Download Bicuspid Aortic Valve Is Associated With Altered Wall Shear Stress

Bicuspid Aortic Valve Is Associated With Altered Wall Shear
Stress in the Ascending Aorta
Alex J. Barker, PhD; Michael Markl, PhD; Jonas Bürk, MD; Ramona Lorenz, MS; Jelena Bock, MS;
Simon Bauer, PhD; Jeanette Schulz-Menger, MD; Florian von Knobelsdorff-Brenkenhoff, MD
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Background—Hemodynamics may play a role contributing to the progression of bicuspid aortic valve (BAV) aortopathy.
This study measured the impact of BAV on the distribution of regional aortic wall shear stress (WSS) compared with
control cohorts.
Methods and Results—Local WSS distribution was measured in the thoracic aorta of 60 subjects using 4-dimensional (4D)
flow-sensitive magnetic resonance imaging. WSS analysis included 15 BAV patients: 12 with fusion of the right-left
coronary cusp (6 stenotic) and 3 with fusion of the right and noncoronary cusp. The right-left BAV cohort was compared with
healthy subjects (n=15), age-appropriate subjects (n=15), and age-/aorta size–controlled subjects (n=15). Compared with
the age-appropriate and age-/aorta size–matched controls, WSS patterns in the right-left BAV ascending aorta
were significantly elevated, independent of stenosis severity (peak WSS=0.9±0.3 N/m2 compared with 0.4±0.3 N/m2 in
age-/aorta size–controlled subjects; P<0.001). Time-resolved (cine) 2D images of the bicuspid valves were coregistered
with 4D flow data, directly linking cusp fusion pattern to a distinct ascending aortic flow jet pattern. The observation of
right-anterior ascending aorta wall/jet impingement in right-left BAV patients corresponded to regions with statistically
elevated WSS. Alternative jetting patterns were observed in the right and noncoronary cusp fusion patients.
Conclusions—The results of this study demonstrate that bicuspid valves induced significantly altered ascending aorta
hemodynamics compared with age- and size-matched controls with tricuspid valves. Specifically, the expression of
increased and asymmetric WSS at the aorta wall was related to ascending aortic flow jet patterns, which were influenced
by the BAV fusion pattern. (Circ Cardiovasc Imaging. 2012;5:457-466.)
Key Words: bicuspid aortic valve ◼ aorta ◼ wall shear stress ◼ magnetic resonance imaging
B
icuspid aortic valve (BAV) occurs in 0.5% to 1.5% of
the population and is accompanied by a high incidence
of morbidity and mortality related to aortic valve dysfunction, aortic aneurysm formation, and dissection.1–4 The cause
of these complications, specifically whether aortopathy is
genetic or hemodynamic in origin, is an ongoing debate with
important implications for interventional planning.5–8 Previous
studies have provided evidence for the presence of BAV as
an inheritable disorder.9–11 However, this alone does not preclude abnormal hemodynamics as a risk factor for postvalvular aortopathy. Growing evidence shows that BAV and cusp
fusion morphology can alter the hemodynamic environment
at the level of the ascending aorta (AAo).12–17 These changes
can result in abnormal aortic wall shear stress (WSS), a wellknown stimulus leading to the expression of transcriptional
factors implicated in vascular remodelling.18
Recent advances in cardiovascular magnetic resonance
imaging (MRI) permit the assessment of aortic valve
morphology and 3-dimensional (3D) blood flow velocity. As
a result, BAV fusion patterns and their lesions can be studied
in parallel with the resulting 3D flow patterns distal to the
valve. Bicuspid cusp morphology has been identified using
the steady-state free precession (SSFP) cine imaging.19 Flowsensitive MRI with full volumetric coverage of the thoracic
aorta (4D flow MRI) can measure and visualize aortic 3D
blood flow patterns, such as flow jets, vortex, or helical flow
patterns.16,20–22 Moreover, analysis tools have been developed
to quantify the distribution of WSS in the entire aorta. Recently
reported applications indicated altered WSS in the presence of
BAV-related flow abnormalities.15,23–26 These studies showed
that BAV was associated with altered aortic flow patterns
(nested flow, helical flow, or retrograde flow) and elevated or
asymmetrically expressed WSS along the circumference of
the aorta wall. However, a detailed investigation of the WSS
Clinical Perspective on p 466
Received January 31, 2012; accepted June 13, 2012.
From the Department of Radiology, Medical Physics (A.J.B., R.L., J.B., S.B.) and Department of Diagnostic Radiology (J.B.), University Medical
Center Freiburg, Germany; Department of Radiology, Feinberg School of Medicine (A.J.B., M.M.) and Department of Bioengineering, McCormick School
of Engineering (M.M.), Northwestern University, Chicago, IL; Working Group on Cardiovascular MRI, Experimental and Clinical Research Center, a Joint
Cooperation of the Charité Medical University and the Max-Delbrueck-Center, Berlin (J.S.-M., F.v.K.-B.); and Department of Cardiology and Nephrology,
HELIOS Klinikum Berlin-Buch, Germany (J.S.-M., F.v.K.-B.).
The online-only Data Supplement is with this article at http://circimaging.ahajournals.org/lookup/suppl/doi:10.1161/CIRCIMAGING.
112.973370/-/DC1.
Correspondence to Alex J. Barker, PhD, Department of Radiology, Northwestern University, 737 N Michigan Ave, Suite 1600, Chicago, IL 60611.
E-mail [email protected]
© 2012 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
457
DOI: 10.1161/CIRCIMAGING.112.973370
458 Circ Cardiovasc Imaging July 2012
distribution in the AAo, its expression as a function of BAV
cusp fusion, and a systematic comparison to controls with
tricuspid valves matched for age and aortic dimension has not
been performed.
It was thus the objective of this study to quantify timeresolved aortic 3D blood flow and WSS in the most common
BAV morphology, a so-called fusion of the right-left (RL)
coronary cusp, and to compare the results to control groups
matched for age and AAo size. Our aim was to investigate
the hypothesis that BAV significantly alters WSS in the AAo
compared with controls with tricuspid valves. In addition,
we analyzed the relationship between BAV morphology and
differences in 3D aortic jet flow patterns to investigate the
structure–function relationship between valvular lesions and
aortic hemodynamics.
Methods
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Study Cohort
The study included 60 participants, divided into 4 groups. Study
group 1: n=15 patients with BAV, who were consecutively referred
for a clinical cardiac magnetic resonance examination to assess aortic
valve morphology and function; control group 1: n=15 healthy young
volunteers with a morphologically normal tricuspid aortic valve and
no history of aortic, heart, or valve disease; control group 2: n=15
age-appropriate subjects with a morphologically normal tricuspid
aortic valve; and control group 3: n=15 age- and aortic size–controlled subjects with a morphologically normal tricuspid aortic valve
and an AAo aneurysm, defined as a diameter in the AAo >4.0 cm
or >2.2 cm/m2.27,28 All patients gave informed consent, and the institutional review boards approved the study. Demographic details are
provided in Table 1.
Magnetic Resonance Imaging
All subjects underwent MRI in our respective clinics (Berlin: 1.5 T
Avanto; Freiburg; 3 T, Trio; Siemens Healthcare, Erlangen, Germany).
ECG-gated, breathhold SSFP cine imaging and echocardiography
were performed to assess BAV morphology and lesion severity
(Figure 1). Slice positioning and imaging parameters were selected,
as previously reported.29,30 In subjects, in whom these valvular planes
were not acquired, transthoracic echocardiography was used to assess valve morphology and function after international guidelines.31
Aortic size measurements were obtained from axial SSFP imaging of
the thorax, as described earlier.32 Four-dimensional flow MRI was acquired in a sagittal oblique covering the thoracic aorta using prospective ECG gating and a respiratory navigator placed on the lung–liver
interface33 (1.5 T scan parameters ranged from echo times=2.3–3.4 ms,
repetition times=4.8–6.6 ms, flip angle α=7–15°, and temporal resolution=38.4–52.5 ms). The field of view was 340–400 × 200–300 mm,
with a voxel size of 1.8–2.1 × 1.8–2.1 × 2.0–2.8 mm3 (3 T scans used
echo times=2.5 ms, repetition times=5.1 ms, flip angle α=7–15°, and
temporal resolution=40.8 ms). The field of view was 400 × 308 mm
with a voxel size of 2.1 × 2.1 × 2.4 mm3. Velocity encoding was adjusted to minimize velocity aliasing (velocity encoding=1.5 m/s for
nonstenotic and 2.0–3.0 m/s for stenotic subjects).
Data Analysis
SSFP cine images were evaluated by a cardiologist regarding aortic
valve morphology, and orifice area was quantified by manual segmentation (CMR42, Circle Cardiovascular Imaging, Calgary, Canada).
Aortic stenosis severity was graded according to international guidelines on the basis of the orifice area.34 Aortic size was assessed on the
level of the midpoint between sinotubular junction and origin of the
innominate artery in accordance with international guidelines.27 The
presence of an ascending aortic aneurysm was defined as a diameter
of the AAo >2.2 cm/m2 or >4.0 cm.27,28 All 4D flow MRI data were
corrected for eddy currents, Maxwell terms, and velocity aliasing.35
Quantification of WSS Distribution
For all 60 subjects, 8 measurement planes were placed at landmarkbased positions in the thoracic aorta covering the proximal AAo, distal
AAo, arch region, and descending aorta (S1S8: Figure 2).27 For these
480 individual aorta planes, the aortic lumen contours were manually
segmented for all time frames to calculate peak velocity and timeresolved WSS distribution, as described previously.23,36 Systolic WSS
(WSSsystole) was calculated at the peak of the flow waveform in S1 and
averaged with the preceding and 3 subsequent time steps to mitigate
measurement noise. Both WSSsystole and WSS averaged over the cardiac
cycle (WSSt_avg) were calculated at local anatomic positions (anterior,
left-anterior, left, left-posterior, posterior, right-posterior, right, and
Table 1. Population Demographics
Study Group
n (female)
BAV All
RL BAV All
RL BAV
Nonstenotic
15 (2)
12 (2)
6 (0)
RL BAV
Stenotic
RL BAV-AI
6 (2)
6 (1)
Control 3
Control 2
Control 1
RN BAV All
Age/Size
Control
Age
Appropriate
Volunteer
3 (0)
15 (2)
15 (3)
15 (3)
Age*
50±17
52±16
41±11
63±11
58±16
30±13
53±19
67±8
23±2
AAo size, cm*
4.1±0.6
4.3±0.6
4.5±0.5
4.0±0.6
4.8±0.2
3.8±1.0
4.2±0.8
3.1±0.2
2.6±0.2
AAo aneurysm†
12
10
5
5
5
2
15
0
0
Aortic stenosis
8
6
0
6
3
2
3
0
0
Mild
1
0
0
0
0
1
3
0
0
Moderate
4
3
0
3
2
1
0
0
0
Severe
3
3
0
3
3
0
0
0
0
AI
6
5
2
3
5
1
4
12
0
Mild
4
3
0
3
3
1
3
12
0
Moderate
2
2
2
0
2
0
1
0
0
Severe
0
0
0
0
0
0
0
0
0
AAo indicates ascending aorta; AI, aortic insufficiency; BAV, bicuspid aortic valve; RL, right-left; RN, right and noncoronary cusp.
Values are displayed as mean±SD.
*No significant differences were found for the RL BAV cohorts as tested against the age/size controls (P>0.05).
†
Aneurysm defined as AAo diameter >4 cm or 2.2 cm/m2.
Barker et al BAV Is Associated With Altered Wall Shear Stress 459
Figure 1. A, Positioning of the aortic valve steady-state free precession slice was performed using an adjusted long axis view of the left
ventricular outflow tract (LVOT). B–D, A normal tricuspid aortic valve (TAV), a nonstenotic right-left (RL) bicuspid aortic valve (BAV), and a
stenotic RL BAV (shown as sRL BAV) at systole (top) and diastole (bottom). Yellow arrows in (C) and (D) show the location of the raphe
between the RL coronary BAV cusps and the black arrow shows the stenotic BAV opening. NC indicates noncoronary cusp.
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right-anterior, ie, A, LA, L, LP, P, RP, R, and RA, respectively) and also
circumferentially averaged. The eccentricity of WSS along the circumference of the aorta wall was defined by the difference between the RA
and LP systolic WSS (ie, RA-LP WSSsystole).15 As previously proposed,
and as confirmed from the maximum measured RA-LP WSS values in
the control populations (Table 2), a WSS eccentricity threshold (RALP) >0.2 N/m2 was used to categorize flows as eccentric.25
Three-Dimensional Flow Visualization and
Coregistration With Valve Morphology
The 2D SSFP scans were interpolated to match the temporal resolution of the 4D flow data. Coregistration of the valve images with the
flow data (Figure 2) allowed the valve cusp morphology to be visualized in parallel with the 3D blood flow pattern in the aorta (EnSight,
CEI Inc, Apex, NC). The 3D flow visualization was based on 3D
streamlines (lines tangent to the velocity field) at peak flow systole.
Statistical Analysis
A Lilliefors test was used to determine parameter normalcy and
whether an analysis of variance or Kruskal-Wallis test was performed. An F or χ2 statistic <0.05 determined whether a multiple comparison using Bonferroni correction was performed.
Significance differences were defined by P<0.05. All data are
expressed as mean±SD.
Results
Valve Morphology and Aortic Dimensions
SSFP cine images (n=12) and echocardiography (n=3)
allowed the assessment of the valve lesion morphology
in all BAV subjects. The BAV cohort (n=15) included 12
patients with a RL fusion of the aortic cusps and 3 patients
with a right and noncoronary cusp (RN) fusion.10,37 Six of
the 12 RL BAV patients and 2 of the 3 RN BAV patients had
moderate (mean orifice area: 1.32±0.26 cm2) or severe (mean
orifice area: 0.87±0.15 cm2) aortic stenosis. SSFP valve
images demonstrating a healthy valve, a nonstenotic RL
BAV, and stenotic RL BAV are shown in Figure 1B and 1C.
In addition, 10 of the 12 RL BAV patients and 2 of the 3 RN
BAV patients were classified as having an AAo aneurysm.
The average aorta size between the age/size controls and
the RL BAV population were well-matched with no
significant differences (P>0.05). The age-appropriate
population was found to be significantly different to the RL
BAV population for aorta size (P<0.001). Additional details
are provided in Table 1.
General Flow Characteristics
Figure 2. A, Aortic valve images (shown at every 3 times steps
starting from left ventricular contraction) were (B) coregistered
with the 4D flow data for 3D flow visualization of a normal subject
with a tricuspid aortic valve. S1–S8 indicate the standardized
positions chosen for flow and wall shear stress quantification.
Note the cohesive systolic streamlines for this healthy subject
(color coding=blood flow velocity) (see also online-only Data
Supplement Movie I).
Hemodynamic parameters calculated directly distal to the aortic valve (position S1) are summarized in Table 2. The average
cardiac output between all groups of the RL BAV population, the age/size-controls, and the age-appropriate group was
matched with no significant differences (P>0.05). Peak velocity was significantly elevated in the RL BAV-all and RL BAVstenotic cohorts compared with the age/size control cohorts
(P<0.001). Compared with the age-appropriate population,
all RL BAV groups exhibited significantly elevated velocity
(P<0.05 or P<0.001).
460 Circ Cardiovasc Imaging July 2012
Table 2. Hemodynamic Quantification at Position S1
Cardiac Output,
L/min
WSSsystole RA,
N/m2
WSSsystole LP,
N/m2
WSSsystole Circum
Avg, N/m2
WSSt-avg RA,
N/m2
WSSt-avg LP,
N/m2
WSSt-avg Circum Avg,
N/m2
Control Group 1
Volunteer
5.2±1.2
0.3±0.1
0.3±0.1
0.4±0.1
0.2±0.1
0.3±0.1
0.3±0.1
4.1±1.0
0.5±0.2
0.3±0.1
0.4±0.1
0.3±0.1
0.2±0.1
0.3±0.1
5.4±2.6
0.4±0.3
0.4±0.2
0.4±0.2
0.2±0.1
0.2±0.1
0.3±0.1
RL BAV all
5.3±1.9
0.9±0.3**,††,‡‡
0.5±0.2
0.8±0.2**,††,‡‡
0.4±0.1*,‡
0.3±0.1
0.5±0.1**,††,‡‡
RL BAV nonstenotic
6.3±1.7
0.8±0.3‡
0.4±0.2
0.7±0.1**,††,‡‡
0.4±0.1
0.3±0.1
0.4±0.1*,†,‡
RL BAV stenotic§
4.3±1.6
1.0±0.3*,‡
0.6±0.2*,†
0.9±0.2**,††,‡‡
0.5±0.2‡
0.3±0.1
0.5±0.1**,††,‡‡
RL BAV-AI
6.5±2.4
1.0±0.4
0.5±0.1
0.8±0.1**,†,‡‡
0.5±0.1‡
0.3±0.1
0.5±0.1**,††,‡‡
<0.001§§
0.003
<0.001
<0.001§§
0.325
<0.001
Control Group 2
Age appropriate
Control Group 3
Age/Size control
Study Group
Overall F or χ2 statistic
0.096
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AI, aortic insufficiency; RL BAV, right–left bicuspid valve fusion pattern; WSS, wall shear stress.
Values are displayed as mean±SD. Footnotes indicate multiple comparisons.
* or ** denotes P<0.05 or P<0.001 compared with volunteers.
† or †† denotes P<0.05 or P<0.001 compared with age appropriate.
‡ or ‡‡ denotes P<0.05 or P<0.001 compared with age/size control.
§ P>0.05 for all values compared with RL BAV nonstenotic.
§§ χ2 obtained from Kruskal-Wallis test.
WSS Measurements
Table 2 reports WSS parameters measured at position S1. Notably,
significantly elevated WSS occurred for both the nonstenotic
and the stenotic RL BAV patient groups compared with the age/
size controls. All RL BAV subgroups were significantly elevated
compared with the age/size controls for the circumferentially
averaged WSSsystole (P<0.001) and WSSt_avg (P<0.05 or P<0.001).
Significant regional differences were found for the rightanterior WSSsystole and WSSt_avg (P<0.001 or P<0.05). Figure 3
compares WSSsystole in the RL BAV group to the age-appropriate,
age/size control groups throughout the thoracic aorta. WSSsystole
was significantly elevated and eccentric in the anterior and rightanterior AAo region of S1–S3 for the RL BAV group compared
with the control groups. In addition, compared with the
age/size controls, 45 of the 56 (80%) RL BAV WSS measurement
locations along S1–S7 were significantly elevated at systole.
Compared with the age-appropriate values, the systolic RL BAV
WSS values were elevated at 12 of the 24 (50%) locations in the
AAo (S1–S3), at S4 the significance values decreased, and all
measurement locations were statistically similar at the level of
the distal arch and beyond (S5–S8; P>0.05).
In both stenotic and nonstenotic RL BAV patients, the
peak systolic WSS location traveled in a right-handed helix,
appearing at the AAo right-anterior or anterior location and
progressing along the flow direction until reaching the level of
the supra-aortic arteries. A comparison of WSS between the
nonstenotic and stenotic RL BAV patients yielded no statistically significant differences for planes S1–S4. Highly eccentric (RA-LP≥0.4 N/m2) peak WSS values were observed to
be colocated with the position of an elevated velocity jet as
shown in Figure 3B and 3C and Figure 4D and 4E (closed and
open black arrows). WSS eccentricity did not occur in the volunteers and control populations. The nonstenotic RN patient
demonstrated a peak WSS eccentricity at the right-posterior
region for the S1 level (Figure 5). For the 2 stenotic RN
patients, peak WSS occurred at the left-anterior position of
slice S1–S3. A complete WSS comparison matrix for all
slice positions and groups is provided in the online-only Data
Supplement Figure.
Three-Dimensional Flow Visualization and
Coregistration With Valve Morphology
Figure 2A and 2B shows representative images for a healthy
tricuspid valve during the ejection period (see also onlineonly Data Supplement Movie I) and its relationship to the
aortic 3D flow pattern. This example illustrates the presence
of normal cohesive systolic aortic flow as represented by 3D
streamlines distal to a normal tricuspid aortic valve. For the
RL BAV patients, the position of the elevated and eccentric
WSS was colocated with observations of a systolic blood
flow jet propagating in a direction opposite to the position
of the fused RL cusp, impinging at the right-anterior region
of the AAo wall (Figures 3 and 4, see also online-only Data
Supplement Movie II). For the 2 patients with stenotic RN
BAV, one displayed a flow jet directed toward the left-anterior
wall of the aortic root, and the other patient did not show a
conclusive flow direction. The nonstenotic RN BAV in Figure
5 shows a markedly different jetting pattern than the RL BAV
pattern. In this RN case, a flow jet is clearly seen to be directed
by the fused cusp toward the right posterior of the aortic root
(Figure 5F).
Discussion
This is the first study to investigate hemodynamic forces at
various levels of the thoracic aorta in BAV patients regarding
a specific valve morphology. The main findings of this investigational series were the following: (1) the RL BAV fusion is
Barker et al BAV Is Associated With Altered Wall Shear Stress 461
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Figure 3. Systolic wall shear stress (WSS) measurements in cohort populations and bicuspid aortic valve (BAV) jetting. A, WSS magnitude
measurements for right-left (RL) BAV, age-appropriate, and age/size control cohorts (at 4 example measurement positions S1–S3, and S6)
plotted on a cylinder representing the anatomic positions: anterior, left-anterior, left, left-posterior, posterior, right-posterior, right, and rightanterior (A, LA, L, LP, P, RP, R, and RA, respectively). Systolic WSS was significantly elevated in A, RA, and LA of the ascending aorta of all
BAV patients (S1–S3 shown) compared with both control populations. Distally, the BAV WSS values returned to age-appropriate values at
the level of the proximal descending aorta (S6). The BAV WSS values were significantly elevated throughout the thoracic aorta compared
with the age/size control group (*P<0.05 and **P<0.001). No statistical WSS differences existed between the nonstenotic and the stenotic
BAV patients. B and C, A nonstenotic and stenotic BAV patient exhibit velocity jets directed toward the right-anterior aortic wall, as indicated by the open black arrows. The position of the velocity jets correspond to the position of elevated WSS (closed black arrows) (see also
online-only Data Supplement Movie II).
associated with significantly elevated WSS at focal regions in
the AAo, (2) this elevation is present in both stenotic and nonstenotic RL BAV patients, (3) the direction of a postvalvular
blood jet appears to be influenced by the position of the fused
cusp, and (4) the aortic wall/jet impingement positions correspond to regions of elevated WSS.
The timing of prophylactic aortic root replacement
associated with BAV disease is a complex decision. The
guidelines for the management of patients with ascending
aortic disease associated with BAV mainly focus on the
absolute size of the aorta, the condition of the BAV, and the
rate of expansion of the aortic aneurysm.34 Information about
the hemodynamic forces exerted on the AAo wall as described
in this study may help to complement the static information of
aortic dimensions and to facilitate more individualized patient
management.
462 Circ Cardiovasc Imaging July 2012
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Figure 4. A–C, Coregistered steady-state free precession images provide anatomic landmarks to locate (D and E) the direction and
propagation of a systolic flow jet. Here, for the right-left (RL) bicuspid aortic valve lesion, the jet is directed toward the right-anterior wall
of the ascending aorta. The jet impacts and travels along the right-anterior aorta wall in a right-handed helical direction.
Association of Aortic Hemodynamics
and Valve Morphology
It has been recognized that the BAV demonstrates abnormal
cusp motion, including folding or wrinkling of the valve tissue and increased cusp doming during the cardiac cycle. This
may result in altered flow characteristics even when the cusps
are not stenotic.3 The present data support this hypothesis. For
example, the nonstenotic RN BAV patient exhibited a flow
jet that is clearly directed by the fused cusp toward the right
posterior of the aortic root (Figure 5F). The RL cusp seen in
Figure 4C and 4D also appears to influence the direction of
postvalvular jet. The position of these jets corresponded to the
peak WSS measurement locations (Figures 3 and 5E). In addition, the maximum systolic WSS for the 2 stenotic RN BAV
patients was located at the left-anterior wall, consistent with
a high velocity gradient directed away from the position of a
fused RN valve.
This is compelling evidence regarding the mechanism by
which a fused cusp and impaired cusp mobility may elevate
local aortic WSS downstream from the aortic valve. This
phenomenon is especially of interest, given the heterogenic
expression of aortopathy in patients with specific valve fusion
patterns and valve lesions.17,37,38 Our findings are consistent
compared with previous reports showing that distinct aortic
root phenotypes may be associated with various cusp orientations in BAV.3 If hemodynamic forces do indeed contribute
to the progression of this disease, then these observations
illustrate a differentiating characteristic between valve fusion
groups beyond genetic predisposition and could be used for
risk stratification and clinical decision making. Additional
patient numbers and longitudinal follow-up are needed to
test this hypothesis. Nevertheless, our findings highlight the
utility of this multimodal MRI for investigating the structure–
function relationship between the valve and the downstream
flow characteristics.39
Of particular interest were the hemodynamic differences
between the age/size controls and the RL BAV population. This
control group represents a condition where all controllable
hemodynamic influences except valve geometry were similar
(ie, age, cardiac output, and aorta geometry). Conversely, the
WSS values at the S1–S6 measurement positions displayed
the most significant intergroup differences of all cohorts.
This highlights patently different WSS present at the AAo
wall for these 2 seemingly similar aortopathies. These results
emphasize that BAV causes a significant alteration to the AAo
hemodynamic environment. However, it still remains unclear
what these results mean regarding the controversy between
the genetic or hemodynamic aortopathy hypotheses.5,7,8
Further longitudinal study is warranted to provide further
insight.
Other studies have applied 4D flow MRI to investigate vortex flow in the sinuses of Valsalva after valve-sparing aortic
root replacement40,41 contributing to an ongoing discussion
Barker et al BAV Is Associated With Altered Wall Shear Stress 463
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Figure 5. A–D, A right and noncoronary cusp (RN) valve fusion shows a jetting pattern toward the posterior wall of the aorta, opposite
from the fused right and noncoronary cusp. E, The peak wall shear stress (WSS) measured for this patient occurs at the RP position
(black closed arrow) instead of at the RA position for right-left (RL) bicuspid aortic valve (BAV) patients. F, As with the RL valve fusion
patient shown in Figure 4, the incomplete opening of the fused cusp appears to influence the direction of the velocity jet (black open
arrow) and thus the position of the peak WSS eccentricity. A indicates anterior; LA, left-anterior; L, left; LP, left-posterior; P, posterior;
RP, right-posterior; R, right; RA, right-anterior.
about the impact of different types of aortic reconstruction
on hemodynamic outcome in valve-sparing surgical repair of
aortic root ectasia. Future studies using postinterventional 4D
flow MRI and WSS quantification in BAV patients after surgery may have the potential to directly evaluate hemodynamic
outcome and thus help optimize interventional techniques.
Comparison of WSS Results to Previous Studies
The measurement of eccentricity and position of elevated
WSS in the RL BAV patients correlated well with 2 known
studies of WSS in BAV patients.15,25 Barker et al15 previously
reported a local WSS eccentricity in a diverse group of BAV
patients examined with 2D PC-MRI using through-plane
velocity encoding; however, the sole significant BAV WSS
differences were noted to be with depressed compared with
a control population (located at the left-posterior position
AAo), which appears to contradict the findings (ie, elevated
WSS) of our present study.23 In actuality, the WSS differences
between these 2 studies stem from the use of through-plane
only encoding versus 3-directional velocity encoding. For
example, when the in-plane velocity components from this
study are not included in the WSS magnitude calculations, the
position and significance of the WSS values agrees with the
previous study (Figure 6). These calculations are supported by
the streamline visualizations in Figures 3 and 4, where the LP
region exhibits highly circumferential velocity components.
Their presence will increase calculation of the 3D WSS
magnitude compared with a simple through-plane magnitude
calculation highlighting the importance of measuring all
velocity components to examine abnormal flow and WSS in
the aorta.16
Similar to a recent study, the systolic local WSS values
between stenotic and nonstenotic BAV patients were not significantly different.25 This emphasizes that the presence of a
nonstenotic bicuspid valve alone represents a flow obstacle
and leads to a significant alteration of the flow pattern.
The previous study also reports a WSS asymmetry similar to that observed here; however, the magnitude of the WSS
values reported at the RA position was higher than ours (1.15
N/m2 for a normal flow cohort and 1.56 N/m2 for helical flow
cohort).25 This is most likely because of the methodology by
which the RA WSS values were calculated. In the Hope et
al WSS study, a maximum WSS value was selected along
an entire quadrant representing the RA position at a single
time point. Our study chose to select a single RA location
averaged at peak systolic WSS over a time period of systole
464 Circ Cardiovasc Imaging July 2012
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Figure 6. Calculated wall shear stress (WSS) magnitude using
through-plane velocity compared with a 3D velocity field measured at position S1. A, The WSS magnitude calculated using
only a through-plane velocity component appears significantly
depressed. B, The WSS magnitude calculated from all principal
velocity directions is significantly elevated. This highlights the
contribution of circumferential (or in-plane) velocity components
to the net WSS magnitude in a complex flow environment. A indicates anterior; BAV, bicuspid aortic valve; LA, left-anterior; L, left;
LP, left-posterior; P, posterior; R, right; RA, right-anterior; RL,
right-left; RP, right-posterior.
consisting of 5 systolic time steps (to mitigate measurement
noise). Neither technique represents a more correct methodology, but this and study demographics may possibly account
for slightly different WSS values reported in these studies.
Nonetheless, we used a similar eccentricity threshold as the
Hope et al study based on the observation that the control
groups never exceeded an eccentricity of 0.2 N/m2. It should
also be noted that both the previous Hope et al and Barker et
al. BAV WSS studies did not group or report WSS according
to valve lesion (rather they chose helicity or retrograde flow
as grouping categories). Qualitative agreement of WSS asymmetry between the 2 morphologically heterogeneous BAV
studies may be because of the 70% prevalence of the RL cusp
fusion phenotype.17
It should also be noted that the Hope et al25 and Barker et al15
studies examined WSS at a single analysis position distal to
the sinotubular junction. In the current study, WSS was examined at 8 positions throughout the thoracic aorta and carefully
selected for reproducibility using anatomic landmarks (such
as the bottom third of the RPA for S1). Given the aggregate
results from these studies, future analysis should further investigate WSS focally at the AAo with additional analysis planes
placed at and just distal to the sinotubular junction.
Study Limitations
The scope of the study did not include longitudinal analysis.
This is necessary to address the question of whether hemodynamic parameters act as potential prognostic metrics for BAVrelated aortopathic events. In addition, although the overall
number of subjects examined was satisfactory for an initial
pilot study (n=60), the BAV cohort consisted of 15 subjects.
Although the power of these numbers was sufficient to establish strong (P<0.001), significant statistical hemodynamic
trends for the RL valve fusion cohort (n=12), it was not sufficient for attempting statistical analysis of alternative valve
fusion morphologies (n=3).
Six of 15 BAV patients had aortic insufficiency (4 mild and
2 moderate). In the presence of aortic insufficiency, cardiac
output will be slightly overestimated because of prospective
ECG gating and a portion of the diastolic backflow being truncated. The cases with regurgitation in the nonstenotic RL BAV
group and aortic insufficiency RL BAV group may explain the
slightly elevated, although statistically insignificant differences regarding cardiac output (Table 2).
The discrete spatial and temporal resolution (≈2 mm3 and
≈40 ms) of the aortic blood flow velocities measured by 4D
flow MRI will result in a systematic underestimation of peak
velocity and WSS.23,24,27 This is the primary reason that stenosis degree was measured via magnetic resonance planimetry.29
Nevertheless, the relative differences between the measured
velocity-derived parameters can still be reliably inferred,
especially if the measurement procedure is consistent between
study populations, as in our cohorts. The procedural stability
of this technique has been shown in many studies reporting
acceptable inter- and intraobserver WSS variability.15,23–25
In addition, we previously performed a detailed investigation of interobserver, intraobserver, and scan–rescan variability WSS error, which used the same 4D flow MRI technique
used in this study.42 The estimation of WSS, which included
additional errors because of plane placement and segmentation, was found to have a maximum error of <10%. Thus, we
applied a 10% worst case error to each measure RA WSSsystole
value on a subject-by-subject basis and retested for significance (ie, each control RA WSSsystole value was increased 10%
and each BAV value was decreased 10%). Given this stress
test, the RA WSSsystole for all RL BAV groups maintained
their significance from Table 2 compared with the age/size
(RL BAV-all, RL BAV-nonstenotic, RL BAV-stenotic: P<0.05)
and age-appropriate groups (RL BAV-all: P<0.05). The variability of local WSS was also addressed in the previous study
with a linear regression analysis demonstrating significant
correlation (P<0.001) of scan–rescan (r=0.87), inter- and
intraobserver comparisons (r=0.88 and r=0.97, respectively).
In a separate WSS study, typical values for WSSsystolic and
WSSt_avg in healthy young control patients were also shown
to have a similar intraobserver variability of 1.6±2.0% and
6.4±7.9%, and an interobserver variability of 7.5±6.5% and
14.7±12.6.24 These results also agree with additional interand intraobserver variability studies specifically performed on
BAV patients, one study which used the exact software tool as
this study.15,25 Furthermore, given that our results incorporate
values measured at both field strengths; intersystem variability is also an important consideration. Thus, we note that the
field dependence of velocity and WSS measurements were
recently reported at 1.5 T and 3.0 T with a correlation between
peak velocities and WSS of r=0.85 and r=0.65, respectively
(P<0.001).43
Conclusion
BAV patients with a RL cusp fusion pattern express significantly different eccentric and focally elevated WSS values
compared with both age- and age/size-controlled populations.
In addition, a distinct flow jet was observed to be associated
with the position of the fused cusp and valvular function. The
flow jet impingement position at the aorta wall corresponded
Barker et al BAV Is Associated With Altered Wall Shear Stress 465
with elevated WSS values and could place this group at-risk
for future aortopathic events. Additional longitudinal data
including the analysis of alternative lesion patterns are necessary to evaluate the utility of WSS as a prognostic marker for
disease progression.
Sources of Funding
Dr Barker is funded by the Whitaker Postdoctoral and Fulbright
Grants. Dr Knobelsdorff-Brenkenhoff is supported by the Else
Kröner-Fresenius Stiftung. Dr Markl is supported by the Northwestern
Memorial Hospital Excellence in Academic Medicine Program
Advanced Cardiovascular MRI Research Center and the Northwestern
Memorial Foundation Dixon Translational Research Grant.
None.
Disclosures
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CLINICAL PERSPECTIVE
This study investigates wall shear stress (WSS) in the thoracic aorta of bicuspid aortic valve (BAV) patients stratified by a
specific valve fusion morphology. The main findings of this investigation are that (1) a right-left BAV fusion pattern was
associated with significantly and focally elevated WSS in the ascending aorta, (2) this elevation was present both in stenotic
and nonstenotic right-left BAV patients, (3) the postvalvular blood flow jet direction was influenced by the position of the
fused cusp, and (4) aortic wall/jet impingement positions corresponded to regions of elevated WSS. Evidence is presented
showing a mechanism by which impaired cusp mobility may elevate local aortic WSS downstream from the aortic valve.
This phenomenon is of interest, given the heterogeneous expression of aortopathy in BAV patients with specific valve fusion
patterns and valve lesions. On the basis of previous findings indicating that increased WSS is associated with altered endothelial cell function and vascular remodeling, the results in this study illustrate WSS patterns as a differentiating characteristic between valve fusion groups beyond genetic predisposition and could be used for risk stratification and clinical decision
making. The guidelines for the management of BAV patients with concomitant aortopathy mainly focus on the absolute size
of the aorta, the condition of the valve, and the rate of aorta expansion. Information about the hemodynamic forces exerted
on the ascending aorta wall as described in this study may help to complement these dimensional measurements and to
facilitate more individualized patient management.
Bicuspid Aortic Valve Is Associated With Altered Wall Shear Stress in the Ascending
Aorta
Alex J. Barker, Michael Markl, Jonas Bürk, Ramona Lorenz, Jelena Bock, Simon Bauer,
Jeanette Schulz-Menger and Florian von Knobelsdorff-Brenkenhoff
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Circ Cardiovasc Imaging. 2012;5:457-466; originally published online June 22, 2012;
doi: 10.1161/CIRCIMAGING.112.973370
Circulation: Cardiovascular Imaging is published by the American Heart Association, 7272 Greenville Avenue,
Dallas, TX 75231
Copyright © 2012 American Heart Association, Inc. All rights reserved.
Print ISSN: 1941-9651. Online ISSN: 1942-0080
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Data Supplement (unedited) at:
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SUPPLEMENTAL MATERIAL
Figure Legend
Supplementary Figure. Comprehensive WSS comparison matrix for all slice positions and
groups. The outer curvature (O), inner curvature (I), right (R) and left (L) sides of the aorta
are used in combination with the slice positions (S1-S8) to provide the anatomic locations for
the WSS measurements.
Supplementary Figure 1
1
Movie Legends
Movie 1. Time-resolved pathlines illustrating a normal tricuspid valve and cohesive flow
throughout the thoracic aorta.
Movie 2. Time resolved pathlines illustrating a stenotic RL BAV valve and abnormal postvalve aortic flow.
2