Aortic stiffness in aortic stenosis assessed by cardiovascular MRI: a comparison between bicuspid and tricuspid valves

Asymptomatic patients with moderate to severe AS were prospectively recruited as part of a multicentre study conducted in the UK (PRIMID-AS study) [15]. Patients with more than mild degree of other valve disease, including aortic regurgitation, were excluded. Asymptomatic controls with no valve disease were also recruited for comparison.

The study was approved by the United Kingdom National Research Ethics Service (11/EM/0410) and written informed consent was obtained from all subjects before participation.

All subjects underwent a comprehensive trans-thoracic echocardiogram as per international guidelines, to quantify AS severity. In addition, mitral inflow velocities and tissue Doppler imaging (TDI) was used to assess diastolic function. Pulsed-wave Doppler was performed at the mitral valve tips to calculate the E/A ratio, and pulsed-wave TDI was used to measure the septal and lateral mitral annular velocity, for calculation of the septal and lateral E/e’.

Cine imaging was performed as previously described [16] on 3T scanners to determine left ventricular (LV) volumes, mass and function. In addition, steady-state free precession (SSFP) cine images of the aortic valve (or gradient-echo if significant artefacts were present), and a high temporal resolution cine image of the ascending (AA) and descending aorta (DA) at the level of the pulmonary artery bifurcation (slice thickness 6 mm, reconstructed to 40 phases, temporal resolution ~ 20 ms, matrix 192 × 256), were acquired. These cine images were used to measure aortic cross-sectional areas throughout the cardiac cycle and calculate distensibility [17] (Fig. 1). A retrospectively gated phase-contrast velocity-encoded sequence (typical parameters: slice thickness 5 mm, VENC 250 cm/s, reconstructed to 100–128 phases, temporal resolution ~ 10 ms, TE 4 ms, matrix 176 × 256), optimised for the study with high temporal resolution and a large number of reconstructed phases, was acquired perpendicular to the ascending and descending thoracic aorta to calculate through-plane flow. As the planning of the slice was far away from the aortic valve, a VENC of 250 cm/s was adequate in most cases, but if aliasing artefact was noted, then a repeat acquisition with a slightly higher VENC was performed. Brachial artery blood pressure was recorded at the time of the aortic cine acquisition to calculate the pulse pressure. A sagittal oblique view of the aortic arch was acquired to calculate the distance between sections for flow measurements in the ascending and descending aorta (Fig. 2). In addition late gadolinium enhancement (LGE) and pre- and post-contrast T1 mapping was performed for calculation of extracellular volume fraction, as previously described [16, 18].

All analyses were performed offline at the core lab, blinded to patient details, by a single observer (AS). LV volume and function were assessed using cvi42 V5 (circle cardiovascular imaging), excluding papillary muscle and trabeculations from the myocardial mass [19]. Valve morphology was classified according to Schaefer [20] with fusion of left and right coronary cusps in type-I BAV and right and non-coronary cusps in type-II BAV patients (there were no type-III patients in this cohort). Aortic root dimensions were measured at the annulus, sinus of Valsalva, sinotubular junction and proximal AA on the standard 3-chamber and the coronal LVOT views and an average was taken. Ascending and descending maximum and minimum aortic areas were measured from the aortic cine at the pulmonary artery bifurcation level. Aortic distensibility (in 10⁻³ mmHg⁻¹) was calculated using the following equation [14, 17]:where Amax and Amin are the maximum and minimum aortic cross-sectional areas, and PP is the pulse pressure, i.e., systolic blood pressure − diastolic blood pressure (mmHg).

PWV was assessed in the segment including the ascending aorta, the aortic arch and the proximal descending aorta up to the level of the pulmonary artery bifurcation (Fig. 2). PWV (in m/s) was calculated from:where Δx is the distance around the aortic arch between the two sections through the ascending and descending aorta, and Δt is the transit time delay of two volume flow rate curves for the descending and ascending aorta. The sagittal oblique view of the aorta was used to measure the distance around the aortic arch (Δx), taking the mean of the two distance measures for the outer and inner borders of the aortic lumen. The software package ‘Jim’ (Version 7, Xinapse Systems) was used to calculate Δt from the volume flow rate curves from the AA and DA. A maximum in the cross-correlation between these curves was used to estimate the transit time of the pressure wave around the arch.

Statistical tests were performed using SPSS 24.0 software (Statistical Package for the Social Sciences). Normality was assessed using the Shapiro-Wilk test, histograms and Q-Q plots. For continuous data, summary statistics are expressed as mean ± standard deviation. Log transformation was performed for non-normally distributed data. An independent sample t test was used to compare normally distributed or log-transformed data between bicuspid and tricuspid patients, and between patients and controls. The Mann-Whitney test was used for non-parametric data comparison. The bicuspid group was further split by their sub-types (type-I, and type-II) and compared to tricuspid patients, using ANCOVA modelling, adjusted to take age into account. All p values < 0.05 were considered statistically significant. Univariate associations of distensibility and PWV were explored using linear regression analysis. Variables were then selected to be entered into a stepwise multivariable model based on statistical significance (p < 0.05) or clinical importance, whilst avoiding co-linear variables.

Of 174 patients recruited, aortic valve morphology classification was possible in 169 (due to missing or unanalysable aortic valve cine imaging in 5 patients), with 63 BAV and 106 TAV patients forming the final population. Distensibility was not measurable in six of these patients due to aortic cine images not being available, and PWV was missing in eight due to missing flow images or artefacts. There was no difference in age and gender distribution between the 23 controls and overall AS group (Table 1). Patients had a higher incidence of hypertension and hyperlipidaemia, although treated hypertension was not excluded from the control group, to assess the incremental effect of AS on LV remodelling. AS patients demonstrated significantly higher LV volumes, mass and mass/volume and more LGE than controls. The aortic root measurements were higher in patients than controls at the annulus and proximal AA levels. The AA and DA areas were higher in patients, with no difference in DA distensibility or PWV, but slightly higher AA distensibility (Table 2).

The univariate associations of AA distensibility and PWV in the patient group, both before and after adjusting for age, are summarised in supplemental Tables 1 and 2. Age was the only independent factor associated with both parameters after entering the following variables into a stepwise multivariable model: age, sex, BMI, valve subtype, diabetes, hypertension (or PP instead for PWV), and eGFR.

We have confirmed findings from previous echocardiographic studies that patients with BAV have a greater degree of AA dilatation compared to tricuspid controls, either with or without valvular stenosis or regurgitation [21], and out of proportion to the degree of valvular dysfunction [2, 22]. Several studies have also looked at the relationship between the morphology of BAV and aortic dimensions, with mixed findings. Novaro et al found type-II BAV patients to have slightly higher mid-ascending aortic dimensions compared to type-I, though this did not reach statistical significance [23]. Type-II BAVs have also been associated with a larger aortic arch and ascending aorta [20]. However, Cecconi et al found no difference in aortic dimensions in 162 younger patients with type-1 and type-II BAV, although the average age of that cohort was only 23.6 years and aortic dimensions did strongly correlate with age [24].

Distensibility and PWV are markers of arterial wall stiffness that are inversely related according to the Bramwell and Hill equation [25] and reflect the elastic properties of the aorta. Aortic distensibility is principally governed by the composition of the aortic wall intra-cellular matrix and luminal mean arterial pressure. Previous MRI studies have also shown that distensibility decreases and PWV increases with age [17, 26, 27], which is the likely reason for the stiffness parameters in our controls, who were older compared to the BAV group. Echocardiographic and MRI studies have found lower distensibility and higher aortic stiffness parameters in BAV patients without significant stenosis or regurgitation, compared to controls [11, 13]. In one echocardiographic study of 32 BAV patients with AS and 32 controls, aortic stiffness index was higher in the BAV group, but there was no significant difference in distensibility between the groups [12]. This suggests that the presence of stenosis may result in progressively reduced distensibility and increased PWV in both bicuspid and tricuspid patients, leading to no significant difference between the two groups. Support for this also comes from marked improvement in aortic stiffness in patients with severe AS 1 year after aortic valve replacement [28].

The exact mechanism leading to dilatation of the aorta in bicuspid patients is unclear. Histopathological studies have demonstrated changes in the AA walls of bicuspid patients including cystic medial necrosis [6]. High rates of apoptosis in the aortic media of bicuspid patients both with and without dilatation have been shown, suggesting that apoptosis is a key mechanism for smooth muscle cell loss in the ascending aortas of bicuspid patients, and supporting the hypothesis of a developmental fault involving the valve and aortic wall [5]. However, a similarly high rate of apoptosis was also found in tricuspid patients with aortic dilatation, suggesting a role of extrinsic forces on the aortic wall, rather than an intrinsic developmental abnormality alone. Cystic medial necrosis can be found in hereditary connective tissue disorders such as Marfan syndrome, which has consistently been associated with increased aortic stiffness [29, 30], but a similar histological picture can also be caused by infection, atherosclerosis or severe shear stress [5].

We have shown a dissociation between aortic dilatation and stiffness in BAV disease, with type-II group having lower stiffness parameters, despite a trend towards a higher AA area, further confounding the theory of intrinsic aortic wall stiffness alone leading to aortic dilatation in bicuspid patients. In fact, there was no correlation between AA distensibility and AA dimensions (Fig. 3d). This may suggest a more central role of asymmetrical flow patterns and worse turbulence [31] that has been demonstrated in BAV compared to TAV [7, 8], which also correlated with the degree of proximal aortic dilatation [32]. Recently, time-resolved three-dimensional phase-contrast MRI, also called 4D flow, has demonstrated right-handed helical flow and right-anterior flow jets in type-I BAV, and left-handed helical flow with left-posterior flow jets in type-II BAV [31].

In abdominal aortic aneurysms (AAA), Wilson et al demonstrated increasing aortic distensibility to be an independent predictor of rupture and suggested that this may be due to failure of aortic wall remodelling, which leads to further dilatation and risk of rupture [33]. This is supported by another study showing no correlation between AAA distensibility and size [34]. The authors speculated that the wall of the rapidly expanding AAA may lose its integrity leading to a paradoxically increased distensibility, which may also in part explain our findings in type-II BAV patients.

There appear to be two key players: age being a key determinant of aortic stiffness, with valve haemodynamics (morphology ± presence of stenosis/regurgitation) being central to aortic dilatation. In a previously published set of young controls using the same methodology, the median AA distensibility was 6.36 × 10⁻³ mmHg⁻¹ and PWV was 3.97 m/s [35], demonstrating much lower stiffness than this group of patients or older controls. Cecconi found no difference in aortic size between young BAV type-I, and type-II patients with no stenosis/regurgitation [24], whereas type-II BAV patients with mixed valve disease (dysfunctional valves) had larger aortas but similar distensibility to type-I patients in Schaefer’s study [36]. Finally, our older cohort of BAV and TAV with AS demonstrated no significant difference in aortic stiffness, despite larger aortas in BAV.