Introduction

Tetralogy of Fallot is the most common, complex congenital heart defect requiring surgery at an early age. Although initial mortality is only 1.1–2.5% [1,2,3], and a majority of patients reach adulthood, subsequent morbidity and particularly pulmonary regurgitation is still common and several patients develop heart failure [4,5,6,7,8]. Left ventricular diastolic dysfunction is also common after corrective surgery [9,10,11] and is a predictor of poor outcome [5] as well as indicative of greater risk of major adverse events [12]. However, the importance of atrioventricular interaction in the setting of pulmonary regurgitation and diastolic dysfunction is not fully understood in patients with repaired Tetralogy of Fallot (rToF).

The geometrical relationship between the left atrium and ventricle has been identified as a mechanism contributing to diastolic filling [13] and recently shown to be associated with survival in patients with heart failure with preserved ejection fraction [14]. As long as the atrial short-axis area is smaller than the ventricular short-axis area, this geometrical relationship yields a net hydraulic force acting on the atrioventricular plane pushing it toward the atrium, thus aiding diastolic filling. The difference between the ventricular and atrial areas is denoted the atrioventricular area difference (AVAD) (Fig. 1) [15]. Since patients with rToF and pulmonary regurgitation (PR) have an underfilled left ventricle due to regurgitation and right ventricular dilatation [16], an altered geometrical relationship between the left atrium and ventricle may be expected. With a smaller left ventricle, the hydraulic force during diastole may be decreased or even reversed in direction, thereby impeding diastolic filling.

Fig. 1
figure 1

Schematic illustration of the left side of the heart describing the atrioventricular area difference. a shows the heart at the beginning of diastole with a larger atrium and smaller ventricle. b shows the heart at the end of diastole with a smaller atrium and larger ventricle and thus a hydraulic force contributing to diastolic filling. Arrows represent the force of the blood acting upon the atrioventricular plane. Solid black and dashed black arrows counterbalance each other while the red arrows represent the net force acting on the atrioventricular plane. The red arrows indicate the direction of the net hydraulic force. The magnitude of the hydraulic force is proportional to the atrioventricular area difference (AVAD) calculated as; ventricular short-axis area—atrial short-axis area. An AVAD less than zero will yield a net hydraulic force acting toward the apex of the heart while an AVAD larger than zero corresponds to a hydraulic force pushing the atrioventricular plane away from the apex of the heart

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The aim was to assess AVAD and to determine whether the hydraulic force aids or impedes diastolic filling in patients with rToF and pulmonary regurgitation, compared to controls.

Methods

Study Design

This study was designed as a retrospective case–control study at a tertiary center for congenital heart defects. The Ethical Review board in Lund, Sweden, approved the study. The study followed the Declaration of Helsinki and written consent was obtained from all participants or their legal guardians before inclusion. Results are presented according to STROBE guidelines for observational studies [17].

Patients were considered eligible if having undergone cardiac magnetic resonance (CMR) imaging including cine images of the left atrium and ventricle after rToF.

Healthy controls underwent CMR as part of studies on healthy cardiac physiology and chosen for the current study by matching to patients’ age, with children being age matched with a range of − 1 to + 2 years, IQR 0.5 years, and adults with a range of 0–4 years, IQR 2 years. All had normal CMR findings and no reported cardiac conditions.

Cardiac Magnetic Resonance Imaging

Cardiac magnetic resonance imaging with retrospective ECG gating was performed in the supine position using one of two 1.5 T scanners (Achieva, Philips Healthcare, Best, the Netherlands; or Aera, Siemens Healthineers, Erlangen, Germany). Short‐axis balanced steady‐state free‐precession images covering the whole heart were acquired. Images were analyzed in the software Segment (http://segment.heiberg.se) [18]. Endocardial borders of the left ventricle were semi-automatically delineated in all timeframes from end systole to end diastole, with manual corrections if needed. Left atrial borders including atrial appendages were manually delineated. Right ventricular endocardium was semi-automatically delineated, with manual corrections if needed, at end systole and end diastole. Two-dimensional free-breathing through-plane phase-contrast imaging was performed in the aorta and pulmonary artery in patients with rToF to quantify effective stroke volume and pulmonary regurgitation. Linear phase background correction was applied. All measurements were done in consensus with two observers (**and**, with 11 and 23 years of CMR experience, respectively).

Atrioventricular area difference was calculated as the largest ventricular short-axis area minus the largest atrial short-axis area at every timeframe from end systole to end diastole, in all subjects [13, 15]. The hydraulic force supports the motion of the atrioventricular plane when the mitral valve is open during diastole and the atrial and ventricular pressures are close to equal. Thus, for didactic purpose when discussing AVAD, end systole is denoted “beginning of diastole” throughout this work.

$$\text{AVAD}\left( {\text{cm}^{2} } \right)\, = \text{ventricular short-axis area}\,\left( {\text{cm}^{2} } \right){-}\,{\text{atrial short-axis area}}\,(\text{cm}^{2}).$$

Beginning of diastole and end diastole were set as the timeframes with the smallest and largest volume of the left ventricle and thus represent ventricular beginning of diastole and end diastole and not atrial time-points. Atrioventricular area difference was indexed to height (AVADi) to account for cardiovascular growth in the pediatric population while avoiding bias due to variation in body mass index [19].

Statistical analysis

Statistical analyses were performed in GraphPad Prism (version 9.5.1, Boston, Massachusetts, USA). Gaussian distribution was not assumed and values are presented as median [interquartile range]. Groups were compared using Mann–Whitney’s unpaired test. Non-parametric Spearman’s test tested for correlation between variables. p values < 0.05 were considered to indicate statistically significant differences.

Results

Table 1 shows subject characteristics. Table 2 and Fig. 2 show cardiac volumes and function for children and adults with rToF compared to controls. Table 3 show AVADi for all groups. All participants with rToF had pulmonary regurgitation. One adult with rToF had mild mitral regurgitation. This same participant also had the largest left atrial end-systolic volume indexed to body surface area (BSA), the second largest left ventricular end-systolic and largest end-diastolic volumes indexed to BSA, and the largest AVADi at beginning of diastole. One child with rToF had current treatment with beta-blockers, all others were without medication. Nine children with rToF (75%) were classified as New York Heart Association (NYHA) class I and 3 children with rToF (25%) as NYHA class II. Ten adult patients with rToF (83%) were classified as NYHA class I and the remaining 2 adult patients (17%) as NYHA class II. One adult patient with rToF was treated with acetylsalicylic acid, all others were without medication.

Table 1 Patient characteristics
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Table 2 Cardiac volumes and function
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Fig. 2
figure 2

Left atrial and ventricular volumes at end systole and end diastole. Children with rToF had smaller left atrial volumes compared to controls. Adults with rToF had smaller left atrial volume at end systole compared to controls and also smaller left ventricular end-diastolic volumes compared to controls. LVESVi Left ventricular end-systolic volume indexed to body surface area, LVEDVi Left ventricular end-diastolic volume indexed to body surface area, rToF repaired Tetralogy of Fallot

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Table 3 Atrioventricular area difference at beginning of diastole and end diastole
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Body mass index variation in the pediatric population was 14.9–23.7 kg/m2 for children with rToF and 14.0–24.3 kg/m2 for controls. Ranges for body mass index z-scores in the pediatric population were − 2.1 to 2.1 for children with rToF and − 2.0 to 1.5 for controls. Two pediatric controls and four children with rToF were classified as overweight (BMI z-scores 1.4, 1.5, 1.1, 1.1, 1.6, 1.7). One child with rToF was classified as obese (BMI z-score 2.1).

Atrioventricular area difference.

Table 3 shows AVADi at beginning of ventricular diastole and at end systole as well as percentage of diastole spent with AVADi > 0 cm2/m. Figure 3 shows that AVADi was higher at beginning of diastole in children with rToF (0.3 cm2/m [− 1.3 to 0.8]) than in controls (− 2.7 cm2/m [− 4.9 to − 1.7], p = 0.015). Also, adults with rToF had a higher AVADi at beginning of diastole (− 0.6 [− 1.5 to − 0.2]) compared to controls (− 3.3 cm2/m [− 3.8 to − 2.8], p = 0.036). No difference was found in AVADi at end diastole for either children or adults with rToF compared to respective controls. No difference was found when comparing percentage of diastole spent with AVADi > 0 between groups.

Fig. 3
figure 3

Atrioventricular area difference indexed to height at beginning of diastole and at end diastole. Children and adults with rToF have a sustained atrioventricular area difference and thus a net hydraulic force contributing to diastolic filling, similar to that of healthy controls, despite a small underfilled left ventricle due to pulmonary regurgitation. AVADi Atrioventricular area difference indexed, rToF  repaired Tetralogy of Fallot

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There was no correlation between degree of pulmonary regurgitation in patients with rToF and AVADi, either at beginning of diastole (children: p = 0.42, adults: p = 0.69) or at end diastole (children: p = 0.97, adults: p = 0.54).

There was no correlation between right ventricular end-diastolic volume indexed to BSA and AVADi at end diastole in patients with rToF (children: p = 0.12, adults: p = 0.33). Furthermore, there was no correlation between left ventricular end-diastolic volume indexed to BSA and AVADi at end diastole in patients with rToF (children: p = 0.77, adults: p = 0.14).

Discussion

The main finding of this study is that the geometrical relationship between the left atrium and left ventricle is normal in children and adults with rToF and pulmonary regurgitation up to 18 [15,16,17,18,19] years after surgical repair, compared to healthy controls. Thus, the direction of the hydraulic force, which is dependent on this geometrical relationship and assessed by AVAD, is sustained and contributes to left ventricular diastolic filling. This is despite the underfilled left ventricle seen in these patients with rToF secondary to pulmonary regurgitation and right ventricular dilatation.

The current study showed that both children and adults with rToF had higher AVADi at the start of diastole compared to controls. However, when comparing duration of diastole with AVADi > 0, i.e., a hydraulic force contributing to diastolic filling, there was no difference between patients and controls. This supports that patients with rToF have a sustained AVAD and a hydraulic force contributing to diastolic filling of the left ventricle. The greater AVADi at start of diastole (i.e., end systole) in children and adults with rToF could be an effect of pulmonary regurgitation that during systole would lead to a smaller ejected volume into the pulmonary artery. This would in turn lead to a concomitant decrease in left atrial area at end systole and thus increased AVADi. At end diastole the geometrical relationship is however preserved.

In comparison, in patients with heart failure with preserved ejection fraction, who also have small left ventricles, AVAD and thus the hydraulic force is low and does not aid diastolic filling [15]. Thus, patients with heart failure with preserved ejection fraction and patients with rToF with pulmonary regurgitation are similar in that the left ventricle is small in both, however the groups differ in AVAD. These somewhat contradicting results can be explained by the pathophysiological differences between patients with heart failure with preserved ejection fraction and rToF with pulmonary regurgitation where the latter exhibit an underfilling of the left ventricle due to regurgitation and has a concomitantly small left atrium and therefore no effect on AVAD is found. On the contrary, patients with heart failure with preserved ejection fraction have smaller ventricles due to lower compliance and high resistance to filling, resulting in a large atrium and thereby lower AVAD. The effects on AVAD and net hydraulic force of having a disproportionately large atrium have also been shown in heart-transplanted patients [20].

The finding of small left ventricular volumes both in children and adults with rToF in the current study is in line with previous studies on left ventricular function in rToF [9, 16]. Also, left atrial volumes were smaller in patients with rToF in the current study, at beginning of diastole for both children and adults and at end diastole for children, compared to healthy controls. Previous reports have been inconsistent regarding atrial volumes in patients with rToF [12, 21,22,23,24]. The small atrial volumes found in the current study can be explained firstly by the young age at which patients with rToF underwent primary repair, median 3 months for children and 9 months for adults. Indeed, two previous studies have concluded that older age at primary repair is associated with greater risk of atrial dilatation [12, 21]. Secondly, subjects in the current study were young at time of CMR, median age 11.5 years for children and 21 years for adults. In the studies reporting dilated left atria, median age at CMR were 28, 35 and 37 years [12, 21, 24].

In the current study AVADi was not related to either left or right ventricular end-diastolic volume, nor was there a relationship between AVADi and degree of pulmonary regurgitation. This highlights the fact that AVAD and the direction of the hydraulic force supporting diastolic filling is dependent on short-axis area differences and not necessarily affected by the simultaneous decrease in left atrial and ventricular volumes which in rToF is due to pulmonary regurgitation.

In this study, one adult with rToF had mild mitral regurgitation whilst maintaining a positive AVADi and a hydraulic force aiding diastolic filling. Mitral regurgitation may lead to larger left atrial and ventricular volumes. However, as long as the relationship between atrial and ventricular area does not change, this will not alter the AVAD and thus the direction of the hydraulic force will be sustained.

In patients with heart failure with preserved ejection fraction, AVAD was a prognostic marker for survival and was proposed to carry information regarding diastolic function beyond traditional measurements [14]. Measures of left sided cardiac function is relevant in rToF as there is evidence that left ventricular function is a strong predictor of ventricular arrhythmias, major adverse events and impaired exercise tolerance [5, 10, 25,26,27]. Additionally, left atrial function is associated with risk of major cardiovascular events in these patients [12, 21]. Atrioventricular area difference is a mechanism that, when altered, would lead to a disturbed diastolic function which may explain the proposed prognostic value of AVAD [14]. The current study did not address the prognostic value of AVAD in patients with rToF. Although these patients exhibited normal AVAD compared to controls repeated measurements over time may uncover diastolic dysfunction at an early stage. When and how often these measurements are to be made needs to be addressed in a longitudinal follow-up study.

Limitations

The study population may be considered small. However, CMR has high precision in measuring differences in cardiac volumes why the numbers are sufficient to show differences in AVADi [28]. As invasive pressure measurements were not performed the exact magnitude of the hydraulic force was not determined. Echocardiographic data was not obtained in this study.

Conclusion

Children and adults with rToF and pulmonary regurgitation have an atrioventricular area difference that do not differ from controls and thus a net hydraulic force that contributes to left ventricular diastolic filling, despite a small underfilled left ventricle due to pulmonary regurgitation.