Predictors of aortic regurgitation and dilatation in children with bicuspid aortic valve

Abstract

Background:

Aortic root and ascending aorta dilatations, along with aortic regurgitation (AR), are prevalent and significant causes of morbidity and mortality in patients with a bicuspid aortic valve. This study investigated the impact of valve morphology, aortic shape, ventricular function, aortic measurements, and serum pro-B-type natriuretic peptide (BNP) levels on AR and dilatation.

Materials and Methods:

The study included 126 patients, grouped based on the degree of valve regurgitation. Demographic and clinical characteristics, serum pro-BNP levels, and echocardiographic measurements were recorded for all patients. Valve morphology, aortic structure, diameters of the aortic root, ascending and descending aorta, ventricular function, and pro-BNP results were analyzed.

Results:

The most frequent valve morphology was cusp fusion, observed in 90 patients (71.4%). In terms of valve morphology, patients with cusp fusion exhibited a higher incidence of moderate AR compared to those with a pure bicuspid valve (P = 0.022). Significant differences in z-scores for the arch, isthmus, and descending aorta were found between valve shapes, with right-noncoronary cusp fusion patients showing higher z-scores (P = 0.005, P = 0.047, P = 0.011, respectively). The mean age and left ventricular diastolic diameter z-scores were higher in the tubular aortic phenotype group (P = 0.037 and P = 0.007, respectively).

Conclusion:

Patients with right-noncoronary cusp fusion should be closely monitored for aortic aneurysm and AR risk, and early preventive treatment should be initiated in these cases.

INTRODUCTION

Bicuspid aortic valve (BAV) is the most commonly encountered cardiac malformation, affecting 1%–2% of the population.[1,2] The clinical spectrum of BAV includes aortic valve dysfunction (regurgitation and/or stenosis) and aortopathy, characterized by dilation of the ascending aorta and/or aortic root.[3] Aortic enlargement is more common in patients with BAV than in the normal population.[4,5] BAV may remain asymptomatic in early life but has the potential to cause significant complications such as aortic dissection, rupture, or progressive valvular dysfunction, especially in adulthood.[6] However, several studies are inconsistent with the idea of a relationship between valve characteristics and ascending aorta dilation.[7,8] Previous adult studies have suggested that the risk factors associated with the progression of aortic dilation include older age, a higher body surface area, and the presence of moderate to severe aortic regurgitation (AR); however, risk factors for aortic dilatation in children with BAV have not been well defined.[9] In pediatric populations, the progression and impact of AR and aortic dilatation associated with BAV are less well understood. Understanding these factors early in life is crucial for risk stratification, timely follow-up, and management. Several studies have examined the prevalence and patterns of aortic dilatation in children with BAV, but data correlating AR severity with aortic measurements and morphologic phenotypes remain limited.

This study aims to evaluate factors affecting the development of aortic root dilatation and aortic insufficiency in pediatric patients with BAV, and to analyze the relationships among valve morphology, aortic dimensions, and clinical characteristics.

MATERIALS AND METHODS

Study population

This retrospective study was conducted at pediatric cardiology outpatient clinics between January 2017 and December 2020. A total of 156 children diagnosed with BAV, seeking consultation for murmur or chest pain evaluation, were initially included. Thirty patients with more than mild aortic stenosis (left ventricular outflow tract [LVOT] systolic flow velocity >2.5 m/s), additional congenital heart diseases, systemic disease (hypertension, diabetes mellitus, obesity, etc.), or a history of interventional or surgical procedures for BAV and arrhythmias were excluded. In addition, children unable to cooperate or whose parents did not consent to participate were excluded from the study. All participants’ physical examination findings, weight-height measurements, and systolic-diastolic blood pressures were recorded. The mean value of three consecutive blood pressure measurements was adopted as the final value. Echocardiographic measurements and serum pro-B-type natriuretic peptide (BNP) were examined on the day of the study. BAV phenotyping was performed as described in the previous literature.[10] The patients were grouped according to the degree of aortic valve regurgitation, as determined by echocardiographic evaluation. This research was reviewed and approved by the Institutional Ethics Committee of our university.

Echocardiography

All participants underwent two-dimensional, Doppler, and M-mode studies using a Philips Epiq 7-model echocardiography device (Philips Medical Systems, Bothell, Washington, USA) with a 5-MHz sector transducer, all performed by the same physician. Left ventricular end-systolic diameters (LVESD), left ventricular end-diastolic diameters (LVEDD), and aortic root diameters, the systolic functions of the left ventricle, were calculated from M-mode echocardiographic procedures in the parasternal long-axis view. Mitral and tricuspid inflow parameters, mitral E, mitral A, tricuspid E, and tricuspid A wave velocity were measured using pulse-wave Doppler echocardiography, and septal-mitral E, A, and S wave velocity using tissue Doppler imaging for the assessment of left ventricular diastolic function. The mitral E/E’ ratio was also calculated. The measurements were conducted using standard procedures as suggested by the American Society of Echocardiography.[11] The phenotype of the aortic valve was determined in the parasternal short-axis and long-axis views. The valve morphology was defined as type 1 for raphe and type 2 for pure type. Type 1 was divided into three groups – right-noncoronary (R-N), right-left (R-L), and left-noncoronary (L-N), according to the fusion type. Type 2 was divided into two groups: Anterior-posterior (A-P) opening and latero-lateral (L-L) opening, according to valve opening.[10]

LVOT systolic and diastolic flow velocities were measured using continuous-wave Doppler. An LVOT peak flow rate higher than 2.5 m/s was considered indicative of aortic stenosis. The severity of AR was classified as none/trivial, mild, and moderate, using semi-quantitative and qualitative echocardiographic methods such as vena contracta width, length and width of the regurgitant jet, jet width/LVOT diameter, and the presence of the reverse diastolic flow in the descending aorta.[12] In addition, in cases where patients have more than one regurgitation jet, the degree of regurgitation was calculated by summing the thickness of each regurgitation jet separately.

Diameters of the aortic annulus were measured at the end of systole, the sinus of Valsalva, the sinotubular junction, the isthmus, the ascending aorta 3 cm distal to the aortic annulus, the proximal aortic arch between the truncus brachiocephalicus and the left carotid artery, and the abdominal aorta at the level of the diaphragm at the end of the diastole. An average of three consecutive beats was taken, and diameters were indexed to the z-scores obtained using Detroit data.[13] All aortic measurements were obtained as previously described by Lacombe et al.[14] In addition, we defined the type of aortic dilatation by dividing it into three aortopathy phenotypes-ascending aorta, aortic root, and tubular.[8]

Statistical analysis

Statistical analyses were performed on SPSS for Windows software (version 24.0; IBM Corp., Armonk, NY, USA). Descriptive statistical methods (mean, standard deviation [SD], median, frequency, ratio, 25^th percentile, and 75^th percentile) were used while evaluating the study data. The skewness, Kolmogorov–Smirnov, and Shapiro–Wilk tests, along with histogram graphs, were used as the criteria for fitting a normal distribution to numerical data. The Chi-square and Fisher’s exact tests were used to compare categorical data between independent groups. Student’s t-test was used to compare mean values for normally distributed continuous variables between two independent groups. A one-way ANOVA test was applied to compare mean values for nonnormally distributed categorical variables between more than two independent groups. The Mann–Whitney U-test was used to compare the median values of nonnormally distributed continuous variables between two independent groups. The Kruskal–Wallis test was used to compare the median values of nonnormally distributed continuous variables between more than two independent groups. P < 0.05 was considered statistically significant.

RESULTS

Patients demographics

The study group consisted of 126 patients with BAV, aged between 2 and 17 years (mean ± SD: 9.7 ± 4.1, median: 9 years). Ninety-four (74.6%) of the patients were boys and 32 (25.4%) were girls. The patients were classified into three groups based on the degree of valve regurgitation. Forty-seven patients (37.3%) had trace or no AR, 53 (42.1%) had mild AR, and 26 (20.6%) had moderate AR. The mean body mass index (BMI) of the patients was 18.01 ± 3.77 kg/m² (median: 17.52 kg/m², range: 11.1–29.6 kg/m²), and a statistically significant difference was observed between the groups according to the degree of valve regurgitation. The patients’ demographic, clinical, and laboratory characteristics are listed in Table 1.

Table 1.

Demographic and clinical characteristics of the patient groups

Degree of AR		None/trivial (n=47)		Mild (n=53)		Moderate (n=26)		P
Male/female, n (%)		13/34 (40.6/36.2)		10/43 (31.3/45.7)		9/17 (28.1/18.1)		0.289
Age (years)		8.83±4.21		9.91±3.79		10.88±4.33		0.110
Weight (kg)		125 (115–157)		138 (125–155)		145 (122–165)		0.163
Height (cm)		26 (19–46)		38 (25–46)		41.5 (23–55)		0.075
BSA (m2)		0.93 (0.75–1.40)		1.23 (0.89–1.38)		1.29 (0.86–1.56)		0.086
BMI		16 (14.6–19.09)		18.4 (15.6–20.7)		19.55 (15–21.8)		0.035
SBP (mmHg)		102.87±12.21		103.19±10.88		104.42±12.3		0.850
DBP (mmHg)		60 (56–65)		60 (59–67)		60 (54–70)		0.527
Pro-BNP (mg/dL)		30.3 (16.5–85.2)		56.6 (32.9–93.4)		39 (20.2–90.4)		0.146
Valve morphology
R-N		10		13		17		0.022
R-L		17		18		6
L-N		6		1		2
L-L		12		15		2
A-P		3		4		0
Aortopathy type
Asc Ao		19		23		16		0.667
AoR		9		10		3
Tubular		4		6		1
Normal		15		14		6

Asc Ao: Ascending aorta, AoR: Aortic root, A-P: Anterio-posterior, DBP: Diastolic blood pressure, L-L: Latero-lateral, R-N: Right-noncoronary, R-L: Right-left, SBP: Systolic blood pressure, BMI: Body mass index, BNP: B-type natriuretic peptide, AR: Aortic regurgitation, BSA: Body surface area

Echocardiographic findings

The most common valve morphology was Type 1, observed in 90 patients (71.4%), comprising the R-L cusp fusion phenotype in 41 patients (32.5%), the R-N cusp fusion phenotype in 40 (31.7%), and the L-N cusp fusion phenotype in nine (7%). Type 2 was observed in 36 (28.6%) patients, with L-L opening in 29 (23.1%) and A-P opening in seven (5.5%). Among the patients with the R-N cusp fusion phenotype, 17 (42.5%) had moderate valve regurgitation, and 13 (32.5%) mild regurgitation. Among patients with the R-L cusp fusion phenotype, six (14.6%) had moderate valve regurgitation, and 18 (43.9%) had mild regurgitation. Of the patients with L-L opening valve, 15 (51.7%) had mild valve regurgitation, and two (6.9%) had moderate regurgitation. A statistically significant relationship was found between valve phenotype and the degree of AR. In terms of valve morphology, patients with cusp fusion exhibited a higher incidence of moderate AR than those with pure bicuspid valves (P = 0.022). The groups were compared in terms of M-mode values. No significant differences were observed in terms of means of left ventricular ejection and shortening fraction and LVEDD/LVESD z-scores between the groups (P > 0.05). No difference was observed between the groups in terms of mitral and tricuspid inflow parameters measured using pulse wave Doppler and tissue Doppler echocardiography (P > 0.05).

Aortic diameter z-scores

No significant differences were found in aortic diameter z-scores between the groups based on AR degree (P > 0.05) [Table 2]. However, statistically significant differences were observed in z-scores measured from the arch, isthmus, and descending aorta (P = 0.005, P = 0.047, and P = 0.011, respectively). The z-scores measured from the aorta and valve shape were compared. Patients with R-N cusp fusion exhibited higher z-scores for these aortic regions compared to the other groups [Table 3].

Table 2.

Distribution of z-scores of patients according to aortic regurgitation

z-scores		None/trivial (n=47)		Mild (n=53)		Moderate (n=26)		P
LVEDD		0.18 (−0.71–0.78)		0.39 (−0.32–0.88)		0.35 (−0.16–1.78)		0.222
LVESD		−0.1±0.93		0.09±0.77		0.16±1.02		0.386
Aortic annulus		1.7±1.09		1.85±1.1		2.09±0.98		0.335
SV		0.23±1.09		0.11±1.22		0.05±1.1		0.792
STJ		0.76 (0.09–1.62)		0.85 (0.03–1.39)		1.05 (0.06–1.63)		0.795
Asc Ao		1.66 (0.52–2.86)		1.32 (0.22–2.7)		1.68 (0.32–2.19)		0.845
Arcus Ao		0.8 (−0.37–1.44)		0.81 (0.07–1.3)		0.81 (0.25–1.2)		0.863
Isthmus Ao		1.16±1.09		1±1.04		1.07±1.13		0.761
Desc Ao		−0.22 (−1.13–0.62)		−0.28 (−1.14–0.35)		0.16 (−0.69–0.68)		0.229
Abdo Ao		−0.51±1		−0.56±0.78		−0.22±0.79		0.252

Abdo Ao: Abdominal aorta, Arcus Ao: Arcus aorta, Asc Ao: Ascending aorta, Desc Ao: Descending aorta, LVEDD: Left ventricular end-diastolic diameter, LVESD: Left ventricular end-systolic diameter, STJ: Sinotubular junction, SV: Sinus valsalva

Table 3.

Aortic z-scores of patients with bicuspid aortic valve according to valve phenotypes

z-scores		R-N		R-L		L-L		A-P		P
Aortic annulus		2.01±1.07		1.65±1.03		2.01±1.06		1.16±1.23		0.114
SV		−0.07±1.12		0.25±0.97		0.23±1.40		0.58±0.87		0.350
STJ		0.72 (−0.03–1.58)		0.87 (0.03–1.42)		0.89 (0.24–1.49)		0.86 (0.3–1.23)		0.890
Asc Ao		1.65 (0.08–2.78)		1.53 (0.32–2.57)		1.63 (1.06–2.62)		1.25 (0.75–1.81)		0.919
Arcus Ao		1.12 (0.49–1.76)		0.39 (−0.78–0.98)		0.54 (−0.16–1.3)		0.92 (−0.93–1.2)		0.005
Isthmus Ao		1.35±1.12		0.75±1.00		1.14±1.00		0.77±1.07		0.047
Desc Ao		0.12 (−0.74–0.55)		−0.76 (−1.3–0.09)		0.11 (−0.22–0.67)		−0.86 (−1.41–1.26)		0.011
Abdo Ao		−0.49±0.96		−0.56±0.69		−0.16±0.83		−1.03±1.20		0.690

Abdo Ao: Abdominal aorta, Arcus Ao: Arcus aorta, Asc Ao: Ascending aorta, Desc Ao: Descending aorta, R-N: Right-noncoronary, R-L: Right-left, L-L: Latero-lateral, A-P: Anterior-posterior, STJ: Sinotubular junction, SV: Sinus valsalva

The distribution of age, gender, BMI, body surface area, systolic blood pressure, diastolic blood pressure, and pro-BNP measurements, LVEDD-LVESD z-scores, valve morphology, and degree of AR according to aortic dilatation types in terms of z-scores was examined. Statistically significant differences were determined between the groups in terms of age and LVEDD z-scores. Mean age and LVEDD z scores were higher in the group with tubular dilatation than in the other group (P = 0.037 and P = 0.007, respectively) [Table 4].

Table 4.

Patients’ demographic, clinical, and echocardiographic features according to aortic dilatation type

		Aortic root dilatation		Asc Ao dilatation		Tubular dilatation		P
Age (years)		9.08±3.83		9.69±4.09		12.93±3.69		0.007
Gender
Female		6		7		2		0.624
Male		30		22		13
Height (cm)		135.39 (120–151)		138.03 (120–155)		150.27 (136–165)		0.085
Weight (kg)		35.96 (21–45.5)		37.60 (22–52)		42.51 (25–53)		0.331
BMI		18.44 (15.38–20.65)		17.89 (14.56–19.9)		18.05 (16.21–19.5)		0.552
BSA		1.14±0.35		1.17±0.44		1.30±0.35		0.391
SBP		101.08±11.08		104.14±14.01		105.60±11.85		0.416
DBP		61.94 (58–69)		62.59 (59–67)		64.40 (59–70)		0.737
Pro-BNP		70.91 (21.52–94.32)		70.91 (28.3–94.14)		47.71 (15.8–55)		0.235
BAV phenotype
R-N		15		12		5		0.255
R-L		6		12		5
L-L		13		4		5
A-P		2		1		0
Degree of AR
None		14		8		5		0.265
Mild		14		11		9
Moderate		8		10		1

A-P: Anterior-posterior, AR: Aortic regurgitation, BAV: Bicuspid aortic valve, BMI: Body mass index, BSA: Body surface area, DBP: Diastolic blood pressure, L-L: Latero-lateral, R-N: Right-noncoronary, R-L: Right-left, SBP: Systolic blood pressure, AR: Aortic regurgitation, BNP: B-type natriuretic peptide, Asc Ao: Ascending aorta

DISCUSSION

BAV was initially described as a valve phenotype with a tendency to develop valve obstruction and regurgitation.[15] However, in recent years, it has been realized that BAV is not only a valve disease, but also a disease of the entire aorta.[4,5] It is important to determine the factors that predict dilatation beforehand, as this can cause life-threatening complications such as rupture and dissection. Early detection and prevention of BAV complications are, therefore, highly important.[16] However, the cause of aortic complications remains unclear.

This retrospective cross-sectional study demonstrates that AR, aortic phenotype, and other factors such as age and left ventricular diastolic function can influence the degree of aortic dilatation in children with BAV. The few studies analyzing risk factors for valve degeneration in BAV have identified age, dyslipidemia, increased BMI, and the presence of raphe.[17] In the present study, mild to moderate valve regurgitation was identified in 56% of cases, and only BMI was found to be associated among the traditional risk factors. Other studies have reported that moderate or more severe AR is associated with higher aortic root and ascending aortic diameter z-scores, although it is unclear whether dilatation causes regurgitation, whether regurgitation causes dilatation, or if they are independent processes.[9,18,19] In contrast to some studies, we found no direct correlation between the degree of AR and aortic dilation, which may be attributed to the exclusion of patients with severe AR.

Valve dysfunction is most common in R-N cusp fusion valve morphology in adult studies, and a poor long-term prognosis has been shown in this group due to the presence of significant hemodynamic lesions.[20,21,22,23] On the other hand, pediatric studies have found that the R-L type was associated with a higher risk of valve dysfunction and earlier presentation of AR.[24,25] The relationship between valve morphology and aortic dilation remains inconsistent in the literature, with some studies reporting a greater propensity for aortic root dilation in R-L cusp fusion phenotypes, while others report a higher prevalence of ascending aorta dilation in R-N cusp fusion cases. Our findings align with previous adult studies suggesting that cusp fusion, particularly the right-noncoronary fusion, is associated with increased risk of moderate AR and aortic dilation.

Previous studies have reported a prevalence of aortic dilatation ranging from 16% to 78% at the sinus of Valsalva and 33%–68% at the ascending aorta.[6] Previous studies have also reported that patients with R-L cusp fusion valve morphology exhibit aortic root dilatation, while patients with R-N cusp fusion valve morphology exhibit ascending aorta dilatation.[21,22] In the present study, the prevalence of aortic dilatation was 64% (28.57% in the aortic root, 23.02% in the ascending aorta, and 11.9% in tubular dilatation). No significant difference was found in terms of valve morphology. The results of the present study revealed higher mean ages and LVEDD z-scores, especially in the group with tubular dilatation, compared to the other groups. A direct correlation between age and aortic dilatation in patients with BAV has also been reported. Inconsistent data have been presented regarding the relationship between BAV morphology and aortic dilatation due to various factors such as patient populations or measurement methods.[7,22] However, a statistically significant difference was observed in the present study in valve morphology in terms of z-scores measured from the arch, isthmus, and descending aorta. Patients with R-N cusp fusion exhibited higher z-scores than those in the other groups.

The most common phenotype of aortopathy in the present study was ascending aorta type (46%), but no significant association was determined between valve morphology and type of aortopathy. Kang et al.[8] suggested that normal aorta was the most common phenotype in BAV patients with A-P opening valve morphology, and that type 3 aortopathy was the most common phenotype in BAV patients with R-L cusp fusion valve morphology. Those authors also reported no difference in ascending aorta dimensions in terms of valve morphology. While we did not find a clear association between valve morphology and specific aortopathy phenotypes, our study emphasizes the need for further prospective studies to clarify these relationships and improve patient risk stratification.

This study has several limitations. The absence of a control group and the retrospective nature of the study reduce the generalizability of the findings. In addition, the exclusion of patients with severe AR means that the full spectrum of valve regurgitation was not represented. Prospective studies with longer follow-up and inclusion of a control group are needed to validate these findings. It is also a limitation that our study did not include a group showing the prevalence and type of aortic dilatation in children with BAV without aortic stenosis or AR. A study including this group is planned in the near future.

CONCLUSIONS

In summary, this study highlights the importance of closely monitoring children with right-noncoronary cusp fusion in terms of their risk for aneurysm and AR. Early identification and intervention are key to preventing the life-threatening complications associated with aortic dilation in these patients.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.