Aortic stiffness and left ventricular diastolic function in children with well-functioning bicuspid aortic valves

Abstract

Aims

Aortic stiffness and diastolic function are abnormal in adults with bicuspid aortic valves (BAVs). The goal of this study was to determine the relationship between aortic stiffness and left ventricular (LV) diastolic impairment in children with well-functioning BAV and no associated congenital heart disease.

Methods and results

This is a retrospective review of echocardiograms in children with isolated BAV (group BAV; N = 50) and healthy frequency-matched controls (group Control; N = 50). We analysed LV systolic and diastolic function, proximal and distal ascending aortic stiffness index (SI), distensibility, and strain. Age range was 0.2–20 (median 11) years. There was no significant difference in blood pressure, normalized LV size and systolic function between the groups. Several parameters of LV diastolic function were lower in group BAV compared with group Control (e.g. septal E′: BAV 12 ± 2.3 cm/s; Control 13.5 ± 1.8 cm/s, P < 0.001). All parameters of proximal and distal ascending aortic elasticity were abnormal in group BAV vs. Control (SI proximal ascending aorta: BAV 4.2 ± 1.6; Control 3.0 ± 0.9, P < 0.001). There was no significant correlation between parameters of aortic elasticity and diastolic function. In a subgroup analysis of children with fusion of the right-non vs. right-left coronary cusps, there was no significant difference for any of the parameters analysed.

Conclusion

Even children with well-functioning isolated BAV have abnormalities in aortic elasticity and diastolic function when compared with the Control group. However, a relationship between the two could not be established.

Introduction

Patients with bicuspid aortic valves (BAVs) are known to have degenerative changes of the aortic wall similar to Marfan syndrome.^1,2 Even though generally the cardiovascular phenotype, and natural history of isolated BAV differs from Marfan syndrome, Fibrillin 1 mutations have been reported in a few patients with BAV who did not carry the clinical diagnosis of Marfan syndrome. This suggests that the genetic disease mechanism may be similar for some patients with BAV.³ On a functional level, the histologic abnormalities of the aorta translate into increased aortic stiffness in adults and children.^4–7 Histologic or functional abnormalities involve not only the ascending aorta, but also the aortic root, descending aorta, and pulmonary artery.^2,8–10 Left ventricular (LV) diastolic dysfunction has been described in adults even if the BAV functions well.^11–13 It is unclear if children with well-functioning isolated BAV have impaired LV relaxation or if this develops later in life. It is the primary hypothesis of this study that in children with isolated well-functioning BAV both aortic elasticity and diastolic function are abnormal, and that there is a relationship between the two. It is our secondary hypothesis that cusp fusion pattern predicts the degree of aortic stiffening.

Methods

This is a retrospective cohort study of 50 patients (age 0–21 years) with isolated bicuspid aortic valves (group BAVs) and 50 control subjects (group Control) of similar age, body surface area (BSA), and gender distribution. Echocardiograms were performed between September 2010 and November 2013.

Exclusion criteria for the BAV group were prior surgical or catheter-based intervention, more than mild aortic stenosis (mean >20 mmHg), more than mild aortic regurgitation, associated repaired or non-repaired cardiac anomalies (e.g. aortic coarctation), LV hypertrophy, or systolic dysfunction. The control subjects were selected from normal echocardiograms performed for evaluation of a heart murmur, chest pain, palpitations, and/or syncope. Patients with known genetic disorders, haematologic, oncologic, or rheumatologic diagnoses were excluded. Baseline characteristics such as gender, age, weight, height, BSA and blood pressure, and heart rate were recorded. The Institutional Review Board approved this retrospective data review.

Non-sedated echocardiograms were performed using the Philips IE33 (Philips Medical Systems, Andover, MA, USA), the GE Vivid 9 (General Electric, Milwaukee, WI, USA), and Siemens Sequoia SC2000 (Siemens Medical Solutions USA, Mountain View, CA, USA) equipment. Probe frequency was selected according to patient size. Echocardiograms were performed according to the paediatric guidelines of the American Society of Echocardiography.¹⁴ Measurements were performed offline (Synapse Cardiovascular version 4.0.9, FUJIFILM Medical Systems U.S.A., Inc.) and averaged over three cardiac cycles. All measurements were performed by one of two investigators (K.C.L. and C.G.W.). Interobserver reliability was previously assessed for all parameters.¹⁵

As previously described, two-dimensional (2D), colour Doppler, blood pool and tissue pulse wave (PW) Doppler and continuous wave Doppler as well as M-mode measurements were made to characterize LV structure, systolic, and diastolic function.¹⁵ Z-scores were used for data analysis as appropriate.¹⁶ For the BAV group, mean gradients across the aortic valve and degree of aortic insufficiency were collected. Measurements of the ascending aorta were obtained at two sites using the trailing edge-to-leading edge method as previously described.¹⁵ In brief, proximal ascending aortic measurements were made from a parasternal long-axis view at the level of the right pulmonary artery. The distal ascending aortic dimension was recorded just proximal to the origin of the innominate artery. A right arm blood pressure was obtained at the time of the echocardiogram. From those measurements aortic distensibility (DI), stiffness index (SI), and strain were derived: $\text{DI}=2(\text{SD}-\text{DD})/[\text{DD}(\text{SBP}-\text{DBP})]{10}^{-6}\text{c}{\text{m}}^2/\text{dyne};$ $\text{SI}=\text{ln(SBP}/\text{DBP)}\times (\text{DD})/(\text{SD}-\text{DD});$ $\text{Strain}=\text{SD}-\text{DD})/\text{DD}.$^17–19

An a priori sample size analysis was carried out using PASS 2008 (NCSS Statistical Software, LLC, Kaysville, UT, USA). Using a previously published study in a similar paediatric population,⁵ we have over 80% power using a two-sided Mann–Whitney test at alpha = 0.017 to detect a difference in SI means of 4.5 ± 1.8 in the BAV group and 3.5 ± 1.0 in the Control group, a difference in DI means of 6.5 ± 2.0 × 10⁻⁶ cm²/dyne in the BAV group compared with 7.8 ± 2.0 × 10⁻⁶ cm²/dyne in the Control group, and the difference in strain means of 16 ± 4.5 vs. 22 ± 4.5% between the two groups. Furthermore, if there were a clinically meaningful correlation between the measures of aortic elasticity and diastolic function, such as in the range of 0.30–0.70, then we would be able to estimate a two-sided 95% confidence intervals for the correlation of width 0.55.

For statistical analysis, continuous variables were expressed as median (range). T-tests for independent or related samples as appropriate were used to compare group means of measures of aortic elasticity and diastolic function. Non-parametric statistics were used in the analyses of SI, DI, and strain by group (BAV/Control) and by age (0–6 years old, 7–12 years old, 13–20 years old) because we observed heteroscedasticity of variances in the outcomes of interest across the levels of independent predictor variables. Therefore, differences between groups at each level of age were compared using the two-tailed Mann–Whitney test for independent samples. Categorical variables were expressed as frequency and compared by the Fisher's exact test. Variables were associated using Pearson's correlation coefficient (r). Where appropriate, Bonferroni correction of alpha level was used to adjust for multiple comparisons (e.g. we used three outcomes to look at aortic elasticity, therefore, α= 0.05/3 = 0.017). Statistical analysis was performed using Statistical Package for Social Sciences, version 19 (IBM SPSS, Chicago, IL, USA).

Results

The age of patients with BAV (N = 50) and control subjects (N = 50) ranged from 2 months to 20 years (mean 10.8 ± 4.9 years). There was no significant difference in age, gender distribution, weight, height, BSA, heart rate, and blood pressure between the two groups (Table 1). In the BAV group, 29 patients (58%) had fusion of the right and left coronary cusps, and 21 patients (42%) had fusion of the right and non-coronary cusps. All BAV patients had at most mild aortic stenosis and/or insufficiency. None of the patients had undergone prior catheter-based or surgical intervention, and no one had associated congenital heart defects. Of note, 11 patients (3 control and 8 BAV) had missing or inadequate pulmonary vein PW Doppler, and 3 BAV patients had no adequate distal ascending aortic images. LV size, and wall thickness normalized to BSA, and shortening fraction were not significantly different between the BAV and Control groups (data not shown).

Table 1.

Baseline demographics of the study population

	BAV (N = 50)	Control (N = 50)
Male/female (n)	38/12	38/12
Age (years)	10.9 (0.2–20.2)	11 (0.3–17.9)
BSA (m2)	1.2 (0.3–2.5)	1.3 (0.3–2.1)
HR (b.p.m.)	82 (49–159)	75 (53–125)
SBP (mmHg)	109 (73–136)	109 (84–137)
DBP (mmHg)	61 (28–91)	60 (46–87)
Aortic valve mean gradient (mmHg)	8 (2–19)	N/A
Aortic regurgitation (n)	19 none	50 none
	14 trivial
	17 mild
Age groups (n)	BAV (RL/RN)	Control
0–6 years	9 (5/4)	13
7–12 years	23 (12/11)	20
13–20 years	18 (12/6)	17

Data are expressed as number (n) or median (range) as appropriate.

The BAV group compared with the Control group had significantly higher mitral A wave velocities and a lower E/A ratio (Table 2). Tissue Doppler was significant for a lower septal and lateral mitral valve annular E′ velocity, and higher corresponding E/E′ ratios in the BAV compared with the Control group (Table 2 and Figure 1A). There was a trend towards increased pulmonary venous A wave velocity in the BAV compared with the Control group, but this did not reach statistical significance following Bonferroni correction. Furthermore, there was no significant difference in left atrial size between the two groups.

Table 2.

Longitudinal systolic and diastolic functions and aortic elastic parameters

	BAV	Control	P
Left atrium
Volume (mL/m2)	19.3 (8.4–27)	19.1 (9.9–19.1)	0.627
Right pulmonary vein Doppler
S (cm/s)	49 (34–64)	48 (32–73)	0.970
D (cm/s)	56 (36–77)	61 (27–81)	0.050
A (cm/s)	23 (16–40)	21 (13–31)	0.021
Mitral valve Doppler
E (cm/s)	100 (62–133)	99 (78–134)	0.694
A (cm/s)	51 (31–93)	42 (29–105)	0.010*
E/A ratio	1.9 (1–3.6)	2.2 (0.8–4)	0.003*
ΔA-dur (ms)	−9 (−130–65)	−5 (−103–24)	0.655
Tissue Doppler, septal
S′ (cm/s)	7.9 (5.3–13.9)	7.7 (6–10.4)	0.170
E′ (cm/s)	12 (7.3–19.2)	13.7 (9.7–17.2)	<0.001*
A′ (cm/s)	7 (4.3–11)	6 (3.6–8.8)	<0.001*
E/E′	8.2 (5.3–13.4)	7.5 (4.7–10.4)	0.002*
Tissue Doppler, lateral
S′ (cm/s)	9.2 (6.3–14.2)	9.4 (6–15.2)	0.274
E′ (cm/s)	17.2 (6.3–28)	19.5 (9.7–28)	0.003*
A′ (cm/s)	6.7 (4–12)	6.0 (3.5–10.4)	0.075
E/E′	6.2 (3.9–10.1)	5.2 (3.5–9.2)	0.014*
Ascending aorta, proximal
SI	3.9 (2–9.4)	3 (1.7–6.4)	<0.001*
DI (10−3 cm2/dyne)	0.0065 (0.0027–0.0121)	0.0083 (0.0037–0.0153)	<0.001*
Strain (%)	15.7 (6.9–26.1)	20.4 (10.6–33.4)	<0.001*
Ascending aorta, distal
SI	3.5 (1.4–7.5)	2.8 (1.5–4.6)	<0.001*
DI (10−3 cm2/dyne)	0.0071 (0.0032–0.0168)	0.0092 (0.0053–0.0174)	<0.001*
Strain (%)	16.4 (9.6–33.6)	20.8 (12.4–32.2)	<0.001*

Data are presented as median (range). P-values considered statistically significant are marked by an asterisk.

Figure 1.

Box plots for septal E′ (A) and proximal ascending aortic SI (B) in the BAV group compared with the Control group.

All parameters of aortic elasticity, i.e. DI, SI, and strain, were highly abnormal in our patients with well-functioning BAV (Table 2 and Figure 1B), when compared with the Control group. This pertained to both proximal and distal ascending aortic measurements. However, no correlation could be established between parameters of diastolic function and ascending aortic elasticity. When controlling for diagnosis, exemplary correlation coefficients of septal E′ with proximal parameters were as follows: DI = −0.069, P = 0.496; SI = 0.098, P = 0.336, strain = −0.003, P = 0.978.

In a subgroup analysis of the two different BAV morphologies, i.e. fusion of the right-non (RN) vs. right-left (RL) coronary cusps, there was no significant difference in any of the parameters of diastolic function, or aortic elasticity indices following Bonferroni correction (data not shown).

When comparing proximal and distal indices of aortic elasticity, there was no significant difference in the Control group. In the BAV group, however, there was a trend towards a lower aortic DI (P = 0.057) and strain (P = 0.036), and a higher SI (P = 0.022), in the proximal ascending aorta compared with the distal ascending aorta (Table 2).

Finally, we evaluated the effect of age on proximal and distal ascending aortic elasticity indices. The aortic elasticity indices of the proximal ascending aorta in the BAV group were impaired in the 7–12 and 13–20 year age groups, but not in the youngest age group (Table 3, Figure 2A and B). For the distal ascending aorta, however, aortic elasticity in the BAV group was impaired in all age groups, although less consistently compared with the proximal ascending aortic measurements (Figure 2C and D).

Table 3.

Effect of age on ascending aortic elasticity parameters in children

Age (years)	BAV			Control
	DI (10−3 cm2/dyne)	SI	Strain (%)	DI (10−3 cm2/dyne)	SI	Strain (%)
Proximal ascending aorta
0–6	0.0075 (0.005–0.012)	4.1 (2.1–6.3)	16.3 (9.6–21.1)	0.0095 (0.0065–0.0123)	3.0 (2.5–3.8)	18.3 (14.9–25.0)
7–12	0.0073 (0.0035–0.012)*	3.4 (2–7.4)*	15.8 (8.8–26.1)*	0.0088 (0.0053–0.0153)	2.5 (1.7–4.4)	22.3 (15.8–33.4)
13–20	0.0047 (0.0027–0.0079)*	4.7 (3–9.4)*	12.3 (6.9–21.3)*	0.0075 (0.0037–0.0125)	3.3 (1.8–6.5)	19.4 (10.6–30.2)
Distal ascending aorta
0–6	0.008 (0.0051–0.0168)*	4.2 (1.4–5.5)	14.4 (9.6–33.6)*	0.0109 (0.0087–0.0156)	2.5 (1.9–3.0)	22.3 (19.2–27.5)
7–12	0.0084 (0.0054–0.0133)	3.1 (2–4.8)	17.6 (9.9–30)*	0.0093 (0.0058–0.0174)	2.6 (1.5–4.0)	21.7 (14.0–32.2)
13–20	0.0055 (0.0032–0.0168)*	4.1 (2.2–7.5)	13.9 (10–25.1)*	0.0068 (0.0053–0.011)	3.3 (2–4.6)	19.6 (12.4–27.4)

Data are presented as median (range). Asterisks mark parameters in the BAV group that are significantly different from the control group (P < 0.017 for parameters of aortic elasticity due to Bonferroni correction).

Figure 2.

Change of proximal (A and B) and distal (C and D) ascending aortic DI (10⁻³ cm²/dyne; A and C), and SI (B and D) with age during childhood in the BAV group (white bar) compared with the Control group (grey bar). P-values are noted in the graphs.

Discussion

We show for the first time that children with well-functioning BAV have not only abnormal ascending aortic elasticity but also abnormalities in some parameters of diastolic function compared with controls. However, no relationship between diastolic function and aortic elasticity could be established.

Increased arterial stiffness has been described in children and adults with BAV and is unrelated to aortic dilation.^7,20 Even though generally the cardiovascular phenotype, genotype, and natural history of isolated BAV is quite different from Marfan syndrome, there have been reports of histologic, genetic, and cardiovascular functional similarities.^{1–3,9,21,22} The histologic abnormalities are thought to lead to increased aortic stiffness in patients with BAV. The latter has been well studied in the adult population and is a risk factor for cardiovascular events and mortality.²³ With increased vascular stiffness the PW velocity is increased, and thus the reflected wave returns to the heart early (i.e. in late systole). This increase in late systolic afterload affects thick–thin myofilament interactions and crossbridge dissociation, which leads to impaired relaxation.^24,25 We recently published that children with repaired aortic coarctation have a linear relationship between proximal ascending aortic stiffness and diastolic impairment, suggesting that diastolic impairment is a secondary phenomenon.¹⁵ The data on children with BAV presented here failed to show such a relationship, in spite of a larger sample size. It is therefore possible that both are intrinsic problems, i.e. diastolic myocardial abnormalities exist independent of aortic valve disease and increased aortic stiffness. We suggest that BAV disease may not be confined to the aorta and aortic valve, and may also involve the myocardium—which could be due to a common genetic variant. It should be noted, however, that the magnitude of changes in both aortic elasticity and diastolic function in the current study is small. While parameters of diastolic function in the BAV group were significantly different compared with our Control group, and a significantly higher number of BAV subjects had septal E′ velocities and/or septal E/E′ ratios outside the normal paediatric range for age (i.e. >2 SDs; P = 0.007 and 0.006, respectively), only 13% of septal E′ and 23% of septal E/E′ in the BAV group were actually outside the normal paediatric range for age.²⁶ Furthermore, this study was retrospective and did not include vascular parameters such as PW velocity, augmentation index, or characteristic impedance. Therefore, a correlation of those parameters with diastolic function cannot be excluded, and there is the possibility of a type I error.

In adults with BAV the data on vascular–ventricular interaction as a mechanism for diastolic dysfunction is controversial. To date, only one study has reported a correlation of LV diastolic parameters with aortic stiffness in adults with BAV, while others failed to show such a relationship.^{11–13,27,28} While this needs to be validated in larger studies, it is possible that vascular–ventricular interaction as a mechanism for diastolic dysfunction increases with patient age and increasing aortic stiffness.

Our secondary hypothesis was that BAV cusp fusion pattern is able to predict the degree of increased aortic stiffness. It has previously been suggested in a similar size study of children with BAV with and without significant valve dysfunction that RL fusion pattern (antero-posterior phenotype) is associated with stiffer aortic roots.⁵ Even though our study was adequately powered, we were not able to reproduce this finding for the ascending aorta. Meanwhile, a large adult study on 191 patients with BAV was also unable to establish a correlation between BAV morphology and ascending aortic stiffness.⁴

Limitations of this study are the retrospective design, lack of longitudinal follow-up, and inability to blind to patient diagnosis. Furthermore, we based our power analysis on aortic root data in children since this data is the closest to our study population.⁵ However, this may not be representative of ascending aortic elasticity. It is therefore possible that the study is underpowered for the subgroup analysis. Finally, right arm blood pressure was used to calculate SI and DI. This could differ from central aortic pressure, which may be a stronger predictor of cardiovascular outcome.²⁹

In conclusion, even children with well-functioning isolated BAV have subtle abnormalities in aortic elasticity and diastolic function. However, a relationship between the two could not be established. Furthermore, cusp fusion pattern in children with well-functioning BAV does not appear to determine ascending aortic stiffness.

Conflict of interest: L.S.: speaker's bureau for Philips; software and research equipment for Siemens.