Introduction
Secundum-type atrial septal defect (ASD) is one of the most common congenital heart defects. It is considered a simple cardiac defect, but patients with ASDs have increased mortality [
1] and long-term morbidity compared to the background population [
2,
3]. Complications occur in patients with an ASD even after spontaneous, percutaneous, or surgical closure [
2,
4] and regardless of the size of the ASD [
5]. The diagnosis of ASD is often made in late childhood or even adulthood. At the time of diagnosis, there are often several concomitant clinical symptoms and findings such as dyspnea on exertion, palpitations, and recurrent pulmonary infections [
6,
7].
Arrhythmia is one of the most frequent complications in patients with ASDs and contributes significantly to increased morbidity and mortality. The arrhythmias are mainly of supraventricular origin, particularly atrial fibrillation or flutter is common [
4,
8,
9]. The incidence of arrhythmias in patients with ASDs increases with increasing age and it is reported that the incidence of atrial fibrillation or flutter is 30% in patients with an ASD who are aged 40–60 years [
10] and 52% in patients aged ≥ 60 years [
11]. Furthermore, patients with ASDs often have abnormalities in the electrocardiogram (ECG). Typical ECG findings in patients with ASDs include alterations in
P-wave morphology, prolonged PR interval, right-axis deviation, and incomplete right bundle branch block (iRBBB) [
12,
13]. ECG abnormalities are found in children with ASD as well [
14,
15]. Altered
P-wave morphology is thought to be related to morphological changes of the atria, especially right atrial enlargement, while iRBBB and right-axis deviation are thought to be a consequence of the right ventricular pressure and volume overload. Thus, the ECG abnormalities are considered secondary to the ASD with a left-to-right shunt that over time will cause a pressure- and volume-overload on the right side of the heart. However, the fact that arrhythmias are seen even in patients with small ASDs and even after closure of the defect raises questions about the etiology and pathophysiology.
We aimed to investigate whether the cardiac electrical system in patients with ASDs is different as early as in the neonatal period. We investigated a large population-based cohort of neonates who had all undergone transthoracic echocardiography and were systematically assessed for ASDs. We described the electrocardiographic characteristics in neonates with ASDs and compared them with matched controls from the same birth cohort.
Discussion
We investigated a large population-based cohort of neonates who have all undergone echocardiography and electrocardiography during the first month after birth and where echocardiograms have been systematically assessed for ASDs using a validated algorithm. Our results show that neonates with ASDs had a longer P-wave duration and a longer PR interval than controls. These differences were already seen during the first week of life. Also, neonates with ASD had a QRS axis that was more rightward shifted than in controls, but this was not present until the second to fourth week after birth.
P-wave variables in patients with atrial septal defects differ from healthy controls, with longer
P-wave duration being a common finding [
23‐
25]. However, most studies include only adult patients or patients who have undergone either surgical or percutaneous closure of the ASD. In 47 pediatric patients with ASDs (mean age, 5.3 years; range, 1 month–17 years), right ventricular conduction delay was seen in 78% and right-axis deviation in 58% of the children. The
P-wave reflects atrial conduction; and prolongation of the
P-wave has been shown to be associated with arrhythmias, especially atrial fibrillation [
26‐
28]. The pathophysiology behind the alterations in atrial conduction seen in ASD patients has been subject to debate. Altered atrial conduction due to atrial dilatation caused by left-to-right shunting has been the predominant hypothesis but emerging evidence points toward abnormal electrical conduction as an independent primary disease mechanism in ASD patients. Thilén et al. found prolonged
P-wave duration in adult patients with ASD compared to controls without differences in right or left atrial size, suggesting a conduction delay in ASD patients irrespective of atrial morphological changes [
29]. O’Neill et al. found a greater burden of atrial fibrosis in patients with a secundum ASD and found especially right atrial fibrosis to be associated with the presence of arrhythmias in these patients [
30].
Our results show that the
P-wave duration and the PR interval are longer than in matched controls as early as the first week of life. His bundle electrograms have documented prolonged PR intervals in children with ASD [
31], which is also in accordance with our findings.
The QRS axis on the ECG is reflecting the average direction of the ventricular depolarization and right-axis deviation is one of the typical findings on the ECG in patients with ASD [
14]. In neonates, however, a rightward-shifted QRS axis is normal [
32]. During the fetal state, the pulmonary vascular resistance is high, and the right ventricle is the dominant ventricle. After birth, the systemic vascular resistance rises while the pulmonary vascular resistance falls, making the left ventricle gradually more dominant. A substudy from the CBHS showed the gradual leftward shift of the QRS axis in neonates during this transition [
33]. Interestingly, we found that the QRS axis in neonates with ASD changed less toward the left compared to controls during the first four weeks after birth. This could indicate that the shunt across the atrial septum in neonates with ASD has implications on either the electrical activity or the structure of the ventricles at this early stage.
In the subgroup of neonates examined at age two to four weeks, we found a higher maximum amplitude of the
S-wave in V6 in the ASD group compared to controls. Also, the maximum amplitude of the
R wave in V1 in the ASD group was higher than in controls, though not statistically significant. Both these ECG findings are known to be associated with right ventricular hypertrophy [
34]. We also found a longer QRS duration in the ASD group at age two to four weeks. Thus, taken together, our findings indicate that the ASD has implications on the right ventricle after only a few weeks of postnatal circulation. In the subgroup examined at age two to four weeks, the heart rate is higher in the ASD group compared to controls. This could physiologically support the assumption that the ASD has implications on cardiac function this early: increased chronotropy maintains cardiac output despite a left-to-right shunt across the ASD.
We have previously presented the echocardiographic characteristics of neonates with ASDs within the CBHS study cohort [
35]. We found that neonates with ASDs (
n = 716) had larger right ventricular (RV) dimensions (RV longitudinal dimension end-diastole: 27.7 mm vs. 26.7 mm; RV basal dimension end-diastole: 14.9 mm vs. 13.8 mm; and RV outflow tract diameter 13.6 mm vs. 12.4 mm, all
p < 0.001) as well as larger atrial volumes than matched controls (right atrial end-systolic volume: 2.9 ml vs. 2.1 ml; and left atrial end-systolic volume 2.0 ml vs. 1.8 ml, both
p < 0.001). Left ventricular dimensions and function did not differ between neonates with ASDs and controls. Hence, there seems to be some association between morphology and electrocardiographic alterations in our cohort of neonates, where
P-wave duration and PR interval might be related to atrial morphology and rightward shift of the QRS axis might be related to larger right ventricular dimensions. However, as prolonged
P-wave duration has likewise been shown in adult patients with ASD without atrial enlargement [
29], there might also be a component of electrocardiographic abnormalities irrespective of morphological alterations.
Arrhythmias contribute to morbidity in patients with ASDs. Udholm et al. [
5] investigated 151 adult patients (mean age 32 years) with small ASDs that were left unrepaired. Despite 80% of the defects had spontaneously closed, 7 days of Holter recording revealed a high prevalence of occult arrhythmias. Our results substantiate the assumption that there is a burden of asymptomatic electrocardiographic alterations in patients with ASD and that the morphological defect in the atrial septum might not be the sole mechanism for morbidity in ASD patients. Current guidelines for the management of ASD patients suggest that ECG recording is included in the routine follow-up of patients with ASD [
36,
37]. Our findings emphasize this recommendation. Physicians need to be aware of the risk of covert electrocardiographic abnormalities and arrhythmias in patients with ASD.
One limitation of our study is the fact that we only have one single TTE and ECG for the neonates, while serial ECGs and TTEs could have provided additional information. Also, at this point, we do not have information on the follow-up of the neonates with ASD examined in the study. The neonates were included prenatally and at the time of echocardiographic assessment, most neonates did not have any symptoms suspicious of ASD, but the ASDs were diagnosed because of the echocardiographic examination and systematic assessment for ASD in this large population-based cohort. Interatrial communications are frequently seen in small children, and we do not know which ones will develop hemodynamic and clinical significance. Complications and comorbidities are found in patients with ASD after spontaneous, surgical, or percutaneous closure of the defect and even in patients where the defect is considered so small that no intervention or follow-up is needed [
38]. To our knowledge, we are the first to describe electrocardiographic changes in asymptomatic neonates with ASDs from a large population-based cohort, which we consider a particularly interesting, and somewhat surprising, finding. This new observation may point toward an early indication of a later problem.
The differences in electrocardiographic parameters between newborns with ASD and controls found in this study are relatively small in absolute numbers. Electrocardiographic values for neonates with ASD in our study cohort are still within age-specific reference values [
32,
34]. Hence, we are careful not to describe the PR interval and
P-wave duration as prolonged, but solely conclude that these parameters are longer in neonates with ASD than in matched controls. Likewise, the QRS axis is not pathologically rightwards shifted in our cohort but is still significantly more rightward shifted in neonates with ASD than in the control group and remains so during the first month. Even if the differences found in this study are relatively small, they do reach convincing statistical significance due to the large sample size. A strength of our study is that we present data on the largest population-based cohort to date systematically assessed for ASD and thus are aware of the diagnosis of ASD this early after birth. The findings cannot be applied directly to a clinical context, but our results contribute with new knowledge on the electroanatomic understanding of ASDs.
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