Download Aortic Dilatation in Patients with Bicuspid Aortic Valve

The
n e w e ng l a n d j o u r na l
of
m e dic i n e
review article
Edward W. Campion, M.D., Editor
Aortic Dilatation in Patients
with Bicuspid Aortic Valve
Subodh Verma, M.D., Ph.D., and Samuel C. Siu, M.D.
From the Division of Cardiac Surgery, St.
Michael’s Hospital, Department of Surgery, University of Toronto, Toronto
(S.V.), and the Division of Cardiology, Department of Medicine, Lawson Research
Institute, London Health Sciences Centre, Western University, London, ON
(S.C.S.) — both in Canada. Address reprint requests to Dr. Verma at the Division of Cardiac Surgery, St Michael’s
Hospital, 30 Bond St., Toronto, ON M5B
1W8, Canada, or at [email protected].
N Engl J Med 2014;370:1920-9.
DOI: 10.1056/NEJMra1207059
B
icuspid aortic valve is the most common congenital heart defect in adults, affecting 1.3% of the population worldwide, and is responsible
for more deaths and complications than the combined effects of all the
other congenital heart defects.1,2 Although aortic stenosis and regurgitation are the
most common complications of a bicuspid aortic valve, dilatation of any or all segments of the proximal aorta from the aortic root to the aortic arch, called bicuspid
aortopathy, is also present in approximately 50% of affected persons.1-4 Accumulating
evidence suggests that the pattern of aortic dilatation in persons with a bicuspid aortic
valve is diverse, possibly reflecting heterogeneity in molecular, rheologic, and clinical
features.4-9 This article provides a brief overview of the basic principles, recent advances,
and recommendations for the treatment of adults with bicuspid aortopathy.
Copyright © 2014 Massachusetts Medical Society.
TER MINOL O GY A ND DEFINI T IONS
A normal aortic valve is composed of three aortic-valve cusps, each semilunar in
appearance. The leaflets are housed within a small dilatation of the proximal aorta
associated with each cusp, called the sinuses of Valsalva or aortic sinuses, and their
association with the respective coronary ostia identifies them: left, right, and noncoronary sinuses. Each cusp is attached to the wall of the aorta by the outward
edges of its semicircular border, and the attachment point between each leaflet is
called a commissure.
A bicuspid aortic valve typically comprises two leaflets of unequal size.2 The
most common fusion pattern involves the right and left cusps (RL fusion pattern,
resulting in an anterior–posterior leaflet orientation; also called the typical pattern), followed by fusion of the right and noncoronary cusps (RN fusion pattern,
resulting in a right–left leaflet orientation; also called the atypical pattern). The
least common pattern involves fusion of the left and noncoronary cusps. In rare
cases, the leaflets are symmetrical or there is no raphe.
The aorta is anatomically divided into the ascending aorta (approximately 5 cm
in length and 20 to 37 mm in diameter),10 aortic arch, thoracic aorta, and abdominal aorta. The aortic root comprises the aortic sinuses, aortic valve, and
coronary ostia; the tubular portion of the ascending aorta begins at a point distal
to the aortic root (sinotubular junction) and ends at the origin of the innominate
artery. The aortic arch is composed of the origins of the innominate artery, the
left common carotid artery, and the left subclavian artery (Fig. 1).
PR E VA L ENCE OF BICUSPID AOR T IC DIL ATAT ION
The reported prevalence of dilatation of the ascending aorta among persons with a
bicuspid aortic valve ranges from 20 to 84%.1,2,7,11-15 This variation is related to differences in study populations, assessment techniques, and aortic-size thresholds,
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Aortic Dilatation
A
Patterns of bicuspid aortopathy
Type 1
Dilatation of tubular
ascending aorta primarily
along convexity of aorta,
with mild-to-moderate
root dilatation
Innominate
artery
Aortic
arch
Type 2
Arch dilatation with
involvement of tubular
ascending aorta, with
relative sparing of root
Tubular
aorta
Thoracic
aorta
Left
coronary
artery
Sinotubular
junction
Right
coronary
artery
B
Aortic
root
Aortic
valve
Type 3
Isolated aortic-root
involvement with normal
tubular ascending aorta
and arch dimensions
Sinus
of Valsalva
Echocardiographic and magnetic resonance examples of bicuspid aortopathy
AscAO
LV
Figure 1. Patterns of Bicuspid Aortopathy, with Representative Findings on Echocardiography and Computed
Tomography (CT).
Panel A shows the biologic features of the aorta and the three types of bicuspid aortopathy. The transthoracic echocardiogram at the left in Panel B shows normal dimensions of the sinuses of Valsalva (arrow) and a dilated ascending aorta. AscAO denotes proximal ascending aorta, and LV left ventricle. The CT images in the middle and at the
right show dilatation of the aortic root and dilatation of the ascending aorta and proximal arch, respectively.
n engl j med 370;20
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1921
The
n e w e ng l a n d j o u r na l
as well as the heterogeneous nature of the disease. All the segments of the ascending aorta are
larger in adults with a bicuspid valve than in those
with a tricuspid aortic valve.
Aortic dilatation begins in childhood and is
progressive. Children born with a bicuspid aortic
valve have a larger ascending aorta that increases
in size at a higher rate than that of matched controls with a tricuspid aortic valve.2 The prevalence
of dilatation at the level of the tubular ascending
aorta increases with age and has been reported to
be 56%, 74%, 85%, 91%, and 88% at the respective age quintiles of younger than 30 years, 30 to
39 years, 40 to 49 years, 50 to 60 years, and older
than 60 years of age.11 The prevalence also varies
widely according to the site of dilatation (annulus,
aortic root, or tubular ascending aorta).7
PAT TER NS OF BICUSPID AOR T IC
DIL ATAT ION
Classification schemes that are based on histologic features,16 morphologic valve-fusion patterns, and hierarchical cluster analyses17 have
been proposed for describing bicuspid aortopathy, but none have been widely adopted.1,4,7,8,17-20
The patterns of aortic involvement can be classified into three types to guide future management. Type 1, the most common type, involves
dilatation of the tubular ascending aorta (particularly along its convexity), accompanied by
varying degrees of aortic-root dilatation (Fig. 1).
This type has been associated with an older age
at diagnosis (>50 years), valvular stenosis, and
the RL fusion pattern.4,8,21,22 Type 2 involves isolated involvement of the tubular ascending aorta
(with relative sparing of the aortic root), frequently extending into the transverse aortic arch
(Fig. 1), and has been associated with the presence of the RN fusion pattern.4,8,17,21,22 Type 3,
also called the root phenotype, involves isolated
dilatation of the aortic root (Fig. 1). This rare type
has been associated with a younger age at diagnosis (<40 years), male sex, and aortic regurgitation and has been proposed to be the form of
bicuspid aortopathy that is most likely to be associated with a genetic cause.4,7,23
PATHOPH YSIOL O GIC A L FE AT UR E S
The development of bicuspid aortopathy has been
attributed to genetic and hemodynamic bases.
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Although the relative contribution of genetics
and hemodynamics remains debated,1,2,4,7,24 both
factors are probably operative.
The evidence supporting a genetic basis includes the following observations: aortopathy is
prevalent in first-degree relatives of patients with
a bicuspid aortic valve25; differences in aortic dimensions in persons with a bicuspid aortic valve
persist even after adjustment for blood pressure,
peak aortic-jet velocity, and left ventricular ejection
time and are also observed in persons with apparently normal-functioning bicuspid valves1,2,7; and
the prevalence of aortic dilatation among persons with a bicuspid aortic valve is greater than
that predicted according to the severity of aortic
stenosis or aortic regurgitation.1,4,7,12,13,26 Autosomal dominant, X-linked, and familial modes
of inheritance have been reported.1,4,7 Abnormal
migration of neural-crest cells has been postulated
as a common pathway that results in a bicuspid
aortic valve and aortopathy.2,7
The histologic changes observed in bicuspid
aortopathy, previously called cystic medial necrosis, are the end result of abnormal regulatory
pathways of vascular smooth-muscle cells within
the aortic media. Abnormal processing of the
extracellular matrix protein fibrillin 1 by vascular smooth-muscle cells initiates detachment of
vascular smooth-muscle cells from the extracellular matrix, leading to the release of matrix
metalloproteinases (MMPs) together with their
tissue inhibitors. The resulting matrix disruption
and elastin and lamellar fragmentation lead to
increased apoptosis of vascular smooth-muscle
cells and disruption of the media layer, adversely
affecting the structural integrity and flexibility
of the aorta (Fig. 2).1,2,7,27,28
The concept that abnormal valve dynamics
lead to bicuspid aortopathy is supported by the
observation that even normally functioning bicuspid aortic valves can have abnormal transvalvular-flow patterns, resulting in regional increases in wall shear stress that are predicted largely
by the morphologic features of the bicuspid valve.4-6
Magnetic resonance imaging (MRI) studies have
shown that an RL fusion pattern results in a flow
jet directed toward the right anterior aortic wall,
which is then propagated in a right-handed helical direction (Fig. 3, and Fig. S1 in the Supplementary Appendix, available with the full text of
this article at NEJM.org).5,6 The increase in regional wall shear stress might be the basis of the
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Aortic Dilatation
A
Elastin and collagen
Fibrillin 1
microfibril
Smooth-muscle
cells
B
Disrupted
elastin and collagen
Loss of fibrillin 1
microfibrils
Smooth-muscle
cell loss
MMP
release
Figure 2. Pathophysiological Features of Bicuspid Aortopathy.
Structural support and elasticity are afforded to the aorta by means of alternating layers of elastic lamellae and
smooth-muscle cells. At the histologic level, the smooth-muscle cells in the aorta in persons with tricuspid valves are
secured to the adjacent elastin and collagen matrix by fibrillin 1 microfibrils (Panel A). The aorta in persons with bicuspid valves may be deficient in fibrillin 1. This deficiency culminates in a disrupted architecture whereby smoothmuscle cells detach, accompanied by a surge in local levels of matrix metalloproteinases (MMPs), leading to loss
of integrity in the extracellular matrix and the accumulation of apoptotic cells. These events may lead to an aorta
with weakened structural integrity and reduced elasticity (Panel B).
association of the RL fusion pattern with dilatation of the aortic root and asymmetric dilatation
of the tubular ascending aorta. Conversely, an RN
fusion pattern results in a flow toward the posterior aorta, with increased wall shear stress at
the right posterior aspect of the aorta (Fig. 3),
leading to dilatation of the aortic arch. These
preliminary observations in small samples of patients are intriguing but require further clarifican engl j med 370;20
tion in unselected populations and linkage to outcomes. Indeed, valve orientation did not predict
events in the three largest outcome studies.29-31
NAT UR A L HIS T OR Y
Aortic aneurysm formation and aortic dissection
are the two major complications of bicuspid aortopathy. The rate of growth of the ascending aorta
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1923
The
A
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B
Right–left fusion pattern
of
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Right–noncoronary fusion pattern
Raphe
Figure 3. Morphologic Features of the Bicuspid Aortic Valve That Influence the Pattern of Aortopathy.
The fusion configuration of the aortic-valve cusps lays the foundation for changes in aortic wall shear stress and the resultant flow pattern. In the right–left fusion pattern (Panel A), the jet is directed toward the right anterior wall of the ascending aorta, where it travels in
a right-handed helical direction to promote dilatation predominantly of the ascending aorta. In the pattern with fusion of the right and
noncoronary cusps (Panel B), the jet is directed toward the posterior wall of the aorta, whereby the pattern of wall shear stress it causes
may promote aortic dilatation within the proximal arch. Further details regarding the influence of morphologic features of bicuspid aortic valve on patterns of aortopathy are provided in Figure S1 in the Supplementary Appendix.
in persons with a bicuspid aortic valve (range,
0.2 to 1.9 mm per year) is considerably higher
than the rate in persons with a tricuspid aortic
valve.7,14,32-38
The aortic diameter at baseline is an important
predictor of aortic expansion. A study involving
88 patients showed expansion rates of approximately 2.1 mm per year among patients with a
bicuspid aortic valve that had an initial aortic diameter of 35 to 40 mm, as compared with a rate
of 5.6 mm per year among patients with an
aortic diameter of more than 60 mm.39 A recent
study involving 416 consecutive patients with a
bicuspid aortic valve showed that an aortic diameter of 40 mm or more at baseline independently
predicted the subsequent development of an aneurysm, as compared with a baseline diameter
of less than 40 mm (hazard ratio, 3.3; 95% confidence interval, 1.5 to 7.2).29 Other predictors of
progression of bicuspid aortopathy include older
age, male sex, elevated systolic blood pressure,
coexisting aortic-valve stenosis or regurgitation,
and morphologic features of the valve (RL fusion
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pattern).2 Prior coarctation repair may provide
protection against rapid aortic dilatation.15
The incidence of aortic dissection, the mostfeared complication of bicuspid aortopathy, was
once estimated to be as high as 5% but has been
much lower in contemporary studies. The incidence of aortic dissection was 0.1% per patientyear of follow-up in a Toronto study involving
642 patients with a bicuspid aortic valve.30 Likewise, in an Olmsted County, Minnesota, study involving 416 patients with a bicuspid aortic valve,
there were two aortic dissections during a mean
(±SD) follow-up of 16±7 years, with an incidence
of 3.1 cases per 10,000 person-years and an ageadjusted relative risk of 8.4.29 The incidence of
aortic dissection was 17.4 cases per 10,000 personyears among patients 50 years of age or older
and 44.9 cases per 10,000 person-years among
patients with a baseline echocardiogram showing an aneurysm. There were no dissections in
patients with an aortic diameter of less than
45 mm at baseline or in those with a normally
functioning aortic valve. Thus, despite a high relanejm.org
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Aortic Dilatation
tive risk that increased with age, the absolute risk
of aortic dissection was quite low. Furthermore,
the 25-year survival rate in the entire cohort was
80% — identical to the survival rate in the general population of Olmsted County.
The low rates of aortic dissection in contemporary series reflect the practice of serial surveillance and surgical intervention once aortic size
exceeds a threshold.29,30 The actual risk in the
absence of surgery is probably higher, since patients with a large aorta will have undergone
surgery. For example, among the 32 patients in
the Olmsted County study who had an aortic
diameter of 45 mm or more at baseline, the
long-term rate of aortic dissection was 7%, but
46% of the patients underwent aortic surgery.29
In the entire study group, the rates of aneurysm
formation and aortic surgery at 25 years were
26% and 25%, respectively, reflecting the effect
of aortopathy on morbidity (Fig. S2 in the Supplementary Appendix).
Patients with a bicuspid aortic valve and an
aortic diameter of less than 50 mm at baseline
who underwent isolated aortic-valve replacement
continued to be at risk for future aortic complications. In a mixed group of patients with aortic
stenosis and those with aortic regurgitation, the
rate of freedom from aortic complications (need
for surgery, aortic dissection, or death) at 15 years
was 43% among patients with an aortic diameter
of 45 to 49 mm, as compared with 86% among
those with an aortic diameter of less than 40 mm,
suggesting that moderate aortic dilatation is an
important risk factor for aortic complications,
even after valve replacement.40 No aortic dissection was observed during follow-up in a more
recent series of patients with aortic stenosis and
concomitant mild-to-moderate dilatation of the
ascending aorta at the time of aortic-valve replacement.23 However, patients with aortic regurgitation and mild-to-moderate dilatation of the aortic
root (root phenotype) were at risk for aortic complications after aortic-valve replacement.
A SSE SSMEN T A ND T R E ATMEN T
DIAGNOSIS
The initial diagnosis of bicuspid aortopathy is
likely to be made with the use of transthoracic
echocardiography (TTE). Although TTE is usually adequate in assessing the aortic root and
proximal ascending aorta, visualization of the
mid-distal ascending aorta and the arch may be
n engl j med 370;20
difficult in adults, in which case either a computed tomographic (CT) or MRI study should be
considered for comprehensive assessment of the
ascending aorta. If there are contraindications to
CT or MRI, then a transesophageal echocardiogram can be obtained.41 MRI is preferable to CT
for serial surveillance since it is not associated
with radiation exposure.
DECISION-MAKING ALGORITHM
Figure 4 outlines a proposed approach to the management of bicuspid aortopathy in asymptomatic
adults. This algorithm integrates U.S., European,
and Canadian recommendations, which are based
largely on expert opinion and observational studies.41-45 Risk factors, particularly smoking and
hypertension, should be aggressively addressed in
all patients with bicuspid aortopathy. Beta-adrenergic blockers, angiotensin-converting–enzyme
inhibitors, and angiotensin-receptor blockers are
the antihypertensive agents of choice. Beta-adrenergic blockers have the theoretical advantage of
reducing aortic wall shear stress, whereas angiotensin-receptor blockers have been shown to reduce the rate of aortic growth in patients with
Marfan’s syndrome.46
Yearly echocardiographic surveillance is recommended in patients who have an aortic root
or an ascending aorta with a diameter of more
than 40 mm, as assessed by means of TTE, and
no concomitant indication for valvular replacement or repair. In patients who have an aortic
root or ascending aorta with a diameter of 40 to
44 mm and no concomitant valvular indication
for intervention, a baseline CT or MRI scan may
be obtained. If ongoing imaging surveillance, by
means of echocardiography, CT, or MRI, reveals
a growth rate exceeding 5 mm per year, surgical
management may be considered.
In patients who have an aortic root or ascending aorta with a diameter of 45 to 49 mm, a CT
or MRI scan should be obtained. If there are
concomitant indications for either valvular or coronary surgery, then a tailored surgical approach
will be required, dictated largely by the aortopathy pattern, perioperative risk, and surgeon
and center experience. In patients with dilatation of the tubular ascending aorta, surgical
options include supracoronary replacement of
the ascending aorta, or if substantial aortic-valve
dysfunction and aortic-root dilatation are also
present, then replacement of the aortic valve, aortic root, and ascending aorta is indicated. In
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1925
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Yearly echocardiography, CT, or
MRI to evaluate
ascending aorta
Proceed to isolated
aortic-valve
replacement
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If rapid progression
(≥5 mm/yr),
consider surgery
Yearly surveillance
with echocardiography, CT, or MRI
Baseline CT or MRI
No
Yearly echocardiography, CT, or
MRI to evaluate
ascending aorta
Proceed to isolated
aortic-valve
replacement
Yes
Consider tailored
surgical approach
based on type of
aortopathy pattern,
perioperative risk,
and surgeon or
center experience
Evaluate the presence
of risk modifiers
Family history
of aortic dissection, aneurysm,
rupture, or
sudden death
Growth rate
≥5 mm/yr
Ratio of aortic
area to body
height >10
No
Yes
Tailored surgical
approach based on
type of aortopathy
pattern, perioperative
risk assessment,
surgeon or center
experience, anticoagulation therapy,
and patient preference
(e.g., aortic-valve
replacement with
supracoronary
replacement of
ascending aorta,
hemiarch, total arch
replacement, aorticvalve repair, sparing
root replacement, or
valved conduit repair)
Valvular indication
Aortic root or ascending
aorta 45–49 mm
Tailored surgical
approach based on
type of aortopathy
pattern, perioperative
risk, and surgeon or
center experience
May consider surgery
No
Yes
Tailored surgical
approach based on
type of aortopathy
pattern, perioperative
risk assessment,
surgeon or center
experience, anticoagulation therapy,
and patient preference
(e.g., aortic-valve
replacement with
supracoronary
replacement of
ascending aorta,
hemiarch, total arch
replacement, aorticvalve repair, sparing
root replacement, or
valved conduit repair)
Consider surgery
Valvular indication
Aortic root or ascending
aorta 50–55 mm
n e w e ng l a n d j o u r na l
of
Figure 4. Decision-Making Algorithm for the Management of Bicuspid Aortopathy.
Management includes risk-factor modification in all persons and includes the treatment of hypertension, treatment of dyslipidemia, and smoking cessation. If the entire ascending
aorta (from aortic root to arch) is not completely visualized by means of transthoracic echocardiography, supplemental MRI or CT is recommended. CT or MRI is also recommended in planning the surgical approach.
Serial transthoracic
echocardiography
May consider CT
or MRI in patients
with aortic root or
ascending aorta
dimensions of
35–39 mm
Yes
Valvular indication
Valvular indication
No
Aortic root or ascending
aorta 40–44 mm
Aortic root or ascending
aorta <40 mm
Transthoracic echocardiogram
The
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Aortic Dilatation
patients with a dilated ascending aorta and aortic
arch, surgical options may include aortic-valve
replacement with supracoronary replacement of
the ascending aorta and hemiarch. In most instances, this intervention will require deep hypothermic circulatory arrest and the potential
use of antegrade cerebral perfusion.
In patients with isolated involvement of the
aortic root, surgical options may include aorticvalve and aortic-root replacement with the use of
a composite valved conduit (Bentall procedure). In
most cases, surgical repair for bicuspid aortopathy
can be achieved with excellent results at an experienced center.47 If aortic-valve surgery will be
performed concurrently with ascending-aorta
replacement, it is important to incorporate nonsurgical factors into the decision-making process,
such as the lifestyle of the patient, need for longterm anticoagulation, and in the case of female
patients, future reproductive plans. A summary of
surgical results from various publications are provided in Table S1 in the Supplementary Appendix.
In the absence of a valvular indication, patients who have an aortic root or ascending aorta
with a diameter of 45 to 50 mm may be considered for surgery only if they have high-risk features such as a family history of aortic dissection, rupture, or sudden death and an aortic
growth rate of more than 5 mm per year. A ratio
of aortic area to body height of more than 10 cm2
per meter has also been recommended for patients of short stature.41 In the absence of these
factors, yearly reassessment of the risk stratification with the use of CT or MRI is suggested.7,37
Surgery has previously been recommended
for patients with an aortic root or ascending aorta
that has a diameter of 5.0 cm or more, with
guidelines recommending a threshold of 5.5 cm
and a more individualized approach.41,42 European guidelines recommend that the aorta be
replaced when the diameter of the aortic root or
ascending aorta is 5.0 cm or more and in the
presence of risk factors including coarctation of
the aorta, systemic hypertension, family history
of dissection, or an increase in the aortic diameter of more than 2 mm per year.43 European
guidelines are in agreement with U.S. guidelines
that recommend a lower threshold for ascending-aorta replacement in patients who are undergoing aortic-valve surgery (aortic diameter, 45 mm)
and when valve repair will be performed at an
experienced center with high rates of success.43
n engl j med 370;20
The 2014 Canadian guidelines recommended
a threshold range (aortic diameter, 50 to 55 mm),
recognizing the importance of also incorporating patient size and patient-specific factors when
deciding on the timing and nature of elective
aorta replacment.45 Prophylactic surgery at the
lower threshold limit of 50 mm would be appropriate in patients with risk factors for aortic
complications (e.g., rapid aortic growth or concomitant aortic-valve disease, connective-tissue
disorders, or genetic syndromes) but may not be
prudent in those at increased risk for complications during surgery. These recommendations
are based on the premise that aortic complications, representing a long-term risk that increases with time, will be avoided if elective
aortic-valve replacement is performed at experienced centers with low mortality (≤1%).45
SPECIAL POPULATIONS
During pregnancy, there are changes in hemodynamic variables as well as changes in the aortic
media, and pregnant women who have a bicuspid
aortic valve and concomitant aortic dilatation are
therefore at increased risk for complications. In
general, women with a bicuspid aortic valve and
an aortic diameter of more than 45 mm should
be advised against pregnancy. Summary recommendations regarding treatment during pregnancy are provided in Table S2 in the Supplementary
Appendix.
Athletes with or without valvular disease who
have a dilated aortic root or ascending aorta
(diameter ≥45 mm) should be advised to participate only in low-intensity competitive sports
(Table S3 in the Supplementary Appendix).
First-degree relatives of patients with a bicuspid
aortic valve should be screened for the presence
of a bicuspid aortic valve and asymptomatic
aortic disease.25,41,43
UNA NS W ER ED QUE S T IONS
A ND F U T UR E DIR EC T IONS
Advances in imaging, biomarker-based risk assessments, and genetics should be used to gain a
better understanding of the mechanisms underlying the development and progression of bicuspid aortopathy. The Beta Blockers and Angiotensin Receptor Blockers in Bicuspid Aortic Valve
Disease Aortopathy (BAV) study (ClinicalTrials
.gov number, NCT01202721) is an ongoing trial
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1927
The
n e w e ng l a n d j o u r na l
of
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that is being conducted by the Canadian Network patients who are most likely to benefit from earand Centre for Trials Internationally. The purpose lier intervention, as well as those for whom watchof this study is to evaluate the efficacy of atenolol ful waiting is appropriate.
and telmisartan in slowing the progression of
bicuspid aortopathy. A trial of medical versus
No potential conflict of interest relevant to this article was
surgical management in patients with a moder- reported.
Disclosure forms provided by the authors are available with
ately dilated ascending aorta (45 to 50 mm) would
the full text of this article at NEJM.org.
be highly informative. Future studies should foWe thank Dr. Hwee Teoh for editorial assistance with an earcus on improving the selection of subgroups of lier version of the manuscript.
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