Abstract
Background
The lifetime morbidity burden of patients with Ebstein anomaly (EA) has not been well described.
Methods and Results
Through an extensive 2‐country register‐based collaboration, patients diagnosed with EA who were born between 1930 and 2017 were identified in Danish and Swedish nationwide medical registries. Each patient was matched by age and sex with 10 control subjects from the general population. Cox proportional‐hazards regression, Fine–Gray competing risk regression, and Kaplan–Meier failure function were used to estimate the morbidity burden. The study included 794 patients diagnosed with EA and 7940 controls, with a median follow‐up period of 33 years. Among patients with EA, approximately half (n=442) had isolated EA, and 28% (n=218) had concomitant atrial septal defect. Patients with complex anatomy demonstrated the highest cardiovascular morbidity burden, followed by those with concomitant atrial septal defect and isolated EA. The lifetime cumulative incidence of supraventricular arrhythmia and ventricular preexcitation in patients with EA, with or without atrial septal defect, was approximately 70% and 19%, respectively. Supraventricular arrhythmia substantially increased the risk of ischemic stroke (hazard ratio [HR] 22.6 [95% CI, 11.1–45.9]). Presence of atrial septal defect significantly affected arrhythmia and heart failure burden compared with isolated EA. In the total cohort of patients with EA, supraventricular arrhythmia onset led to an immediate high incidence of heart failure, with a 10‐year cumulative incidence of 18%.
Conclusions
The natural history of EA, whether isolated or not, involves a substantial burden of cardiovascular morbidity and thus a highly vulnerable long‐term prognosis.
Keywords: congenital heart disease, Ebstein anomaly, long‐term outcome, morbidity, nationwide
Subject Categories: Congenital Heart Disease, Arrhythmias, Heart Failure, Ischemic Stroke, Epidemiology
Nonstandard Abbreviations and Acronyms
- DNPR
Danish National Patient Register
- EA
Ebstein anomaly
- SNPR
Swedish National Patient Register
The adult population of patients with congenital heart disease has now surpassed that of the pediatric population, reflecting improvements in diagnostics and tailored treatment. 1 , 2 This demographic shift has prompted increased efforts to improve quality of life and ameliorate morbidity. Ebstein anomaly (EA) is a rare congenital heart disease 3 that is defined by malformation and apical displacement of the tricuspid valve, resulting in an incompetent tricuspid valve with a dysfunctional right ventricle. As for patients with congenital heart disease in general, 4 , 5 , 6 , 7 the survival of patients with EA has improved in the modern era, 8 , 9 and increasing attention is being paid to the prevention, identification, and treatment of morbidity. The onset and cumulative burden of morbidity, primarily heart failure and arrhythmia, depends on the lesion severity and presence of concomitant congenital cardiac malformations. 10 However, the natural history regarding morbidity risk in patients with EA is unknown, mainly owing to low birth prevalence, limited or loss to follow‐up, and potential referral bias. By combining data from nationwide medical registries in Denmark and Sweden, we aimed to elucidate the lifetime burden of morbidity across the whole spectrum of morphological phenotypes in both operated and unoperated patients with EA who were born in the period from 1930 to 2017.
Clinical Perspective.
What Is New?
The lifetime burden of cardiovascular morbidity, particularly arrhythmia and heart failure, in patients with Ebstein anomaly (EA) is high, and it is correlated with the presence of concomitant congenital cardiac malformations.
Patients with isolated EA were mostly spared from arrhythmia and heart failure before their fourth decade of life, contrary to patients with nonisolated EA who were prone to these morbidities continuously throughout life, with onset at birth.
Coexistence of atrial septal defect seemed not to be as beneficial as previously thought, with an increased risk of arrhythmia and heart failure compared with isolated EA.
What Are the Clinical Implications?
Regular follow‐up of patients with EA at specialized centers throughout life is necessary to prevent, detect, and treat early signs of major cardiovascular morbidity and avoid clinical deterioration.
Development of supraventricular arrhythmia in patients with EA entails a substantial risk of ischemic stroke, so anticoagulation therapy, either alone or in combination with antiarrhythmic intervention to prevent progression to heart failure, should be considered early.
The mechanism by which cardiovascular morbidity, particularly arrhythmia and heart failure, develops in patients with isolated EA and patients with EA with concomitant ASD requires further research.
METHODS
Data Availability Statement
The data were merged, stored, and analyzed using the servers from Statistics Denmark. In accordance with the directive from the central authority on Statistics Denmark, the data underlying this article cannot be shared publicly.
Study Population and Design
All hospital data in Denmark and Sweden are collected in nationwide medical registries and linked to personal identification numbers that are unique to citizens. This has been the case since 1968 in Denmark and since 1947 in Sweden. Data from the DNPR (Danish National Patient Registry11, 12 and the SNPR (Swedish National Patient Registry)13 were collected separately to identify patients diagnosed with EA who were born in the period from 1930 to 2017. The DNPR and SNPR consist of inpatient and outpatient contacts. The former has been mandatory since 1978 in Denmark and 1987 in Sweden, and the latter has been mandatory since 1995 in Denmark and 2001 in Sweden. Health care in Denmark and Sweden is funded by the government; thus, it is free of charge for all citizens and is equally accessible irrespective of disease and health care category. All retrieved diagnoses were coded according to the International Classification of Diseases (ICD) system. The structure and content of the DNPR and SNPR have been described in detail previously. 8 The Danish Civil Registration System 14 and the Total Population Register 15 in Sweden were used to identify 10 randomly selected subjects from the general population without congenital heart disease matched by birth year, sex, and country of residence at the time of diagnosis of the matched case. Data from Denmark and Sweden were merged before all statistical analyses.
Morbidity and Mortality
Data on arrhythmias, arterial hypertension, ischemic stroke, chronic pulmonary disease, diabetes, infective endocarditis, heart failure, ischemic heart disease, pulmonary hypertension, and renal disease were collected. The complete list of the codes used to identify morbidity in the DNPR and SNPR is embedded in Table S1. The date of death was retrieved from the Danish Register of Cause of Death 16 and the Swedish National Cause of Death Register 17 with data available for research since 1970 and 1952, respectively.
Definition and Validation
The codes 746.54 (ICD, Eighth Revision [ICD‐8]), 746C (ICD, Ninth Revision [ICD‐9]), and Q22.5 (ICD, Tenth Revision [ICD‐10]) were used to identify patients with EA in the DNPR and SNPR. Patients who were diagnosed with EA postmortem by autopsy were not included. In Denmark, ICD‐9 was never in use. ICD‐8 was used until 1994, after which time ICD‐10 was adopted. Patients with a diagnosis of right‐sided valvular pathology from ICD‐8 in Denmark were manually validated by one of the main investigators to ensure inclusion of patients with a confirmed EA diagnosis only. All patients diagnosed with EA using ICD‐10 in Denmark were included. In Sweden, all aforementioned editions of the ICD have been used. Patients with EA diagnosed using ICD‐8 in Sweden were included only if a specific code for EA, either in ICD‐9 or ICD‐10, was given subsequently at any given time. All patients diagnosed with EA using ICD‐9 or ICD‐10 in Sweden were included. Patients with truncus arteriosus and univentricular heart were excluded (n=29).
Operative management was defined as all types of cardiac surgery. EA‐related operative management was defined as (1) tricuspid valve surgery; (2) atrial septal defect (ASD) closure; (3) antiarrhythmic surgery; (4) cavopulmonary anastomosis; (5) cardiac transplantation. Isolated EA was defined as no concomitant congenital cardiac malformation. ASD only was defined as EA with a concomitant ASD as the only concomitant congenital cardiac malformation. Complex was defined as EA with any other congenital cardiac malformation. Major cardiovascular events were defined as arrhythmia, ischemic stroke, heart failure, acute myocardial infarction, EA‐related surgery, and death. The codes used to identify surgical interventions and concomitant congenital cardiac malformations in the DNPR and SNPR are presented in Tables S2 and S3, respectively.
Ethical Approval
The Danish Patient Safety Authority and The National Data Protection Agency (no. 3–3013‐2652/1) approved the collaboration and merging of data. Approval was obtained from the Regional Healthcare Authority and Data Protection Agency (The Capital Region of Denmark, no. P‐2020‐10; The Central Region of Denmark, no. 1–16–02‐678‐18). Furthermore, approval was obtained from the Swedish Ethical Review Authority (no. 2020–05874), the National Board of Health and Welfare (DNR: 8773/2017), and Statistics Sweden (no. 244587/8927402). The data were merged and stored anonymously at Statistics Denmark, informed consent was therefore irrelevant to obtain. The article adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.
Statistical Analysis
Follow‐up started at birth and continued until death or the end of follow‐up (December 31, 2017), whichever came first. The date of the first event was obtained for each morbidity and used in the statistical models.
Categorical data are described as numbers with percentages. Continuous data are described as medians with interquartile ranges. Incidence rates are reported as the number of events per 10 000 person‐years and were computed as the number of events divided by the total follow‐up time of the population. The risk of morbidity is reported as the hazard ratio (HR) computed using the Cox proportional‐hazards regression model. Individuals became at risk at the date of birth, the underlying timescale was age in years, and estimates were compared with corresponding matched controls from the general population. Risk estimates were stratified by the presence of concomitant congenital cardiac malformations. Cumulative incidences were computed using Fine–Gray's competing risk regression analysis, 18 with risk starting at the date of birth, using age as the underlying timescale and death as the competing risk. The Kaplan–Meier failure function was used to calculate the cumulative incidence of major cardiovascular events, including death, with risk starting at birth. In the subanalysis investigating the incidence of heart failure and stroke after supraventricular arrhythmia onset, risk started at the date of the first supraventricular arrhythmia diagnosis, using time since supraventricular arrhythmia onset as the underlying timescale and death as the competing risk. Patients were excluded if they had developed the end point before the exposure. The assumption of proportionality was verified graphically by log‐minus‐log plots for the Cox proportional‐hazards regression model and Fine–Gray's competing risk regression analysis.
Analyses and data management were performed using Stata (version 18, StataCorp. LP, College Station, TX, USA).
RESULTS
Baseline Characteristics
We identified 794 patients diagnosed with EA and 7940 controls. The demographics of the cohort are outlined in Table 1. Approximately half of the patients with EA (n=442 [56%]) had isolated EA, and almost one third had concomitant ASD. Operative intervention was performed in 43% of the patients with EA (n=340) during follow‐up, predominantly EA‐related (80%) and other congenital cardiac (15%) interventions. Nonetheless, 88% of the patients had a native tricuspid valve at the end of follow‐up. The patients underwent a median of 2 EA‐related interventions (total range: 1–8) during follow‐up.
Table 1.
Demographics of Patients With EA and Matched Controls From the General Population
| Patients (n=794) | Controls (n=7940) | |
|---|---|---|
| Female sex, n (%) | 418 (52.6) | 4180 (52.6) |
| Follow‐up, y (IQR) | 32.7 (16.5–56.2) | 33.5 (19.9–56.7) |
| Age at diagnosis, y (IQR) | 18.0 (0.5–40.6) | |
| Concomitant cardiac malformations, n (%) | ||
| ASD | 218 (27.5) | |
| Pulmonary stenosis or pulmonary atresia | 105 (13.2) | |
| Ventricular septal defect | 87 (11.0) | |
| Transposition of the great arteries* | 39 (4.9) | |
| Coarctation of the aorta | 26 (3.3) | |
| Aortic stenosis | 22 (2.8) | |
| Tetralogy of Fallot | 22 (2.8) | |
| Atrioventricular septal defect | 17 (2.1) | |
| Mitral valve disease | 14 (1.8) | |
| Arrhythmia, n (%) | ||
| Supraventricular | 223 (28.1) | 212 (2.7) |
| Ventricular | 36 (4.5) | 19 (0.2) |
| Ventricular preexcitation† | 88 (11.1) | 4 (<0.1) |
| Operative intervention, n (%)‡ | 340 (42.8) | |
| Age at first intervention, y (IQR) | 18.1 (2.5–43.4) | |
| Type of intervention, n (%) | ||
| Tricuspid valve surgery | 73 (9.2) | |
| ASD closure | 122 (15.4) | |
| Antiarrhythmic | 144 (18.1) | |
| Cavopulmonary anastomosis | 23 (2.9) | |
| Heart transplant | 8 (1.0) | |
| Other congenital cardiac surgery | 148 (18.6) | |
Data are presented as absolute numbers with percentages or as medians with IQRs (P25–P75). ASD indicates atrial septal defect; EA, Ebstein anomaly; IQR, interquartile range; and TGA, transposition of the great arteries.
Includes both left and right isomerism and congenital corrected TGA.
Only available in the Ninth and Tenth Revisions of the International Classification of Diseases (ICD) coding system.
Patients represent 1 or several categories of operative intervention.
Morbidity
Overall, patients with EA displayed a high cardiovascular and noncardiovascular morbidity burden, independent of the presence of concomitant congenital cardiac malformations. The cumulative incidences of arrhythmia, heart failure, ischemic heart disease, and ischemic stroke in patients with EA and matched controls are graphically illustrated in Figure 1. In general, the burden of cardiovascular morbidity, particularly heart failure and arrhythmia, was highest in patients with a complex anatomy, but it was still significant in those with isolated EA.
Figure 1. Cardiovascular morbidity.
Cumulative incidence of arrhythmia (A), heart failure (B), ischemic heart disease (C), and ischemic stroke (D), in patients with EA and matched controls from the general population with death as the competing risk. Estimates were stratified by predefined groups with respect to concomitant congenital cardiac malformations. ASD indicates atrial septal defect; and EA, Ebstein anomaly.
The HR for arrhythmia was high, both in the total cohort of patients with EA and when stratified by concomitant congenital cardiac malformations when compared with matched controls (Tables 2, 3, respectively). The presence of ASD had a significant influence on the burden of arrhythmia and resulted in an earlier onset and higher cumulative incidence compared with patients with isolated EA (Figure 1). Dissecting the types of arrhythmias and restricting the analysis to patients with EA with or without concomitant ASD, supraventricular arrhythmia was the most common, increasing gradually from birth and reaching a cumulative incidence of ≈30% at the age of 60 years (Figure 2). Ventricular arrhythmia was less common, reaching a cumulative incidence of ≈6% at the age of 60 years. The onset of ventricular arrhythmia shifted toward an older age compared with the onset age of supraventricular arrhythmia, increasing around the third decade of life. The cumulative incidence of ventricular preexcitation at the age of 60 years was ≈17%. In the total population of patients with EA, the lifetime cumulative incidence of ventricular preexcitation was 19%. The specific HRs for supraventricular arrhythmia, ventricular arrhythmia, and ventricular preexcitation in patients with EA with or without concomitant ASD are presented in Table 4. After adjusting for heart failure, the HRs for supraventricular arrhythmia and ventricular arrhythmia were reduced (HR, 10.0 [95% CI, 7.9–12.6] and HR, 9.2 [95% CI, 4.7–18.0], respectively).
Table 2.
Overall Morbidity Estimates in Patients With EA and Matched Controls From the General Population
| Number of events (% of total number of patients) | Incidence rate per 10 000 person‐years | HR (95% CI) | |||
|---|---|---|---|---|---|
| Patients | Controls | Patients | Controls | ||
| Arrhythmia | 285 (35.9) | 239 (3.0) | 116.2 | 7.9 | 19.7 (16.5–23.5) |
| Arterial hypertension | 97 (12.2) | 536 (6.8) | 35.0 | 17.9 | 2.3 (1.8–2.8) |
| Chronic pulmonary disease | 22 (2.8) | 147 (1.9) | 7.7 | 4.9 | 1.7 (1.1–2.7) |
| Diabetes | 26 (3.3) | 243 (3.1) | 9.1 | 8.1 | 1.2 (0.8–1.7) |
| Heart failure | 119 (15.0) | 123 (1.5) | 42.9 | 4.1 | 12.0 (9.3–15.5) |
| Infective endocarditis | 20 (2.5) | 8 (0.1) | 7.0 | 0.3 | 26.8 (11.8–60.8) |
| Ischemic heart disease | 74 (9.3) | 304 (3.8) | 26.3 | 10.1 | 2.8 (2.2–3.7) |
| Ischemic stroke | 32 (4.0) | 73 (0.9) | 11.3 | 1.9 | 5.0 (3.3–7.5) |
| Liver disease | 9 (1.1) | 44 (0.6) | 3.1 | 1.5 | 2.2 (1.1–4.5) |
| Pulmonary hypertension | 48 (6.0) | 11 (0.1) | 17.2 | 0.4 | 48.7 (25.2–93.8) |
| Renal disease | 48 (6.0) | 156 (2.0) | 17.1 | 5.2 | 3.6 (2.6–4.9) |
Risk estimates of patients with EA were computed with matched controls from the general population as reference. CI, confidence interval; EA indicates Ebstein anomaly; and HR, hazard ratio.
Table 3.
Morbidity Estimates in Patients With EA and Matched Controls From the General Population Stratified by Concomitant Congenital Cardiac Malformations
| Number of events (% of total number of patients) | Incidence rate per 10 000 person‐years | HR (95% CI) | |||
|---|---|---|---|---|---|
| Patients | Controls | Patients | Controls | ||
| Isolated EA | |||||
| Arrhythmia | 146 (33.0) | 176 (4.0) | 90.9 | 9.6 | 13.1 (10.5–16.4) |
| Heart failure | 51 (11.5) | 88 (2.0) | 28.7 | 4.8 | 6.9 (4.9–9.8) |
| 2.7 (1.8–4.0)* | |||||
| Ischemic heart disease | 44 (10.0) | 233 (5.3) | 24.9 | 12.8 | 2.1 (1.5–2.9) |
| Ischemic stroke | 12 (2.7) | 53 (1.2) | 6.7 | 2.9 | 2.4 (1.3–4.6) |
| EA and atrial septal defect only | |||||
| Arrhythmia | 50 (46.3) | 28 (2.6) | 141.3 | 6.1 | 36.9 (22.4–60‐9) |
| Heart failure | 25 (23.1) | 19 (1.8) | 60.4 | 4.1 | 19.6 (10.5–36.8) |
| 5.8 (2.7–12.6)* | |||||
| Ischemic heart disease | 17 (15.7) | 37 (3.4) | 39.6 | 8.1 | 6.3 (3.5–11.4) |
| Ischemic stroke | 8 (7.4) | 9 (0.8) | 18.9 | 2.0 | 10.0 (3.8–25.8) |
| Complex | |||||
| Arrhythmia | 89 (36.5) | 35 (1.4) | 181.2 | 4.8 | 55.5 (36.5–84.5) |
| Heart failure | 43 (17.6) | 16 (0.7) | 73.8 | 2.2 | 40.7 (22.5–73.4) |
| 21.7 (10.5–44.8)* | |||||
| Ischemic heart disease | 13 (5.3) | 34 (1.4) | 21.1 | 4.7 | 4.7 (2.5–8.8) |
| Ischemic stroke | 12 (4.9) | 11 (0.5) | 19.5 | 1.5 | 16.6 (7.2–38.7) |
Risk estimates of patients with EA were computed with matched controls from the general population as reference. CI, confidence interval; EA indicates Ebstein anomaly; and HR, hazard ratio.
Adjusted for supraventricular arrhythmia.
Figure 2. Arrhythmias.
Cumulative incidence of ventricular preexcitation (A), ventricular arrhythmia (B), and supraventricular arrhythmia (C) in patients with EA with or without concomitant ASD and matched controls from the general population with death as the competing risk. ASD indicates atrial septal defect; and EA, Ebstein anomaly.
Table 4.
Specific Arrhythmia Estimates in Patients With EA, Either Isolated or With Concomitant ASD, and Matched Controls From the General Population
| Arrhythmia | Number of events (% of total number of patients) | Incidence rate per 10 000 person‐years | HR (95% CI) | ||
|---|---|---|---|---|---|
| Patients | Controls | Patients | Controls | ||
| Supraventricular | 311 (56.5) | 293 (5.3) | 15.3 | 11.9 | 14.0 (11.2–17.5) |
| Ventricular | 42 (7.6) | 35 (0.6) | 2.0 | 1.5 | 16.7 (9.0–30.8) |
| Preexcitation | 64 (11.6) | 48 (0.9) | 3.1 | 1.9 | 159.9 (58.1–440.0) |
Risk estimates of patients with EA were computed with matched controls from the general population as reference. ASD indicates atrial septal defect; CI, confidence interval; EA, Ebstein anomaly; and HR, hazard ratio.
The cumulative incidence of heart failure in patients with isolated EA, concomitant ASD, and complex anatomy at the age of 60 years was ≈6%, ≈16%, and ≈40%, respectively (Figure 1) compared with ≈2% in the general population. In patients with isolated EA, heart failure was negligible before the fourth decade of life compared with patients with concomitant ASD in whom the incidence increased during adolescence. The HRs for heart failure in the total cohort and in the subcohorts stratified by concomitant congenital cardiac malformations are presented in Tables 2 and 3, respectively.
Figure 3 illustrates the cumulative incidence of heart failure after the onset of supraventricular arrhythmia in the total cohort with EA. The incidence rate was highest immediately following arrhythmia diagnosis, yielding a 10‐year cumulative incidence of 18%.
Figure 3. Heart failure and ischemic stroke following arrhythmia onset.
Cumulative incidence of heart failure (A) and ischemic stroke (B) in the total cohort of patients with EA with death as the competing risk. EA indicates Ebstein anomaly.
Ischemic heart disease and ischemic stroke were negligible before the fourth decade of life in both patients with EA and controls (Figure 1). The cumulative incidence of ischemic heart disease at the age of 60 years was ≈9%, ≈14%, and ≈20% in patients with isolated EA, ASD only, and a complex anatomy, respectively, and higher than that of the controls (≈7%). A similar pattern was seen for ischemic stroke. The HR for patients with isolated EA was double that of their matched controls. Comparatively, patients with EA and concomitant ASD had a 10‐fold increased HR for ischemic stroke than their matched controls. Furthermore, patients with EA with supraventricular arrhythmia demonstrated an HR of 22.6 (95% CI, 11.1–45.9) for ischemic stroke compared with patients without supraventricular arrhythmia. The 20‐year cumulative incidence of ischemic stroke following arrhythmia onset was 7% (Figure 3).
The presence of ASD mediated a higher cumulative incidence of infective endocarditis throughout life compared with patients with isolated EA and matched controls, in whom the condition was rare (Figure S1). The cumulative incidence was even higher in patients with a complex anatomy, demonstrating a 60‐year cumulative incidence of almost 20% compared with 5% in patients with EA with concomitant ASD.
Major Cardiovascular Event
Major cardiovascular events were common in patients with EA (Figure 4). The 20‐ and 50‐year cumulative incidences were 12% (95% CI, 9%–16%) and 37% (95% CI, 31%–42%), respectively, in patients with isolated EA. The corresponding estimates for patients with EA and concomitant ASD only were 32% (95% CI, 24%–41%) and 73% (95% CI, 63%–82%), respectively. The 50‐year cumulative incidence of major cardiovascular events in patients with a complex anatomy was 83% (95% CI, 76%–89%). Arrhythmia, intervention, and death were the most frequent events contributing to early attrition before the age of 20 years in patients with isolated EA.
Figure 4. Major cardiovascular events.
Cumulative incidence of a major cardiovascular event in patients with EA and matched controls from the general population. Estimates are stratified by predefined groups with respect to concomitant congenital cardiac malformations. An event was defined as arrhythmia, ischemic stroke, heart failure, acute myocardial infarction, EA‐related surgery, or death. ASD indicates atrial septal defect; and EA, Ebstein anomaly.
Interventions
Cardiac interventions were common in patients with EA, irrespective of the presence of concomitant congenital cardiac malformations (Figure S2). The cumulative incidence of EA‐related interventions (tricuspid valve surgery, antiarrhythmic intervention, or ASD closure) in patients with EA with or without concomitant ASD increased gradually from birth and continuously throughout life (Figure S3). At the age of 60 years, ≈30% of the patients had undergone an EA‐related intervention. The corresponding HR for EA‐related intervention was 43.5 (95% CI, 30.3–62.4) compared with controls.
DISCUSSION
This population‐based 2‐country study of 794 unselected patients with EA born from 1930 through 2017 revealed the lifetime morbidity burden across the whole spectrum of morphologies and concomitant congenital malformations. The low birth prevalence is one of the main obstacles in extending our knowledge of EA. Consequently, there are scant published data available on the morbidity burden. Linking nationwide medical registry data from Denmark and Sweden, which have a combined population of approximately 16.2 million, this study generated several important findings. First, major cardiovascular events were common in patients with EA and correlated with the presence of concomitant congenital cardiac malformations, where patients with a complex anatomy demonstrated the highest morbidity burden and need for operative interventions, followed by patients with concomitant ASD only and patients with isolated EA, respectively. Second, the lifetime cumulative incidence of supraventricular arrhythmia and ventricular preexcitation in patients with EA with and without ASD was 70% and 19%, respectively. Third, the presence of ASD had a significant impact on the burden of arrhythmia and was associated with an earlier onset and an almost 3‐fold higher cumulative incidence at the age of 40 years compared with EA in isolation (16% versus 6%). A similar pattern was seen with regard to heart failure. Heart failure was negligible before the fourth decade of life in patients with isolated EA, reached 6% at the age of 60 years, and yielded a lifetime HR of 6.9 (95% CI, 4.9–9.8). Finally, ≈20% of the total cohort had developed heart failure 10 years after the onset of supraventricular arrhythmia.
The most frequent concomitant congenital cardiac malformation in patients with EA is ASD. 19 , 20 In our cohort, almost one third had ASD, and ASD was the only concomitant lesion in ≈14% of the patients. Pulmonary stenosis or pulmonary atresia and ventricular septal defect were the second and third most prevalent lesions, present in 13% and 10% of the patients, respectively. Notably, almost half of the cohort had an isolated lesion.
Overall, the population with EA was prone to cardiovascular events. Patients with isolated EA had an event‐free survival superior to that of patients with nonisolated EA. The high rate of events during the first year of life in both patients with isolated and patients with nonisolated EA likely represents a severe physiology and congenital heart disease‐related complications, with the need for intervention or eventual sudden cardiac death. Notably, patients with EA with ASD as the only concomitant lesion had their highest rate of events during adolescence and adulthood. Our data set did not allow the dissection of causality. However, although ASD is protective against heart failure by relieving the right ventricle from volume overload in some cases, it could hypothetically be the substrate for atrial enlargement predisposing to supraventricular arrhythmia. 21 , 22 , 23 Furthermore, ASD may allow for paradoxical embolism 24 whether the right ventricle fails or not.
The incidence of heart failure in patients with EA with concomitant ASD was trivial until the second decade of life, after which time the incidence increased significantly, along with a substantial increase in the incidence of arrhythmia during the same age span. Additionally, the hazard for heart failure seemed to mainly be driven by arrhythmia, supporting that the onset of arrhythmia can result in rapid clinical deterioration. However, it is also possible that arrhythmia is a marker of heart failure, beyond aggravating the physiology, in a vicious cycle. In patients with isolated EA, heart failure reached a lower than anticipated cumulative incidence at the age of 60 years and was negligible before the fourth decade of life. More specifically, 5% of the patients had developed heart failure at the age of 60 years. Comparatively, this figure was reached 20 and 40 years earlier in patients with concomitant ASD and in patients with a complex anatomy, respectively. Similar to the patients with concomitant ASD, arrhythmia seemed to drive the burden of heart failure.
EA is strongly associated with intrinsic and acquired arrhythmias of supraventricular and ventricular origin; however, the reported rates vary depending on the constitution of the study population and the study design. EA results in a tricuspid annulus with an incomplete fibrous ring, which allows direct muscular connection between the right atrium and right ventricle. This creates the substrate for accessory atrioventricular connections and ventricular preexcitation, which have been reported in up to 44% of patients. 25 , 26 , 27 , 28 In our unselected cohort of patients with EA, we found a lifetime cumulative incidence of ventricular preexcitation of ≈19%. Acquired supraventricular arrhythmias (eg, focal atrial tachycardia, atrial macro‐reentry, and atrial fibrillation or flutter) are also commonly associated with EA, particularly in adult patients, with the substrate being progressive atrial enlargement, presence of ASD with disturbances in Bachmann's bundle, or secondary to myocardial scar tissue after previous cardiac intervention. In a Taiwanese population‐based cohort of 410 patients with EA, 22% had developed atrial fibrillation by the age of 60 years, 29 and de Miguel et al. demonstrated a lifetime prevalence of atrial fibrillation of 28% in a cohort of 682 patients with EA. 30 Comparatively, 30% of patients with EA with or without ASD as the only concomitant lesion had developed supraventricular arrhythmia (ie, paroxysmal supraventricular tachycardia or atrial fibrillation or flutter) by the age of 60 years in our cohort. Interestingly, the 60‐year cumulative incidence of arrhythmia was 17% in patients with isolated EA and 40% in patients with concomitant ASD. Although it seems that the presence of ASD adds a significant load to the total burden of arrhythmia in the population with EA, the data should be interpreted with caution as we lack granular clinical data. Although the long‐term estimates for arrhythmia in patients with isolated EA correspond to those seen in patients with isolated ASD diagnosed in childhood 31 and isolated ventricular septal defect, whether surgically closed or not, 32 the long‐term estimates in patients with EA with concomitant ASD roughly correspond to those seen in patients with unclosed isolated ASD diagnosed later in life. 22 These thought‐provoking findings suggest that the significant burden of arrhythmia associated with EA might be driven by the presence of substrates generated by ASD (ie, the ASD itself and the consequent atrial remodeling and enlargement), whereas EA in isolation is spared. In patients with EA, supraventricular and ventricular arrhythmias are associated with sudden death, 28 and atrial fibrillation is associated with a 2‐fold increased hazard for heart failure hospitalization. 30 Additionally, our data demonstrate a 22‐fold increased hazard for ischemic stroke in the presence of supraventricular arrhythmia. These circumstances, combined with the high probability of intrinsic, manifest, or concealed arrhythmia (ie, accessory atrioventricular pathways and ventricular preexcitation) highlight the importance of meticulous follow‐up to detect and manage arrhythmias early and thus prevent heart failure and sudden cardiac death, which are the leading causes of death in patients with EA. 8 , 28 This seems to be particularly important in patients with concomitant ASD. Furthermore, the high burden of ischemic stroke in patients with supraventricular arrhythmia highlights the importance of considering early treatment with anticoagulant drugs.
The incidence of endocarditis was trivial in patients with isolated EA. Although our data set did not allow us to probe potential explanations, we hypothesize that the higher burden of endocarditis in patients with nonisolated EA might be due to turbulent blood flow through septal defects, concomitant valve pathology, or recurrent operative interventions.
Diabetes, arterial hypertension, and ischemic heart disease were more common in patients with EA than in the general population. Traditional cardiovascular risk factors certainly play a role, but one could also speculate that a yet unknown cardiovascular and metabolic phenotype shared among all congenital heart diseases exists independent of lesion severity. 32 , 33 , 34 , 35 , 36 Irrespective of the underlying cause, optimal primary and secondary prevention is paramount.
Patients with EA exhibit a spectrum of prognostic outcomes, with mortality rates showing considerable variability. Moreover, there exists a significant vulnerability to long‐term cardiovascular morbidity within this patient population. As such, effective counseling of both patients and parents regarding the unpredictable nature of the prognosis is paramount. Providing comprehensive information about the potential risks and challenges associated with EA empowers individuals to make informed decisions regarding their health care and fosters a collaborative approach between health care providers and patients in managing this complex condition.
Limitations
This study has some limitations that should be considered. The national medical registries do not include clinical data. Consequently, we were unable to dissect the impact of cardiac morphology and function on morbidity outcomes. More specifically, we were unable to stratify the degree of apical displacement of the tricuspid valve or tricuspid regurgitation, and likewise, we were unable to provide more granular information on right atrial (including atrialized right ventricle) volumes, left ventricular function, and shunt data on intracardiac communications. Moreover, these inherent shortcomings required us to classify patients into 3 groups: isolated EA, EA and ASD only, and complex. It is important to note that not all patients designated as complex necessarily exhibited a complex anatomy concerning hemodynamics and prognosis.
Data on socioeconomic status, work participation, mental health status, and medication were not available.
Some specific diagnosis codes (eg, ventricular preexcitation) were introduced in ICD‐9 (Sweden) and ICD‐10 (Denmark). Thus, subjects with disease before their introduction remained undiagnosed, and subjects who survived until its introduction were eventually diagnosed later in life. These circumstances might have resulted in underestimation and potentially a rightward shift in the cumulative incidence illustrated as an increase in incidence later in life. The same applies to outpatients diagnosed with cardiovascular morbidity before the introduction of the outpatient contacts in the DNPR and SNPR. However, we believe it is of minor importance as major cardiovascular morbidities, such as heart failure, arrhythmia, ischemic stroke, and ischemic heart disease, commonly result in hospitalization.
CONCLUSIONS
In this large, 2‐country, nationwide, registry‐based cohort study, patients with EA demonstrated a high cardiovascular morbidity burden, with the most common being heart failure and arrhythmia. Patients with a complex anatomy were prone to develop heart failure and arrhythmia continuously throughout life with onset at birth, while patients with isolated EA developed these morbidities after the fourth or fifth decade of life. Patients with isolated EA demonstrated a 13‐fold higher risk of arrhythmia, and the presence of ASD generated an almost 40‐fold higher risk compared with their corresponding matched controls. In both these groups, arrhythmias seemed to drive heart failure risk, even though the risk of heart failure was 3‐ to 6‐fold higher in the absence of arrhythmia. Furthermore, arrhythmia of supraventricular origin mediated a substantial risk of ischemic stroke, and anticoagulation therapy should be considered early in these patients. Coexistence of ASD seemed not to be as beneficial as previously thought, with an earlier onset and an increased total burden of cardiovascular events in terms of arrhythmia, heart failure, stroke, and infective endocarditis. Thus, ASD should not consequently be considered as beneficial in patients with EA, but it should spawn an increased awareness of the early signs of cardiovascular morbidity. Overall, patients with EA display a spectrum of prognostic outcomes, including considerable variability in mortality rates, alongside a significant vulnerability to long‐term cardiovascular morbidity. Therefore, it is crucial to provide comprehensive counseling to both patients and parents, emphasizing the unpredictable nature of the prognosis.
Sources of Funding
This work was supported by the Novo Nordic Foundation in Denmark [grant number NNFSA170030576], the Swedish State under an agreement between the Swedish Government and County Councils (the ALF‐agreement) [grant numbers 236 611 and 917 361], the Swedish Heart and Lung Foundation [grant number 20180644], and the Children's Heart Foundation [grant number 3/23 FO].
Disclosures
None.
Supporting information
Tables S1–S3
Figures S1–S3
Acknowledgments
This work was performed at the Adult Congenital Heart Unit, Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Cardiothoracic Surgery, Rigshospitalet, Copenhagen, Denmark. The authors thank Emily Woodhouse, PhD, from Edanz (www.edanz.com/ac) for editing a draft of this article.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.124.037127
This article was sent to John L. Jefferies, MD, MPH, Guest Editor, for review by expert referees, editorial decision, and final disposition.
For Sources of Funding and Disclosures, see page 10.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Tables S1–S3
Figures S1–S3
Data Availability Statement
The data were merged, stored, and analyzed using the servers from Statistics Denmark. In accordance with the directive from the central authority on Statistics Denmark, the data underlying this article cannot be shared publicly.