Hemodynamic interplay of ventricular, atrial and aortic function in patients after arterial switch operation: insights from cardiac MRI

IntroductionOther Section

• Introduction
• Methods
• Results
• Discussion
• Conclusions
• Acknowledgments
• Footnote
• References

The arterial switch operation (ASO) has markedly extended the life expectancy of patients with transposition of the great arteries (TGA), allowing many patients to survive well into adolescence and adulthood (1). With the increased time of post operative surveillance since the introduction of the ASO, the long-term consequences of cardiac surgery and of the underlying pathology are becoming evident and may adversely affect outcomes for this patient group (2).

A persistent post-operative impairment in left ventricular (LV) function, as well as reduced left atrial (LA) function and aortic distensibility (AD) have been noted in this patient population (3,4). Especially the role of impaired LA function (3) and reduced aortic bioelasticity are potential drivers of disease progression (4). More recently it has been noted that TGA patients also have a higher burden of myocardial fibrosis (5,6). The interplay between these pathophysiological alterations in the genesis of a post-operative phenotype characterized by systolic dysfunction, and potentially progressing to heart failure has not been much investigated. Importantly, in patients with heart failure and preserved ejection fraction (EF), it has recently been recognized that dynamic afterload alterations, might lead to diastolic dysfunction and impaired cardiac output reserve (7). Likewise, extensive myocardial fibrosis might lead to a more restrictive physiology of diastolic dysfunction over time also affecting systolic function and presenting as decreased left ventricular global longitudinal strain (LV-GLS) (8,9). This recent evidence has been suggestive of a complex interplay between impaired aortic function as cause of increased LV afterload, and reduced LA function, as a surrogate for diastolic function, with both pot potentially affecting ventricular properties (4,10). To what degree these adverse effects are present in patients with TGA post ASO, interact with each other, and are associated with myocardial fibrosis is largely unknown.

Therefore, we aimed to assess LV function, atrial and aortic function, and myocardial fibrosis in patients with TGA after ASO. We hypothesized that LV-GLS, LA reservoir function, and AD are associated with each other, meaning that patients after ASO have both LV systolic and diastolic function mediated through the interplay of those three factors.

MethodsOther Section

• Introduction
• Methods
• Results
• Discussion
• Conclusions
• Acknowledgments
• Footnote
• References

Study cohort

All participants in the present study underwent a cardiac magnetic resonance imaging (CMR) assessment between March 2007 and December 2018 at the Department of Congenital Heart Disease and Pediatric Cardiology of the University Hospital in Kiel, Schleswig-Holstein. Imaging data obtained by Magnetic Resonance Imaging (MRI) were analyzed retrospectively and were in part, previously published (4). Clinical data were collected retrospectively from medical records.

The study population included 81 TGA patients after ASO, who underwent a CMR examination as part of their routine clinical follow-up. For comparison to healthy controls, a total of 30 MRI examinations from volunteers without cardiovascular disease and normal cardiac anatomy were available. Healthy volunteers were recruited from outpatients, medical students, healthy children of hospital staff, or the Department of Pediatric Neurology.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional ethics board of the University of Kiel (Nos. A168/07 and D422/11). All subjects or their parents or guardians (for minors) provided written informed consent to participate in the study, which was approved by the local ethics committee. The scans of controls, including additional CMR sequences for sedated pediatric patients, were conducted as part of the protocol approved by the local ethics committee.

MRI measurement

CMR studies were performed with a 3.0-Tesla CMR scanner (Achieva 3.0T, Philips Medical Systems, The Netherlands), using a phased-array coil for cardiac imaging, or in small children with a phased-array coil for extremities (SENSE Cardiac coil, SENSE Flex-L coil, Philips Medical Systems). For very young participants, typically those younger than 7 years, sedation with propofol and midazolam was used. During examination heart rate, respiratory motion, oxygen saturation, and noninvasive blood pressure were monitored. Healthy controls did not receive any contrast injections.

CMR analysis was carried out with the MEDIS SUITE software (Medis Medical Imaging Systems, Leiden, The Netherlands) and ViewForum (Philips Medical System, Extended Workstation, Version 2.6.3.5).

End-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), and EF of both ventricles were determined using ViewForum. All ventricular volumes were indexed to body surface area (BSA).

For 2D feature tracking MRI, QStrain in Medis Suite MR (Modul Q-StrainMedis, Version 3.0.18.10, Medical Imaging Systems BV, Leiden, The Netherlands) was utilized. The cine frame with the smallest LV cavity area was set as end-systolic, and the frame with the largest LV cavity area was set as end-diastolic. Manual tracing of the endocardial and epicardial borders was performed in both phases to determine GLS and peak systolic longitudinal strain rate (GLSR).

Aortic cross-sectional areas were measured from oblique or double oblique cine images of the thoracic aorta during minimal and maximal distension in the cardiac cycle at four locations: the aortic root at the level of the sinuses of Valsalva, the ascending aorta (AAo), the descending aorta (DAo) at the level of the pulmonary arteries, and the DAo at the diaphragm. These measurements were used to describe aortic dimensions, as well as to evaluate AD. AD was calculated using the formula:

$$Distensibility\left[{10}^{-3}mmH{g}^{-1}\right]=\frac{\left({\text{A}}_{\max }-{\text{A}}_{\min }\right)}{{\text{A}}_{\min }x\left({\text{P}}_{\max }-{\text{P}}_{\min }\right)}$$[1]

where A_min and A_max are the minimal and maximal aortic cross-sectional areas, and P_min and P_max are the diastolic and systolic blood pressures, respectively. Blood pressure was recorded with a sphygmomanometer on the right upper arm during CMR.

Pulse wave velocity (PWV) was assessed from phase-contrast flow velocity measurements in two predefined aortic segments in the ascending and descending at the level of the pulmonary arteries. Flow versus time curves from phase-contrast cine images for these two locations were used to determine the time delay (Δt) of the distal flow curve relative to the proximal flow curve using a validated method based on cross-correlation of the systolic upstroke portions of the flow waveforms (11). The distance (Δx) between the two positions along a midline of the aortic lumen was measured on angulated sagittal images for the aorta. PWV was calculated using the formula:

$$\text{PWV}\left(\frac{m}{s}\right)=\frac{\Delta x}{\Delta t}$$[2]

LA volumes were quantified using Simpson’s rule and manual planimetry of axial cine images. Measurements were taken at three cardiac cycle phases: maximal LA volume before mitral valve opening (LAV_max), volume before LA contraction (LAV_bac), and minimal LA volume at mitral valve closure (LAV_min). From these volumes, additional LA functional parameters were derived as described before (12).

Statistical analysis

For normally distributed data, normality was assessed by the Kolmogorov-Smirnov test, and the results are expressed as mean ± standard deviation. Non-normally distributed data are reported as median and interquartile range (IQR). Student’s t-test and Mann-Whitney U-test were used for comparing continuous variables, while Fisher’s exact test was used for comparing categorical variables. The correlation of normally distributed continuous variables was assessed by Pearson’s method, and otherwise the Spearman rank-sum test was used.

The relationship of the contractile-to-passive LA volume ratio with age was analyzed by group (TGA patients and controls) with a general additive model (GAM) in which age in each group was represented by a cubic spline and the second predictor represented the patient group to account for any overall difference between the two groups.

To investigate the combined effect of AD, LA reservoir function, and GLS we conducted a mediation analysis (PROCESS Version 3.3 by Andrew F. Hayes). ‘Model 4’ of the package was used to predict the direct and indirect effects of the dependent variable X (AD) on the independent variable Y (GLS) as well as the mediator effect of another variable M (LA reservoir function).

A two-sided P value of α≤0.05 was considered statistically significant. The statistical analyses were conducted using IBM SPSS Statistics software (version 25.0, IBM Corp., Armonk, NY, USA) and the R software (R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing, Vienna, Austria).

ResultsOther Section

• Introduction
• Methods
• Results
• Discussion
• Conclusions
• Acknowledgments
• Footnote
• References

Demographics and clinical characteristics

Between March 2007 and December 2018, 81 TGA patients and 30 heart-healthy control subjects were examined at the Department of Congenital Heart Disease and Pediatric Cardiology of the University Hospital in Kiel, Schleswig-Holstein, which included a magnetic resonance imaging examination. Demographics and clinical characteristics of the study cohort are shown in Table 1. TGA and control patients showed no significant differences with regard to age or BSA, while patients with TGA were more often male. At the time of MRI examination, all TGA patients were in a post-ASO state. Preoperatively, a complex form of TGA was present in a total of 9 patients. Most patients underwent surgery using the Lecompte technique. The median age at the time of surgery was 8 days (IQR, 5–23 days). Severe valve pathologies were present in a total of 3 TGA patients. One TGA patient had severe aortic valve insufficiency, another had pulmonary valve stenosis, and in a third case, there was pulmonary valve insufficiency. There were 8 patients known to have relevant coronary artery stenoses. These 8 patients were younger than the TGA patients without coronary problems [7.9 (IQR, 3.9–14.4) vs. 17.1 (IQR, 10.9–21.4); P=0.02], and more frequently suffered from mitral valve insufficiency (38% vs. 6.8%; P=0.03 for Fisher’s test).

Magnetic resonance imaging

MRI results are summarized in Table 2. There was no significant difference between TGA patients and controls with regard to heart rate or systolic blood pressure, while TGA patients had lower diastolic blood pressure and correspondingly lower mean arterial pressure (MAP).

Left and right ventricular function was preserved in both groups, with no relevant differences with regard to ventricular dimensions. Cardiac output tended to be higher in TGA patients (P=0.06) and left ventricular mass index was higher in TGA patients (P=0.001). Strain analysis was only available for patients with TGA and median GLS was preserved as compared to normal ranges reported in the contemporary literature (13). Median extracellular volume fraction (ECV) was 28% with 25% of the population having an ECV above 33.9%. Of note, the presence of coronary anomalies (defined as all coronary origins besides 1LCx-2R) was not associated with higher ECV [median ECV in patients with no coronary anomalies was 29% (IQR, 25% to 36%), median ECV in patients with coronary anomalies was 28% (IQR, 26% to 29%), P=0.29].

Left atrial and aortic function

Table 3 focuses on the differences in left atrial and aortic function. LAV_max was significantly lower (P=0.002) in TGA patients resulting in lower LA-EF reservoir (P<0.001, Figure 1A) without LAV_min (P=0.97) differences as compared to healthy controls. LAV_total and LAV_passive were lower in TGA patients (P<0.001, respectively), while LAV_active (P=0.98) was similar to controls. This resulted in a reduced LA-passive-EF (P<0.001, Figure 1B), but preserved LA-EF-active in TGA patients (P=0.34, Figure 1C). The ratio of LAV_active to LAV_passive (LAV_{active/passive}) and LAV_active to LAV_total (LAV_active/total) were significantly shifted towards active LA function in TGA patients (P<0.001, respectively, Figure 2A,2B).

Figure 1 Differences in (A) LA-EF reservoir, (B) LA-EF-passive and (C) LA-EF active between TGA and control patients. LA-EF, left atrial ejection fraction; TGA, transposition of the great arteries.

Figure 2 Differences in LA ratios between TGA and control patients. (A) LA active to passive emptying volume ratio; (B) LA active to total emptying volume ratio. LA, left atrium; TGA, transposition of the great arteries.

TGA patients had significantly impaired AD at the level of the aortic root, the AAo, as well as the proximal DAo, (P<0.001, P<0.001 and P=0.001, respectively), while no differences in the distal DAo were observed (P=0.24). Consistent with the reduction of AD, the PWV was increased in patients with TGA compared to controls (P<0.001). Notably the above mentioned differences were preserved after adjustment for differences with regard to sex.

Effects of aging on LA function and PWV

A GAM model predicted that the contractile-to-passive LA volume ratio was higher in TGA patients compared to controls (P<0.001) and in addition, there was a significant variation of this parameter with age (P=0.006) in the TGA group but not in healthy controls (P=0.42). As shown in Figure 3, contractile-to-passive LA volume remains relatively constant in both groups up to approximately 10 years of age but is higher in TGA patients. After the first decade of life there is a significant increase of the contractile-to-passive LA volume ratio in TGA patients. In TGA patients, the variation of the contractile-to-passive LA volume ratio showed a similar pattern of change with time since the switch operation (P=0.002 for spline representing time since switch), as seen for the variation with age. Further in TGA patients, PWV increased significantly with age, in contrast to normal volunteers, in whom no significant change was observed for ages up to approximately 30 years (Figure S1).

Figure 3 The relationship of the contractile-to-passive LA volume ratio with age in a general additive model. The atrial contractile-to-passive volume ratio was relatively constant over the approximately 30-year-age range covered in this study, and significantly lower compared to TGA patients post ASO, suggesting preserved passive atrial function. In TGA patients, the contractile-to-passive LA volume ratio remained relatively constant over the first decade of life and in older patients there was a significant increase with advancing age, indicative of diastolic dysfunction at a relatively young age. The solid lines show the predictions from a general additive mode in which age was represented by a cubic spline and the second predictor represented the patient group. LA, left atrium/atrial; TGA, transposition of the great arteries; MRI, magnetic resonance imaging; ASO, arterial switch operation.

Interplay of ventricular fibrosis, LA function and AD

LAV_{active/passive} as well as LAV_active/total showed the strongest correlation to myocardial fibrosis assessed by ECV (Figure 4A,4B), while there was no association of LA-EF-reservoir or AD with ECV. On the other hand, LA-EF-reservoir (Figure 5A), LA-EF-passive (Figure 5B), LA-EF-active (Figure 5C), AD and PWV (Figure S2A,S2B) were associated with peak systolic GLS. AD and total LA-EF correlated (r=0.23, P=0.05).

Figure 4 Correlations between LA ratios and extracellular volume fraction in TGA patients. (A) LA active to passive emptying volume ratio; (B) LA active to total emptying volume ratio. LA, left atrium; TGA, transposition of the great arteries.

Figure 5 Correlations between LA ejection fraction parameters and global longitudinal strain in TGA patients. (A) LA-EF reservoir; (B) LA-EF passive; (C) LA-EF active function. LA, left atrium; LA-EF, left atrial ejection fraction.

A mediation model was used to investigate the direct and indirect effects of AD and LA-EF-reservoir function on peak systolic GLS. This model showed that there was a highly significant moderated effect (Figure 6, P<0.001). AD exerted a direct effect on systolic ventricular function (β=−0.2833), and on LA-EF-reservoir (β=0.2087). LA-EF-reservoir had the strongest effect on systolic ventricular function (β=−0.3193) and mediated 29% of the effect of AD on systolic ventricular function (mediated β=−0.066).

Figure 6 Mediation analysis among AD, left atrial reservoir function and systolic ventricular function. Mediation analysis showed that both AD and left atrial reservoir function exhibit direct effects on systolic ventricular function represented by global peak longitudinal strain of the left ventricle. Parts of the effect of AD on ventricular function are additionally mediated through left atrial reservoir function. AD, aortic distensibility; LA, left atrium.

DiscussionOther Section

• Introduction
• Methods
• Results
• Discussion
• Conclusions
• Acknowledgments
• Footnote
• References

This retrospective study provides new evidence that aortic stiffness after ASO impairs atrio-ventriculo-arterial coupling, which in turn is associated with reduced systolic LV performance. A previous study in young and middle-aged volunteers had already demonstrated a similar effect of age-related aortic stiffening on LV relaxation, but the mechanism remained unclear (14). Our study of TGA patients suggests that the increase in aortic stiffness with advancing age is accelerated in TGA patients, compared to healthy controls. In healthy controls, age-related changes in AD and PWV are typically not significantly different up to an age of approximately 30 years. Further findings of our cohort can be summarised as follows: (I) TGA patients show a significantly impaired LA function—mainly characterised by reduced reservoir function; (II) a shift from passive to active LA function which is associated with diffuse myocardial fibrosis (i.e., ECV); (III) an impairment in AD; and (IV) that the impairment in LA-EF-reservoir as well as AD contribute to impaired LV systolic function both directly but also by effecting each other as shown in mediation analysis.

ASO has dramatically improved the prognosis for patients with TGA by not only reducing perioperative but also long-term mortality compared to other operative techniques such as Senning or Mustard. Overall, 82% to 96% of patients after ASO are alive 20 years after their initial surgery (15,16). This opens up significant challenges for physicians as more and more ASO patients reach adolescence and adulthood, not only presenting with the initial congenital condition, but also the hemodynamic and postoperative sequelae of their underlying condition after ASO. This increases the need for physicians to improve the hemodynamic understanding of the long-term consequences of these factors, which was the aim of the present study, with a focus on atrial and aortic function.

LA function is an established prognostic factor both in patients with congenital heart disease, but also in adults with acquired heart disease (17-19). While there is an abundance of data on LA function after atrial switch operation, the number of reports on ASO is scarce. A small case series (n=9) study of TGA patients provided evidence of an impairment of atrial volumes after both ASO and atrial switch operation, as well as a reduction in LA-EF. We were able to confirm these findings, but in contrast to those reports, LA active EF was preserved in our cohort (2). The LA passive EF represents the most important component with regard to the diastolic function as 70% of the ventricular filling is recruited in this phase (20). Previous reports of a reduction in LA-EF-reservoir in patients after ASO attributed the impairment to general effects concomitant to cardiac surgery, such as LA fibrosis or adhesion due to scarring and pericardiotomy. Similar effects were observed post-operatively in patients with Fallot-Tetralogy (21,22). It is quite possible that pericardiotomy alone, as it is necessary for cardiac surgery, could explain large portions of our observed differences in LA function between TGA patients and controls (23). However, with regard to this it is important to underscore two observations made within our study: (I) LA-EF-reservoir correlated positively with AD and negatively with GLS, meaning better reservoir function was associated with better aortic and ventricular function. (II) The change in LA function from a passive to a more active mode was associated with AD and ECV. This is further underscored by the fact that patients with TGA showed a deviation of physiological LA function at young adolescence age, as compared to healthy controls, indicating unhealthy aging of atrial function. Traditionally it has been proposed that the atrium is primarily impaired in the surgical process in patients after atrial switch operation, and as a sequel is transferring adverse effects on consecutive systems of the cardiovascular system (2). In line with this concept, it might seem counterintuitive that significant alterations in LA function are still observed even when surgically left untouched in the process of ASO. Our data—at least partially—explain this effect by observing that the atrium is adversely affected by alterations in the cardiovascular system. The atrium could be adversely affected by increased ventricular fibrosis, as well as increasing stiffness of the aorta. While the association of reservoir function and AD has previously been established (4), the correlation between impaired LA-EF-reservoir and ventricular systolic function as well as diffuse fibrosis is a novel finding. As LA passive EF is an important determinant of ventricular filling and correspondingly SV and cardiac output, this correlation is not surprising. The triad of impaired ventricular filling, accompanied by diffuse myocardial fibrosis and increased vascular stiffness strikingly resembles the phenotype observed in older patients who present with heart failure with preserved ejection fraction (HFpEF) (24). Interestingly, in centenarians similar observations with regard to the interplay of aortic function and myocardial stiffness were made, reflecting on the notion that TGA patients show early aging as indicated by Figure 3 (25). In line with this LA-EF-active likely represents the dynamic part of ventricular filling, while the passive function is possibly largely mandated by myocardial fibrosis and stiffness (26). In patients with TGA both atrial and ventricular fibrosis might be attributed to early stages of disease during foetal life and the first days of life till ASO, where the saturation in the coronaries is lower than normal (27,28). The importance of LA function is further underlined by the fact that atrial function has recently been identified as a main determinant for elevated ventricular filling pressures in the presence of HFpEF (29).

Similar observations were also made among patients with hypertrophic cardiomyopathy, a pathophysiologically severe form of a classic HFpEF phenotype, where a shift from passive to active atrial function is observed in early disease stages (30,31). Only in patients with advanced disease is the reduction in passive function accompanied by a reduction in active function leading to a deterioration of ventricular filling (30-32). While our cohort clearly does not display the typical epidemiological features of HFpEF, it is worthwhile to note that the physiological alterations are comparable. This might be especially interesting as the lack of long-term data on heart failure in patients with TGA after ASO, makes it all the more important to identify potential pathomechanistic processes that determine long-term outcomes and should be targeted for proper screening and potential treatment of this vulnerable population. In light of this, it could be worthwhile to not only closely monitor LA function, but also ventricular diastolic properties in these patients.

The analysis with a mediation model showed that it is not sufficient to investigate isolated components of the circulation like the atria, ventricle or the aorta for a comprehensive evaluation of pathophysiological processes. Integrating atrial, ventricular and aortic function in one common model might allow the identification of novel pathophysiological processes. As an example, impaired aortic function—manifested by reduced distensibility—can exhibit direct negative effects on the ventricle by increasing afterload (10). This by itself can induce or propagate ventricular diastolic dysfunction and lead to atrial impairment. The impairment in aortic function through this mechanism may harm atrial homeostasis, which in turn can negatively affect ventricular properties, creating a vicious cycle where the sum of the individual effects is greater than their individual contribution.

Limitations

The study has all the innate limitations of a retrospective study, and most findings should primarily be seen as hypothesis-generating. The cohort size is small in terms of power for statistical inferences, but 81 patients with TGA after ASO with CMR imaging represent a typical cohort size for a single-center study of congenital heart disease. Our observations were mainly made by comparing to healthy controls, which have obviously not undergone cardiac surgery. Therefore, potential effects that might have been caused by the operation alone, such as pericardiotomy, cannot be determined. However, some of our results are in line with previous reports that have for example identified early diffuse fibrosis in patients with congenital heart disease that have not undergone cardiac surgery (6). Inter- and intra-observation reliability for ECV, GLS and AD were not evaluated for this study, but is overall excellent as shown previously, including for ECV as estimated for this study (33). Furthermore, neither GLS nor ECV data were available for control patients precluding direct comparisons for GLS and ECV. Lastly, to address a potential concern that elevated right ventricular pressures and ventricular overload may have biased some of our results we repeated the analysis after exclusion of patients with severe aortic regurgitation, pulmonary stenosis and or pulmonary regurgitation and obtained essentially unchanged findings, including for the mediation model.

ConclusionsOther Section

• Introduction
• Methods
• Results
• Discussion
• Conclusions
• Acknowledgments
• Footnote
• References

The present study examined the long-term hemodynamic outcomes in TGA patients post ASO, focusing on atrial and aortic function. LA-EF-reservoir and AD were impaired as compared to controls. This was linked to shifts from passive to active atrial function and was associated with increased ECV, indicative of diffuse myocardial fibrosis correlations of LA-EF-reservoir and AD with GLS suggest that atrial and aortic dysfunctions both impair ventricular performance. Mediation analysis revealing a significant dependence between atrial and aortic function suggests that the effect of aortic stiffness on peak systolic LV strain is mediated by LA function.

These findings resemble mechanisms seen in HFpEF, implying potentially comparable pathophysiology in TGA patients post-ASO. Comprehensive assessments of atrial, ventricular, and aortic functions might be crucial for managing long-term outcomes. Prospective studies are needed to confirm these findings and explore potential therapeutic interventions.

AcknowledgmentsOther Section

• Introduction
• Methods
• Results
• Discussion
• Conclusions
• Acknowledgments
• Footnote
• References

None.

FootnoteOther Section

• Introduction
• Methods
• Results
• Discussion
• Conclusions
• Acknowledgments
• Footnote
• References

Provenance and Peer Review: This article was commissioned by the Guest Editor (Harald Kaemmerer) for the series “Current Management Aspects of Adult Congenital Heart Disease (ACHD): Part VI” published in Cardiovascular Diagnosis and Therapy. The article has undergone external peer review.

Data Sharing Statement: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-494/dss

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-494/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-494/coif). The series “Current Management Aspects of Adult Congenital Heart Disease (ACHD): Part VI” was commissioned by the editorial office without any funding or sponsorship. I.V. serves as an unpaid editorial board member of Cardiovascular Diagnosis Therapy from February 2024 to January 2026. K.P.K. is a consultant to Edwards LifeSciences and ReCor Medical, none of these activities are related to the present work. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional ethics board of the University of Kiel (Nos. A168/07 and D422/11). All subjects or their parents or guardians (for minors) provided written informed consent to participate in the study, which was approved by the local ethics committee. The scans of controls, including additional CMR sequences for sedated pediatric patients, were conducted as part of the protocol approved by the local ethics committee.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

ReferencesOther Section

• Introduction
• Methods
• Results
• Discussion
• Conclusions
• Acknowledgments
• Footnote
• References

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