Aortic Dilatation in Patients with Bicuspid Aortic ValveThe aorta is anatomically divided into the...

review article

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 370;20 nejm.org may 15, 20141920

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 Sur-gery, University of Toronto, Toronto (S.V.), and the Division of Cardiology, De-partment of Medicine, Lawson Research Institute, London Health Sciences Cen-tre, Western University, London, ON (S.C.S.) — both in Canada. Address re-print requests to Dr. Verma at the Divi-sion 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/NEJMra1207059Copyright © 2014 Massachusetts Medical Society.

Bicuspid aortic valve is the most common congenital heart de-fect 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 seg-ments 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.

TER MINOL O GY A ND DEFINI TIONS

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 non-coronary 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 pat-tern), 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 ab-dominal 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 LENCE OF BICUSPID AORTIC DIL ATATION

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 dif-ferences in study populations, assessment techniques, and aortic-size thresholds,

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Aortic Dilatation

n engl j med 370;20 nejm.org may 15, 2014 1921

Innominateartery

Aorticarch

Tubularaorta

artery

AorticAortic

Thoracicaorta

Sinotubularjunction

Sinusof Valsalva

Aorticroot

Aorticvalve

Leftcoronary

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LeftLeft

Rightcoronary

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RightRight

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Patterns of bicuspid aortopathyA

Type 1Type 1

Type 2

Type 3Type 3

Echocardiographic and magnetic resonance examples of bicuspid aortopathyB

Isolated aortic-rootinvolvement with normaltubular ascending aorta

and arch dimensions

Arch dilatation with involvement of tubularascending aorta, with

relative sparing of root

Dilatation of tubularascending aorta primarilyalong convexity of aorta,with mild-to-moderate

root dilatation

LVAscAO

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 echo-cardiogram at the left in Panel B shows normal dimensions of the sinuses of Valsalva (arrow) and a dilated ascend-ing 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.





as well as the heterogeneous nature of the dis-ease. 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 con-trols 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 respec-tive 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 AORTIC DIL ATATION

Classification schemes that are based on histo-logic features,16 morphologic valve-fusion pat-terns, and hierarchical cluster analyses17 have been proposed for describing bicuspid aortopa-thy, but none have been widely adopted.1,4,7,8,17-20 The patterns of aortic involvement can be classi-fied into three types to guide future manage-ment. Type 1, the most common type, involves dilatation of the tubular ascending aorta (par-ticularly 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 iso-lated involvement of the tubular ascending aorta (with relative sparing of the aortic root), fre-quently extending into the transverse aortic arch (Fig. 1), and has been associated with the pres-ence 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 diag-nosis (<40 years), male sex, and aortic regurgita-tion and has been proposed to be the form of bicuspid aortopathy that is most likely to be as-sociated with a genetic cause.4,7,23

PATHOPH YSIOL O GIC A L FE AT UR ES

The development of bicuspid aortopathy has been attributed to genetic and hemodynamic bases.

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 in-cludes the following observations: aortopathy is prevalent in first-degree relatives of patients with a bicuspid aortic valve25; differences in aortic di-mensions 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 appar-ently normal-functioning bicuspid valves1,2,7; and the prevalence of aortic dilatation among per-sons 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 Auto-somal 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 ne-crosis, 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 vascu-lar smooth-muscle cells initiates detachment of vascular smooth-muscle cells from the extracel-lular 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 bi-cuspid aortic valves can have abnormal transval-vular-flow patterns, resulting in regional increas-es 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 heli-cal direction (Fig. 3, and Fig. S1 in the Supple-mentary Appendix, available with the full text of this article at NEJM.org).5,6 The increase in re-gional wall shear stress might be the basis of the



Aortic Dilatation


association of the RL fusion pattern with dilata-tion of the aortic root and asymmetric dilatation of the tubular ascending aorta. Conversely, an RN fusion pattern results in a flow toward the pos-terior 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 pa-tients are intriguing but require further clarifica-

tion in unselected populations and linkage to out-comes. 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 aor-topathy. The rate of growth of the ascending aorta

Elastin and collagen

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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 bi-cuspid valves may be deficient in fibrillin 1. This deficiency culminates in a disrupted architecture whereby smooth-muscle 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).





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 approxi-mately 2.1 mm per year among patients with a bicuspid aortic valve that had an initial aortic di-ameter 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 diam-eter of 40 mm or more at baseline independently predicted the subsequent development of an an-eurysm, as compared with a baseline diameter of less than 40 mm (hazard ratio, 3.3; 95% con-fidence 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

pattern).2 Prior coarctation repair may provide protection against rapid aortic dilatation.15

The incidence of aortic dissection, the most-feared complication of bicuspid aortopathy, was once estimated to be as high as 5% but has been much lower in contemporary studies. The inci-dence of aortic dissection was 0.1% per patient-year of follow-up in a Toronto study involving 642 patients with a bicuspid aortic valve.30 Like-wise, in an Olmsted County, Minnesota, study in-volving 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 age-adjusted relative risk of 8.4.29 The incidence of aortic dissection was 17.4 cases per 10,000 person-years among patients 50 years of age or older and 44.9 cases per 10,000 person-years among patients with a baseline echocardiogram show-ing 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 rela-

Right–left fusion patternA

RapheRapheRaphe

Right–noncoronary fusion patternB

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 pat-tern. 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 aor-tic valve on patterns of aortopathy are provided in Figure S1 in the Supplementary Appendix.



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 gen-eral population of Olmsted County.

The low rates of aortic dissection in contem-porary series reflect the practice of serial surveil-lance and surgical intervention once aortic size exceeds a threshold.29,30 The actual risk in the absence of surgery is probably higher, since pa-tients 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 Sup-plementary 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 compli-cations. 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 dissec-tion 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 replace-ment.23 However, patients with aortic regurgita-tion and mild-to-moderate dilatation of the aortic root (root phenotype) were at risk for aortic com-plications after aortic-valve replacement.

A SSESSMEN T A ND TR 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 usu-ally adequate in assessing the aortic root and proximal ascending aorta, visualization of the mid-distal ascending aorta and the arch may be

difficult in adults, in which case either a comput-ed 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 echocardio-gram 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 man-agement of bicuspid aortopathy in asymptomatic adults. This algorithm integrates U.S., European, and Canadian recommendations, which are based largely on expert opinion and observational stud-ies.41-45 Risk factors, particularly smoking and hypertension, should be aggressively addressed in all patients with bicuspid aortopathy. Beta-adren-ergic blockers, angiotensin-converting–enzyme inhibitors, and angiotensin-receptor blockers are the antihypertensive agents of choice. Beta-adren-ergic blockers have the theoretical advantage of reducing aortic wall shear stress, whereas angio-tensin-receptor blockers have been shown to re-duce the rate of aortic growth in patients with Marfan’s syndrome.46

Yearly echocardiographic surveillance is rec-ommended 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 replace-ment 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 ascend-ing 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 cor-onary surgery, then a tailored surgical approach will be required, dictated largely by the aor-topathy pattern, perioperative risk, and surgeon and center experience. In patients with dilata-tion 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, aor-tic root, and ascending aorta is indicated. In





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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 in-stances, this intervention will require deep hy-pothermic circulatory arrest and the potential use of antegrade cerebral perfusion.

In patients with isolated involvement of the aortic root, surgical options may include aortic-valve 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 ex-perienced center.47 If aortic-valve surgery will be performed concurrently with ascending-aorta replacement, it is important to incorporate non-surgical factors into the decision-making process, such as the lifestyle of the patient, need for long-term anticoagulation, and in the case of female patients, future reproductive plans. A summary of surgical results from various publications are pro-vided in Table S1 in the Supplementary Appendix.

In the absence of a valvular indication, pa-tients who have an aortic root or ascending aorta with a diameter of 45 to 50 mm may be consid-ered for surgery only if they have high-risk fea-tures such as a family history of aortic dissec-tion, 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 pa-tients of short stature.41 In the absence of these factors, yearly reassessment of the risk stratifica-tion 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 Euro-pean 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 diam-eter of more than 2 mm per year.43 European guidelines are in agreement with U.S. guidelines that recommend a lower threshold for ascend-ing-aorta replacement in patients who are under-going aortic-valve surgery (aortic diameter, 45 mm) and when valve repair will be performed at an experienced center with high rates of success.43

The 2014 Canadian guidelines recommended a threshold range (aortic diameter, 50 to 55 mm), recognizing the importance of also incorporat-ing 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 ap-propriate in patients with risk factors for aortic complications (e.g., rapid aortic growth or con-comitant aortic-valve disease, connective-tissue disorders, or genetic syndromes) but may not be prudent in those at increased risk for complica-tions during surgery. These recommendations are based on the premise that aortic complica-tions, representing a long-term risk that in-creases with time, will be avoided if elective aortic-valve replacement is performed at experi-enced centers with low mortality (≤1%).45

SPECIAL POPULATIONS

During pregnancy, there are changes in hemody-namic 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 recom-mendations regarding treatment during pregnan-cy 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 par-ticipate 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 QUES TIONS A ND FU T UR E DIR EC TIONS

Advances in imaging, biomarker-based risk as-sessments, and genetics should be used to gain a better understanding of the mechanisms under-lying the development and progression of bicus-pid aortopathy. The Beta Blockers and Angioten-sin Receptor Blockers in Bicuspid Aortic Valve Disease Aortopathy (BAV) study (ClinicalTrials .gov number, NCT01202721) is an ongoing trial





that is being conducted by the Canadian Network and Centre for Trials Internationally. The purpose of this study is to evaluate the efficacy of atenolol and telmisartan in slowing the progression of bicuspid aortopathy. A trial of medical versus surgical management in patients with a moder-ately dilated ascending aorta (45 to 50 mm) would be highly informative. Future studies should fo-cus on improving the selection of subgroups of

patients who are most likely to benefit from ear-lier intervention, as well as those for whom watch-ful waiting is appropriate.

No potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank Dr. Hwee Teoh for editorial assistance with an ear-lier version of the manuscript.

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