DOI: 10.1161/CIRCULATIONAHA.113.007282
“Nature vs. Nurture” in Bicuspid Aortic Valve Aortopathy:
More Evidence that Altered Hemodynamics May Play a Role
Running title: Uretsky et al.; BAV aortopathy and hemodynamics
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
Seth Uretsky, MD; Linda D. Gillam, MD, MPH
Dept
De
p off Cardiovascular
pt
C rdiovascular Medicine, Morristown
Ca
Morr
rrris
isto
t wn Medical Center,
to
Centter,
er Morristown,
M rristown, NJ
Mo
Ad
ddr
dres
ess for
for Correspondence:
C rr
Co
rres
esp
ponden
nd ncee:
Address
Lind
ndaa D. G
i la
il
lam,, M
D,, MPH
P
Linda
Gillam,
MD,
Do
oroothyy andd Ll
L
oydd Hu
oy
H
uck
ck C
ha , De
hair,
D
part
pa
rtme
ment
nt ooff Ca
C
rddiova
rdi
iovasc
scul
ullar M
ed
dic
iciine
ine
Dorothy
Lloyd
Huck
Chair,
Department
Cardiovascular
Medicine
Morristown Medical Center, Cardiac Administration #5
100 Madison Avenue
Morristown, NJ 07962,
Tel: 973-971-4947
Fax: 973-290-7145
E-mail: [email protected]
Journal Subject Code: [30] CT and MRI
Key words: Editorial, bicuspid aortic valve, magnetic resonance imaging, aortic disease
1
DOI: 10.1161/CIRCULATIONAHA.113.007282
There is no disease more conducive to clinical humility than aneurysm of the aorta.1
William Osler
Bicuspid aortic valve (BAV) is a common congenital cardiac malformation affecting 1 to 2% of
the population with a predilection for males.2 While patients with BAV often develop aortic
aneurysms requiring surgical intervention,3, 4 the formation of aortic aneurysms is variable and
there are currently no good predictors of aneurysm formation. While studies have shown that
patients with BAV have genetically inherited aortic disorders that predispose them to aneurysm
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
development,5, 6there is ongoing controversy concerning the degree to which altered
hemodynamics (“nurture”) and genetics (“nature”) interact. The study of Mahade
Mahadevia
deeviia et aall iin
n tthis
his
issue
ssue of Circulation7 provides important additional support for the argument that altered flow
pa
attter
ernns
ns due
due to
to abnormal
ab
bnormal
no
in
nde
deeed play a rolee in
i BAV
BAV aortopathy.
patterns
valve architecture do indeed
Phase contrast
cont
co
n ra
nt
rast
st MRI
MRI has
has
as been
been
een used
useed too measure
meassure changes
chan
ch
ange
gess inn blood
ge
blo
lood
od velocity
vel
elooci
city
ty and
and flow
flo
low
w with
with
h
standard
tan
nda
dard
r techniques
rd
tec
echn
h iq
hn
quees measuring
meaasu
asurin
in
ng these
thes
th
esee parameters
es
para
pa
rame
ra
meteers
me
r in
in 2 dimensions,
dim
men
ensiion
o s, or
or “through
“tthr
hrou
ough
gh plane”.
plaane
ne””. 44D
DM
MRI
RI
allows the spe
speed
peed
pe
ed aand
nd ddirection
irreccti
tion
on ooff ao
aortic
ort
r icc fflow
low
lo
w to bbee vi
visualized
isu
sual
aliz
al
ized
iz
ed aand
nd m
measured
easu
ea
sure
su
redd ov
re
over
ver ttime
im
me in all threee
dimensions, thereby providing not only informative images but an improved tool for the study of
flow disturbances. One of the more active areas of research using 4D MRI has been in BAV
aortopathy with the hope that understanding flow disturbances will give new insight into BAVassociated aneurysm formation.
Prior studies8-10 using 4D-MRI, have demonstrated altered ascending aortic wall sheer
stress (WSS) in patients with BAV and have suggested a mechanistic link between the alteration
in aortic outflow caused by the fusion of BAV cusps and the development of ascending aortic
aneurysms. 8-13 However these studies have focused primarily on BAV patients with right and
2
DOI: 10.1161/CIRCULATIONAHA.113.007282
left coronary cusp fusion, a reflection of the fact this is the most common form of BAV. Using
echocardiography and MDCT to study 167 subjects with BAV, Kang et al have reported an
association between the frequency of different patterns of aortopathy and BAV morphology.14
However, no prior study has attempted to provide a mechanistic link between BAV morphology,
alterations in aortic outflow and aortic pathology in the same study cohort.
The study of Mahadevia et al in this issue of Circulation7 expands on earlier studies by
using 4D MRI to study the impact of the morphologic type of BAV cusp fusion on perturbations
in aortic outflow, and the subsequent aortopathy that results. The authors studied aortic flow in
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
15 healthy volunteers, 30 matched aorta-size controls, and 30 BAV patients all of whom had
aortic dilation (> 40 mm at one or more levels). The authors further divided the B
AV ggroup
ro
roup
oup
BAV
based on morphology of the fused cusps into those with right and left coronary cusp (RL) fusion
an
nd ri
righ
ghtt an
gh
andd no
onn-co
coronary cusp (RN) fusion. Ca
Case
es with the rar
rer
e lef
efft and
an non-coronary cusp
and
right
non-coronary
Cases
rarer
left
ffusion
usiion
o variantt w
e e no
er
ot repr
rrepresented
epr
preese
esente
enteed in th
he st
tudy. Th
The st
tudy
udy’s
y’ in
inc
clusio
clu
ionn ooff eequal
qual
qu
al nnumbers
umbe
um
b rss ((15)
be
155 ooff
15)
were
not
the
study.
study’s
inclusion
pati
pa
tien
ti
en
nts
t w
ith
it
h RL
L aand
n tthe
nd
hee lless
esss co
omm
mmon
on R
N fusi
ffusion
usi
sion
on iss no
otaabl
blee si
sinc
n e pr
nc
prio
iorr 4DMR
44DMRI
DMR
MRII he
emoddynnam
namicc
patients
with
common
RN
notable
since
prior
hemodynamic
tudies99,, 10 have
hav
av
ve focused
fo
ocu
cuse
seed predominantly
prred
edom
omin
om
inan
in
an
ntl
t y onn RL
RL patients.
pati
pa
tiien
nts
t . Thus,
Thus
Th
us,, this
us
this
i is
is the
the first
firs
fi
rstt study
rs
stud
st
udyy that
ud
tha allows
studies
meaningful comparison of the hemodynamics of RL vs. RN subjects.
To characterize the hemodynamic effects of BAV, the authors measured wall shear stress
(WSS), flow angle, and flow asymmetry (measured as normalized flow displacement) at three
points along the ascending aorta, all using 4D MRI. To provide a framework for assessing the
potential impact of hemodynamics on aortic morphology, they categorized aortopathy as type 1
(dilated root), type 2 (enlargement of the tubular portion of the ascending aorta) and type 3
(diffuse involvement of the entire ascending aorta and transverse arch) as has been previously
reported.14
3
DOI: 10.1161/CIRCULATIONAHA.113.007282
The authors confirmed prior studies demonstrating that systolic WSS was significantly
higher among patients with BAV compared to the matched aorta-size controls.9 Additionally,
they noted different distributions of the locations of maximal WSS in RL vs. RN BAV
morphologies, although these differences did not reach statistical significance. While flow angle
was not statistically different between BAV and aorta-size controls, flow displacement was
greater at the sinotubular junction for both RL and RN BAV patients vs. aorta-size controls but
in the distal ascending aorta only for RN patients who were more likely to have type 3
aortopathy.
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
In patients with BAV, aortic outflow may not be directed parallel to the long axis of the
vessel as is normal, but may be displaced in a pattern that is dictated by the morphology
morp
pho
holo
logy
gy of
of the
the
fused aortic cusps. In this study, the authors reported that patients with RL fusion tended to have
ao
orttic flow
flow
low that
th was
was
as predominantly directed toward
towa
ward
wa
rd the right-anterior
right-anter
errio
i r aortic
aorrtic
ao
rt wall, while those
aortic
w
ith
h RN fusion
on had
had flow
flo
l w that
that tended
ten
endded
ded ttoward
oward
d th
he right-posterior
right-po
post
po
steeriior wa
wall
ll. A
ortic
icc fflow
low am
low
amon
on
ng th
thee
with
the
wall.
Aortic
among
ao
ort
rtic
icc-s
-siz
izee controls
cont
co
ntro
ro
olss was
was more
mor
oree central
ceent
ntrral
al and
andd parallel
paral
alle
al
l l to
le
o th
he llong
he
ongg ax
on
axi
is ooff tthe
he aaorta,
he
orta
or
t , si
ta
sim
milar
mil
la tto
o tthat
hatt of
ha
of
aortic-size
the
axis
similar
healthy volu
unttee
eers
rss. Th
Thee au
uth
thor
o s ar
argu
gu
ue th
that
at B
AV m
orrph
p ol
olog
ogyy di
og
dict
c attes ddisplacement
ct
ispl
is
plac
pl
a em
ac
emen
entt of
en
o the aortic
volunteers.
authors
argue
BAV
morphology
dictates
jet and the portion of the aorta that experiences high WSS, ultimately leading to aneurysm
development.
Several previous studies have also used 4D MRI flow in patients with BAV. Barker et al.
studied 60 subjects including 15 patients with BAV (12 of whom had RL fusion), 15 healthy
volunteers, 15 age appropriate volunteers, and 15 age and aorta sized controls.9 They found that
peak velocities of aortic flow were significantly greater in patients with RL fusion than in all 3
control groups. They also suggested that there was a difference in aortic flow patterns between
RL vs. RN BAV morphology but their assertion was limited by the fact that only 3 RN subjects
4
DOI: 10.1161/CIRCULATIONAHA.113.007282
were studied. With a much larger RN cohort, the current study argues this point much more
effectively.
In a related study, Hope at al. compared 20 patients with tricuspid aortic valves to 26
patients with BAV (21 with RL fusion) using 4D MRI flow.10 While 19 BAV subjects had
eccentric flow, 7 subjects had normal flow, something less commonly encountered in the current
study. Inspection of the flow asymmetry maps in the Mahadevia study7 (figure 4) suggests that
some BAV patients had central flow but fewer than in the Hope study. The difference may
reflect that fact that in the Hope study, only 9 subjects had aortic dilation, all but one of these
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
occurring in the group with eccentric flow. If there is, as suggested, a link between eccentric
flow and aortic enlargement, including only BAV patients with enlarged aortas in
n tthe
h M
he
ahad
ah
adev
ad
evia
Mahadevia
tudy might be expected to favor finding more asymmetric flow patterns. In addition, Hope et al
study
us
sed
dm
oree qu
or
qualit
ittat
ativ
ive definitions of asymmetry th
tha
an the quantitat
tiv
i e peak
peeak
ak velocity mapping
used
more
qualitative
than
quantitative
ech
hni
n que usedd in
in the
the current
cu
urr
rren
entt study.
en
stud
stud
dy.
technique
Va
Vari
riat
ri
atio
at
ionn in
n tthe
he ddegree
he
egreee of fflow
eg
low
lo
w as
sym
ymme
metr
me
tryy w
itth
th ssome
omee pa
om
ppatients
tien
ents
t w
ts
ith BA
ith
BAV
V ha
hav
vinng nnormal
orrmaal
Variation
asymmetry
with
with
having
central flow raises
rai
a se
s s the
the question
q essti
qu
tion
o of whether
whe
heth
ther
th
er tthose
hose
ho
s w
se
itth no
orm
rmal
a fflow
al
low
o aare
re less
les
esss likely
l ke
li
kely
ly to
to develop
d velop
de
with
normal
aortopathy. In a second study, Hope et al provided support for this hypothesis by studying the
longitudinal association between 4D MRI acquired flow data and aortic enlargement in BAV
patients.12 They studied 12 tricuspid aortic valve controls and 13 BAV patients (all with RL
fusion) and performed follow-up MRI studies at 4.3 ± 2.9 years. They found that overall, BAV
patients had significantly higher growth in aortic size compared to controls (0.8 vs. 0.1 mm/yr,
p=0.004) while BAV patients with abnormal flow had significantly higher growth rate compared
to BAV with normal flow (1.0 vs. 0.0 mm/yr, p=0.02). Of the hemodynamic parameters used,
Hope et al found that flow displacement correlated better with aortic growth than either
5
DOI: 10.1161/CIRCULATIONAHA.113.007282
maximum velocity or WSS, in keeping with the observation in the Mahadevia study that flow
displacement better discriminated between study groups than flow angle. It appears, therefore,
that flow displacement, as a quantitative measure of flow asymmetry is an important parameter
to include in future studies of BAV aortopathy.
The association between abnormal flow and aneurysm formation warrants additional
study in a larger group of patients that includes those with normal aortas, with an additional
question being whether patients with BAV who initially have central flow develop abnormal
flow when there is superimposed calcification and/or valve dysfunction (stenosis/regurgitation).
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
The current study reports that 87% of RL patients had type 2 aortopathy with 53% and
34% of RN subjects having types 1 and 3 aortopathy respectively. These findings
gss ddiffer
i fe
if
ferr fr
from
om
those
hose of Kang who noted that there was no significant difference in the prevalence of type 1 and
aortopathy
the
BAV
only
right-left
2 ao
ort
rtop
opat
op
athy
at
hy iin
n th
he BA
B
V phenotypes and that on
nly
ly 332%
2% of the righ
ght-leeft ccoronary
gh
oronary fusion subjects
(48%
aortas)
had
type
aortopathy.
48%
% of thosee with
wi h enlarged
enl
n arrge
gedd ao
aort
rtas
as)) ha
as
ad typ
pe 2 ao
orttopaath
hy.14 IInn bett
bbetter
etter
er aagreement
greeeme
m nt w
with
ithh th
it
tthee cu
current
urrrent
study,
tud
udy,
y Kang
y,
Kan
ng et al
al did,
did, however,
howev
oweveer, note
note that
that
hat patients
pattieent
pa
n s with
with
h either
eit
ithe
her right-non
he
righ
ri
ghht-n
-non
-n
on orr left-non
left
le
f -nnonn fusion
ft
fusio
io
on
(grouped
grouped together
togget
ethe
h r in their
he
the
heir study)
stu
tudy
dy)) were
dy
wer more
mor
oree likely
liike
kelly too have
hav
avee type
type 3 aortopathy
aor
orto
or
topa
to
path
pa
thyy than
th
th
han those
tho
hose
s with
right-left fusion. The explanation for these differing findings is uncertain but may reflect the
smaller sample size in the Mahadevia study, selection bias or incompletely captured confounding
variables such as valve dysfunction. Thus the link between BAV phenotype and the type of
aortopathy remains incompletely characterized.
In comparing the Mahadevia study to prior reports and assessing the generalizability of
its findings, it would be helpful to have additional information concerning the way in which the
study groups were identified as well as study group characteristics. There were no subjects with
normally sized aortas, none whose aortic pathology did not fit into the classification scheme used
6
DOI: 10.1161/CIRCULATIONAHA.113.007282
and none with more than moderate valve dysfunction. It would also be interesting to know about
potential confounding variables such as the coexistence of coarctation or other congenital
anomalies, hypertension, valve calcification, and medications such as beta blockers and/or
vasodilators. The way in which aorta-size matched subjects were identified is also unclear. Were
they matched at both levels measured? Better characterization of valve dysfunction in individual
subject groups would also be helpful. Since once can assume that normal subjects had no
stenosis or regurgitation, it would be interesting to know if, for example, all 10 moderate aortic
regurgitation subjects fell into one BAV phenotypic group, since the study of Barker et al15
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
reported differences in WSS between groups with flow reversal ratios greater than or less than
0.10. Better characterization of the degree and distribution of aortic stenosis andd tthe
hee m
methods
etho
etho
hods
ds
used for quantitation would likewise be helpful as patient with aortic stenosis tend to have higher
velocity
ve
elo
oci
city
ty aaortic
orti
or
ticc fl
ti
flow
ow which may also impact aneu
aneurysm
ury
r sm formation. Al
A
Along
on
ng th
tthis
is line, a follow-up
study
tud
dy that includes
inclu
lude
d s patients
pati
pa
t en
ents
ts with
wit
ithh severe
sevver
se
vere valve
valvve dysfunction
dyssfu
uncttio
tion
on in
in large
larg
la
rg
ge enough
en
nouugh numbers
num
mbeers
r to
to address
ad
ddr
dres
esss the
impact,
mpa
pact
ct,, if any,
ct
any
ny,, of
of regurgitation
reg
eguurgi
gita
gi
tatiion
on or
or stenosis
sten
st
enos
o is on
os
on flow
flow
w characteristics
chaaraact
cteeris
erissti
t cs and
and
n aortopathy
aort
rtop
oppatthy would
woul
ould
ld aalso
lsoo be
ls
be
interesting.
nteresting.
It would be useful to know whether the radiologists performing the hemodynamic
analysis were blinded, to the degree possible, to valve and aortic phenotype. Additionally, in a
method that requires manual input at multiple steps, inter- and intra-observer variability data
would also be informative particularly since the authors suggest that flow displacement could be
an important tool for future studies.
Despite the intuitive appeal of the study findings, the relation of hemodynamics to aortic
phenotype must be viewed as preliminary. In figure 5, the authors recognize this and
appropriately note that the study numbers were too small for meaningful statistical analysis.
7
DOI: 10.1161/CIRCULATIONAHA.113.007282
Similarly WSS measurement displays (Figure 3) appear different for RL vs. RN subjects but
statistical significance was demonstrated only in the comparison to aorta-size matched subjects.
It would be interesting to speculate as to why RN but not (in this series) RL subjects had type 1
aortopathy, since valve flow angles and flow displacement at the sinotubular junction level were
comparable in both groups. Although the authors assessed the type of aortopathy according to
BAV cusp fusion morphology, perhaps a direct and tighter correlation between the anatomic
region of aneurysm formation and the site of maximal WSS and/or jet impingement would be
informative.
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
As the authors acknowledge, additional studies with larger and more clearly defined
study
recruiting
patients
tudy groups and longitudinal follow-up are essential. Given the challenges in rec
eccru
uitin
ingg pa
in
pati
tien
ti
ents
with multiple BAV morphologies and the large number of potentially confounding clinical
variables,
studies
accomplished
multicenter
va
ariiab
able
less, ssuch
le
uch st
uc
tudie
udi s would likely be best accom
ompplished with a m
om
ulti
tiice
cennter trial and multicenter
participation
that
part
tic
i ipation in rregistries
eg
gisstrriees su
ssuch
uch
ch aass th
tha
at ccreated
at
reateed by
by the
thee University
Uniive
verrsit
i y of
it
of Michigan
Mic
i hi
higa
gann (NCT01756220).
(NCT
(NCT
T01
0 75
7 62
6220
20).
0.
The
ability
MRI
such
current
Th
he ab
abil
ilit
ityy to iinclude
ncclu
ude ggenetic
ene icc ddata
enet
ataa and
at
and 4D
DM
RI pparameters
aramete
mete
ters
rs suc
uchh ass tthose
uc
hoosee ppresented
reeseent
nted
ed iin
n the
the cu
urrren
ent
study
Without
data,
impossible
determine
whether
tudy would be hhighly
ighl
ig
h y de
hl
ddesirable.
siira
rabl
b e. W
i hoout ssuch
it
uchh da
uc
ataa, it iiss im
mpo
poss
ssib
ss
i lee tto
ib
o de
dete
term
te
rmin
rm
inee wh
in
whet
e her 4D
MRI flow data have prognostic value or whether they should be used to guide the management
of BAV patients. However it is clear that 4D MRI, using the measures of wall shear stress and
flow asymmetry employed in the current study, is a valuable tool is studying potential links
between BAV morphology, associated flow disturbances and aortopathy. Given the prevalence
of BAV and the clinical impact of associated aortopathy, such studies deserve a high priority.
Conflict of Interest Disclosures: None.
8
DOI: 10.1161/CIRCULATIONAHA.113.007282
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Kansal
P,, Fed
Fedak
Malaisrie
C,, Mc
McCarthy
P,,
7.. Mahadevia
Mahadevia R,
R, Barker
Bark
rker
rk
er A,
A, Schnell
Schhnel
Sc
hnel
elll S,
S Entezari
Entezzarri P,, K
ans
nssal
al P
F
edak P,
P M
alai
aiisr
sriie
ie C
McCa
Cart
Ca
rthy
hy P
Collins
C
olllin
i s J, Carr
Car
arrr J,, Markl
Markkl M. Bicuspid
Bicu
Bi
c sp
s id
d aortic
aorrtic cusp
cu fusion
fussio
ionn morphology
morrph
mo
rphollogy alters
altterrs aortic
aortic
aor
i 3d
3d outflow
outf
ou
tfllow
patterns,
expression
aortopathy.
Circulation.
patt
pa
tter
tt
errns
n , wa
wall
ll sshear
hear
ar sstress
trresss an
andd ex
xpr
preessi
essiionn ooff ao
ort
r opa
opathy
hy. Ci
hy
Circ
rcul
ulat
ul
attio
on. 201
22014;129:XX-XXX.
014;1
14;1
129
29:X
:XXX-XX
XXX
XX.
X.
AJ,
Staehle
Bock
Markl
Analysis
complex
8. Barker AJ
J, St
Stae
aeehl
hlee F, Boc
o k J,, JJung
oc
ungg BA
un
BA,, Ma
Mark
rkll M. A
rk
naly
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"Nature vs. Nurture" in Bicuspid Aortic Valve Aortopathy: More Evidence that Altered
Hemodynamics May Play a Role
Seth Uretsky and Linda D. Gillam
Circulation. published online December 17, 2013;
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