Diagnosis and management issues in thoracic aortic aneurysm

Anna M. Booher, MD, and Kim A. Eagle, MD Ann Arbor, MI

Thoracic aortic enlargement is an increasingly recognized condition that is often diagnosed on imaging studies performed for unrelated indications. The risk of unrecognized and untreated aortic enlargement and aneurysm includes aortic rupture and dissection which carry a high burden of morbidity and mortality. The etiologies underlying thoracic aortic enlargement are diverse and can range from degenerative or hypertension associated aortic enlargement to more rare genetic disorders. Therefore, the evaluation and management of these patients can be complex and requires knowledge of the pathophysiology associated with thoracic aortic dilation and aneurysm. Additionally, there have been important advances in the treatment available to patients with thoracic aortic disease, including an increased role of endovascular therapy. Given the risk of mortality, increased clinical recognition and advances in therapeutics, the American College of Cardiology, American Heart Association and related professional societies have recently published guidelines on the management of thoracic aortic disease. This review focuses on the pathophysiology and various etiologies that lead to thoracic aortic aneurysm along with the diagnostic modalities and management of asymptomatic patients with thoracic aortic disease. (Am Heart J 2011;162:38-46.e1.)

Thoracic aortic aneurysm

Thoracic aortic aneurysms (TAA) are diagnosed most commonly on an imaging study performed for an unrelated indication. Thoracic aortic dilation occurs with an estimated incidence of 5.6 to 10.4 cases per 100,000 patient-years and an estimated prevalence of up to 4.2% of the general population without hypertension.1,2 Dilation is defined as a measurement that exceeds the range of normal for a given age and body size. Aneurysm is defined as a 50% increase above this range. Clinically, TAA are typically silent until a complication presents. Rarely, depending on size and location, TAA can present with dysphagia, hoarseness, chest or back pain, signs, or symptoms of aortic insufficiency.3 Although a relatively rare process as compared to other cardiovascular diseases, the devastating consequences of untreated or undiagnosed TAA (ie, rupture, dissection) elevate its clinical importance.

aneurysm include specific genetic mutations or predisposition leading to decreased contractile function of vascular smooth muscle cells. This process then leads to excess inflammatory mediators (transforming growth factor-B [TGFB], penin-argrotensin-aldosterone system [RAS], and insulinlike growth factor-1 [IGF-1]) and increased activation of stretch pathways which, in turn, increase proteoglycan and matrix metalloproteinase production. This inflammatory milieu furthers tissue degradation and results in progressive aortic wall weakening and subsequent aortic dilation. Histologically, the pattern of cystic medial necrosis and loss of elastic fibers are commonly seen as the end result of this biochemical pathway.4

Natural history
In general, isolated idiopathic or degenerative ascending aortic aneurysms will have a rate of growth of 0.1 cm/y. Natural history studies have shown that after an aneurysm reaches 6 cm in the ascending aorta and 7 cm in the descending aorta, the complication rates are greatly increased.5 In addition, if the aorta is N5 cm at the time of diagnosis, the growth rate may be accelerated, up to 0.1 to 0.15 cm/y. This more rapid increase in size increases the risk of aortic complications. Certain inherited conditions, discussed in detail below, that cause a predisposition to TAA may also contribute to accelerated growth.6

Pathophysiology
The pathophysiologic basis for TAA is complex and related, in part, to underlying conditions that predispose patients to aortic dilation. Although the specific pathophysiologic pathways are still being assessed, a general scheme for explaining the clinical findings of thoracic aortic
From the University of Michigan Health Center, Ann Arbor, MI. Submitted November 9, 2010; accepted April 11, 2011. Reprint requests: Anna M. Booher, MD, Clinical Instructor, Division of Cardiovascular Medicine, Cardiovascular Center, University of Michigan Health System, 1500 E. Medical Center Drive, 2344, Ann Arbor, MI 48109. E-mail: amanion@med.umich.edu 0002-8703/$ - see front matter 2011, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2011.04.010

Etiology
Various etiologies of TAA are listed in Table I. In older patients, the most common etiology of TAA is a degenerative process associated with increased age; however, hypertension, tobacco abuse, hyperlipidemia, and genetic factors can result in acceleration of growth.6

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Table I. Etiology of thoracic aortic aneurysm

Etiology Degenerative aneurysms Atherosclerotic Details Most common Associated with hypertension, age, smoking More commonly involves the descending aorta and arch

Genetically triggered aneurysm syndromes Marfan syndrome Most common inherited connective tissue disease Mutation in FBN-1 gene leads to decreased tensile strength of the aorta Estimated that 75% of patients will have a dilated aortic root Aggressive vasculopathy linked to TGFBR1 or 2 mutation Early detection and intervention is important N50% have tubular/ascending aneurysm 20% sinus of Valsalva involvement Faster rate of growth than aneurysms associated with a three leaflet valve 1/3 with bicuspid valve and coarctation of the aorta Ascending aortic aneurysm

Loeys-Dietz Syndrome

Bicuspid aortic valve

Turners syndrome

Familial non-syndromic thoracic aortic aneurysm Dilated aorta syndrome Absence of other connective tissue disease Family history dissection/aneurysm Aortitis Infectious

Syphilis (historical) Salmonella Staphylococcal species Mycobacterium

Non infections/inflammatory

More common: Giant cell and Takaysu arteritis Less common: Behcets, Cogans syndrome, relapsing polychondritis Rare: Rheumatoid arthritis, spondyloarthropathies Typical location is at the aortic isthmus Complications include rupture, pseudoaneurysm, chronic dissection with secondary aneurysm formation Aneurysm due to growth and pressure differential of false lumen

Trauma

Chronic aortic dissection

The inheritance pattern in those with genetically triggered aneurysm syndromes is not fully elucidated but is thought to be autosomal dominant with reduced penetrance, which accounts for the phenotypic variability that can be seen in these cases.7 Nearly 20% of patients who develop a TAA will have a family history of aortic disease, and a familial pattern should be suspected in patients who present at a young age.8,9 These genetically triggered TAA tend have the most aggressive rate of growth and are more likely to require intervention.

bicuspid aortic valve disease, and the recently described Loeys-Dietz syndrome.

Genetically triggered thoracic aortic aneurysm syndromes

Inherited conditions that affect the aorta include the Marfan syndrome, Ehlers Danlos (ED), Turners syndrome,

Marfan syndrome The Marfan syndrome is a well-defined, autosomal dominant disorder that involves skeletal, ocular, dural, and cardiovascular findings. The diagnostic criteria have recently been revised and are described in the revised Ghent nosology (see online Appendix).10 Compared to the diagnostic criteria published in 1996,11 the more recent revision places more emphasis on the presence of aortic root aneurysm (defined as an aortic size of 2 Z-score above the normal range) and ectopic lentis as the predominant clinical features of the disease. The presence of family history of Marfan syndrome only requires one of the following to definitively make the diagnosis: an aortic

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Table II. Imaging the thoracic aorta

Modality MDCT angiography Advantages Disadvantages

Rapid image acquisition (20-30 seconds) Need for iodinated contrast 3D reconstruction allows multiple views/orientations Radiation exposure (10-20 mSv) Ability for post image processing of concern in young patients requiring serial imaging Faster imaging times reduce time to diagnosis in Image artifactsparticularly in aortic root potentially unstable patients may be improved by ECG gating Aortic size can be overestimated due to oblique cuts through lumen. Caution with use of gadolinium in renal failure Need for breath hold Time consuming (10-30minutes at minimum) depending on center Not for use in unstable patients (distance of equipment/staff for resuscitation from patient) Cannot visualize entire aorta May be limited by technical difficulties Semi-invasive Requires conscious sedation and patent/secure airway

MRI/MR angiography

No Radiation No iodinated contrast 3 D, multi planar and high resolution Dynamic and functional information available May be appropriate for serial imaging over many years.

Transesophageal No radiation echocardiography No iodinated contrast Can be performed at the bedside, Immediate information availability Excellent evaluation of valve function, pericardial effusion and left ventricular function Can visualize aorta from root to gastroesophageal junction junction Doppler interrogation of true and false lumen

root aneurysm, ectopic lentis, a pathogenic fibrillin-1 (FBN1) mutation, or systemic features on physical exam. The absence of a family history requires the presence of an aortic aneurysm and one of the following: ectopic lentis, pathogenic FBN-1 mutation, systemic features, or aortic enlargement not meeting Z-score 2 with both ectopic lentis and FBN-1 mutation. Typically, the aortic dilation seen in the Marfan syndrome is localized to the aortic root but may extend into the ascending aorta and is associated with an accelerated growth rate (up to 0.2-0.3 cm/y) as compared with degenerative aneurysms. Defects in the FBN-1 gene have been found to lead to excess TGF-B signaling and subsequent increased tissue degradation and weakening of the aortic wall.12,13 Histologically, the aortic tissue in patients with Marfan syndrome have a fraction of the elastin of normal aortas and increased elastin fragmentation.14 The end result of these processes predisposes patients with the Marfan syndrome to a high risk of aortic complications at a relatively young age. The criteria for operative repair in these cases is outlined below and is more aggressive than in patients with degenerative aneurysms. In many cases, the aortic valve is morphologically normal and may be able to be resuspended/ reimplanted at the time of aortic repair.15,16

impaired, and subsequently, these patients can have significant complications including gastrointestinal complications and uterine rupture in pregnancy. The vascular tissue in these patients is very weak and difficult to safely manipulate in the operating room, even in experienced hands. These patients require specialized care.17

Vascular ED Patients with vascular ED represent a rare but extremely high risk group. Vascular ED syndrome is an inherited connective tissue disease that results from a defect in type III procollagen due to mutations in the COL3A1 gene. Vascular ED syndrome affects 1 in 5 to 20,000 births. Vascular and connective tissue integrity is markedly

Familial nonsyndromic thoracic aortic aneurysm syndromes Familial nonsyndromic thoracic aortic syndromes is a term applied to patients with a family and personal history of aortic aneurysm without meeting strict criteria of known syndromes. This syndrome can include patients with a dilated aorta and a family history of dissection or rupture or sudden unexplained death and are becoming increasingly recognized. Up to 20% of patients with an isolated thoracic aortic aneurysm will have a family member with a similar history.6 These patients tend to present at a younger age (mean 55 years) and have a faster rate of growth than degenerative/sporadic aneurysms (up to 0.2 cm/y). The ascending thoracic aorta is more commonly involved (80%) than the descending aorta (20%). The variable penetrance and expression of the identified mutations (ACTA 2, MYH11 [also associated with patent ductus arteriosis], and TGFBR2) make definitive diagnosis difficult.18,19 ACTA2 may account for up to 14% of genetic mutations associated with familial syndromes and testing for ACTA-2 is a class IIa recommendation in the most recent guidelines for patients with a thoracic aortic aneurysm and a family history of thoracic aortic aneurysm and/or dissection.16 ACTA2 encodes smooth muscle a2 actin. The deficiency of smooth muscle a2 actin leads to decreased numbers and disorganization of

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Table III. Thoracic aortic aneurysm - chronic medical therapy

Medication First-line agent: -Blockers Second Line Agents: Angiotensin Receptor Blockers ACE inhibitors Titrate to effect Dosage Goal of therapy Heart rate b60 beat/min

Start at a low dose and titrate to BP goals

Blood pressure b130/80 mm Hg Use in all pts with Marfan syndrome

Third-line agent: Start at a low dose and titrate to above goals Use as needed to attain BP goal b130/80 mm Hg Calcium-channel blocker (dihydropyridine) Highest dose that patient can tolerate to reach goals. Goal LDL b70 ng/dL if atherosclerosis Statins LDL b100 ng/dL if no atherosclerosis Tobacco cessation aids Varenicline Chantix Buproprion Nicotine replacement Standard dosing Smoking cessation

vascular smooth muscle cells with subsequent loss of elastic fibers leading to decreased adaptation to stress in aortic tissue and aneurysm formation.20

Bicuspid aortic valve Bicuspid aortic valve (BAV) disease occurs in 1-2% of the general population and is the most commonly recognized congenital abnormality in adulthood.21 The association with BAV and aortopathy/aneurysm formation has been well established. Embryologically, the aortic valve and the ascending aorta share the same neural crest origin.22 The aortic tissue in patients with BAV is similar to that in patients with the Marfan syndrome. Histologically, aortic tissue in BAV patients shows medial degeneration, increased matrix metalloproteinase activity and decreased FBN-1 in the aortic wall.23 Subsequent weakening of the aortic wall leads to accelerated growth rates for, BAV associated aneurysms, up to 0.2 cm/y.24 Aortic aneurysm associated with BAV can occur in up to 50% of cases and involve the root through the proximal arch.25 However, coarctation of the aorta is also highly associated with a BAV (up to 50% of coarctation patients will have a BAV), suggesting that the abnormal aortic tissue may extent into the distal arch or proximal descending aorta.26 BAV is thought to be an inherited condition, and like the other inherited conditions discussed, is likely autosomal dominant inheritance with reduced penetrance. The heritable nature of BAV is supported by data that shows that even in first degree relatives of patients with BAV who have normally functioning three leaflet valve, there is evidence of aortopathy with increased size, less distensibility, and increased wall stiffness in the absence of a BAV.27 For this reason, screening of the aortic valve and proximal ascending aorta with echocardiography or another modality should be recommended for first-degree relatives of patients with BAV.16

Overall, it is estimated that 25% of patients with a BAV will require an intervention to the valve, aorta, or both during their lifetime.28 BAV is also associated with a risk of endocarditis in up to 2% of cases. However, antibiotic prophylaxis before dental work or other procedures is not recommended in the most recent American College of Cardiology/American Heart Association guidelines on this topic.29 Criteria for operative repair in cases of BAV associated aneurysm is outlined below and is dependent both on the size of the aneurysm and concomitant valvular dysfunction. However, given the elevated rate of aortic expansion in patients with BAV, early elective repair based on the size of the aneurysm alone may be indicated, irrespective of the valve disease severity.30 If aortic valve stenosis or insufficiency is the indication for intervention, the abnormal aortic tissue should also be addressed and potentially replaced at the time of valve surgery if the diameter exceeds N4 to 4.5 cm.31

Loeys Dietz syndrome Loeys Dietz is a recently described syndrome that involves defects in TGFBR1 or TGFBR2. Phenotypic characteristics include hypertelorism, cleft palate or split uvula along with some shared characteristics with the Marfan syndrome. Patients with this syndrome are at high risk at a young age for aortic dilation, rupture or dissection. For this reason, very early operative intervention is recommended at ascending aortic diameters of 4.2 cm by transesophageal echocardiography (TEE) or 4.4 to 4.6 cm by computed tomography (CT).16,32

Initial diagnosis and subsequent workup

Once thoracic aortic dilation is suggested by any imaging modality, further workup and confirmatory imaging should be performed.

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Table IV. Size criteria for elective surgical intervention

Condition Degenerative thoracic aneurysm Chronic aortic dissection Chronic traumatic dissection/ Pseudoaneurysm Intramural hematoma Penetrating ulcer Marfan Syndrome Vascular Ehlers Danlos Turner Syndrome Bicuspid aortic valve Familial TAA and dissection Location and size Ascending aorta or arch N5.5 cm or Descending aorta N 6 cm

Ascending 4.0-5.0 cm or Descending 5.5 cm

Loeys Dietz syndrome

Any site 4.2 cm by TEE (internal diameter) N4.44.6 cm by CT/MRI (external diameter) Any site Consider operation at size N5.05.5 cm Consider concomitant aortic root or ascending replacement if N4.5 cm

Computed tomography scan technique There can be significant variability in CT scan technique depending on the protocol used and the institution at which the CT scan is performed. Due to this variability, it is recommended that patients with a concern for TAA undergo a CT scan which specifically addresses the entire aorta. This is to evaluate the extent and size of the aneurysm but also detect disease in distant portions of the aorta, which may occur in up to 20% of cases.33,34 Computed tomography should ideally be performed with contrast and be of acceptable quality to comment on the precise location of the aortic abnormality, the maximal dimension taken perpendicular to the axis of flow, specific measurements at the aortic root, sinotubular junction, ascending, arch, and several measurements of the descending aorta at pre-specified anatomical landmarks. The study should be of sufficient quality to assess for coexisting intramural hematoma, penetrating ulcer and branch vessel involvement of aneurysmal disease.16 Magnetic resonance imaging Magnetic resonance imaging (MRI) is an acceptable alternative to CT in stable patients with suspected thoracic aortic disease. Excellent anatomic detail and some information on valvular function are available from MRI. A comprehensive MR examination of the thoracic aorta may include many components, including black blood imaging (to evaluate aortic morphology and size and aortic wall contour) basic spin-echo sequences, noncontrast white blood imaging, and contrast-enhanced MR angiography using gadolinium based agents.35 The lack of ionizing radiation can make MRI a useful tool for long term surveillance of TAA, particularly in younger individuals where the accumulated potential cancer risk from repeated imaging is important. Magnetic resonance imaging reporting should sufficiently address the aorta in the same detail as outlined above with CT scanning. Echocardiography If a CT or MRI has been performed that adequately assesses the aorta, it is also reasonable to obtain a transthoracic echocardiogram to screen for aortic stenosis or insufficiency, underlying bicuspid aortic valve, or other valvular disease which may alter the way in which these patients are followed and treated. In addition, evaluation of the aortic root can be suboptimal in cross-sectional imaging modalities given the asymmetry of the aortic root and artifact caused by cardiac motion. Therefore, transthoracic or transesophageal echocardiography can be a complimentary tool in which to evaluate the anatomy of the aortic root.36 However, transthoracic echocardiography can be technically limited in its evaluation of the ascending (tubular) aorta, may not be sufficient for imaging the entire ascending aorta and arch, and therefore is generally not

Any patient with a growth rate of N0.5 cm/year Patients undergoing aortic valve repair or replacement

Most typical location is in the descending aorta.

Screening for associated conditions and high-risk features by history and physical examination Patients with TAA should be screened for the presence of concomitant genetic or familial disorders which increase their individual risk of aneurysm progression or complications. This evaluation should include a thorough family history to evaluate for sudden or unexplained death and history of aneurysm or dissection. Additional historical data should include the evaluation of fevers, night sweats, arthralgias, headaches, and other constitutional symptoms that could point to a systemic inflammatory or infectious condition. Finally, risk factor analysis for coronary artery disease (CAD) and symptoms that can be attributed to CAD should be elucidated and workup for CAD pursued as appropriate. A careful physical examination to evaluate for physical features characteristic of the Marfan or Loeys Dietz syndromes, cardiac auscultation to evaluate for pathologic murmurs, and a careful peripheral vascular exam should be performed. Imaging The relative advantages and disadvantages of the available techniques to evaluate the thoracic aorta are outlined in Table II. However, there are certain considerations of serial imaging in stable patients with TAA which should be addressed.

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Table V. . Surveillance imaging guidelines for asymptomatic TAD Surveillance imaging guidelines for asymptomatic TAD

Accelerated growth: If growth rate N0.5cm/year but size is b5.0cm then consider early operative repair.

sufficient not sufficient alone in the initial imaging workup of suspected aortic disease.

Medical therapy in TAA

Aggressive antihypertensive therapy is the main component of nonsurgical therapy in patients with stable thoracic aortic aneurysm. Though not based on strong evidence, smoking cessation, and possibly lipid lowering therapy and lifestyle modifications are also important aspects to medical management in these patients (Table III). Medical therapy in TAA has been most studied in the Marfan population, and the findings of these investigations can serve as a prototype for medical therapy in other TAA syndromes, given the commonalities in the proposed pathophysiologic pathways that these conditions share.37 -Blockers have been shown to decrease the rate of aortic dilation, presumably due to decrease in left ventricular dp/dt and aortic sheer stress.38 The use of -blockers in patients with the Marfan syndrome carries a Class I (level of evidence B) recommendation in the recent guidelines.16 Similarly, Habashi et al and others have recently shown that argrotensin receptor blocker (ARBs) may be important in preventing aneurysm growth in the Marfan syndrome due to down-regulation of TGF-B and its effects.39,40 Angiotensin-converting enzyme inhibition may also have a beneficial effect on modifying the inflammatory milieu and in decreasing vascular smooth muscle apoptosis.41,42 Tight control of blood pressure is a Class I indication in the most recent guidelines and the specific use of ACE inhibitors, and ARBs are a Class IIa indication (level of evidence B).16 Although mostly studied in abdominal aortic aneurysm, statin therapy has the potential to mediate inflammatory markers that may contribute to aneurysm expansion and should be used to meet an low-density lipoprotein (LDL) goals as outlined by the National Cholesterol Education Program guide-

lines and to a goal LDL of b70 mg/dL in atherosclerotic aneurysms.43-46 However, there are no data that specifically support their use in nonatherosclerotic or inherited TAA.

Criteria for surgical or endovascular intervention

Aortic size criteria for surgical intervention in asymptomatic patients with TAA as recently published in the TAD guidelines are illustrated in Table IV. Symptomatic patients should undergo urgent surgical evaluation as pain could represent aneurysm expansion or rupture.16 In general, all patients with an ascending aortic aneurysm of 5.5 cm and descending aneurysm of 6 cm should be offered an open surgical or endovascular procedure, depending on the location and overall surgical risk. Size criteria for intervention are smaller in those with high-risk conditions such as the Marfan syndrome, vascular ED, Turner's syndrome, or bicuspid aortic valve.5,47-49 The data for intervening on bicuspid valveassociated aneurysm at this size is taken in part from single-center observations that evaluated patients who underwent isolated aortic valve replacement for bicuspid valve dysfunction. Those with ascending aortic dimensions of N4 to 4.5 cm at the time of aortic valve replacement had an increased risk of late aortic complications.50-52 The Loeys Dietz syndrome has the smallest recommended cutoff point of all genetically triggered TAA at a size of N4.2 cm by TEE (or N4.4-4.6 cm by CT angiography). Owing to its aggressive natural history, some have even recommended prophylactic replacement at a size of 4.0 cm.32 However, absolute size criteria for intervention on the aorta do not take into account natural variation in aortic size across gender and body size. Davies et al and others have proposed an aortic size indexing method that helps correct for body size.53 For example, a small woman (body surface

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area [BSA] 1.5 kg/m2) with an aortic measurement of 4.5 cm may be at a higher risk for aortic complications than a larger person with a BSA of 2.1 and the same aortic measurement. Therefore, smaller patients may have a smaller cutoff for intervention due to the larger relative aneurysm size. The role of body size has also been specifically evaluated in the Marfan syndrome population. Based on data from a single institution, the recent thoracic aortic disease guidelines (Class IIa, Level of evidence C) suggest that, in cases of the Marfan syndrome, it is reasonable to prophylactically replace the aortic root in patients with an ascending aortic area (cm2) to height (m) ratio of N10 to account for body size in the timing of repair.54

Surgical technique
Open surgery Aortic root and ascending aorta. Replacement of the portion of the aorta that is aneurysmal with a dacron or woven graft via an open approach is the most commonly performed operation for TAA in the ascending aorta. The root and ascending should be considered separately from the aortic valve in cases of proximal aortic aneurysm, that is, in cases of isolated ascending aneurysm, the valve and root should be spared if at all possible. In the Marfan population, the guidelines recommend (with level of evidence B) that patients should have excision of the sinus of Valsalva with a modified David reimplantation operation of the aortic valve when feasible, as the aortic valve itself in these patients is often normally functioning.55 Aortic arch. Surgical repair of an isolated aortic arch aneurysm is challenging, carries an increased risk of stroke due to embolization of atherosclerotic material and involves the use of hypothermic circulatory arrest and cerebral perfusion techniques.3 In these cases, branched grafts are typically used to replace the affected portion of the arch and the great vessels.56 Descending aorta. Given the morbidity associated with open procedures of the descending aorta, including spinal cord injury, endovascular therapy is becoming more common, when anatomically feasible, in management of TAA in the descending and thoracoabdominal aorta.16 Endovascular therapy in thoracic aortic disease and aneurysm Although relatively safe in high volume centers, open thoracic aorta repair still carries a significant morbidity and mortality. This is particularly true in repair of the descending aorta with some reports suggesting a postoperative paraplegia risk of nearly 15%.57,58 Although this complication may be mitigated by techniques such as distal aortic perfusion, lumbar drainage and hypothermic circulatory arrest, thoracic endovascular aortic repair (TEVAR) is taking on an increased role in the management of these patients, in particular, those who are older and with more comorbid medical

conditions. Thoracic aortic stent grafting has also been used in traumatic descending aortic dissection/rupture with results that are similar to open repair.59-61 There is evidence from meta-analysis and device trials that periprocedureal and late-term mortality in stable patients undergoing endovascular repair of descending TAA is less than traditional open repair and associated with fewer episodes of neurologic injury.62,63 Most thoracic endografts today are used to treat descending thoracic aneurysm disease between the left subclavian and the celiac arteries. The proximal edge of the stent graft may have to cover the left subclavian in order to provide an adequate border around the portion of the aorta excluded with the stent graft. To facilitate these cases, a carotid-subclavian bypass may be done in preparation of TEVAR. Carotid-carotid artery bypass can also be performed if the surgeon/operator feels that the left carotid also needs to be covered with the stent graft. Although not yet mainstream, it appears in some small series that TEVAR into the aortic arch may be possible with the advent of branched stent grafts.64 Currently, approximately 25% of patients will be anatomically unsuitable for endovascular repair. Exclusion criteria include unfavorable landing zones for the stent either proximally or distally to the portion of the aorta that needs that needs to be excluded. Unfavorable landing zones may increase the risk of endoleak and may be due to acute angulation of the aorta, heavy atherosclerotic burden, or large aneurysm extent. Poor peripheral arterial access is also a potential exclusion criteria and important to consider in patients with concomitant peripheral arterial disease.65 The long-term durability of TEVAR is not yet known. However, some series have suggested that up to 20% of patients may have an endoleak, most of which can be managed percutaneously (type I).66 Therefore, after TEVAR, patients require ongoing follow-up and serial imaging. Computed tomography is the preferred modality to monitor for TEVAR related complications.

Surveillance imaging Surveillance imaging is an important aspect of care in patients with asymptomatic TAA. The imaging timeline will depend on the site, etiology, and size of the aneurysm at presentation. A proposed approach to imaging these patients adapted from the 2010 guidelines on management of thoracic aortic disease is presented in Table V.

Conclusions
Thoracic aortic disease is complex and encompasses many disease states and presentations. The mortality associated with aneurysm related complications is high, and complex aortic syndromes should be managed at high-volume centers with expertise in aortic disease. Outcomes in these centers may be improved compared

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to centers with lower volume.67 However, understanding of the disease process, medical therapy, follow-up, and indications for surgical intervention is important for all cardiovascular physicians to be familiar with in order to ensure optimal management of these patients.

17. 18.

Disclosures
No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.

19.

20.

References
1. Clouse WD, Hallett Jr JW, Schaff HV, et al. Improved prognosis of thoracic aortic aneurysms: a population-based study. JAMA 1998; 280:1926-9. 2. Palmieri V, Bella JN, Arnett DK, et al. Aortic root dilatation at sinuses of valsalva and aortic regurgitation in hypertensive and normotensive subjects: The Hypertension Genetic Epidemiology Network Study. Hypertension 2001;37:1229-35. 3. Isselbacher EM. Thoracic and abdominal aortic aneurysms. Circulation 2005;111:816-28. 4. Campa JS, Greenhalgh RM, Powell JT. Elastin degradation in abdominal aortic aneurysms. Atherosclerosis 1987;65:13-21. 5. Coady MA, Rizzo JA, Hammond GL, et al. What is the appropriate size criterion for resection of thoracic aortic aneurysms? J Thorac Cardiovasc Surg 1997;113:476-91 discussion 489-91. 6. Coady MA, Rizzo JA, Goldstein LJ, et al. Natural history, pathogenesis, and etiology of thoracic aortic aneurysms and dissections. Cardiol Clin 1999;17:615-35 vii. 7. Cripe L, Andelfinger G, Martin LJ, et al. Bicuspid aortic valve is heritable. J Am Coll Cardiol 2004;44:138-43. 8. Biddinger A, Rocklin M, Coselli J, et al. Familial thoracic aortic dilatations and dissections: a case control study. J Vasc Surg 1997; 25:506-11. 9. Coady MA, Davies RR, Roberts M, et al. Familial patterns of thoracic aortic aneurysms. Arch Surg 1999;134:361-7. 10. Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476-85. 11. De Paepe A, Devereux RB, Dietz HC, et al. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62:417-26. 12. Judge DP, Dietz HC. Therapy of Marfan syndrome. Annu Rev Med 2008;59:43-59. 13. Neptune ER, Frischmeyer PA, Arking DE, et al. Dysregulation of TGFbeta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 2003;33:407-11. 14. Halme T, Savunen T, Aho H, et al. Elastin and collagen in the aortic wall: changes in the Marfan syndrome and annuloaortic ectasia. Exp Mol Pathol 1985;43:1-12. 15. Gott VL, Greene PS, Alejo DE, et al. Replacement of the aortic root in patients with Marfan's syndrome. N Engl J Med 1999;340:1307-13. 16. Hiratzka LF, Bakris GL, Beckman JA, et al. ACCF/AHA/AATS/ACR/ ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of

21. 22.

23.

24.

25.

26.

27.

28. 29.

30.

31.

32.

Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation 2010;121:e266-369. Germain DP, Herrera-Guzman Y. Vascular Ehlers-Danlos syndrome. Ann Genet 2004;47:1-9. Vaughan CJ, Casey M, He J, et al. Identification of a chromosome 11q23.2-q24 locus for familial aortic aneurysm disease, a genetically heterogeneous disorder. Circulation 2001;103: 2469-75. Guo D, Hasham S, Kuang SQ, et al. Familial thoracic aortic aneurysms and dissections: genetic heterogeneity with a major locus mapping to 5q13-14. Circulation 2001;103:2461-8. Guo DC, Pannu H, Tran-Fadulu V, et al. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet 2007;39:1488-93. Roberts WC. The congenitally bicuspid aortic valve. A study of 85 autopsy cases. Am J Cardiol 1970;26:72-83. Bonderman D, Gharehbaghi-Schnell E, Wollenek G, et al. Mechanisms underlying aortic dilatation in congenital aortic valve malformation. Circulation 1999;99:2138-43. Nataatmadja M, West M, West J, et al. Abnormal extracellular matrix protein transport associated with increased apoptosis of vascular smooth muscle cells in marfan syndrome and bicuspid aortic valve thoracic aortic aneurysm. Circulation 2003;108 (Suppl 1):II329-34. Davies RR, Kaple RK, Mandapati D, et al. Natural history of ascending aortic aneurysms in the setting of an unreplaced bicuspid aortic valve. Ann Thorac Surg 2007;83:1338-44. Fazel SS, Mallidi HR, Lee RS, et al. The aortopathy of bicuspid aortic valve disease has distinctive patterns and usually involves the transverse aortic arch. J Thorac Cardiovasc Surg 2008;135:901-7, 907 e1-2. Tadros TM, Klein MD, Shapira OM. Ascending aortic dilatation associated with bicuspid aortic valve: pathophysiology, molecular biology, and clinical implications. Circulation 2009;119:880-90. Biner S, Rafique AM, Ray I, et al. Aortopathy is prevalent in relatives of bicuspid aortic valve patients. J Am Coll Cardiol 2009;53: 2288-95. Siu SC, Silversides CK. Bicuspid aortic valve disease. J Am Coll Cardiol 2010;55:2789-800. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007;116:1736-54. Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 2006;114:e84-231. Friedman T, Mani A, Elefteriades JA. Bicuspid aortic valve: clinical approach and scientific review of a common clinical entity. Expert Rev Cardiovasc Ther 2008;6:235-48. Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 2006;355: 788-98.

46 Booher and Eagle

American Heart Journal July 2011

33. Clouse WD, Marone LK, Davison JK, et al. Late aortic and graftrelated events after thoracoabdominal aneurysm repair. J Vasc Surg 2003;37:254-61. 34. Lawrie GM, Earle N, DeBakey ME. Long-term fate of the aortic root and aortic valve after ascending aneurysm surgery. Ann Surg 1993; 217:711-20. 35. Francois CJ, Carr JC. MRI of the thoracic aorta. Cardiol Clin 2007; 25:171-84 vii. 36. Tops LF, Wood DA, Delgado V, et al. Noninvasive evaluation of the aortic root with multislice computed tomography implications for transcatheter aortic valve replacement. JACC Cardiovasc Imaging 2008;1:321-30. 37. Lacro RV, Dietz HC, Wruck LM, et al. Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome. Am Heart J 2007;154:624-31. 38. Ladouceur M, Fermanian C, Lupoglazoff JM, et al. Effect of betablockade on ascending aortic dilatation in children with the Marfan syndrome. Am J Cardiol 2007;99:406-9. 39. Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006;312:117-21. 40. Brooke BS, Habashi JP, Judge DP, et al. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. N Engl J Med 2008;358: 2787-95. 41. Ahimastos AA, Aggarwal A, D'Orsa KM, et al. Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial. JAMA 2007;298: 1539-47. 42. Yetman AT, Bornemeier RA, McCrindle BW. Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. Am J Cardiol 2005;95: 1125-7. 43. Kertai MD, Boersma E, Westerhout CM, et al. Association between long-term statin use and mortality after successful abdominal aortic aneurysm surgery. Am J Med 2004;116:96-103. 44. Sukhija R, Aronow WS, Sandhu R, et al. Mortality and size of abdominal aortic aneurysm at long-term follow-up of patients not treated surgically and treated with and without statins. Am J Cardiol 2006;97:279-80. 45. Diehm N, Becker G, Katzen B, et al. Statins are associated with decreased mortality in abdominal, but not in thoracic aortic aneurysm patients undergoing endovascular repair: propensity score-adjusted analysis. Vasa 2008;37:241-9. 46. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486-97. 47. Gravholt CH, Landin-Wilhelmsen K, Stochholm K, et al. Clinical and epidemiological description of aortic dissection in Turner's syndrome. Cardiol Young 2006;16:430-6. 48. Milewicz DM, Dietz HC, Miller DC. Treatment of aortic disease in patients with Marfan syndrome. Circulation 2005;111:e150-7. 49. Pepin M, Schwarze U, Superti-Furga A, et al. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 2000;342:673-80.

50. Borger MA, Preston M, Ivanov J, et al. Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease? J Thorac Cardiovasc Surg 2004;128:677-83. 51. Matsuyama K, Usui A, Akita T, et al. Natural history of a dilated ascending aorta after aortic valve replacement. Circ J 2005;69: 392-6. 52. Svensson LG, Kim KH, Lytle BW, et al. Relationship of aortic crosssectional area to height ratio and the risk of aortic dissection in patients with bicuspid aortic valves. J Thorac Cardiovasc Surg 2003; 126:892-3. 53. Davies RR, Gallo A, Coady MA, et al. Novel measurement of relative aortic size predicts rupture of thoracic aortic aneurysms. Ann Thorac Surg 2006;81:169-77. 54. Svensson LG, Khitin L. Aortic cross-sectional area/height ratio timing of aortic surgery in asymptomatic patients with Marfan syndrome. J Thorac Cardiovasc Surg 2002;123:360-1. 55. Fazel SS, David TE. Aortic valve-sparing operations for aortic root and ascending aortic aneurysms. Curr Opin Cardiol 2007;22: 497-503. 56. Patel HJ, Deeb GM. Ascending and arch aorta: pathology, natural history, and treatment. Circulation 2008;118:188-95. 57. Patel HJ, Shillingford MS, Mihalik S, et al. Resection of the descending thoracic aorta: outcomes after use of hypothermic circulatory arrest. Ann Thorac Surg 2006;82:90-5 [discussion 95-6]. 58. Svensson LG, Crawford ES, Hess KR, et al. Experience with 1509 patients undergoing thoracoabdominal aortic operations. J Vasc Surg 1993;17:357-68 discussion 368-70. 59. Go MR, Barbato JE, Dillavou ED, et al. Thoracic endovascular aortic repair for traumatic aortic transection. J Vasc Surg 2007;46: 928-33. 60. Chung J, Owen R, Turnbull R, et al. Endovascular repair in traumatic thoracic aortic injuries: comparison with open surgical repair. J Vasc Interv Radiol 2008;19:479-86. 61. Nienaber CA, Rousseau H, Eggebrecht H, et al. Randomized comparison of strategies for type B aortic dissection: the INvestigation of STEnt Grafts in Aortic Dissection (INSTEAD) trial. Circulation 2009; 120:2519-28. 62. Walsh SR, Tang TY, Sadat U, et al. Endovascular stenting versus open surgery for thoracic aortic disease: systematic review and meta-analysis of perioperative results. J Vasc Surg 2008;47: 1094-8. 63. Makaroun MS, Dillavou ED, Wheatley GH, et al. Five-year results of endovascular treatment with the Gore TAG device compared with open repair of thoracic aortic aneurysms. J Vasc Surg 2008;47: 912-8. 64. Wei G, Xin J, Yang D, et al. A new modular stent graft to reconstruct aortic arch. Eur J Vasc Endovasc Surg 2009;37:560-5. 65. Jackson BM, Carpenter JP, Fairman RM, et al. Anatomic exclusion from endovascular repair of thoracic aortic aneurysm. J Vasc Surg 2007;45:662-6. 66. Alsac JM, Khantalin I, Julia P, et al. The Significance of Endoleaks in Thoracic Endovascular Aneurysm Repair. Ann Vasc Surg 2011;25: 345-51. 67. Knipp BS, Deeb GM, Prager RL, et al. A contemporary analysis of outcomes for operative repair of type A aortic dissection in the United States. Surgery 2007;142:524-8 [discussion 528 e1].

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Appendix
Revised Ghent criteria for the diagnosis of Marfan syndrome Diagnosis of Marfan syndrome Without family history Aortic Z-score 2 or dissection and one of the following: 1. Ectopic lentis 2. Pathogenic FBN-1 mutuation 3. Systemic features: 7 points 4. Ectopic lentis and FBN-1 mutation with aortic enlargement. With family history One of the following: 1. Ectopic lentis or 2. Systemic feature score 7 or 3. Aortic Z-score 2 over age of 20 or 4. Aortic Z-score 3 below age 20 Scoring system for systemic features Systemic feature Wrist and thumb sign Wrist or thumb sign Pectus carinatum Pectus excavatum/chest asymmetry Hindfoot deformity Pneumothorax Dural ectasia Protrusio acetabuli Reduced US/LS and increased arm/height and lack of severe scoliosis Scoliousis or kyphosis Reduced elbow extension Facial features Skin striae Myopia N3 diopters Mitral valve prolapse Point score 3 2 2 1 2 2 2 2 1

1 1 1 1 1 1

*Aortic dimension as measured at the sinus of Valsalva. Z-Score taken from previously published data. Facial features (3/5 to get one point): malar hypoplasia, retrognathia, downslating palpebral fissues, enophthalmos, dolichocephaly.