Impaired Distensibility of the Proximal Aorta in Fetuses With Tetralogy of Fallot

Abstract

Background

Increased aortic wall stiffness, which even persists after repair, has been reported in patients with tetralogy of Fallot (TOF). We aimed to observe the distensibility of the ascending aorta and descending aorta in fetuses with TOF and explore its relation with aortic blood flow volume and aortic and pulmonary annular size.

Methods and Results

Twenty‐three fetuses with TOF and 23 gestational age–matched normal fetuses were included in this prospective cross‐sectional study. The distensibilities of the ascending aorta and descending aorta were assessed by aortic strain (AS), which was defined as follows: 100×(maximum internal diameter in the systolic phase–minimum internal diameter in the diastolic phase)/minimum internal diameter in the diastolic phase. The maximum internal diameter in the systolic phase and minimum internal diameter in the diastolic phase of the ascending aorta and descending aorta were measured by M‐mode echocardiography. Associations between AS and aortic blood flow volume and aortic and pulmonary valve diameters were assessed in both groups. AS of the ascending aorta in TOF group was lower than that in controls (20.48%±4.19% versus 28.17%±4.54%; P<0.001), whereas there was no significant difference in the descending aorta. The multivariate regression model demonstrated that AS was significantly related to aortic valve size (P=0.014) and aortic blood flow volume (P=0.022) in fetuses with TOF, whereas only aortic blood flow volume was significantly correlated with AS in the control group (P=0.01). No significant association was found between AS and pulmonary valve size.

Conclusions

Impaired distensibility of proximal aorta was observed in fetuses with TOF. Both intrinsic abnormalities of the aortic wall and aortic volume overload probably play roles in the altered aortic distensibility.

Nonstandard Abbreviations and Acronyms

AS

aortic strain

D_max

maximum internal diameter in the systolic phase

D_min

minimum internal diameter in the diastolic phase

GA

gestational age

PV

pulmonary valve

TOF

tetralogy of Fallot

Clinical Perspective.

What Is New?

• Fetuses with tetralogy of Fallot presented impaired aortic strain of the ascending aorta by routine M‐mode echocardiography.

What Are the Clinical Implications?

• Intrinsic abnormalities of the aortic wall and aortic volume overload seem to play roles in the impaired distensibility of the proximal aorta in fetuses with tetralogy of Fallot.

Increased aortic wall stiffness has been reported in patients with tetralogy of Fallot (TOF), even after repairment. ¹ , ² , ³ Histopathologic studies have demonstrated that patients with TOF exhibit aorta media abnormalities, including fragmentation of elastic fibers, loss of smooth muscle cells, and an increase in grand substance. ⁴ These intrinsic histologic changes of the aortic wall in TOF occur even as early as infancy and in neonates. ⁵ , ⁶ Aortic elasticity is important to maintain aortic reservoir function and coronary circulation. ⁷ Saiki et al found that aortic stiffness is markedly increased in the proximal than the distal aorta in infants with TOF before corrective surgery. ³ A greater degree of histological abnormalities, such as elastic fragmentation and disarrayed elastic lamination, was also found in the ascending aorta compared with the descending thoracic aorta. ⁶ The presence of elastin in the vessel wall plays an important role in the aortic elastic properties, and the elastic lamellae begin to develop early in fetal life. ⁸ Using velocity vector imaging, we recently showed that the mean longitudinal strain and global circumferential strain of the ascending aorta were decreased in the fetuses with TOF. ⁹ Nevertheless, data on the distal segment are still lacking. As the access to proper instrumentation makes it difficult to obtain these parameters in a routine clinical setting, we attempted to investigate alterations in aortic distensibility in both the ascending and descending aorta by M‐mode echocardiography.

A previous study reported that significant enlargement of aortic size is presented in fetuses with TOF, ¹⁰ but the pathophysiological mechanisms of aortic dilatation are probably multifactorial and remain to be elucidated. There have been animal and human fetal experiments demonstrating that aortic distension waveforms are associated with pressure waveforms. ¹¹ The aortic diameter change is a measurement of its distensibility. M‐mode strain has been applied as one of the indexes to assess the aortic elastic properties in children and adults. ¹² , ¹³ Because of an inability to directly measure fetal blood pressure, we intended to acquire strain of the ascending and descending aorta by M‐mode echocardiography to observe the changes of aortic distensibility in fetuses with TOF and explore their relation with aortic blood flow volume and aortic and pulmonary annular size.

METHODS

The data that support the findings of this study are available from the corresponding author on reasonable request.

A prospective cross‐sectional study was conducted in the Second Xiangya Hospital of Central South University in China between February 2021 and July 2022. Written informed consent was obtained from all families, and the study was approved by the Ethics Committees of the Second Xiangya Hospital.

Women whose pregnancies had an echocardiographic indication of TOF were recruited from our center. The diagnosis of TOF was based on morphological criteria, including a subaortic ventricular septal defect, an aortic root override, and infundibular pulmonary stenosis (atresia and an absent pulmonary valve [PV] were excluded). Gestation‐matched, normal pregnancies were collected as controls. The exclusion criteria included the following: (1) multiple‐gestation pregnancies; (2) small size for gestational age (GA), defined as the estimated fetal weight below the 10th percentile; (3) fetuses with associated structural and chromosomal abnormalities; (4) persistent fetal arrhythmia; and (5) maternal complications, including gestational diabetes, preeclampsia, and thyroid diseases.

Routine obstetric ultrasound and complete echocardiography were performed for each fetus by one operator using a Voluson E8 system (GE Healthcare, Milwaukee, WI) with an RAB 4–8‐D curvilinear probe or a Voluson E10 system (GE Healthcare) with an RAB 2–5‐D curvilinear probe. GA was calculated on the basis of the crown‐rump length obtained at first‐trimester ultrasound. Fetal biometry was measured, and the estimated fetal weight was calculated using the Hadlock formula. ¹⁴ The pulsatility index of the umbilical artery was obtained in the free loop of the umbilical cord. The pulsatility index of the middle cerebral artery was measured at the proximal segment after its origin from the circle of Willis. Delivery characteristics included GA at delivery, mode of delivery, Apgar score, and birth weight.

Evaluations of Cardiovascular Data by Echocardiography

Diameter distensibility of the ascending and descending aorta was assessed by M‐mode echocardiography (Figure 1). The minimum internal diameter in the diastolic phase (D _min), and the maximum internal diameter in the systolic phase (D _max) were measured. D _max was measured at the maximal anterior motion of the aortic wall, whereas D _min was obtained at the end of diastole. Aortic strain (AS) was calculated using the following formula: $100\times (D_{\max }‐D_{\min })/D_{\min }$. ¹² , ¹⁵ Fetal arteries were measured at predefined locations. Ascending aorta was measured below the innominate artery and above the sinotubular junction. Descending aorta was measured below the ductal artery and above the diaphragm. The image was then enlarged as appropriate (with the aorta occupying at least 30% of the screen). The ultrasound sampling line was kept close to 90° to the aortic wall. All measurements were performed in resting fetuses; fetal motion, such as breathing movements, was avoided. The measurements of aortic diameter were made from the same cardiac cycle. Three consecutive cardiac cycles were measured, and the mean was used.

Figure 1. Measurement of the maximum and minimum internal diameters to assess aortic strain from the M‐mode echocardiography.

Ascending aorta was measured below the innominate artery and above the sinotubular junction. Descending aorta was measured below the ductal artery and above the diaphragm. A and C, Normal fetuses of 23+1 and 31+1 weeks, respectively. B and D, Fetus with tetralogy of Fallot of 23+6 and 31+3 weeks, respectively. D _max indicates maximum internal diameter in the systolic phase; and D _min, minimum internal diameter in the diastolic phase.

Standard and multiple views of each fetal heart were obtained to evaluate the cardiac morphometry and hemodynamics. The dimensions of the arterial and atrioventricular valves were measured at their maximal size following the inner‐to‐inner edge model and were converted automatically to z‐scores based on GA, as previously reported. ¹⁰ , ¹⁶ The aortic blood flow volume was calculated as follows: $\mathrm{\pi }/4\times {\mathrm{d}}^2\times \mathrm{VTI}\times \mathrm{HR}$, where d is the diameter of the aortic valve and VTI is the velocity time integrals of the aortic artery, and then further adjusted by the estimated fetal weight. ¹⁷ , ¹⁸ Heart rate (HR) was obtained by automatically tracing the spectrum waveform. All Doppler evaluations were performed in the absence of fetal breathing and body movements. Each measurement was made in triplicate, and the average value was used for analysis.

Statistical Analysis

All the data are presented as the means with SDs or frequencies with percentages, as appropriate. The Shapiro‐Wilk test and histograms were used to assess for normal distribution. The clinical features and cardiovascular parameters were compared between the fetuses with TOF and controls using the Student t test, Mann‐Whitney U test, or χ² test. Fetuses with TOF were further divided into 3 subgroups: fetuses with PV z‐score <−4 (n=8), fetuses with −2>z‐score≥−4 (n=10), and fetuses with z‐score ≥−2 (n=5). A z‐score of −4 was chosen for the reason that −4 is a commonly accepted cutoff between moderately and severely hypoplastic PV. Differences of AS in 3 groups were analyzed by one‐way ANOVA with least significance difference (LSD) method. The relations between AS and aortic blood flow volume, aortic valve, and PV size were evaluated by multivariate regression analysis in TOF and control group. Because blood flow volume was significantly correlated with AS only when the aortic valve size was excluded, aortic valve size may play as a mediator in the correlation between blood flow volume and AS in TOF. Therefore, we also presented a regression model excluding aortic valve size to demonstrate the relation between blood flow volume and AS in TOF group. To assess interobserver variability, AS was independently measured by a second reader, who was blinded to the clinical data of 10 normal fetuses and 10 fetuses with TOF that were randomly selected. To assess intraobserver variability, a single observer then analyzed the data arising from these cases twice, with 1‐day intervals between the analyses. Bland‐Altman plots were drawn for interrater and intrarater agreement. A value of P<0.05 was considered to indicate a statistically significant difference. All statistical analyses were conducted using SPSS software version 20.0 and GraphPad Prism 8.

RESULTS

A total 28 fetuses with TOF were initially enrolled, but 5 cases were excluded, including 2 with inadequate images and 2 that were lost to follow‐up. One additional fetus was excluded because of postnatal detection of extracardiac malformation. Finally, 23 fetuses confirmed TOF postnatally, and 23 GA‐matched normal controls were studied. Fetal and postnatal outcomes are outlined in Table 1. The GA at birth was 37.67±1.44 and 38.63±1.14 weeks, respectively. No statistically significant differences were observed in maternal age, fetoplacental Doppler value, estimated fetal weight at diagnosis, and birth weight in the TOF and control groups. A total of 18 (39.1%) fetuses were delivered via cesarean section. During the follow‐up periods, 5 (21.7%) TOF cases underwent cardiac surgery.

Table 1.

Clinical and Cardiovascular Data in the Controls and Fetuses With TOF

Variable	TOF (n=23)	Control (n=23)	P value
Maternal age, y	30.56±3.38	30.09±2.95	0.833
GA at scan, wk	27.49±3.66	27.60±3.59	0.766
EFW at scan, g	1138±535	1161±541	0.733
MCA‐PI	1.70±0.26	1.80±0.25	0.701
UA‐PI	1.00±0.14	1.02±0.17	0.742
Cardiovascular parameters
Mitral annulus diameter, mm	8.40±1.45	8.18±1.54	0.62
Mitral annulus diameter, z‐score	0.14±0.74	−0.29±0.47	0.054
Tricuspid annulus diameter, mm	8.72±1.66	9.02±1.69	0.548
Tricuspid annulus diameter, z‐score	0.06±0.70	0.05±0.37	0.936
Aortic valve diameter, mm	5.26±1.13	4.36±0.84	0.004
Aortic valve diameter, z‐score	1.35±1.00	−0.03±0.58	<0.001
Pulmonary aorta valve diameter, mm	3.45±1.04	5.16±1.09	<0.001
Pulmonary aorta valve diameter, z‐score	−3.87±1.99	−0.36±0.64	<0.001
Aortic blood flow volume, mL/min per kg	275.02±81.44	180.81±39.51	<0.001
Heart beat, bpm	148±6	146±7	0.256
Ascending aorta
D max, mm	6.24±1.46	5.03±0.94	0.002
D min, mm	5.21±1.28	3.94±0.87	<0.001
Aortic strain, %	20.48±4.19	28.17±4.54	<0.001
Descending aorta
D max, mm	4.03±0.59	4.40±0.74	0.099
D min, mm	3.32±0.51	3.61±0.64	0.144
Aortic strain, %	21.46±3.44	22.17±3.12	0.503
Postnatal outcome
Birth weight, g	3057±435	3231±298	0.118
GA at birth, wk	37.67±1.44	38.63±1.14	0.016
Apgar score at 1 min	9.00±0.85	9.35±0.65	0.158
Apgar score at 5 min	9.56±0.51	9.74±0.45	0.221
Cesarean delivery, n (%)	11 (47.8)	7 (30.4)	0.227
NICU, n (%)	2 (8.7)	0 (0)	0.489
Follow‐up period, m	4.7±2.6	…	…
Cardiac surgery, n (%)	5 (21.7)	…	…

Data are given as mean±SD unless otherwise indicated. Bpm indicates beats per minute; D _max, maximum internal diameter in the systolic phase; D _min, minimum internal diameter in the diastolic phase; EFW, estimated fetal weight; GA, gestational age; MCA, middle cerebral artery; NICU, neonatal intensive care unit; PI, pulsatility index; TOF, tetralogy of Fallot; and UA, umbilical artery.

The D _max and D _min of ascending aorta in the fetuses with TOF were significantly larger than in the controls (6.24±1.46 versus 5.03±0.94 mm and 5.21±1.28 versus 3.94±0.87 mm, respectively; P=0.002 and P<0.001, respectively), whereas AS significantly decreased in the TOF group compared with the control group (20.48%±4.19% versus 28.17%±4.54%; P<0.001). AS of the ascending and descending aorta did not differ in TOF group with different degree of pulmonary aorta hypoplasia. No significant difference was noted in the diameters and strain of the descending aorta between the 2 groups. Compared with the controls, the aortic valve diameter and z‐score were significantly larger in TOF group (5.26±1.13 versus 4.36±0.84 mm and 1.35±1.00 versus −0.03±0.58; both P<0.001). Meanwhile, there was no significant difference in the atrioventricular valve diameter, but fetuses with TOF exhibited noticeable higher aortic blood flow volume than the controls (275.02±81.44 versus 180.81±39.51 mL/min per kg; P<0.001; Table 1; Figures 2 and 3).

Figure 2. Aortic strain of ascending aorta (AAO) and descending aorta (DAO) in the controls (n=23) and the fetuses with tetralogy of Fallot (TOF) (n=23).

*P<0.001.

Figure 3. Aortic strain of ascending aorta (AAO) and descending aorta (DAO) in the group with tetralogy of Fallot (TOF) with different degrees of pulmonary stenosis: fetuses with pulmonary valve (PV) z‐score <−4 (n=8), fetuses with −2>z‐score≥−4 (n=10), and fetuses with z‐score ≥−2 (n=5).

The multivariate regression model in fetuses with TOF demonstrated a significant correlation between AS and aortic valve size (AS=−2.744×aortic valve size+24.5; r ²=0.469; P=0.014) after adjustments for aortic blood flow volume and pulmonary aorta valve size. When aortic valve size was excluded, there was a significant correlation between AS and aortic blood flow volume (AS=−0.025×aortic blood flow volume+25.97; r ²=0.513; P=0.022). No significant association was found between AS and z‐score of PV diameter. In the control group, AS is significantly related to aortic blood flow volume (AS=−0.063×aortic blood flow volume+16.65; r ²=0.565; P=0.01; Table 2).

Table 2.

Determinants of AS, Multivariate Regression Model

Independent variables	Coefficient	SE	Standardized coefficient	P value
Fetuses with tetralogy of Fallot
Aortic blood flow volume, mL/min per kg	−0.002	0.012	−0.033	0.89
Aortic valve size, z‐score	−2.744	1.013	−0.656	0.014
Pulmonary aorta valve size, z‐score	−0.045	0.367	−0.021	0.904
Fetuses with tetralogy of Fallot (aortic valve size excluded)
Aortic blood flow volume, mL/min per kg	−0.025	0.01	−0.477	0.022
Pulmonary aorta valve size, z‐score	−0.327	0.403	−0.156	0.428
Control group
Aortic blood flow volume, mL/min per kg	0.063	0.022	0.551	0.01
Aortic valve size, z‐score	−1.599	1.575	−0.204	0.323
Pulmonary aorta valve size, z‐score	−0.077	1.425	−0.011	0.957

AS indicates aortic strain.

The intraclass correlation coefficients of interobserver and intraobserver for AS of ascending aorta were 0.827 (95% CI, 0.619–0.927) and 0.859 (95% CI, 0.68–0.941), respectively; and the values were 0.885 (95% CI, 0.733–0.953) and 0.858 (95% CI, 0.68–0.941) for descending aorta, respectively. Bland‐Altman plots demonstrated mean difference and 95%CI for interrater and intrarater agreement of AS of 2 segments (Figure S1).

DISCUSSION

Our study demonstrated decreased AS of the ascending aorta in fetuses with TOF, suggesting impaired aortic distensibility of proximal aorta. Both intrinsic abnormalities of the aortic wall and aortic volume overload play roles in the alterations of aortic distensibility of the proximal aorta. Impaired elastic properties of proximal aorta are associated with the aortic valve size and are independent of the degree of pulmonary artery stenosis in TOF.

We noted that AS of the proximal aorta was significantly decreased in TOF, whereas there was no obvious change in the AS of the distal aorta. In our previous research, velocity vector imaging was applied to assess aortic elastic properties in 76 fetuses with TOF and 76 controls. The results revealed that the mean longitudinal strain and global circumferential strain of ascending aorta in fetuses with TOF were less than those in normal group. ⁹ Velocity vector imaging is an echocardiographic technique to evaluate cardiac function and arterial elasticity by using 2‐dimensional speckle tracking, ¹⁹ but the frame rate in this technique was still relatively low compared with the fetal heartbeat. M‐mode echocardiography has been used routinely in the clinical practice, and it has obvious advantages in temporal resolution. The alterations of M‐mode strain in proximal aorta in present work are similar to the aortic elastic properties assessed by velocity vector imaging. The aorta's elastic properties depend largely on the presence of scleroprotein content in the vessel wall. ⁸ The impaired aortic distensibility that we observed in fetuses with TOF in this study might indicate the altered intrinsic abnormalities of the aortic wall. Niwa et al demonstrated the prevalence of great arterial medial abnormalities of smooth muscle, elastic fibers, collagen, and ground substance in a variety of forms of congenital heart disease. ⁴ Subsequent studies found that marked histological abnormalities of the aortic media of the ascending aorta are presented in TOF from infancy with or without repairment. ⁵ , ⁶ An animal experiment conducted on chicken embryos revealed that the elastic matrix of the walls of great vessels was impaired when the cardiac neural crest is ablated. ²⁰ Discrepancy between aortic distensibility of ascending and descending aorta also corresponded with those in children and neonates with TOF. Saiki et al and Seki et al demonstrated that aortic elasticity is decreased in infants and children with TOF before corrective surgery, and that abnormal aortic mechanical property is confined to the proximal aorta regardless of the operative status of TOF. ³ , ²¹ The decreased AS only presented in ascending aorta but not in the descending aorta and could be associated with the different histological changes in the 2 segments. Tan et al demonstrated greater degrees of medionecrosis, fibrosis, and elastic fragmentation in the ascending aorta, whereas the descending thoracic aorta showed near normal histology. ⁶ Our findings suggested that histological abnormalities of the proximal aortic wall in TOF might present early in the human fetuses.

Our study found that aortic valve size was negatively associated with aortic distensibility in fetuses with TOF. Aortic root dilatation is known to be a feature of TOF and may lead to aortic regurgitation, aortic dissection, and rupture. ²² Wu et al and Jatavan et al demonstrated significant enlarged aortic valve diameters in cardiac assessment of fetal TOF. ¹⁰ , ²³ In this study, aortic valve diameters of TOF group were larger than those of the controls. Cheung et al found central arterial stiffening may contribute to progressive dilatation of the aortic root in children after TOF repair. ²⁴ Seki et al demonstrated that increased aortic wall stiffness is correlated with the increase in aortic diameter in infants and children with TOF before corrective surgery. ²¹ Our results are consistent with the findings of these studies in children. In addition, histological analyses also showed that the risk of aortic dilatation is 15.97 times higher in patients with a histopathological abnormal aorta, ⁵ and histology grading scores correlated with aortic root dilatation. ⁶ The finding in this study further indicated that intrinsic abnormalities of the aortic wall may contribute to the decreased distensibility in TOF.

Moreover, our study demonstrates that aortic blood flow volume in fetuses with TOF was elevated, and the impaired aortic distensibility is related to the increased aortic blood flow volume, whereas aortic distensibility is positively correlated with the aortic flow volume in the normal fetuses. This is likely attributed to the aortic wall volume overload. Because of the presence of the overriding artery, the aorta receives blood flow from both ventricles in TOF. Prior research showed that increased distention stress on the aortic wall may lead to decreased elasticity of the aortic wall. ²⁵ Therefore, aortic blood volume load may also play a part in the impaired aortic elastic properties in fetuses with TOF.

Prior studies demonstrated that PV size or z‐score has implications for neonatal outcomes and the timing and type of surgical management. In this work, AS did not differ in TOF groups with different degrees of pulmonary artery hypoplasia, and no significant correlation was found between AS and PV size. A study by Tan et al on the human ascending aorta found that histological changes, such as fibrosis and elastic fragmentation, were significantly greater in TOF than in the control group, whereas there was no significant difference between the pulmonary stenosis and pulmonary atresia subgroups. ⁶ We suppose that alterations in proximal arterial elastic properties were independent of the degree of pulmonary artery stenosis in fetuses with TOF. However, the mean longitudinal strain and global circumferential strain changed notably within subgroups of TOF in our previous study. This may be attributed to the different indicators and methods we used and the sample size. As the cases in the subgroups of TOF are small in this work and few studies investigated the direct linkage between aortic elasticity and the degree of pulmonary artery stenosis, future studies with larger samples are warranted.

This study has some limitations. First, the sample size of the TOF group is relatively small (n=23). Second, although M‐mode ultrasound has high temporal resolution, its accuracy may be decreased when imaging fetuses at small GA and some fetal positions. The depth, sample frame, and waveform speed were adjusted to minimize any potential impact of these variables. Third, as this was a cross‐sectional study, all conclusions are based on a single mid‐to‐late trimester observation. During the follow‐up period, only 5 cases underwent postnatal surgery, which made it difficult for us to explore the value of conventional or novel indicators in predicting the optimal age of intervention or appropriate surgical approaches. Longitudinal studies are needed to further investigate these questions.

CONCLUSIONS

There was significantly impaired AS of the proximal aorta in fetuses with TOF. Both intrinsic abnormalities of the aortic wall and aortic volume overload seem to play roles in the altered aortic distensibility in the human fetuses. Impaired aortic elastic property during fetal life found in this study would facilitate follow‐up of cardiovascular disease after birth.

Sources of Funding

This study was supported by the National Natural Sciences Foundation of China (grants 81871372 and 81501497) and Natural Science Foundation of Changsha (kq2208341).

Disclosures

None.

Supporting information

Figure S1