Clinically Pertinent Controversies and UncertaintiesThoracic Aortic Aneurysm March 2, 2010:841–57 measurements may be feasible. Oftentimes, however, im-ages are insufﬁcient to

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Journal of the American College of Cardiology Vol. 55, No. 9, 2010© 2010 by the American College of Cardiology Foundation ISSN 0735-1097/10/$36.00P

STATE-OF-THE-ART PAPER

Thoracic Aortic AneurysmClinically Pertinent Controversies and Uncertainties

John A. Elefteriades, MD,* Emily A. Farkas, MD†

New Haven, Connecticut; and St. Louis, Missouri

This paper addresses clinical controversies and uncertainties regarding thoracic aortic aneurysm and its treat-ment. 1) Estimating true aortic size is confounded by obliquity, asymmetry, and noncorresponding sites: bothechocardiography and computed tomography/magnetic resonance imaging are necessary for complete assess-ment. 2) Epidemiology of thoracic aortic aneurysm. There has been a bona fide increase in incidence of aorticaneurysm making aneurysm disease the 18th most common cause of death. 3) Aortic growth rate. Although avirulent disease, thoracic aortic aneurysm is an indolent process. The thoracic aorta grows slowly—0.1 cm/year.4) Evidence-based intervention criteria. It is imperative to extirpate the thoracic aorta before rupture or dissec-tion occurs; surgery at 5.0- to 5.5-cm diameter will prevent most adverse natural events. Symptomatic (painful)aneurysms must be resected regardless of size. 5) Development of nonsize criteria. Mechanical properties of theaorta deteriorate at the same 6 cm at which dissection occurs; elastic properties of the aorta may soon becomeuseful intervention criteria. 6) Medical treatment of aortic aneurysm. Medical treatment is of unproven value,even beta-blockers and angiotensin-receptor blockers. 7) A genetic disease. Even non-Marfan aneurysms have astrong genetic basis. 8) Need for biomarkers. Virulent but silent, TAA cries out for a biomarker that can predictthe onset of adverse events. Pathophysiologic understanding has led to identification of promising biomarkers,especially metalloproteinases. 9) Endovascular therapy for aneurysms. Endovascular therapy has burgeoned,despite the fact that the EVAR-2, DREAM, and INSTEAD trials showed no benefit at mid-term over medical orconventional surgical therapy. We must avoid “irrational exuberance.” 10) Inciting events for acute aortic dissec-tion. Recent evidence shows that dissections are preceded by a specific severe exertional or emotional event.11) “Silver lining” of aortic disease. Proximal aortic root disease seems to protect against arteriosclerosis. (J AmColl Cardiol 2010;55:841–57) © 2010 by the American College of Cardiology Foundation

ublished by Elsevier Inc. doi:10.1016/j.jacc.2009.08.084

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his review of the key issues in thoracic aortic aneurysmisease maintains a clinical focus, calling on basic science asirectly needed in addressing topics that arise daily in theare of patients. We call extensively on data reported orurrently emerging from the Yale Center for Aortic Diseasewith its database including 3,000 patients, 9,000 imagingtudies, and 9,000 patient-years of observation), but weupplement liberally with key information from other lead-ng aortic centers.

stimating True Aortic Size (andeconciling Discrepant Reports) Can Be Difficult

t is important to know the size of the aorta because keyecisions regarding management of aortic aneurysms de-end on size. However, the question “How big is the aorta?”s not always easy to answer.

The following specific sources of error are encounteredegularly in the clinical practice of aortic care.

rom the *Yale University School of Medicine, New Haven, Connecticut; and theSaint Louis University School of Medicine, St. Louis, Missouri.

cManuscript received May 28, 2009; revised manuscript received August 24, 2009,

ccepted August 31, 2009.

nherent level of resolution of current imaging technologies.radiologist may report an increase in size of 1 or 2 mm

etween the current scan and the previous scan. However,e cannot reliably detect so small a change, be it on

chocardiography (echo), computed tomography (CT), oragnetic resonance imaging (MRI). Unlike the precise

hysical sciences, in clinical aortic size estimation, oneannot have confidence in a measured change of �3 or 4m, and even this level of precision requires carefully

scertaining that similar levels of the aorta are beingeasured.

nclude or exclude the aortic wall itself in a measurement?here is no consensus on whether the aortic wall should be

ncluded or excluded in the aortic diameter, whether the tests made by echo, CT, or MRI. This may make a differencef several millimeters in the calculated measurements. On aoncontrast CT image, for example, it is most comfortableo measure the entire aortic wall, including the lumen andall; on the other hand, on a contrast image, it may be more

omfortable to measure the luminal shadow alone.imitations of specific imaging modalities. Echocardio-raphic images of the ascending aorta are often beautifully
risp. However, a transthoracic echocardiogram can only

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842 Elefteriades and Farkas JACC Vol. 55, No. 9, 2010Thoracic Aortic Aneurysm March 2, 2010:841–57

visualize the proximal severalcentimeters of the ascendingaorta, to just above the sinotubu-lar junction in a patient withgood echo windows (Fig. 1).Thus, echo will miss an aneu-rysm of the mid-portion of theascending aorta. This may ex-plain, for example, why thetransthoracic electrocardiogrammay give a reading of 4.3 cm,whereas the CT scan shows 5.4cm. Each modality is accurate forthe portion of the ascending

orta accessible to that type of image. Even transesophagealcho is limited by the interposed tracheal air column andan be “blinded” to the upper portion of the ascending aortaFig. 2).

A CT scan with axial images cannot properly evaluate theery proximal portion of the ascending aorta. The entireortion of aorta between the annulus and the coronaryrteries usually represents a distance of only 1 or 2 cm. Axialmaging planes may miss an aneurysmal dilation in this

Figure 1 Limitations of Transthoracic Echocardiography

Limited distance above the aortic valve (AV) for which the ascending aorta (Ao)can be seen on transthoracic echocardiography. Schematic (A) and actualechocardiographic (B) image. Panel A illustration by Rob Flewell. AMVL � ante-rior mitral valve leaflet; IVS � interventricular septum; LA � left atrium; LV �

left ventricle; LVPW � left ventricular posterior wall.

Abbreviationsand Acronyms

CT � computedtomography

Echo � echocardiography

IRAD � InternationalRegistry of AorticDissection

MMP � matrixmetalloproteinase

MRI � magnetic resonanceimaging

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ocation. Also, it can be exceedingly difficult to be certainhether a given axial cut is above or below the aorticalve—a key distinction if one is to take a diametereasurement based on that cut (Fig. 3). Furthermore, it is

aïve to believe that the plane of the aortic valve is confinedo the plane of the axial images (perpendicular to theongitudinal axis of the body). Even the normal annulus maye skewed. Furthermore, as the ascending aorta elongates,he aortic valve plane is forced into a more vertical orienta-ion, rendering even more difficult the assessment of size onxial images (Fig. 4). In modern CT scanners, reconstruc-ions are done not only in axial, but also in sagittal andoronal planes, but the resolution in the nonaxial recon-tructions is often insufficient to permit precise assessmentf aortic shape or diameter.In addition, motion artifact can adversely affect the

esolution of CT images of the aorta, producing changes iniameter as great as 7.5% to 27.5%, although technology ismproving, especially with gated tomographic angiography1–3).

MRI is inherently a multiplane modality that can provideeaningful axial, sagittal, and coronal images. Depending

Figure 2 Limitations of Transesophageal Echocardiography

Limited distance above the aortic valve for which the ascending aorta can beseen on transesophageal echocardiography. The tracheal air column interfereswith visualization of the upper ascending aorta. Schematic (A) and actual echo-cardiographic image (B). Panel A illustration by Rob Flewell. RV � right ventri-cle; other abbreviations as in Figure 1.

n the resolution of a particular set of images, accurate

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843JACC Vol. 55, No. 9, 2010 Elefteriades and FarkasMarch 2, 2010:841–57 Thoracic Aortic Aneurysm

easurements may be feasible. Oftentimes, however, im-ges are insufficient to permit accurate measurement.

Old-fashioned ascending aortography is exceptional inroviding crisp images of the aortic contour. The morphol-gy of the proximal aortic root can be seen beautifully,ncluding the loss of the normal “waist” seen above theoronary ostea in annuloaortic ectasia (Fig. 5). The shape ofhe aorta is ideally seen angiographically. This can facilitateccurate surgical planning. However, diameter measure-ent from angiographic images is not always simple to

alculate or very accurate, and measurements are moreommonly made from echo, CT, or MRI.

eometric complexity. The human aorta is geometrically

Figure 3 Limitations of Axial Imaging

Difficulty in determining whether a given axial computed tomography (CT) imageis still in the aorta or passing partially through the aorta and the left ventricular(LV) outflow track. This factor can lead to gross misinterpretations of aorticdiameter. (A) and (B) differ by only 1 CT level, yet yield markedly differentdiameters. Is panel B still in the aorta? Does it represent the dimension at thesinuses or does it run obliquely through both aorta and LV outflow tract? It canbe difficult or impossible to ascertain these answers when a purely axial tech-nique is used.

omplex. The ascending aorta is not truly or totally vertical.

he aortic arch poses an additional challenge because anxial image through the aortic arch will produce an oblongather than a circular contour; measuring the long axis ofhis oblong contour is misleading because this does notepresent a true aortic diameter. (See also the followingection, The Dilated Thoracic Aorta Grows Slowly, in anndolent Fashion) The same holds true for any otherortion of the aorta that takes a sharp curve, as oftenappens at the peridiaphragmatic portion. As the aortailates, it often elongates as well. The only way that anlongating aorta can “stay in the chest” is by becoming

Figure 4 Confounding of Ascending Aortic MeasurementsDue to Elongation and “C” Shape of Ascending Aorta

Aortogram (A) and schematic (B) showing gross elongation of the ascendingaorta, forcing the aorta into a C shape and obligating the aortic valve to take anearly vertical plane of orientation. On an axial computed tomography image,this common anatomy would markedly confound measurement of proximal aor-tic diameter. Note the difference between a horizontal diameter (as in an axialimage) and a diameter perpendicular to the long axis of the aorta. Figure illus-tration by Rob Flewell.

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ortuous or S shaped. Furthermore, in comparing measure-ents over time, one can easily be misled by diameters taken

rom even slightly different longitudinal levels of the aorta.lso, even in a given cross section, the aorta will not be a

rue circle (Fig. 6). The measured girth may vary dependingn which particular geometric diameter is selected. This cane especially true even on good-quality transesophagealcho, which may not “see” all diameters of the aorticnnulus and aortic root; asymmetric dilation of 1 sinus, forxample, may escape detection.

Knowing the dimension of the aorta is vitally important.s can be seen from the previous descriptions and images,easuring the thoracic aortic is not a mean feat. In some

ases, it may be difficult to reconcile discrepant studies or tochieve an ultimate measurement that encompasses theeparate “realities” of different imaging modalities.

In comparing serial imaging studies, it is important tovoid the temptation to compare with the previous image.

Figure 5 Loss of Normal “Waist” at Sinotubular Junction:A Sign of Intrinsic Aortic Disease

Aortograms depicting normal aortic contour (with a “waist” [arrow] above thecoronary arteries) (A) and the abnormal aortic contour (with no “waist”) ofMarfan-like annuloaortic ectasia (B). Figure illustration by Rob Flewell.

he aneurysmal aorta grows slowly, approximately 1 mm

er year on average (4). Thus, looking at closely spacedmages may miss even inexorable growth—the way a parentoes not notice children growing. Rather, it is imperative toompare with the very first available image, even if it meansearching or sending for early studies (5).

It is important to remember as well that size is not thenly important imaging criterion; shape matters as well,specially loss of the normal “waist” of the aorta at theinotubular junction (Fig. 5). Loss of this normal indenta-ion is an indication of intrinsic aortic disease, which shouldaise attention and concern about future aortic events.

horacic Aortic Aneurysms Increasing in Frequency

t is not easy, from an epidemiologic standpoint, to deter-ine whether the apparent increase in number of patients

een with thoracic aortic aneurysm is due to increasedetection (reflecting the frequency with which CT scans arerdered in the current era) or to a bona fide increase in thencidence of this disease. Some available evidence suggestshe latter (6).

Aneurysm disease is usually silent unless an imaging studyappens to have been performed; thus, true incidence is hardo estimate. Lethal thoracic aortic dissections are also oftenisdiagnosed as myocardial infarctions (7,8).The most recent data available from the Centers forisease Control and Prevention indicate that aneurysm

isease is the 18th most common cause of death in allndividuals and the 15th most common in individuals olderhan age 65 years, accounting for 13,843 and 11,147 deathsn these 2 groups, respectively (9). Note that aneurysmauses more deaths than human immunodeficiency virusisease. These figures almost certainly represent underesti-ates of the impact of aortic diseases due to the reasons

reviously mentioned. Experts have suggested that 30,000o even 60,000 deaths per year in the U.S. represents aeasonable estimate (10). The incidence of aortic disease isertain to increase as our population ages.

Figure 6 Which Is the True “Diameter?”

Geometric complexity of measuring aortic diameter.Figure illustration by Rob Flewell.

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The concept that aortic disease is truly increasing inncidence is based on evidence from geographic regions withtable populations with little out- or in-migration, as stud-ed in Minnesota and Sweden (11,12). Analysis in theseegions suggests a true, bona fide increase in the incidence ofortic disease. This is seen clearly in Figure 7.

he Dilated Thoracic Aorta Grows Slowly,n an Indolent Fashion

lthough a virulent disease, thoracic aortic aneurysm is anndolent process. The thoracic aorta grows very slowly—atpproximately 0.1 cm per year. The descending aorta growsbit faster than the ascending (Fig. 8). Previous estimatesad failed to account for negative observed growth (mea-urements of any object will vary around the mean) andther statistical complexities, leading to overestimates ofctual growth. Dr. John Rizzo of our team developedxponential equations specifically for the purpose of accu-ately estimating growth rates (13).

In fact, reports of rapid growth of the thoracic aorta aresually reflective of measurement error—specifically,easuring across an oblique portion of the aorta, espe-

ially the aortic arch (Fig. 9). The only condition that weave encountered in which the thoracic aorta truly growsapidly in a short time occurs when there has been anntercurrent aortic dissection; this should be suspected in

circumstance in which the diameter of the aorta trulyas grown rapidly.

vidence-Based Size Criteria foreplacement of the Dilated Aorta Are Now Available

he poor prognosis after realized dissection indicates how

Figure 7 Increase in Incidence of Aortic Aneurysm

Note increased incidence of ruptured abdominal aortic aneurysm in the totalpopulation of Malmö, Sweden, between 1971 and 2004. Adapted, with permis-sion, from Acosta et al. (12). Figure illustration by Rob Flewell.

ritically important it is to intervene before aortic dissection

ccurs. Our studies of the natural history of the enlargedorta have defined criteria that predict when dissection andupture are likely to occur in an enlarged thoracic aorta.

We started by analyzing the lifetime risk of rupture orissection. Analysis revealed sharp “hinge points” in theortic size at which rupture or dissection occur. These hingeoints are seen at 6 cm in the ascending aorta and 7 cm inhe descending aorta (Fig. 10). It is important to interveneefore the aorta reaches these hinge-point dimensions.pecifically, as seen in the figure, an individual with thoracicortic aneurysm incurs a 34% lifetime risk of rupture orissection by the time that his or her ascending aorta reachesdiameter of 6 cm. As seen in Figure 10, the descending

orta, for inexplicable reasons, does not rupture until a largerimension.To calculate yearly growth rates required even more

obust data, which have now become available in ouratabase. This analysis reveals that the incidence of rupture,issection, or death increases in a roughly linear fashion ashe aorta grows, reaching maximal levels at an aorticimension of 6 cm (Fig. 11).There is something special about the dimension of 6 cm,

hich we shall see is important mechanically as well aslinically.

Figure 8 Growth Rate of the Aneurysmal Thoracic Aorta

This is a virulent, but indolent process. Figure illustration by Rob Flewell.

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These data have permitted us to formulate evidence-ased guidelines for surgical intervention for thoracic aorticneurysms. These guidelines have been widely adopted. Theimple fact is that the vast majority of ruptures, dissections,nd aneurysm-related deaths can be prevented by pre-

Figure 9 Measurement Error From MeasuringAcross an Oblique Portion of the Aorta

Note that an axial measurement (A) would far overestimate the true aorticdiameter compared with the coronal view (B), all due to obliquity of a tortu-ous aorta. Arrows indicate discrepant diameter.

Figure 10 Depiction of “Hinge Points” for Lifetime Natural Hist

The y-axis lists the probability of complication; complication refers to rupture or dising aorta. Arrows indicate discrepant diameter. Adapted, with permission, from Cotion of thoracic aortic aneurysm? J Thorac Cardiovasc Surg 1997;113:476–91. Fig

mptive extirpation of the aneurysmal thoracic aortaefore the critical dimension of 6 cm is reached. Wesually recommend intervention for the ascending aortat 5.5 cm; we use a criterion of 5.0 cm for patients with

arfan syndrome, bicuspid aortic valve, or family historyf aortic dissection (14).It should be emphasized that these criteria apply to

symptomatic aneurysms.Symptomatic aneurysms should be resected regardless of size.

ymptoms are a harbinger of aortic rupture or dissection andust not be ignored. However, symptoms are rare in this

isease; only approximately 5% of patients are symptomaticefore an acute aortic event occurs. For the other 95% ofatients, the first symptom is often death. Ascending aneu-ysms can produce retrosternal pain that is not exertional inature, and descending aneurysms can produce interscapular backain. Attention to these symptoms can be literally lifesaving.

Now, it may be questioned whether 1 set of size criteria forurgical intervention can be applied to all individuals, regardlessf body size. In fact, it is indeed appropriate to make body sizeorrections, especially for very small or very large individuals.ur data now have become so robust that we have been able to

etermine appropriate criteria for interventions based on anortic size index, which takes into account both aneurysm sizend the patient’s body surface area (Fig. 12).

issections Can and Do Occasionallyccur at Small Aortic Sizes

e have known for some years that dissections do occa-ionally occur at small aortic sizes (Fig. 11). A recent paperrom the International Registry of Aortic DissectionIRAD) noted that a good number of the aortic dissectionsn their registry occurred at sizes below our recommendedntervention criterion of 5.5 cm (15) (Fig. 13). Insightfully,he IRAD authors recognized the dangers of amending size

omplications at Various Sizes of the Aorta

n. The x-axis shows aneurysm size. (A) The ascending aorta. (B) The descend-A, Rizzo JA, Hammond GL, et al. What is the appropriate size criterion for resec-ustration by Rob Flewell.

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riteria for surgical intervention downward, and they did notecommend any such change for fear of promoting surgicalarm in operating on small aortas.

Figure 11 Yearly Rates of Rupture, Dissection, or Death Relate

Note that the likelihood of rupture, dissection, or death within the coming year alsture or dissection and for rupture, dissection, or death are lower than the sum ofcounted only once in the combined categories.) These data underlie the conclusioloons to 5.5 cm. Adapted, with permission, from Elefteriades (14). Figure illustrati

Figure 12 Aortic Size Index Nomogram

Adapted, with permission, from Davies RR, Gallo A, Coady MA, et al. Novel measusize predicts rupture of thoracic aortic aneurysms. Ann Thorac Surg 2006;81:169

The key to reconciling our observational studies thatmall aortas pose only a low risk with the IRAD observationf a substantial number of dissections occurring at small

Aortic Size

s sharply for aneurysms that reach 6 cm or larger. (The rates indicated for rup-es in individual categories because patients with multiple complications wereaneurysms in the ascending aorta need corrective surgery when the artery bal-Rob Flewell.

t of relative aorticigure illustration by Rob Flewell. BSA � body surface area.

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izes lies in recognition of the “at-risk” denominator pool ofatients. Our Yale studies present danger rates for patientsnder observation at our institution with small aortas;ndeed, their risk of aortic events, although not zero, isow—too low to justify surgical intervention. For the IRADatients with dissection, however, these were drawn fromhe general population at large. Whether the distribution ofortic sizes is normal or paranormal, the number of at-riskatients increases dramatically as one moves toward normalrom the largest aortic sizes in the distribution curveFig. 14). In fact, it is likely that there are millions ofatients in the U.S. with aortas between 4 and 5 cm. Oneould certainly cause harm by operating prophylactically onll of them. In fact, if one were to divide the numerator ofbserved dissections in IRAD by a denominator of millions,he observed yearly percentage rate of dissection in the smallizes would be very small. Such interpretation supports, asRAD concluded, that we maintain our current surgicalntervention criteria.

In fact, to this point, we recently tested our interventionlgorithm in real time in the real-world setting of our Yaleortic Center (unpublished data analyzed by Amer Trivedi,006). We longitudinally followed patients triaged, basedn our algorithm (surgery for symptoms or size �5.5 cm), tobservational management (Fig. 15). As a matter of fact,ot a single patient triaged to medical therapy died ofupture during follow-up. This is powerful information

Figure 13 Dissections Do Occur at Small Sizes

Distribution of aortic size at the time of presentation with acute type A aorticdissection (cm). Purple bars indicate patients with diameters �5.5 cm.Adapted, with permission, from Pape et al. (15). Figure illustration by RobFlewell.

alidating the safety of medical management for small aortic

neurysms. On the other hand, among patients triagedlgorithmically to the surgical arm who were too ill forurgery or who refused surgery, the rate of aortic eventseading to death was indeed very high, validating surgicalherapy for patients meeting the algorithm criterion.

Size is a very helpful criterion, and, beyond symptoms, it ishe best intervention criterion in the current state of the art.

onsize Engineering Criteria Are Evolving

e performed a detailed engineering analysis on the aorticall in patients with ascending aortic aneursyms. We did

his by epiaortic echo at the time of aortic surgery.A full spectrum of engineering calculations regarding theechanical properties of the dilated aorta can be determined

ia measurement of 6 independent variables: aortic pressuren systole and diastole, aortic diameter in systole andiastole, and aortic wall thickness in systole and diastole.These measurements have shown that as the aorta en-

arges, distensibility of the aortic wall decreases, so that by

Figure 14 Huge General Population at Risk Explains theOccurrence of Some Dissections at Small Sizes

Depiction of a normal distribution curve of aortic size (marked in SDs). Notehow small the “tails” of such a curve are. Large aneurysms would reside farout in the tails. While dissections do occur at small dimensions, note how rap-idly the at-risk group increases in number as the putative criterion diametergoes from d1 to d2. We anticipate that millions of Americans harbor small tho-racic aortic aneurysms, making for a very large denominator of vulnerablepatients, and a correspondingly low likelihood of dissection at small sizes. Seethe “Dissections Can and Do Occasionally Occur at Small Aortic Sizes” sectionfor details. Figure illustration by Rob Flewell.

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pproximately 6 cm in size, the aorta becomes a rigid tube16). The result is that because the aneurysmal aortic wallannot “stretch” in systole, the full force of cardiac contrac-ion is translated into wall stress. The correlate of thishenomenon is that the enlarged aorta demonstrates a veryigh wall tension. These findings are shown in Figure 16.he dotted line in Figure 16B represents the ultimate

trength of human aorta. As seen in Figure 16B, duringpisodes of moderate hypertension, part of everyday life, anndividual with a 6-cm aorta will “flirt” with the ultimateursting strength of human aortic tissue. This has clinicalonsequences that we explore in the following text.

Please note how beautifully the engineering data dovetailith the clinical data. It is at 6 cm that the mechanicalroperties of the aneurysmal aorta deteriorate markedly. It isrecisely at 6 cm that the malignant behaviors of the dilateduman aorta—rupture and dissection—commonly becomeanifest, as discussed previously.We are currently replicating our intraoperative mechan-

cal measurements with simultaneously accrued transesoph-geal measurement of mechanical properties. If we canonfirm that similarly reliable measurements can be maderansesophageally, then mechanical properties may become alinically relevant parameter. Periodic outpatient calculations ofechanical properties, say distensibility and wall stress, may

rove good predictors of rupture and dissection. Thus, me-hanical properties may be useful to supplement symptoms andize as criteria for prophylactic aortic intervention.

Recent, preliminary evidence from Europe suggestshat similar measurement of mechanical properties can beade by MRI, and that such measurements may dem-

Figure 15 Flow Diagram of Medically-Treated Patients

Figure illustration by Rob Flewell. f/u � follow-up; INOP � inoperable; MEDRx � m

nstrate regions of the aneurysm at high risk of disrup- s

ion (17,18). In addition, preliminary studies from Europelso suggest that evidence of enhancement on positron emis-ion tomography may be an indicator of the “activity” ofn aneurysm, possibly preceding or predicting rupture19,20).

rug Therapy for Thoracicortic Disease Is Largely Unproven

s drug therapy effective for the treatment of chronicneurysms? Patients with chronic aneurysms are oftenreated with beta-blocking medications to decrease theirulence of the systolic impact on the aortic wall. Of course,ypertension must be controlled in aneurysm patients to

imit the disruptive forces on the aortic wall, and this goal innd of itself may involve the use of beta-blockers. Theffectiveness of beta-blockers in aneurysm disease, however,s largely unproven and somewhat controversial, but thisherapy has become standard practice. One long-durationohns Hopkins study of a moderate-size group (n � 70) of

arfan patients provides support (21), but there is alsoeason for doubt regarding this therapy, especially foron-Marfan patients (22,23). Concerns revolve around aumber of issues: There is evidence that beta-blockersecrease the elasticity of the aortic wall, already deficient inneurysmal aortas. There is concern about the side effects ofeta-blockers in young people because treatment is often aifetime decision. Finally, there is concern about a paradox-cal adverse impact (increased mortality) in a blinded,andomized, controlled trial of beta-blockers for abdominalneurysm (24). Nonetheless, we do not object to the current

ly treated; sx � symptoms; sx-ic � symptomatic.
edical
tandard practice of prescribing beta-blockers for aneurysm

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isease at present because the negative evidence is not yetverwhelming. A great deal of excitement was generated byrecent report by Habashi et al. (25) showing dramatic

uppression of aneurysm disease by the angiotensin receptorlocker losartan in an animal model of Marfan syndrome.linical trials are under way to investigate this excitingotential avenue of treatment (26,27).Investigation of other medical treatments has also been

erformed (23). The antibiotic doxycycline, a matrix me-alloproteinase (MMP) inhibitor, has been tested in large-cale clinical trials in abdominal aneurysm patients andhows promise (28,29). Other drugs that hold theoreticalromise and have undergone some animal or clinical testingnclude anti-inflammatory agents (cyclooxygenase inhibi-ors), statin drugs, immunosuppressants (rapamycin), andngiotensin receptor blockers (losartan) (30,31). None are ofroven clinical benefit at this time.Our findings (see the following text) that acute exertion

nd emotion can precipitate the onset of acute aorticissection have led to lifestyle alterations as part of the

Figure 16 In Vivo MechanicalProperties of Human Ascending Aorta

(A) Distensibility values in normal aortas and aortic aneurysms of differentdiameters. Distensibility of ascending aortic aneurysms decreases rapidly asdiameter increases to very low values at dimensions �6 cm. (B) Exponentialrelationship between wall stress and aneurysm size in ascending aortic aneu-rysms. The purple columns represent a blood pressure of 100 mm Hg, and thepink columns represent a blood pressure of 200 mm Hg. The lines at 800 to1,000 kPa represent the range of maximum tensile strength of the humanaorta. Figure illustration by Rob Flewell.

edical management of aortic aneurysms. In susceptible m

atients with known chronic aortic enlargement, we advisegainst heavy weight lifting (32–34) and insist on a jobhange when heavy lifting is involved. We advise susceptibleatients to seek attention when severely emotional personalr family situations arise, so that sedative medications can berescribed to prevent massive blood pressure spikes. Ourndings that acute exertion and emotion often underlie thenset of acute aortic dissection constitute another reason-ble rationale for beta-blocker therapy, with the intent oflunting pressure spikes.

horacic Aortic Aneurysm Is a Genetic Disease

arfan syndrome, based on any of a large number ofutations on the fibrillin gene, is a well-known cause of

ortic dissection. Patients with Marfan syndrome, if deniedurgical intervention, run a 50% risk of the development ofortic dissection during their lifetime. Marfan syndromeccounts for approximately 5% of all cases of aortic dissection.

The genetics of Marfan syndrome have been elucidatedor decades. However, Marfan disease explains only approx-mately 5% of known thoracic aortic aneurysms. The ques-ion arises whether genetic abnormalities explain some ofhe remaining 95% of patients with thoracic aortic aneu-ysm. The answer is a resounding “yes.”

The Yale database has allowed us to recognize that manyatients with aortic dissection do not fit any acknowledgedyndrome of collagen vascular disease. In fact, Marfanyndrome and the other named syndromes account fornly the “tip of the iceberg” of thoracic aortic aneurysmnd dissection. Our studies have indicated a strongenetic component in patients with thoracic aortic aneu-ysm and dissection among those patients without

arfan syndrome.Our construction of nearly 500 family trees of patients

ith thoracic aortic aneurysm or dissection has indicatedhat 21% of our probands have at least 1 family memberith a known aneurysm somewhere in the arterial tree

35,36). The patients with positive family trees showed aigher rate of growth of their aortas and presented at anarlier age, 2 findings that strongly support the influence ofn inherent genetic defect of the aortic wall. Our familyrees indicate that the predominant method of inheritance isutosomal dominant, but other genetic patterns are ex-ressed as well. The true rate of inheritance is likely muchigher than 21%, as many family members may haveneurysms without being aware of their presence.

Our most recent analysis indicates that the location of theneurysm in the proband has a strong impact on the site athich aneurysms develop in family members (36). Specifi-

ally, probands with ascending aortic aneurysm have familyembers with predominantly ascending aortic aneurysms

Fig. 17). However, probands with descending thoracicneurysms most commonly have family members withbdominal aortic aneurysms. This analysis fits a concept thatneurysm disease divides itself into 2 entities at the liga-
entum arteriosum: above the ligament is 1 disease and

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elow the ligament is another (Fig. 18). Above the liga-entum, the disease is nonarteriosclerotic, in contradistinc-

ion to below, where arteriosclerosis is abundant.

enetic Testing for Clinicalurposes Is Still Controversial

he genetics of Marfan syndrome have been fully charac-erized; any one of hundreds of specific mutations on thebrillin-1 gene can result in the Marfan phenotype. Dr.iana Milewicz has done groundbreaking work on the

enetics of aneurysm disease, identifying multiple mutationsesponsible for aortic aneurysms occurring in families37–40). These mutations include thoracic aortic aneurysmnd dissection 1 (which accounts for 20% to 30% of familialases), familial aortic aneurysm 1, transforming growthactor-beta receptor 2 (which accounts for 5% of cases), andyosin heavy chain 11.Yet, currently, Marfan syndrome is diagnosed on a clinical

asis, and the thoracic aortic aneurysm and dissection andther mutations remain laboratory tools. Thoracic aortic an-urysm is multigenetic; consequently, no easy, comprehensive,ull aortic genetic screen is currently generally available. Ge-etic testing is rarely ordered clinically. Researchers in the field,owever, are eager to accrue additional blood or sputumpecimens for investigative purposes.

Our own group has undertaken intensive efforts aimedoward identifying the specific genetic aberrations thatnderlie these family transmissions of aortic disease, in theope of developing a widely sensitive genetic screening testor thoracic aortic aneurysm. We studied 30,000 ribonucleiccid (RNA) expression patterns in the blood of patientsith thoracic aortic aneurysm and compared them with

hose of control patients. We found that a 41-singleucleotide polymorphism panel could discriminate quiteell between patients with and without aneurysm from a

Figure 17 Relationship of Aneurysm SiteBetween Proband and Family Members

Note that the location of the proband aneurysm influences the location ofaneurysms in the family members. Note that probands with ascending aneu-rysms have family members with ascending aneurysms, whereas probands withdescending thoracic aneurysms are more likely to have family members withabdominal aortic aneurysm. Adapted, with permission, from Lorelli et al. (44).Figure illustration by Rob Flewell.

lood test alone (Fig. 19) (41).

This “RNA signature” is �80% accurate in determiningrom a blood test alone whether a patient has an aneurysm.

e hope that this may result in a screening test for familyembers or even for the general public. This level of

ccuracy far exceeds that of the prostate-specific antigen testsed for prostate cancer.In collaboration with colleagues at Celera Diagnostics in

alifornia, we have also performed genomewide scans foreoxyribonucleic acid single nucleotide polymorphisms as-ociated with thoracic aortic aneurysm and dissection. Weave studied �500 Yale patients and their spousal controls

n this manner. Results are encouraging, with several singleucleotide polymorphisms strongly predicting the aneurysmisease. Replication studies from our European collectionites are currently under way.

Figure 18Aortic Aneurysm Is Really 2 Diseases:Ascending Disease Differs Markedly FromDescending/Abdominal Disease

Note that thoracic aneurysm disease divides naturally into 2 patterns, sepa-rated at the ligamentum. Above the ligamentum, the aorta is thin, but notatherosclerotic; below the ligamentum, as with abdominal aortic aneurysms,heavy arteriosclerosis and calcification predominate. Figure illustration byRob Flewell. PA � pulmonary artery.

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iomarkers for Thoracic Aorticneurysm May Be on the Horizon

horacic aortic aneurysm is a virulent, potentially lethalisease. It is also a predominantly silent disease. Thisombination of circumstances cries out for discovery ofiomarkers for this disease—blood tests that can detectneurysms in the general population, monitor the progressf an aneurysm, and predict complications in those patientsnown to be affected. We recently reviewed the nascent fieldf biomarkers in aortic diseases, and the cardinal messagesf this review are described in the following paragraphs (42)Table 1).

D-dimer is a byproduct of fibrin degradation and a usefuliomarker in acute aortic dissection. D-dimer is 99% sensi-ive in the detection of acute aortic dissection (43), except

Figure 19 The RNA Signature Test for Thoracic Aortic Aneurysm

In the hierarchical cluster diagram on the left (A), each vertical line represents acates underexpression and red indicates overexpression (as indicated in C). Notedepending on phenotype. In the figure on the right (B), note that if all the greens wAs it turns out, the overall accuracy was �82%.

otential Biomarkers in Aorticiseases (for Diagnosis and/or Monitoring)Table 1 Potential Biomarkers in AorticDiseases (for Diagnosis and/or Monitoring)

Indicators of ongoing thrombosis

D-dimer

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Matrix metalloproteinases

Inflammatory markers

Cytokines

CD4�CD28� T cells

C-reactive protein

Markers of collagen turnover

Elastin peptide

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Endothelin

Hepatocyte growth factor

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Genetic markers

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erhaps in intramural hematoma. If the D-dimer is notlevated, the patient does not have aortic dissection. How-ver, D-dimer is extremely nonspecific, being elevated inulmonary embolism and coronary thrombosis, essentiallyn any state in which thrombosis and thrombolysis proceed.he extent of D-dimer elevation reflects the longitudinal

xtent of aortic dissection, predicts the mortality of aorticissection, and differentiates from myocardial infarction.owever, because D-dimer elevation occurs after the dissec-

ion, it is not useful as a predictor.MMPs are known to be intimately involved in the

athogenesis of aortic aneurysm and dissection. Their use inhe monitoring of aortic disease is in the earliest stages. Itas been shown that MMP elevation signals recurrent bloodow in an aneurysm after endovascular therapy (44,45).Inflammation and collagen degradation are also known to

e involved in the pathogenesis of aortic aneurysms. Ac-ordingly, inflammatory markers and indicators of collagenurnover are being investigated as potential biomarkers inortic diseases. CD4�CD28� T cells and elastin peptide areeing investigated, in those 2 categories, respectively.mooth muscle heavy chain myosin has also shown someromise.We are also hopeful that our RNA signature test, whicheasures up- and down-regulation of aneurysm-relatedNAs, may be a useful marker of aneurysm activity androve helpful in the detection and monitoring of disease.deally, with this RNA panel, we would like to be ableiologically to predict rupture and dissection in the long-erm course of aneurysm disease (Fig. 19).

Imaging studies have advanced dramatically in depictinghe aneurysmal thoracic aorta. Imaging is not enough,owever. We need to be able to detect aneurysm disease inhe general population. We need to be able to predict the

t, and each horizontal line represents an RNA. In the grid (A), the green indi-diagram on the left (A) how the overexpression and underexpression cluster,gether and all the reds were together, the test would have been 100% accurate.

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ufficient as a predictor. It is hoped that in the future,iomarkers will supplement size in prediction of adversevents and enhance the decision to proceed to pre-emptiveurgical extirpation of the aneurysmal human aorta.

tent Therapy for Degenerativeneurysms Is Burgeoning, But itay Be “The Emperor’s New Clothes”

complete review of the debate over the effectiveness oftent therapy for thoracic aortic aneurysm (or abdominalneurysm) is beyond the scope of this article. However, thisopic is of such profound importance in the current era thatcommentary is appropriate.Two points deserve emphasis. First, the decision to treat

n aneurysm must be made with the same rigor forndovascular therapy as for open surgical therapy. We mustalance the intense pressure from departments, hospitals,nd industry to perform procedures and use devices with aull understanding of the disease of thoracic aortic aneurysmnd a respect for the patient. Although a virulent disease,horacic aortic aneurysm is an indolent one. As seen inigure 20, a thoracic aortic aneurysm usually does not takepatient’s life (in asymptomatic patients) until several years

fter diagnosis (46). In addition, as can be seen in Figure 20,his disease takes life generally when the aneurysms are largesee the line in the graph for aneurysms �6 cm). Theresence of a small thoracic aneurysm is not a validndication for endovascular therapy just because stent ther-py is available.

Second, the fundamental rationale of endovascular ther-py for degenerative aneurysms is questionable (47). Spe-ifically, one may question how a device inside the aorta,nd not attached to the aorta, can prevent the enlargementf the aorta. Stents were designed originally to preventtheroma from encroaching on the lumen of a vessel. In thease of an aneurysm, we are asking the stent to do thepposite: to prevent the outward expansion of the aorta.

Figure 20 Survival With Thoracic Aneurysms of Various Sizes

Five-year hazard estimates are illustrated for patients as a function of initialaneurysm size (p � 0.0045). Adapted, with permission, from Elefteriades et al.(5). Figure illustration by Rob Flewell.

ne would think that any potential restraining device wouldeed to be placed outside, not inside, the aorta. Thisoncern is compounded by the fact that stents for an aorticneurysm exert a radially directed force, which would benticipated to encourage outward enlargement of the aorta.

In fact, the generally sparse data available to date thatave matured to mid-term or beyond are very discouraging

n terms of the effectiveness of endovascular therapy foregenerative aneurysm. (Early “effectiveness” is meaninglessecause most patients would be alive at 1, 2, or 3 years, evenbsent any therapy at all, as demonstrated in Fig. 20.) At theecent International Aortic Symposium in Liege, Belgium48), where the latest midterm data on abdominal aorticneurysms were presented, the conclusion was frankly thatndovascular therapy is not effective, in essence representingsham” therapy (low risk, no benefit). This was based onata from 3 studies (representing the best scientific evidencevailable):

. EVAR-2 (Endovascular Aneurysm Repair Trial 2). TheEVAR-2 trial compared endovascular aneurysm repair(EVAR) with no specific therapy (medical therapy). Thekey graph (49) presented in Figure 21 shows no benefitfrom stent grafting compared to no therapy. (This was atrial for abdominal aortic aneurysms.) The all-causemortality curves for EVAR and medical therapy aresuperimposable, as are the curves for aneurysm-relatedmortality. There is simply no evidence of benefit.

. DREAM (Dutch Randomised Endovascular AneurysmManagement). The DREAM trial compared EVARwith traditional surgical therapy. The midterm follow-upin the DREAM trial found that at 2 years, the survivalcurves cross, and, from that point on, stent-treated

Figure 21Data From the EVAR-2 Trial Showing No Benefitof Stent Therapy of Abdominal Aneurysm OverMedical Therapy

Mortality curves in EVAR-2 (Endovascular Aneurysm Repair Trial 2), showing nobenefit from endovascular therapy of abdominal aortic aneurysms. Adapted,with permission, from the EVAR Trial Participants (49). Figure illustration byRob Flewell.

patients have poorer survival than surgically treated

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patients (50). (This was a trial for AAA.) That is, EVARshows an early advantage, because surgery has somemortality, but this advantage is lost because EVAR hasno durable benefit. (The graph is dramatic. It was shownat the International Aortic Symposium in Liege, Bel-gium [48].)

. INSTEAD (INvestigation of STEnt Grafts in PatientsWith Type B Aortic Dissection). The INSTEAD trial,conducted by the noted authority Professor Neinaber inGermany, investigated stent therapy for patients doingwell beyond 2 weeks after uncomplicated type B aorticdissection. The hope was that “tacking down” the dis-section flap would lead to later benefit. Contrary toexpectations, the INSTEAD trial found severe earlymortality and complications subsequent to stent therapy.There was no survival advantage over medical therapyalone. These results were also presented in Belgium, but,as a negative study, have yet to be published.

These extremely discouraging midterm data should raiseserious flag of caution regarding endovascular therapy in

he current state-of-the-art for degenerative aneurysms. Toorrow a term from the lay economic press, we must avoidirrational exuberance” in the application of endovascularherapies for degenerative aneurysms.

Further amplifying the need for caution are the recentndings that endovascular therapy exerts a serious emo-ional toll on patients (who experience extreme anxietyiving from scan to scan, in fear of need for ancillaryrocedures) (51) and that the radiation burden from fre-uent repeated scans for surveillance of unreliable stents isorrisome (52). The enthusiasm for endovascular therapyust be balanced as well against the tremendous advances in

pen therapy for thoracic aortic aneurysm, which have set aery high standard of safety and effectiveness for endovas-ular therapies to surpass or even to equal (53,54).

he Date and Time That Acuteortic Dissection Occurs Is Not Random

ow does aortic dissection pick a specific time to occur?ow is it that dissection picks January 4, 2009, at 5:03 PM

the moment that this sentence is being written) to occur?he authors formerly believed that the occurrence of dis-

ection in a susceptible patient was random. They do nothink so any longer.

It is interesting that aortic dissection has long beennown to occur in circadian and diurnal patterns, with areponderance of instances in the winter months and in thearly morning hours. The reasons behind these patterns arenknown, but these characteristics correlate with the seasonnd time of day when blood pressure is known to be highest.

Studies at Yale have added another interesting dimensiono our understanding of the timing of aortic dissection inusceptible individuals. Specifically, we have found thatxtreme exertion or emotion may precipitate acute aortic
issection (55). e
Let us presume that a patient is rendered susceptible toortic dissection due to his genetic makeup and thenonsider what factors or forces might precipitate dissectiont 1 particular moment in time.

A few years ago, we noticed a cluster of healthy youngeight lifters who had presented to Yale with acute ascend-

ng aortic dissection and required urgent surgery. Weeported this cluster in JAMA (33). We did a biomechanicaltudy on ourselves and found that, during severe weightifting, we reached blood pressures approaching or exceeding00 mm Hg (Fig. 22) (32). These are levels of hypertensionimply not seen in any type of cardiac care, be it in the coronaryare unit or in the cardiothoracic surgical unit. We hypoth-sized that extreme elevation of blood pressure during liftingas a factor in the cluster of dissections that we had treated

n weight lifters. After publication of our original report, weeceived cases from around the country. We did a follow-upeport enumerating 31 similar cases of acute aortic dissec-ion in the setting of weight lifting or severe strainingctivity (34). Nearly all these dissections occurred in youngen with previously unknown moderate aortic enlargement

4 to 5 cm). Based on this evidence, we recommendedoutine screening of all athletes embarking on weight liftingr other heavy athletic activity. We saw this as the onlyeans to protect these young athletes from needless death.

t is interesting and reassuring that the Olympic Committeeow requires an echocardiogram for every athlete competing

n the Olympics. We would like to see this prescriptionxtended to college and high school athletes.

We subsequently did another study in which we con-acted each patient or family member whom we had treatedor acute aortic dissection at Yale University. This investi-ation implicated emotion as well as exertion as an etiologicactor in the acute onset of aortic dissection. Specifically, weound that a majority of patients could recall a specific

Figure 22 BP Response to WeightLifting: Extreme Hypertension

Note the marked elevation in blood pressure (BP) for these 3 scientists asthey lift various percentages of their body weight in the bench press. Adapted,with permission, from Elefteriades (32). Figure illustration by Rob Flewell.

pisode of severe emotional upset (notification of a cancer

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iagnosis, losses at the casino, or illness in a loved one) orxtreme exertion at the time of their dissection (Fig. 23).

These studies, looking at aneurysm and dissection fromultiple viewpoints—clinical, biologic, genetic (mendelian

nd molecular), mechanical, epidemiologic—permit formu-ation of the following schema for the onset of acute aorticissection in a specific individual at a specific time (Fig. 24).The susceptibility to aortic aneurysm and dissection is set

rom birth by genetics. The aorta is destroyed over time, ateast in part by excess proteolysis by the MMPs. The aortanlarges as its wall is damaged. As the aorta enlarges, theechanical properties deteriorate, with loss of distensibility

nd imposition of excess wall tension. An acute hypertensivevent supervenes, usually emotional or exertional, and ex-eeds the tensile limit of the aortic wall, producing an acuteortic dissection.

Silver Lining in the Cloud of Aneurysm Disease

ndeed, there is a silver lining in the cloud of thoracic aorticneurysm disease. This silver lining is protection fromrteriosclerosis in patients with ascending aortic aneurysmr dissection.

Figure 23 Precipitating Events for Acute Aortic Dissection

Emotional or exertional events immediately preceding the onset of the pain ofacute aortic dissection. Adapted, with permission, from Hatzaras et al. (55).Figure illustration by Rob Flewell.

Figure 24 Conceptual PathwayLeading to Acute Aortic Dissection

Overall schematic understanding of how aortic dissection picks a specific timeto occur. See “The Date and Time That Acute Aortic Dissection Occurs Is NotRandom” section for details.

n

We noticed, in the course of operating on patients withscending aortic aneurysm and dissection, that their arteriesended to be arteriosclerosis free. Specifically, the femoralrteries, which are cannulated for cardiopulmonary bypass,re usually soft and pliable, without any arterioscleroticlaque or even a fatty streak. These are generally pristinerteries, like those of a teenager, despite the patient’s age.

We followed up by analyzing the total body arterialalcium score in patients with and without ascending aorticneurysm or dissection. We used calcium score as a proxyor arteriosclerosis (Fig. 25). We found that the calciumcore was significantly lower in patients with ascendingortic aneurysm or dissection than in age- and sex-matchedontrols (56). Subsequent to this clinical finding, we iden-ified in the literature molecular biological studies thatorroborate that a high MMP state such as aneurysmisease would be expected to show lower arterioscleroticurden, partly by lysis of developing plaques by the MMPs.MPs are thought to be proaneurysmal and antiathero-

enic (57,58).Therefore, patients with ascending aortic aneurysm or

issection, although they have a virulent aneurysm disease,eem, in some measure, to be protected from the arterio-clerosis, which is the leading killer of Americans.

dvances in Diagnosis andreatment Envisioned for the Near Future

ne may fairly expect to see the following major advances iniagnosis and treatment of aortic diseases in the relatively

Figure 25 “Silver Lining” in Ascending AneurysmDisease: Protection From Arteriosclerosis

The total body calcium index in patients with ascending aortic aneurysms anddissection as well as in matched controls. Note that male sex (G), hyperten-sion (HTN), smoking, dyslipidemia (Dyslip), diabetes mellitus (DM), andadvanced age led to higher calcium scores, as would be expected. Note thatascending aortic dissection (Dis.) and annuloaortic ectasia (AAE) were protec-tive against calcification. Adapted, with permission, from Achneck et al. (56).Figure illustration by Rob Flewell.

ear future:

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• Population screening will be improved, first by generalrecognition in the medical community of the familialpatterns of aortic disease and then by novel (genetic)mass screening techniques.

• Selection criteria for surgical intervention will gobeyond symptoms and size. We anticipate that thefollowing modalities may be applied:X Biomarkers that indicate impending rupture or

dissection may come into play (including potentialRNA expression indexes).

X Mechanical properties of the aorta (distensibilityand wall tension) may be assessed noninvasively andapplied as intervention criteria.

X Imaging modalities (including positron emissiontomography) may be found to be predictive ofaneurysm “activity” and guide timing of surgery.

• Stent therapies may advance to achieve truly durableresults (in contradistinction to currently disappointinglack of effectiveness in preventing death or rupture).This may require paradigm shifts in the design ofendovascular prostheses.

• Genetic elucidation of these diseases will advance evenfurther, permitting enhanced understanding of thepathophysiology of aneurysm disease and improveddiagnosis.X Understanding of genetic alterations resulting in

aneurysms may suggest avenues to pharmacologictherapy (with conventional drugs designed to short-circuit the mechanism of aneurysm formation andprogression). In particular, we look forward toseeing whether the angiotensin receptor blockerdrug losartan meets its high expectations.

X Understanding of genetic alterations may ulti-mately permit gene therapy in children or adults toprevent the development or progression of aorticdiseases.

Medical science has done much to tame this virulent diseasend to improve the prospects for affected patients in the 100ears since Osler’s famous quote (59) that “There is no diseaseore conducive to clinical humility than aneurysm of the

orta.” The current advances in genetic and molecular under-tanding of aneurysm disease are considerable. There is greatromise that current scientific techniques will yield additionaliant advances, perhaps elevating the playing field from timelyurgical “plumbing” interventions (albeit challenging and thrill-ng) to early recognition and genetic-based prevention ofhoracic aortic aneurysms and dissections.

cknowledgmenthe authors thank Maryann Tranquilli, RN, for her assis-

ance in identifying pertinent radiographic images.

eprint requests and correspondence: Dr. John A. Elefteriades,ardiac Surgery, Yale University School of Medicine, Boardman, 333 Cedar Street, New Haven, Connecticut 06510. E-mail:
[email protected].
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ey Words: aneurysm y aortic y diagnosis y genetics y thoracic.

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