.Ventricular arrhythmias are typically uncommon though patients with Kearns-Sayre syndrome have been shown to have a similar high incidence of conduction system disease and ventricular tachycardia (Wiseman et al., 2022).The association of AV nodal conduction system disease seen in patients with tachyarrhythmia is of interest.Whether the association in this cohort is genetically or hemodynamically derived is unknown and needs ongoing analysis.
While the overall survival rates in this population remains poor, the outcomes in this cohort were not driven by concomitant electrical system disease or tachy-arrhythmia.In patients requiring antiarrhythmic medications, all arrhythmias were successfully controlled and neither the use of anti-arrhythmic medication or arrhythmia was associated with an outcome of death.Whether tachyarrhythmia in infancy may predict rhythm abnormalities at older age is unclear given the small population and high early mortality rate.
As the progression of care and its impact upon the survival of the Trisomy 18 population changes, questions of conduction system disease and arrhythmia in later stages of childhood will need ongoing evaluation.

| LIMITATIONS
There were several limitations stemming from the retrospective and descriptive nature of this study.Trisomy 18 remains a complex population to care for and end of life decisions are multifaceted.End of life decisions such as "do not resuscitate" directives and the level of care varies and cannot be accounted for in review.Deep phenotyping and electrical work up in some scenarios is still lagging and no patient with QTc prolongation had genetic testing.Several patients had no ECG performed and several families opted for comfort care without intervention which likely leads to an underestimation of potential clinical arrhythmia or conduction system prevalence.Cause of death cannot be determined for those families with comfort care and we cannot completely exclude arrhythmia as a cause of death in that scenario.
Furthermore, sample size was significantly limited and does not allow for robust statistical analysis.

| CONCLUSIONS
In conclusion, in this cohort of patients with Trisomy 18, there was a high incidence of both mild conduction system disease as well as frequent incidence of tachy-arrhythmia in the newborn period, particularly ventricular arrhythmias.In the period of infancy, the mild AV nodal involvement was stable and did not require intervention.Tachyarrhythmias, although common, were manageable utilizing routine care and did not have early implications or deleterious effect on survival.Patients with Trisomy 18 will likely benefit from early additional rhythm monitoring but mild electrical abnormalities do not appear to be a marker of worsened outcome.
type I second degree block.No patient had complete heart block and no patient required temporary or permanent pacing.Of the 5 patients with first degree AV block, 4 patients (80%) also had concomitant tachy-arrhythmia.Mild to moderate QTc prolongation was common and seen in 35% of the patients with 22% having a QTc between 440 and 470 ms and 9% having a QTc > 470 ms.The maximum QTc in the patients with QTc prolongation was 458 ms (442-495).No patient had documented torsades, t-wave alternans or other stigmata of long QT syndrome.No patient had a known family history of long QT syndrome though extensive family history pedigrees were not performed in all patients.3.2 | Tachy-arrhythmiaTachy-arrhythmias were common and encountered in 22% of the cohort of which 9% of patients required anti-arrhythmic medications and 4% required electrical cardioversion.Beta blockers were used in three patients: one patient with atrial flutter post electrical cardioversion, one patient in combination with digoxin for SVT and one T A B L E 1 Comparison of Trisomy 18 patients with and without arrhythmia.