Predicting rupture, death and dissection : the natural history of thoracic aortic disease

Transcription

1 Yale Unversty ElScholar A Dgtal Platform for Scholarly Publshng at Yale Yale Medcne Thess Dgtal Lbrary School of Medcne 200 Predctng rupture, death and dssecton : the natural hstory of thoracc aortc dsease Ryan Robert Daves Yale Unversty Follow ths and addtonal works at: Recommended Ctaton Daves, Ryan Robert, "Predctng rupture, death and dssecton : the natural hstory of thoracc aortc dsease" (200). Yale Medcne Thess Dgtal Lbrary Ths Open Access Thess s brought to you for free and open access by the School of Medcne at ElScholar A Dgtal Platform for Scholarly Publshng at Yale. It has been accepted for ncluson n Yale Medcne Thess Dgtal Lbrary by an authorzed admnstrator of ElScholar A Dgtal Platform for Scholarly Publshng at Yale. For more nformaton, please contact elscholar@yale.edu.

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8 Predctng Rupture, Death and Dssecton: The Natural Hstory of Thoracc Aortc Dsease A Thess Submtted to the Yale Unversty School of Medcne n Partal Fulfllment of the Requrements for the Degree of Doctor of Medcne by Ryan Robert Daves 200

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10 Daves et al. - The Natural Hstory of Thoracc Aortc Dsease Acknowledgements ABSTRACT Predctng Rupture, Death, and Dssecton: The Natural Hstory of Thoracc Aortc Dsease Ryan R. Daves, Mchael A. Coady, John A Rzzo, John A. Elefterades, Secton of Cardothoracc Surgery and fschool of Epdemology and Publc Health Yale Unversty School of Medcne, New Haven, CT Background - Thoracc aortc aneurysms and dssectons are serous, potentally fatal dseases. Ablty to estmate smply the yearly rate of rupture/dssecton would greatly enhance clncal decson makng for specfc patents. Methods - Data on 668 patents (44m, 254f) (medan age 65.8 yrs) wth thoracc aortc dsease was en tered nto a computerzed database over nne years. 35 magng studes were avalable. 304 patents were dssecton-free at presentaton; ther natural (unoperated) hstory was followed for rupture, dssecton, and death. In order to assess the mpact of famlal clusterng of aortc or aneurysmal dsease, famly ped grees were obtaned through telephone nqury of 28 (42m, 76f) patents wthout Marfan syndrome (MFS). Results - 5-year survval n unoperated patents was 54% at 5 years. Aortc sze was a very strong pre dctor of rupture, dssecton, and mortalty. For aneurysms a 6.0 cm n dameter: rupture occurred at 3.6% per year, rupture or dssecton at 6.4% per year, death at 0.8%, and death, rupture or dssecton at 4.% per year. At sze a 6.0 cm, the odds rato for rupture was ncreased 5-fold {p = 0.004). Electve, pre emptve surgcal repar restored lfe-expectancy to normal. Of 28 patents contacted, 44 (8.9%) had one or more frst-order relatves wth aneurysmal dsease. Patents wth non-mfs famlal aggregaton were smlar to those wth sporadc dsease, but had a trend toward hgher growth rates and mortalty (odds rato.594, p = 0.524). Conclusons - Ths study ndcates that () Thoracc aneurysm s a lethal dsease. (2) famlal aggregaton occurs n 9% of cases and may carry a worse prognoss (3) Aneurysm sze has a profound mpact on rup ture, dssecton and death. (4) For counselng purposes, the patent wth an aneurysm exceedng 6 cm can expect a yearly rate of rupture or dssecton of at least 6.4% and a death rate of 0.8%. (5) Electve surgcal repar restores survval to near normal. Ths analyss strongly supports careful radologc follow-up and electve, pre-emptve surgcal nterventon for the otherwse lethal condton of large thoracc aortc aneu rysm.

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12 Daves et al. - The Natural Hstory of Thoracc Aortc Dsease Acknowledgements ACKNOWLEDGEMENTS I have worked on ths project throughout my tme n medcal school, and t could not have been completed wthout the help and gudance of a substantal number of people. Obvously, I would lke to thank my mentor, John Elefterades, MD, Chef of the Secton of Cardothoracc Surgery. Invaluable gudance and assstance n all parts of ths work was provded by Mchael Coady, MD, MPH, who was a general surgery resdent at Yale and has moved on to Stanford, CA to complete hs tranng n thoracc sur gery. In addton to frst ntroducng me to the project, he provded day-to-day gudance n data collecton, statstcal analyss, and the wrtng of scentfc artcles. Other people who I should thank for ther help nclude: Lee J. Goldsten, MD, and John A. Rzzo, PhD. I would also lke to thank Graeme L. Hammond, M.D. for hs close readng of the manuscrpt and hs assstance n preparng the fnal verson. Rhaea Mller has provded vtal assstance throughout my tme workng wth the Secton of Cardothoracc Surgery. The personnel n the laboratory of Rchard P. Lfton, M.D., Ph.D., especally Dr. Lfton and Carol Nelson-Wllams, have provded gudance on the genetc as pects of the project and assstance n collectng DNA from patents. Personnel n the lab also performed the genetc analyss descrbed below. Fnally, I would lke to thank my parents and famly for ther support throughout my educaton at Yale. Portons of the work descrbed n ths thess were presented at: the 79th Annual Meetng of the New England Surgcal Socety, Toronto, ONT, Canada, Sept. 25th to 27th, 998, the 7st Scentfc Sesson of the Amercan Heart Assocaton, Atlanta, GA, Oct. 998, and the 37th Annual Meetng of the Socety of Thoracc Surgeons, New Orleans, LA, Jan. 29th to 3st, 200, and publshed n pror form."5 Portons of the work descrbed n ths thess were funded by Grant-n-Ad CT-BP97-GR-45 from the Amercan Heart Assocaton, Dallas, Tex.

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14 Daves et al - The Natural Hstory of Thoracc Aortc Dsease Acknowledgements Further portons were performed whle the author was supported by a tranng grant n the form of a Medcal Student Research Tranng Fellowshp from the Howard Hughes Medcal Insttute, Chevy Chase, MD

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16 Daves et al. - The Natural Hstory of Thoraac Aortc Dsease Table of Contents TABLE OF CONTENTS Abstract. Table of Contents.v Tables.v Fgures. v Equatons...x Abbrevatons...x Introducton.. Anatomy and Physology of the Thoracc Aorta. Structural Protens of Arteral Walls. The Structure of the Aorta.I Classfcaton of Thoracc Aortc Dsease.2 Dssecton.5 Penetratng Ulcer.4 Intramural Hematoma.5 Famlal Aggregaton...6 Thoracc Aortc Aneurysms.6 Hstory.6 Etology.7 Natural Hstory...7 Treatment.2 The Inhertance of Thoracc Aortc Dsease.3 Marfan Syndrome and Inherted Connectve Tssue Dsease.3 Famlal Inhertance rs Patents wthout Systemc Connectve Tssue Dsease. 4 mpact of Famlal Aggregaton on Natural Hstory.4 Statement of Purpose...6 Methods_ Patents and Data Collecton.8 Intal Recrutment of Study Populaton.8 Prospect ve Recrutment of Study Populaton.8 All.Patents. 9 Statstcal Analyss.22 Growth Rate Analysts.22 Analyss of Complcaton Rates n Thoracc Aortc Aneurysms.23 Determnaton of Famly Hstory and Genetc Analyss.24 Patent Collecton and Data Analyss.. 24 Genetc Analyss.26 Results..._...27 Characterstcs of the Entre Study Populaton.27 Aneurysm Growth Rates.27 Analyss of complcatons.29 Demographc and Clmes! Characterstcs of the Study Populaton.29 Complcaton Rates.30 The Impact of Genetc Factors on Natural Hstory.4 Demographc and Clncal Characterstcs of the Study Populaton.4 v

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18 Daves et al. - The Natural Hstory of Thoradc Aortc Dsease Pedgree Analyss. Aneurysm Growth Rates Long-Term Survval. Dscusson. References Table of Contents Aneurysm Growth Rates..47 Analyss of Complcatons..47 The Impact of Genetc Rsk Factors.49 Summary

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20 Table of Tables Daves et al. - The Natural Hstory of Thoracc Aortc Dsease TABLES Table. Classfcaton of thoracc aortc aneurysm.3 Table 2. Dstrbuton of 92 end-ponts.2 Table 3. Demographc characterstcs of 668 patents wth thoracc aortc dsease.27 Table 4. Multvarate estmates of aneurysm growth rates.28 Table 5. Demographc nformaton on 304 patents ncluded n analyss of complcatons.29 Table 6. Intal aortc sze (cm) n 304 patents wth thoracc aortc aneurysms.30 Table 7. Aneurysm sze (cm) at the tme of complcaton.32 Table 8. Unvarate analyss of rupture and dssecton.33 Table 9. Unvarate analyss of rupture/dssecton and death.34 Table 0. Logstc regresson of rsk factors for rupture or dssecton (dependent varables).35 Table. Proportonal hazards regresson of factors predctng ncreased rates of rupture or dssecton. (dependent varables).36 Table 2. Proportonal hazards regresson of factors predctng ncreased rates of rupture (dependent varables).37 Table 3. Proportonal hazards regresson of factors predctng ncreased rates of complcatons (rupture, dssecton or death) pror to surgery (dependent varables).39 Table 4. Comparson of demographc patents between patents wth known (+ or -) famly hstory and those wth unknown famly hstory. (Numbers are percentages unless otherwse ndcated).4 Table 5. Demographcs and clncal characterstcs of patents wth non-mfs-related famlal thoracc aortc dsease.42 Table 6. Comparson of patents wth sporadc, nmfs famlal, and MFS-related aortc dsease.43 Table 7. Comparson of aortc growth rate accordng to dssecton status n patents wth sporadc, nmfs famlal, and MFS-related thoracc aortc aneurysms. 44 Table 8. Proportonal hazards regresson of factors predctng decreased long-term survval when famlal hstory s ncluded as a rsk factor (dependent varables).45 v

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22 Daves et al - The Natural Hstory of Thoraac Aortc Dsease Table of Fgures FIGURES* Fgure. Dagrammatc representatons of the molecular structure of collagen. Fgure 2. Hypothetcal mechansm for the stretchng of elastn molecules. Adapted from Alberts et al.5. Fgure 3. Elastc van Geson staned secton of the an aorta (orgnal magnfcaton X 20).2 Fgure 4. Computed tomography (CT) of patent wth a large aortc aneurysm. (A concomtant dssecton s vsble n the left posteror porton of the aorta).3 Fgure 5. A. The three layered aortc wall, the ntma (red) lnes the lumen, the adventta (yellow) forms the external layer, and the meda (pnk) sts between. B. A tear through the ntma allows a column of blood to splt the layers of the meda.3 Fgure 6. Computerzed tomography (CT) of a patent wth a classc type B aortc dssecton.3 Fgure 7. The classfcaton of aortc dssecton. Included wth the Stanford classfcaton s the ncdence of ntmal tears n each regon of the aorta based on autopsy studes. Adapted from a dagram by Ergn and Grepp.3.4 Fgure 8. Dagram of PAU.4 Fgure 9. A. MR mage (sagttal vew) of a patent wth a penetratng atherosclerotc ulcer. B. MR mage (axal vew) of a patent wth a penetratng atherosclerotc ulcer.5 Fgure 0. Dagram of IMH.5 Fgure. Transthoracc echocardogram (TEE) of a patent wth an ntramural hematoma.5 Fgure 2. Early depcton of Galen.6 Fgure 4. Estmated effect of aneurysm sze on rsk of complcaton (rupture or dssecton) for ascendng/arch and descendng/thoraco-abdomnal aneurysm locaton. Adapted from Coady et al Fgure 5. Pedgree of a famly demonstratng aggregaton of thoracc aortc dsease dentfed by Ncod, et al.57.4 Fgure 6. Multvarable estmates of aneurysm growth rates by ntal aortc sze and locaton.27 Fgure 7. Hstogram of ntal aortc sze and aneurysm locaton...28 own. v

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24 Daves et al - The Natural Hstory of Thoracc Aortc Dsease Table of Fgures Fgure 8. Hstogram of ntal aortc sze n 304 patents.29 Fgure 9. Incdence of acute dssecton or rupture as a functon of ntal aneurysm sze.30 Fgure 20. Incdence of rupture as a functon of ntal aneurysm sze.3 Fgure 2. Incdence of acute dssecton as a functon of ntal aneurysm sze.3 Fgure 22. Kaplan-Meer cumulatve ncdence of rupture or dssecton. Fve-year hazard estmates are llustrated for patents as a functon of ntal aneurysms sze, p = Fgure 23. Average yearly rate of rupture or dssecton by ntal aortc sze.36 Fgure 24. Average yearly rate of rupture by ntal aortc sze.37 Fgure 25. Kaplan-Meer cumulatve ncdence of rupture. Fve-year hazard estmates are llustrated for patents as a functon of ntal aneurysm sze, p = Fgure 26. Kaplan-Meer cumulatve ncdence of dssecton. Fve-year hazard estmates are llustrated for patents as a functon of ntal aneurysms sze,/? = Fgure 27. Average yearly rate of dssecton by ntal aortc sze.38 Fgure 28. Kaplan-Meer cumulatve survval pror to operatve repar. Fve-year survval estmates are llustrated for patents as a functon of ntal aneurysm sze, p = Fgure 29. Average yearly rate of death by ntal aortc sze.38 Fgure 30. Average yearly rate of rupture, dssecton or death based on ntal aortc sze.38 Fgure 3. Average yearly rates of all negatve outcomes by ntal aortc sze.39 Fgure 32. Kaplan-Meer cumulatve survval. Fve-year survval estmates are llustrated for patents as a functon of ntal aortc sze, p = Fgure 33. Kaplan-Meer cumulatve survval. Fve-year survval estmates are llustrated for patents as a functon of aneurysm locaton, p = Fgure 34. Kaplan-Meer cumulatve survval. Fve-year survval estmates are llustrated for patents as a functon dssecton status, p = Fgure 35. Kaplan-Meer cumulatve survval. Fve-year survval estmates are llustrated for patents as a functon of the treatment receved,/? = Fgure 36. Kaplan-Meer cumulatve survval. Fve-year post-operatve survval estmates are llustrated for patents as a functon of the urgency of the surgcal procedure, p = v

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26 Daves et al. The Natural Hstory of Thoracc Aortc Dsease Table of Fgures Fgure 37. Prevalence of comorbdtes analyzed by the presence of a famly hstory.43 Fgure 38. Pedgrees for 26 famles wth nmfs famlal aortc dsease.44 Fgure 39. Kaplan-Meer cumulatve survval pror to operatve repar. Fve-year survval estmates are llustrated for patents as a functon of famlal hstory, (p = 0.997).45 Fgure 40. Kaplan-Meer cumulatve survval. Fve-year survval estmates are llustrated for patents as a functon of famlal hstory, (p = ).45 Fgure 4. Kaplan-Meer cumulatve survval. Fve-year survval estmates are llustrated for patents as a functon of whether or not we were able to ascertan a famly hstory, (p ).46 IX

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28 Daves et al. - The Natural Hstory of Thoracc Aortc Dsease Table of Equatons EQUATIONS Equaton. Tradtonal growth rate formula.8 Equaton 2. Grepp s formula for predcton of rupture wthn one year of sze measurement. Equaton 3. Multvarable estmaton of aneurysm growth rates. 22 Equaton 4. Natural log of Equaton 3.22 Equaton 5. Rearrange Equaton 4.23 Equaton 6. Estmated regresson (IV estmaton) for patents wth and wthout chronc dssecton.23 Equaton 7. Defnton of growth rates.23 Equaton 8. Combne Equatons 3 and 7.23 Equaton 9. Rearrange Equaton 8.23

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30 Daves et al. - The Natural Hstory of Thoracc Aortc Dsease Abbrevatons ABBREVIATIONS The frst appearance of an abbrevaton occurs n parentheses followng the full term. The fol lowng table s provded for reference purposes: AAA abdomnal aortc aneurysm CAD coronary artery dsease CHF congestve heart falure Cl confdence nterval CMN cystc medal necross CT computed tomography CVA cerebrovascular accdent EDS-IV Ehlers-Danlos Syndrome Type IV F-AAA famlal abdomnal aortc aneurysm IEL nternal elastc lamna IMH ntramural hematoma MFS Marfan syndrome MRI magnetc resonance magng nmfs famlal non-marfan syndrome-related famlal PAU penetratng atherosclerotc ulcer SMC smooth muscle cell TAA thoracc aortc aneurysm TEE transesophageal echocardogram TTE transthoracc echocardogram

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32 Introducton Daves et al. - The Natural Hstory of Thoracc Aortc Dsease INTRODUCTION Anatomy and Physology of the Thoracc Aorta Structural Protens of Arteral Walls Collagen (especally types I and III) and elastn are the most mportant structural protens n the aorta.6 7 Collagens consst of three polypeptde chans whch col around each other to form threestranded ropes or collagen fbrsf^ (Fgure ) whch aggregate nto cable-lke collagen fbers.5 Secreted elastn molecules, on the other hand, form extensve cross-lnks to generate a net work of fbers and sheets. The exact mechansm for ther subsequent elastcty s not completely under stood, but Fgure 2 llustrates one hypothess. The Fgure. Dagrammatc representatons of the molecular structure of collagen. (A) An ndvdual a-chan composed of trplet repeats (Gly-XY), X and Y are usually (but not necessarly) prolne and hydoxyprolne. (B) A completed collagen fbrl, a left-handed trple helx formed of three u-chans (n dfferent colors). Only the glycne molecule s small enough to ft nto the tght nteror of the helx. Adapted from Alberts et al.5 elastn core of the clastc fber s covered n a sheath elastc fber of mcrofbrls. The mcrofbrllar protens appear to act as scaffoldng for the subsequent deposton of elastn, and may also play a role n tssue homeosta ss.50,. They nclude fbrlln-, whose encodng gene, FBN, has been dentfed as the defectve gene n Marfan syndrome (MFS). Stretch Relax The Structure of the Aorta The aorta s an elastc artery wth three de fned layers: the ntma, meda and adventta. (Fgure 3) The ntma conssts of a sngle layer of endothelal cells supported by a layer of collagenous Fgure 2. Hypothetcal mechansm for the stretchng of elastn molecules The elastn molecules are shown n green joned together by the covalent cross-lnks (red) to form a network. When relaxed, they form a loose conglomeraton of fbers (upper mage), but when stretched, adopt a lnear structure. Adapted from Alberts et al.5

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34 Introducton Daves et al. - The Natural Hstory of Thoracc Aortc Dsease tssue rch n clastn. Ths subendothelal tssue also contans fbroblasts and cells smlar to smooth muscle cells (SMC) known as myontmal cells; these two cells types are both thought to contrbute to the elaboraton of extra-cellular components. The meda s a broad, hghly elastc layer com posed of SMC wthn a matrx of clastn, collagen, and Fgure 3. Elastc van Geson staned secton of the aorta (orgnal magnfcaton X 20) demonstratng the nternal elastc lamna (IEL) ground substance. The elastc fbers are arranged as elastn), has fenestrae that allow substances to dffuse to noursh cells deep wthn the aortc wall. The meda comprses a mxture of crcumferental lamallae. In the thoracc aorta there are (A) and the outer part of the meda have small blood vessels (vasa delneatng the ntma from the meda (M). The IEL (composed of smooth muscle cells and retcular and elastc fbers. The adventta vasorum) and elastc and collagenous fbers. approxmately 45 to 56 lamallae, whereas the abdomnal aorta contans only Ths may contrbute to the hgher prevalence of abdomnal aortc aneurysm (AAA) compared to thoracc aortc aneurysm (TAA).6 The elastc lamellae play a central role n crculatory physology: durng systole, the dameter of the lamellae ncrease, then, durng dastole, the elastc fbers recol: mantanng forward blood flow durng dastole.7 Thus the elastc fbers functon as shock absorbers for the knetc energy of the flud shockwave whch strkes the aortc wall wth each cardac contracton.*2 The medal SMC control vascular ress tance, perform a macrophage-lke functon, and secrete collagen nto the extracellular matrx/ Deposton of collagen contnues throughout lfe, but humans are unable to synthesze elastc fbers n adulthood lttle elastn synthess can be detected after nfancy.22 The adventtal layer surrounds the meda and mantans the maxmal aortc dameter.23 It s com posed of loose connectve tssue consstng of fbroblasts, elastc fbers and collagen. Unlke the meda, the adventtal elastc fbers are not organzed nto lamellae. Collagen n the adventta lmts the maxmal ex panson of the vessel and thereby determnes ts burstng strength Whte et al. postulated that aneurysm formaton may depend on a loss of elastn s ablty to return the aorta to a normal dameter, whereas aneu rysm growth may depend on the balance between degradaton and deposton of collagen.26 Classfcaton of Thoracc Aortc Dsease Thoracc aortc dsease conssts of a number of dfferent dsease processes, all of whch may lead to rupture and catastrophc hemorrhage. These processes nclude aneurysms, dssectons, penetratng athe rosclerotc ulcers (PAU) and ntramural hematomas (IMH). Although classfed separately, these are all

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36 Introducton Daves et al. - The Natural Hstory of Thoracc Aortc Dsease ntcr-rclated pathologes, and dstnctons between them have been made to facltate descrptons of clncal presentaton. Aneurysms TAA s smply a localzed dlataton of the thoracc aorta (Fgure 4). The natural hstory and optmal therapy of TAA var es based on the locaton and extent of the aneurysm. Therefore, Fgure 4. Computed tomography (CT) of patent wth a large aortc aneurysm. (A concomtant they arc classfed largely on the bass of locaton (Table ). dssecton s vsble n the left posteror porton of the aorta). Ascendng aortc aneurysms comprse approxmately 50% of TAA, aortc arch aneurysms 0%, and descendng and thoraco Table. Classfcaton of thoracc aortc aneurysm* abdomnal the remanng 40%.29 Ascendng aortc annulus of aortc valve to orgn of the nnomnate artery Trans\ erse aortc arch- orgn of nnomnate artery Dssecton to left subclavan artery Descendng aortc: lowest margn of left subclavan Aortc dssecton occurs when a tear n the aortc ntma artery to aortc daphragmatc hatus Thoracoabdomnal (Crawford's classfcaton) Type I and nner layer of the meda allows blood to course freely along Type II a false lumen n the outer thrd of the meda. The result s a ds proxmal descendng aorta to upper abdomnal aorta proxmal descendng aorta to below the orgn of the renal arteres Type III Dstal half of descendng aorta ex secton flap that traverses the aortc lumen, dvdng the aorta nto true and false lumna (Fgure 5 and Fgure 6). The msno- tendng nto the abdomen Type IV Most of/the entre abdomnal aorta * Adapted from a table by Ptt and Bonser. mer dssectng aortc aneurysm has been used to descrbe ths process. But n the acute settng, dlataton of the aorta does not occur. Rather, f the patent survves the acute event, gradual dlataton of the false lumen wll result." Therefore, we prefer the term aortc dssecton to ndcate the splttng of the meda by Fgure 5. A. The three layered aortc wall, the ntma (red) lnes the lumen, the ad Fgure 6. Computerzed tomography (CT) of a patent wth a ventta (yellow) forms the external layer, and the meda (pnk) sts between. B A tear classc type B aortc dssecton through the ntma allows a column of blood to splt the layers of the meda presence of both true and false lumna. Ths Note the ntmal flap and leads to the ntmal flap crossng the lumen, and dvdng t nto the true lumen (upper left) and false lumen (lower rght) 3

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38 Introducton Daves et al. - The Natural Hstory of Thoracc Aortc Dsease crculatng blood, and the term aortc aneurysm to ndcate a dla taton of the aorta. Clncally, dssectons dentfed wthn 2 weeks of the onset of symptoms are classfed as acute', subsequently they arc termed chronc. There are two classfca ton systems whch ndcate the extent of the dssecton n the aorta. The smplfed DcBakey classfca ton conssts of three types, whle the smpler and more commonly used Stanford classfcaton rec ognzes two. (Fgure 7) Fgure 7. The classfcaton of aortc dssecton. The top row shows the Stanford classfcaton, the bottom the smplfed DeBakey classfcaton Penetratng Ulcer Stanford type A ncludes any dssecton wth nvolve ment of the aorta proxmal to the left subclavan artery, (ths ncludes both DeBakey type I, whch extend the length of the aorta, and DeBakey type II, whch are confned to the proxmal aorta). Stan ford type B and DeBakey type III are equvalent categores comprsng dssectons lmted to the aorta In PAU, atheromatous dstal to the left subclavan artery Included wth the Stanford classfcaton s the ncdence of ntmal tears n each regon of the aorta based on autopsy studes. Adapted from a dagram by Ergn and Grepp.30 plaques ulcerate and dsrupt the nternal elastc lamna. The ulcer then penetrates through the ntma nto the aortc meda.3 (Fgure 8). Although ths may precptate a localzed ntramedal ds secton, n contrast to classcal aortc dssecton, ths localzed process s lmted by areas of severe calcfcaton assocated Fgure 8. Dagram of PAU. A. An atherosclerotc plaque penetrates through the wth the locally advanced atherosclerotc ntma nto the meda. B Wth tme, an ntramural hematoma may form, but t wll be lmted n extent by fbrotc and calcfed tssue. dsease.3435 The natural hstory and optmal 4

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40 Introducton Daves et al. - The Natural Hstory of Thoracc Aortc Dsease treatment of PAU s only now begnnng to be ex plored36 as better magng teehnques (ncludng MRI. Fgure 9) allow for non-operatve dagnoss. Intramural Hematoma Whereas classcal aortc dssectons are thought to begn wth a tear whch allows blood to dssect rapdly along a plane n the outer thrd of an ntrnscally dseased meda, IMH s thought to oc cur followng rupture of the vasa vasorum n the aortc wall.34 Ths was frst descrbed n 920 by Krukenberg as a dssecton wthout ntmal tear. A dagrammatc representaton of IMH can be seen n Fgure 0, and Fgure II shows the appearance of IMH on transthoracc echocardogram. The rela tonshp between IMH, PAU, and classcal dssecton has not been establshed. They may n fact le on a contnuum wth dssecton, and much Fgure 9. A MR mage (sagttal vew) of a patent wth a penetratng atherosclerotc ulcer. The penetratng atherosclerotc ulcer s dagnosed by work remans to clarfy ther pathophysology, natu- Fgure 0. Dagram of IMH vsualzaton of a dstnct ulcer crater n the absence of an ntmal Hap or false lumen B MR mage (axal vew) of a patent wth a penetratng atherosclerotc ulcer Blood n the meda (possbly secondary to a rupture of the vasa vasorum leads to a concentrc hematoma wthout ntmal tear Fgure. Transthoracc echocardogram (TEE) of a patent wth an ntramural hematoma Note the absence of ntmal dsrupton or penetratng atherosclerotc ulcer. 5

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42 Daves et al. The Natural Hstory of Thoraac Aoruc Dsease Introducton ral hstory, and relatonshp to classcal dssecton.34 Famlal Aggregaton Because ths paper examnes famlal aggregaton as a rsk factor for complcatons n thoracc aortc dsease, and no standardzed termnology exsts for the varous types of aggregaton descrbed n the lterature, t s mportant to defne the use of some terms. Patents wth the dagnoss of MFS, MFS-related syndromes, or other nherted systemc dseases of the connectve tssue are referred to as syndromc pa tents. Those patents wthout such a hstory, but whose famles do llustrate famlal aggregaton or clusterng' of dsease are termed non-syndromc famlal aggregaton or non-mfs-related famlal aggre gaton (abbrevated throughout ths paper as nmfs famlal), because n thoracc aortc dsease MFS s the predomnant nherted syndrome nvolvng a connectve tssue defect. Those patents wthout any evdence of famlal aggregaton are termed sporadc. Thoracc Aortc Aneurysms Hstory Arteral aneurysms have been recognzed snce at least the 2nd century AD, when Galen (Fgure 2) s credted wth the frst descrpton. At the tme, he recognzed the catastrophc mplcatons of aneurysm rupture, notng. f an aneursm be wounded, the blood s spouted out wth so much volence that t can scarcely be arrested. 37 The great anatomst Vesalus s credted wth the frst correct clncal dagnoss, n 557,37 Snce then, speculaton as to the cause or causes of aneurysm have contnued unabated; unfortunately, almost 450 years later, they reman to a large extent unclear. Fgure 2. Early depcton of Gaen. Courtesy Cushng/Whtney Medcal Lbrary at Yale Unversty, Hstorcal Lbrary. Dfferent studes wll defne famlal aggregaton dfferently, for example, they may nclude famles wth a hstory of sudden death, but wthout confrmed aortc dsease, or they may nclude any famly member or restrct t to frst-degree famly members. Our def nton wll be explaned below n the Methods secton. The defnton used n other studes wll be noted where approprate. 6

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44 Daves et al The Natural Hstory of Thoracc Aortc Dsease Introducton Much of what we do know about thoracc aortc aneurysms (TAA) has been extrapolated from studes of abdomnal aortc aneurysms (AAA); less scentfc evdence s avalable on TAA. Whle the known rsk factors descrbed n the abdomnal aorta are probably mportant n the thorax, dfferences be tween AAA and TAA necesstate a complete understandng of TAA ndependent of abdomnal dsease. Etology Normal vessel wall bology nvolves a balance between the dstendng forces placed on the aorta by the flow of blood under pressure and the ablty of the aorta (through the structural ntegrty of the aortc wall) to resst dlataton and elastcally rebound when the pressure pulse of each cardac systole has passed. Therefore, factors whch ether () decrease the ablty of the aorta to resst dstenton or, (2) ncrease the dstendng forces would be expected to result n aneurysmal dlataton. In aortas weakened by processes such as genetc defects, atheroscleross or nflammaton,38"0 normal agng,4,42 prolonged hypertenson,35 or cgarette smokng,43"7 factors ncreasng the load on the aorta may ncrease the rsk of aneurysmal dlata ton. These factors nclude hypertenson,48'52 the process of dlataton tself, and the locaton of the weakenng along the course of the aorta. Thus, the etology of aortc dsease nvolves a complex nterplay between a varety of factors contrbutng to weakness of the arteral wall and ncreased aortc wall pres sure.53 Natural Hstory Epdemology: Incdence and Prevalence Because aortc aneurysms are a frequently slent dsease, precse estmates of ncdence and prevalence have been dffcult to obtan. Changes n the ncdence and prevalence due to changng dsease patterns have further complcated the matter.50,54,55 The most recent evdence suggests that the ncdence of TAA s approxmately 5.9 per 00,000 patent-years.29 Ths s consstent wth publshed autopsy rates of 437 per 00,000 n women and 489 per 00,000 n men.56 Tradtonally the ncdence has been thought to be hgher n men than women;57'59 however, ths lkely reflects the greater number of men seen n a referral populaton and possbly a hgher rate of recog nzed syphltc aneurysms n men, rather than a true dfference n the occurrence of aneurysms n the two sexes. 29 7

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46 Daves et al. - The Natural Hstory of Thoracc Aortc Dsease Introducton Growth Rates of Thoracc Aortc Aneurysms One mght expect that the calculaton of aortc growth rates s a smple process. Smply take the last sze measurement (S;), subtract the frst sze measurement (Sf) and then dvde by the tme nterval (7) between them: Equaton. Tradtonal growth rate formula Gr = S-Sf T However, that method s hghly subject to measurement error, especally when the tme between studes s short. In order to account for measurement error, some groups truncate negatve growth rates to zero; others exclude them from analyss. These dvergent methods may explan some of the varaton n ther results. In studes of descendng and thoraco-abdomnal aortc aneurysms, growth rates have vared from 0.2 cm/yr60 to 0.32 cm/yr6. The varaton among growth rates when all stes are measured together s even hgher: 0.0 cm/yr62 to 0.42 cm/yr63. Despte the dspartes n the exact rates, some consensus exsts as to whch factors are assocated wth hgher relatve rates. Chronc obstructve pulmonary dsease (COPD) has been assocated wth faster growth rates n multple studes.5-60 The reason for ths assocaton s not clear. Although one mght pos tulate that t reflects dfferences n smokng behavor,6 or genetc dfferences n susceptblty to connectve tssue dsease leadng to both ncreased rsk of COPD and ncreased aneurysm expanson rates.60 Alterna tvely, thoracc physology and mechancs, whch undergo sgnfcant changes n patents wth COPD, may nfluence the expanson rate n these patents. Intal aortc sze greater than 5 cm has been assocated wth hgher relatve growth rates,664 as has the presence of renal falure64. Interestngly, as noted above, a hstory of hypertenson has not been found to be assocated wth ether faster growth rates or an ncreased susceptblty to rupture.6 65 The only ex cepton to ths, the study by Masuda et al.,64 measured dastolc blood pressure rather than examnng a hstory of hypertenson. Ths supports the dea that adequate treatment of hypertenson mtgates the po tentally ncreased rsk assocated wth a hstory of such dsease; follow-up wth seral blood pressure measurements s the only way to clarfy the relatonshp. Fnally, the presence of chronc dssecton has

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48 Daves et al. - The Natural Hstory of Thoraac Aortc Dsease Introducton been dentfed as a predctor of hgher growth rates n our prevous work;66 however, ths has not been shown unversally.6 Complcatons: Rupture and Dssecton The man complcatons assocated wth aneurysms are rupture and dssecton, ether of whch may result n subsequent death. As noted above the slent nature of TAA has made epdemologcal char acterzaton of the dsease dffcult. In addton, the hgh mortalty rates and the selecton of patents for surgery lead to several sources of bas n studes of predctors of complcatons. Few groups have at tempted systematc statstcal analyss of rsk factors for complcatons n TAA to enable the optmal selecton of patents for surgcal extrpaton of ther aneurysm. Learnng from Abdomnal Aortc Aneurysms Research nto the complcatons of AAA has provded some nsghts nto the behavor of aortc aneurysms. However, gven the dfferences between the dseases, extrapolaton of those results to TAA should be done cautously, especally snce surgery for the thoracc aorta carres sgnfcantly dfferent rsks than surgery of the abdomnal aorta. Tradtonally, sze has been the best predctor of AAA rupture.67,68 Szlagy showed that the natu ral (unoperated) hstory of AAAs > 6 cm had 5 year survval of only 6%, compared wth survval of 48% n those wth smaller aneurysms.69 Hypertenson and COPD are ndependently predctve of hgher rupture rates.68,70 7 Because the ncdence of COPD s so ntertwned wth the prevalence of tobacco use, t has been dffcult to separate the nfluence of the two factors.72 But, n studes whch have examned both to bacco use and COPD, COPD has consstently been the stronger predctor.68 7 The mpact of hgher expanson rates on rupture rsk has smlarly been dffcult to separate from the related ncrease n absolute aortc dameter. Some studes have found both to be predctve, whle oth ers have not.68 Dr. Cronenwett succnctly summarzes the dffculty n obtanng a full understandng of the natural hstory of aortc dsease: It would requre... a large seres of patents wth comparably szed AAAs but dfferent expanson rates.followed wthout nterventon, to determne whether expanson rate per se, or only fnal AAA sze s an ndependent predctor of rupture. Unfortunately, these results are not avalable. 68 9

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50 Introducton Daves et al. - The Natural Hstory of Thoracc Aortc Dsease Thoracc Aortc Aneurysms Untl recently, most of our knowledge of the natural behavor of TAA (outsde of what we have learned from analyss of AAA) was derved from a small number of observatonal studes, and some popu laton studes. The frst systematc nvestgaton of TAA was done by Boyd n 924 Whle ths study descrbed the consequences of rupture, t made no effort to examne rsk factors for rupture. Populaton studes have revealed an ncdence of ruptured TAA of approxmately 5 per 00,000 populaton.74 Cumula tve rsks for patents wth TAA are substantal: Bckerstaff, et al.29 reported a cumulatve rupture rate of 5% for aneurysms wthout dssecton. Mortalty followng rupture was a devastatng 94%. Subsequent work by Kampmeer suggested that arch aneurysms have a worse prognoss,75 but no other attempt to de lneate groups at ncreased rsk was attempted. Whle many of these studes followed large populatons, they dd not attempt to use detaled statstcal analyses to understand predctve factors for rupture and thereby establsh crtera for surgcal nterventon. More recently, Presslcr and McNamara followed a group of 260 patents and looked at the tmng of rupture.57 Late rupture (more than three days followng dagnoss or onset of symptoms) accounts for 9% of TAA rupture, and 68% of TAA ruptures occurred more than one month after dagnoss.57 Rupture accounted for 44% of deaths n ther seres.57 However, of these studes addressed the mportant queston of whch patents were at hghest rsk for early rupture. Prevous work n our group showed that hgh ntal aortc sze was hghly predctve of rupture and dssecton.66 In the ascendng Hnge pont at 7 cm *- I «50 aorta, the odds of ncurrng rupture (/) c c or dssecton wth aneurysms of 6.0 to 6.9 cm was 4.27 tmes that for «40 c/) co (0 o 0) o c E 30 o C aneurysms of 4.0 to 4.9 cm. In de $ c scendng aortas, a smlar Desc/TA <D S3 O (0 u -Q 0 O Q. L. Q. phenomenon occurred for the 7.0 to 7.9 cm range (ndcatng ther lower -% 4 5 / 6 Aneurysm sze (cm) propensty for rupture). We dent fed dramatc hnge ponts n the Asc/arch «5 o Q. 20 Fgure 3. Estmated effect of aneurysm sze on rsk of complcaton (rupture or dssecton) for ascendng/arch and descendng/thoraco-abdomnal aneurysm locaton. Adapted from Coady et al.66 0

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52 Daves et al. - The Natural Hstory of Thoraac Aortc Dsease Introducton ncdence of complcatons at these sze ranges (Fgure 3). However, separate analyses were not per formed to dentfy other rsk factors for ether rupture or dssecton. Furthermore, ths data provded a statc snap-shot" of rsk and faled to examne the rsk of complcatons over tme, so that a patent followed for one month who ruptured had the same mpact on the analyss as a patent who ruptured followng a fveyear follow-up. The group at Mount Sna Equaton 2. Gnepp s formula for predcton of rupture wthn one year of sze measurement led by Dr. Grepp has publshed de Probablty of rupture wthn year = -e ^j65) taled analyses of the ncdence of where In A = (age) (pan) {COPD) rupture n patents wth descendng or thoraco-abdomnal aneurysms (descendng dameter, cm) (ascendng dameter, cm) Usng a logstc regresson analyss they were able to provde a multvarable equaton to enable the predc ton of rupture wthn one-year based on specfc patents characterstcs (Equaton 2). However, thenanalyss was lmted to aneurysms of the descendng aorta, and ther work dd not analyze the ncdence over tme but nstead looked at ncdence wthn a set tme perod. Intutvely, one would expect that hypertenson would ncrease the rsk of rupture and dssecton, but that has not been demonstrated n any studes.65,66 Ths may be due to the fact that patents wth dent fed aneurysms tend to be treated medcally wth (3-blockade, thereby mnmzng the effect of a hstory of hypertenson.65 Ths possblty s supported by the fact that although hypertenson predcts hgher ntal aortc szes,6 t does not predct hgher growth rates n most seres.6,66 (A study by Masuda, et al76 s one excepton). Juvonen and assocates dentfed chronc obstructve pulmonary dsease (COPD) as the rsk factor most predctve of rupture.65 Ths s consstent wth studes of AAA as descrbed above. Growth rates measurements have been hghly varable (see Growth Rates on page 8). So t s not surprsng that examnaton of growth rates as a rsk factor for rupture has been nconsstent. Some studes have correlated hgher growth rates wth rupture,6 but others have not been able to demonstrate a smlar assocaton.60 It s mportant to note that complcatons other than rupture or dssecton may occur n these pa tents. These less catastrophc complcatons nclude aortc regurgtaton whch may occur n ascendng t

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54 Daves et al. The Natural Hstory of Thoracc Aortc Dsease Introducton aneurysms,77 hoarseness due to compresson of the recurrent laryngeal nerve by aortc arch aneurysms, and dysphaga or dyspnea due to pressure on the esophagus or trachea.73'75 Mortalty Despte ther rarty, aortc aneurysms (both AAA and TAA) are the 3th most common cause of death n the Unted States, and ther prevalence appears to be ncreasng,78'79 Overall 5-year survval n patents wth TAA s only 56%.80 In 964, Joyce, et al. demonstrated that patents wth aneurysms less than 6.0 cm n dameter had a 5-year survval rate of 6%, whle those wth aneurysms larger than 6.0 cm had a 5-year survval rate of only 38%.59 Snce then, lttle work has further delneated nsk factors predctve of mortalty n ths populaton, and no further examnaton of the predctve power of aortc sze on mortalty has been done (probably because of the large sample szes and detaled follow-up requred). Mortalty n these patents may be attrbuted to both dssecton and rupture.8'83 Our prevous work has shown that survval s sgnfcantly worse n patents wth descendng or thoraco-abdomnal aortc aneurysms (39% at 5 years) than n aneurysms of the ascendng aorta or aortc arch (77%,p ^.(Bl).66 In addton patents wth a concomtant dssecton have poor long-term prognoss ndependent of aneurysm locaton (46% at 5 years).84 Symptomatc aneurysms also have poor prognoss when compared to asymptomatc dsease (5 year survval 26.9% versus 58.3%).84 Treatment Advances n the surgcal treatment of thoracc aortc dsease have led to sgnfcantly mproved early and late results n recent years. However, surgcal repar of the thoracc aorta stll carres sgnfcant rsk. Because aortc aneurysms are often asymptomatc untl rupture or dssecton, dentfyng those pa tents who are at rsk for complcatons s central to optmal surgcal therapy. Operate early on patents at low rsk and the rsk of complcatons may not justfy the rsk of surgery, but operate too late and rupture or dssecton may occur, necesstatng an emergent nterventon wth hgher morbdty and mortalty. Some patents clearly requre surgcal nterventon, ncludng those wth Type A dssectons, those who are symptomatc, and those wth rapdly enlargng aortas. However, a substantal porton of patents lack these ndcatons for surgery but reman at rsk for serous complcatons. Identfyng those patents at hghest rsk remans a sgnfcant challenge. 2

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56 Daves et al. The Natural Hstory of Thoracc Aortc Dsease Introducton Rupture occurs n 32% to 68% of patents not treated surgcally, and -, 3-, and 5-year survval estmates for patents not undergong surgcal repar are approxmately 65%, 36%, and 20% respec tvely.29,57 85 In contrast, mortalty from electve repar at experenced centers may be as low as 2%, although estmates range as hgh as 9%.66,86 The hgh mortalty rate (up to 2%)66 from emergent proce dures renforces the need to dentfy patents at rsk for rupture and operate sooner and electvely. For patents not consdered good operatve canddates, the optons for medcal therapy are lmted. Currently, (3-blockade s the manstay of medcal treatment. It s thought to exert benefcal effect through a reducton n pulse-pressure, mean pressure, and heart rate.87 Although t has been shown to reduce the rate of aortc root dlataton and the development of aortc complcatons n patents wth Marfan syn drome,88 ts use n non-mfs patents has recently come under sgnfcant scrutny because of ts effects on vascular wall complance. The Inhertance of Thoracc Aortc Dsease Marfan Syndrome and Inherted Connectve Tssue Dsease Systemc dsorders of connectve tssue protens, such as Marfan syndrome (MFS) and EhlersDanlos syndrome type IV (EDS-TV, resultng from defectve synthess of type III collagen), are known causes of domnantly nherted aortc dsease. In the case of MFS, 99 dfferent mutatons n the fbrlln- gene (FBN) have been dentfed n patents wth MFS and Marfan-related syndromes.89 Patents wth MFS and related syndromes present wth a varety of connectve tssue symptoms, ncludng skeletal man festatons,90,9 ocular manfestatons,90 and cardovascular manfestatons (especally aortc root enlargement and Type A dssectons) To date, no genotype-phenotype correlaton between the physcal locaton of the genetc defect and the systemc manfestatons of dsease has been dentfed.93 In MFS, mutatons n FBN cause abnormaltes n the synthess and extracellular deposton of f brlln. Patents wth decreased amounts of deposted fbrlln- have more severe cardac complcatons and undergo aortc surgery at an earler age.94 The pathogeness of the mutant FBN gene to be of the domnant negatve type, where the phenotypc expresson depends on the presence of the mutant fbrlln- rather than decreased concentraton of wld-type proten.95'97 Addtonally, the mutant-type proten may 3

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58 Introducton Daves et al - The Natural Hstory of Thoraac Aortc Dsease dsturb aortc wall homeostass n the adventtal layer.0 Further work must be done to defne the precse relatonshp between defectve fbrlln synthess and aortc dlataton. Famlal Inhertance n Patents wthout Systemc Connectve Tssue Dsease Famlal aggregaton of AAA n patents wthout known heredtary connectve tssue dsorders, was notced as early as Subsequently, Tlson and colleagues descrbed 50 famles n whch more than one ndvdual had been dagnosed wth AAA.99'0 Further work demonstrated that 9% to 33% of patents wth AAA had a famly member who also had clncally dagnosed dsease.0 l0? Famlal aggregaton of aneurysms and dssectons n 0T0 patents wth thoracc aortc dsease was noted as early as 967,05 but further case studes were not added untl after the ncreased nterest n famlal AAA (Fgure 4).04 '06 Bddnger Ot4m=] 0 O & (!) 6 h et al. went further and n a case-control study, examned the prevalence of thoracc aortc dsease (TAA, aortc dssecton, and sudden death) n probands wth dsease compared to the Fgure 4. Pedgree of a famly demonstratng aggrega ton of thoracc aortc dsease dentfed by Ncod, et al!m Crcles represent women and squares men. Affected members are represented by black crcles or squares. Possbly affected members are represented by grey crcles or squares. Dagonal bars ndcate deceased members. famles of ther healthy spouses.07 The relatve rsk for tho racc aortc dsease n the famles of probands ranged from.8 to 0 for ssters and brothers respectvely. More recently, research groups have begun to examne these patents for molecular and genetc defects. Two separate groups have dentfed patents n whom dsease can be attrbuted to mutatons n FBN, the same gene mplcated n MFS Thus mutatons n FBN can cause a range of phenotypc dsease from solated aortc dsease to systemc MFS: agan no genotype-phenotype correlaton has been postulated. Less clear was whether or not other genes mght be responsble for non-mfs-related famlal aggregaton; especally snce these two reports examned a total of only three probands. Impact of Famlal Aggregaton on Natural Hstory The natural hstory of aneurysms due to MFS and MFS-related dsorders reveals poor long-term prognoss n these patents. In 972, mean age at death was 32 years, but by 993 t was 4 years, and me dan expected survval n the lvng populaton had ncreased from 48 to 72 years.' '0J'' However, patents wth MFS are more lkely to have aortc regurgtaton n assocaton wth ascendng aneurysms than pa- 4

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60 Daves et al. - The Natural Hstory of Thoracc Aortc Dsease tents wthout hypertenson.2 Introducton Also, despte mproved survval, patents wth MFS contnue to requre repeat aortc surgery at hgher rates (25% versus 0% for non-mfs-related aneurysms).2 Because of small sample szes, the natural hstory of aortc dsease n patents wth nmfs famlal dsease as compared to sporadc cases has not been adequately assessed. Bddnger et al. have performed the only analyss for thoracc aortc dsease. They noted that there was no statstcally sgnfcant dfference n the ncdence of hypertenson n the probands versus ther spouses/controls; however, the controls were unaffected ndvduals, not ndvduals wth sporadc aortc dsease.07 More substantal work has been done examnng the mpact of famly hstory on the course of dsease n AAA.034 Darlng et al., found that patents wth famlal AAA and a female famly member wth an aneurysm had an ncreased rsk of rupture (63% versus 37%,p < 0.05).3 They used the term black wdow syndrome to descrbe ths n creased rsk. On the other hand, there was no dfference between the patents wth sporadc and famlal AAA n terms of anatomc extent of dsease, multplcty of aneurysms, or assocated occlusve dsease. 5

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62 Statement of Purpose Daves et al The Natural Hstory of Thoracc Aortc Dsease STATEMENT OF PURPOSE Thoracc aortc dsease conssts of four enttes: aneurysm, dssecton, PAU and IMH, all of whch have hgh mortalty and morbdty rates. On the other hand, surgcal repar of the aorta, partcularly regons wth branch vessels to the bran or spnal cord s dffcult, and t carres substantal rsk of paraplega, stroke and death. Therefore, n order to provde realstc prognostc nformaton, gude the tmng of surgery, and ultmately mprove the outcome n these patents, detaled knowledge of the rsk factors assocated wth poor outcomes both wth and wthout surgery s requred. Heretofore, anecdotal evdence has been the manstay of lterature on dseases of the thoracc aorta. Thus, despte detaled knowledge of the hstopathology assocated wth aneurysm and dssecton, the etologc events leadng to aneurysmal dlataton n some people and dssecton n others despte pathologc fndngs smlar to healthy controls reman unknown. Instead, successve authors have postulated dfferent theores whch have been dffcult to substantate expermentally and unhelpful n establshng hgh-rsk groups for complcatons (outsde of the comparatve rsk assocated wth type A versus type B dssec tons). Despte an extensve lterature examnng autopsy fndngs, descrbng technques for surgcal re par and reportng post-operatve outcomes, lttle lterature has focused on the queston of whch patents mert surgery and when. Small sample szes and early selecton for surgery have mtgated the statstcal power of most seres. Our group has publshed a frequently cted report66 examnng sze as a rsk factor for complcatons, but even ths paper examnng 230 patents lacked the statstcal power to look at com plcaton rsk over tme. Some rsk factors, ncludng the mpact of a famly hstory, were also gnored. The group led by Dr. Grepp at Mount Sna have publshed the only prospectve examnaton of rupture,65 but t was lmted to patents wth descendng and thoraco-abdomnal aneurysm, and dd not address those patents wth ascendng or arch aneurysms. Gven the apparent dfferences between the behavor of aortc dsease n patents wth MFS and n those wthout syndromc famly hstory,66 non-syndromc patents wth a famly hstory may also be at hgher rsk for rupture. Although famly hstory of AAA has been extensvely examned, lttle s known about non-syndromc famly hstory n TAA, and ts mpact on outcome has not been assessed. 6