Characteristics and Outcomes of Ascending Versus Descending Thoracic Aortic Aneurysms

Accepted Manuscript Characteristics and Outcomes of Ascending versus Descending Thoracic Aortic Aneurysms Joshua S. Vapnik, BA, Joon Bum Kim, MD, PhD, Eric M. Isselbacher, MD, Brian B. Ghoshhajra, MD, Yisha Cheng, BA, Thoralf M. Sundt, III, MD, Thomas E. MacGillivray, MD, Richard P. Cambria, MD, Mark E. Lindsay, MD, PhD PII:

S0002-9149(16)30308-3

DOI:

10.1016/j.amjcard.2016.02.048

Reference:

AJC 21738

To appear in:

The American Journal of Cardiology

Received Date: 28 October 2015 Revised Date:

7 February 2016

Accepted Date: 16 February 2016

Please cite this article as: Vapnik JS, Kim JB, Isselbacher EM, Ghoshhajra BB, Cheng Y, Sundt III TM, MacGillivray TE, Cambria RP, Lindsay ME, Characteristics and Outcomes of Ascending versus Descending Thoracic Aortic Aneurysms, The American Journal of Cardiology (2016), doi: 10.1016/ j.amjcard.2016.02.048. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Characteristics and Outcomes of Ascending versus Descending Thoracic Aortic Aneurysms

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Joshua S. Vapnik BAa,b,*, Joon Bum Kim MD, PhDa,c,f,* , Eric M. Isselbacher MDa,b, Brian B. Ghoshhajra MDe, Yisha Cheng, BAa,b, Thoralf M. Sundt III MDa,c, Thomas E. MacGillivray MDa,c ,

* These authors contributed equally to this work a

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Richard P. Cambria MDa,d, and Mark E. Lindsay MD, PhDa,b,#

Massachusetts General Hospital Thoracic Aortic Center and the Divisions of bCardiology,

Cardiac Surgery, dVascular and Endovascular Surgery, and eRadiology, Harvard Medical

School, Boston, Massachusetts, USA; f

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c

Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, University of Ulsan

College of Medicine, Seoul, South Korea #

Mark E. Lindsay, MD, PhD

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Corresponding Author:

Simches Research Building

Boston, MA 02214 (P) 617-643-3458

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185 Cambridge Street, Room 3224

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[email protected]

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Abstract: Thoracic aortic aneurysms (TAs) occur in reproducible patterns, but etiologic factors determining the anatomic distribution of these aneurysms are not well understood. This study

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sought to gain insight into etiologic differences and clinical outcomes associated with repetitive anatomic distributions of TAs. From 3,247 patients registered in an institutional Thoracic Aortic Center database from July 1992 through August 2013, we identified 844 patients with full aortic

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dimensional imaging by computerized axial tomography (CT) or magnetic resonance imaging (MRI) scan (mean age 62.8 ± 14 years, 37% female, median follow-up 40 months) with TA

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diameter > 4.0 cm and without evidence of prior aortic dissection. Patient demographic and imaging data was analyzed in three groups: isolated ascending aortic aneurysms (AAs) (n=628), isolated descending thoracic aortic aneurysms (DTAs) (n=130), and combined AA and DTA (mixed thoracic aortic aneurysm, MTA) (n=86). Patients with DTA had more hypertension (82% vs. 59%, p<0.001) and a higher burden of atherosclerosis (88% vs. 9%, p<0.001) than

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AA. Conversely, patients with isolated AA were younger (59.5 ± 13.5 years vs. 71.0 ± 11.8 years, p<0.001) and contained almost every case of overt, genetically-triggered TA. Patients with isolated DTA were demographically indistinguishable from patients with MTA. In follow up,

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patients with DTA/MTA experienced more aortic events (aortic dissection/rupture) and had higher mortality than patients with isolated AA. In multivariate analysis aneurysm size (OR [1.1],

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95% CI [1.07-1.16], p<0.001) and the presence of atherosclerosis (OR [5.7], 95% CI [2.0216.15], p<0.001) independently predicted adverse aortic events. We find that DTA with or without associated AA appears to be a disease more highly associated with atherosclerosis, hypertension, and advanced age. In contrast, isolated AA appears to be a clinically distinct entity with a higher burden of genetically triggered disease.

Key Words: Thoracic Aortic Aneurysm, Aortic Dissection, Atherosclerosis

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Introduction: Aneurysms of the aorta occur in repetitive anatomic patterns. Divergent etiologies

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between anatomic categories of aortic aneurysm have been suggested based on comparison between thoracic aortic aneurysms (TAs) and abdominal aortic aneurysms (AAAs). Over the last century, the ratio of TAs to AAAs in population-based studies has declined, suggesting separable risk factors1, 2. Since these initial studies, the divergence of etiologic factors has been

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more convincingly demonstrated. For example, using a cohort of 341 patients referred for aneurysm surgery, Ito and coworkers elegantly demonstrated a clear enrichment of

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dyslipidemia, atherosclerosis, and coronary artery disease in patients with AAA versus a combinatorial group of TA3. In contrast, differences between aneurysms within the thorax have received less attention. Although expert opinion has held that ascending thoracic aortic aneurysms (AAs) and descending thoracic aortic aneurysms (DTAs) likely have different

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etiologies, there has been scant experimental evidence to support these conclusions4, 5. This study aims to evaluate the differences in patient characteristics and outcomes among three groups of patients: those with isolated AAs, those with isolated DTAs, and those with both AA

Methods:

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and DTA or mixed aneurysms (MTA).

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Patients treated in the Thoracic Aortic Center at Massachusetts General Hospital are

prospectively registered in our institutional database, which records baseline patient characteristics, aortic interventions, and follow-up outcomes. We identified 3,247 adult patients (age ≥17 years) with TA who were diagnosed from July 1992 through August 2013. We searched for computed tomography (CT) or magnetic resonance imaging (MRI) of the aorta. Aortic diameters were measured at ascending, arch, descending thoracic, and thoracoabdominal segments of the aorta. Diameters were recorded for analyses if ≥ 40 mm.

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Patients were excluded if they had no thoracic aortic segment with a diameter of ≥ 40 mm or if there was evidence of preexisting aortic dissection, aortic repair, intramural hematoma, or aortitis.

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Patient groups were assigned by the location of maximal aortic dimension. The ascending thoracic aorta was defined as the segment between the aortic valve and the right brachiocephalic artery (i.e., both the aortic root and tubular portion of the ascending aorta). The

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descending aorta was defined as the segment between the ostium of the left subclavian artery and the diaphragm. The AA group was defined as those with an ascending aortic diameter ≥ 40

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mm but no other segment ≥ 40 mm. The DTA group was defined as those with a descending aortic diameter ≥ 40 mm but no other segment ≥ 40 mm. The MTA group was defined as those with both ascending and descending aortic diameters of ≥ 40 mm. Isolated aneurysm of the aortic arch was excluded from analysis.

Aortic aneurysms secondary to overtly identifiable genetic influence including BAV associated

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TA and TGFβ vasculopathies6, such as MFS or Loeys-Dietz syndrome (LDS), were identified by examination of the medical records. The primary endpoint was defined as a composite of adverse aortic events that include acute aortic dissection, rupture, and sudden death not

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explained by causes other than aortic diseases. Kaplan-Meier estimate of potential follow-up (KM-PF) (median follow up) of the cohort (40 months) was determined as previously described7.

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Patients who underwent elective aortic surgery before the aortic events or who died of causes other than aortic disease were regarded as censored at the time of such events. Abdominal aortic aneurysm (AAA) was defined as an infrarenal aortic diameter of ≥ 40 mm. Aortas were examined for mural atheroma (significant luminal irregularity) or mural calcification. Patients were designated as having aortic atherosclerosis if
significant luminal irregularity or calcifications were identified in the aortic wall on these studies.

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R statistical software, version 3.1.2. was used for statistical analyses. Categorical variables were presented as frequencies and percentages, and continuous variables were expressed as mean ± SD. Demographic variables were analyzed with Students t-test or Anova,

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as appropriate. Kaplan–Meier curves were plotted to display conditional probability of adverse aortic events and Log-rank tests were used to compare between-group differences in the rates. To determine independent risk factors of adverse aortic events, the Cox-proportional hazards

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models were used. Variables with a P value of ≤0.20 in univariable analyses were candidates for the multivariable Cox models, which involved a stepwise backward elimination technique and

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only variables with a p value of <0.10 were used in the final model. All reported P values were 2-sided, and a value of P<0.05 was considered statistically significant.

Results:

The study strategy is illustrated in Figure 1. Full aortic imaging was available on 844

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patients with no evidence of aortic dissection, intramural hematoma, or aortitis. The total study group was divided based on pattern of aneurysm location. Table 1 displays baseline demographics and clinical characteristics for all patients. Interestingly, patients with MTA were

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almost indistinguishable from DTA, while AA patients showed distinct differences from DTA and MTA in almost all examined categories. Compared to DTA, patients with AA were younger, less

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likely to be female, and less likely to have diabetes mellitus, hypertension, and a history of smoking. These differences were reflected in significantly higher rates of antihypertensive medication use in the DTA group (Table 1s). History of prior CABG was less common in the AA group than in the DTA or MTA groups. TGFβ vasculopathies and BAVs were markedly enriched in the AA group versus either the DTA or MTA groups. It has been hypothesized that patients with genetically-triggered aortic disease may be identified earlier than those with sporadic disease based on either anthropomorphic manifestations (e.g., as seen in MFS) or physical exam findings such as a heart murmur (e.g., as with BAV). To determine if the observed 5

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demographic differences in patient groups were attributable to the influence of overtly identifiable genetically-triggered disease and early referral we reanalyzed the groups excluding the diagnosis of BAV and TGFβ vasculopathies. Interestingly, differences in age, as well as in

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rates of diabetes mellitus, hypertension, and CABG remained statistically significant after censor of these diagnoses (Table 2). Since the demographics of MTA and DTA patients were

essentially indistinguishable, these groups were combined for further analysis into a single

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DTA/MTA group (Figure 1).

We next examined the aneurysm characteristics on CT and MRI to determine whether

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distinctions could be made between groups (Table 3). There was a dramatically higher prevalence of atheroma and aortic calcium in the DTA/MTA group compared with the AA group. In general, maximal aortic diameters were larger in patients with DTA/MTA than AA (Table 3 and Figure 2). To determine if the imaging and demographic differences we have observed were more closely related to aneurysm size instead of anatomic location, we analyzed variables

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in tertiles according to aneurysm diameter. The observed demographic differences (Table 1) were found to persist regardless of aneurysm size tertile (Table 2s). Given that those with TAs are at risk of aortic dissection, aortic rupture, aortic repair, and

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death, we analyzed study groups with respect to occurrence of these adverse events (Tables 4 & 5). Aortic repair occurred more than twice as often among those with DTA/MTA than those

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with AA (Figure 3A), with more than half the DTA/MTA patients having undergone aortic repair within 5 years (Figure 3, panel A). All cause mortality was also significant greater in the DTA/MTA group compared with the AA group (Figure 3, panel B). Overall adverse aortic event rates were similarly significantly higher in the DTA/MTA vs.

the AA groups (Table 5), with the Kaplan-Meier curves separating as early as one year of follow-up (Figure 3, panels C and D). Of acute aortic syndromes, those in the AA group suffered exclusively type A aortic dissection, whereas those in the DTA group suffered exclusively type B aortic dissection. Interestingly, patients with MTA suffered only type B aortic dissection. Table 6 6

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summarizes the univariable and multivariable risk factor analyses of adverse aortic events based on aneurysm distribution. On multivariable analyses, maximal aortic diameter (HR 1.12) and atherosclerosis (atheroma +/- aortic calcium) (HR 5.7) emerged as significant independent

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predictors of aortic events. Freedom from aortic events vs. these risk factors is depicted in Figure 4.

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Discussion

Regional differences in aortic structure and function have been recognized for some time, and the susceptibility of the abdominal aorta for degenerative aneurysm is well

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recognized2, 8. Demographic differences between patients with different TA distributions have not been systemically examined. Some information has come indirectly from observations in thoracic aortic dissection (rather than TA), where patients with type B aortic dissection are known to be older and have more hypertension than patients with type A aortic dissection9.

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Many aortic dissections occur in the absence of TA10, 11, making these observations difficult to translate to aneurysm patients. Descending aortic aneurysms have been described to have worse late outcomes, but these observations were from older studies that did not define the

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extent of thoracic aortic aneurysmal involvement12. The ubiquity of thoracic CT or MRI imaging in the modern era allows for the full characterization of aneurysmal distribution during routine

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clinical care of most patients with aortic disease. This study endeavored to analyze differences between patient populations representing different anatomic distributions of TA. We report that patients with a DTA are older, more hypertensive, more likely to have atherosclerotic aneurysms, and less likely to have overt genetically-triggered conditions than their AA counterparts (Figure 5). The profile of our cohort shows that atherosclerotic burden is heavily skewed towards DTA and MTA patient groups. Significantly more patients in the DTA and MTA cohorts were identified as atherosclerotic on imaging and had a higher burden of CABG and AAA. These data

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resemble the pattern seen in aneurysm patients who show significant skewing of atherosclerotic phenotypes in AAA versus TA patients3. Interestingly, there is a female enrichment in the DTA group versus either the AA group in our study (Table 1) or typical AAA cohorts. This

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phenomenon has been previously observed in AAA cohorts13 and the etiology for this skewing remains unknown. The abdominal aorta has been known to express susceptibility to

atherosclerosis, demonstrated elegantly by classical experiments in canines14, 15 and the descending thoracic aorta is known to exhibit a higher atherosclerotic burden than the

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ascending thoracic aorta in the absence of aneurysm16. These differences may be driven by

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intrinsic factors of the aorta such as regional biologic variation driven by genetic background. Variation involved in AAA has been shown to be at genetic loci shared by other forms of atherosclerotic associated disease (LRP117, LDLR18, 9p2119, and SORT120) such as myocardial infarction and peripheral arterial disease. In contrast, analysis of common variation in TA has only revealed the involvement of FBN121, which has never been implicated in other

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cardiovascular diseases and is well known as the locus causal for MFS22. The clinical data presented here suggest that within the thoracic aorta, the descending aorta shares a profile similar to the abdominal aorta in relation to susceptibility and expression of atherosclerosis.

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Again the developmental origin of the tissue may be playing a role, considering the shared mesodermal origin of descending thoracic and abdominal aorta, in contrast to the mostly

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ectodermal derived ascending thoracic aorta23, 24. Aortic repair was common in this population over time (34.0% overall). Despite

guideline-directed timely prophylactic aortic repair in our center, there were still 26 acute aortic events (Aortic dissection or rupture) during follow-up. Anatomically, the site of aortic events were highly associated with the anatomic pattern of aortic aneurysm, with patients in the AA group almost exclusively experiencing type A aortic dissection and patients with DTA experiencing only type B aortic dissection or rupture. Interestingly in the MTA group, expressing aortic enlargement of both the ascending and descending aorta, the observed aortic events

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remained exclusively in the DTA (Table 5). We hypothesize that this may be related to the close demographic and risk factor similarities between patients with MTA and those with DTA (Table 1). The pattern of dissection we observed in the DTA/MTA cohort is similar to clinical

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observations in dissection populations that have found that type B aortic dissection tends to occur in older individuals with a high prevalence of hypertension and atherosclerosis9, 25.

In this mixed population of TA patients, we observed significantly higher rates of aortic events among those with DTA/MTA than AA. This phenomenon has been previously observed

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in mixed aneurysm populations12. Although in univariable analysis aneurysm location predicts

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adverse aortic events, in multivariate analysis it is the presence of atherosclerosis and not the location of the aneurysm that predicts aortic events (HR=5.7). Atherosclerosis has been associated with increased medial degeneration in aortic aneurysms and is closely associated with aortic dissection26-29, and these data further support this important pathologic association. Acknowledgements:

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J.B.K. is supported by the AATS Graham Traveling Fellowship. M.E.L. is supported by the

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Fredman Fellowship in Aortic Disease Research and the Toomey fund for Aortic Dissection.

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1.

Johansson G, Markstrom U, Swedenborg J. Ruptured thoracic aortic aneurysms: A study of incidence and mortality rates. Journal of Vascular Surgery 1995;21:985-988

2.

Melton LJ, 3rd, Bickerstaff LK, Hollier LH, Van Peenen HJ, Lie JT, Pairolero PC, Cherry

RI PT

KJ, O'Fallon WM. Changing incidence of abdominal aortic aneurysms: A populationbased study. American Journal of Epidemiology 1984;120:379-386 3.

Ito S, Akutsu K, Tamori Y, Sakamoto S, Yoshimuta T, Hashimoto H, Takeshita S.

SC

Differences in atherosclerotic profiles between patients with thoracic and abdominal aortic aneurysms. The American Journal of Cardiology 2008;101:696-699 Isselbacher EM. Thoracic and abdominal aortic aneurysms. Circulation 2005;111:816828 5.

M AN U

4.

Ruddy JM, Jones JA, Spinale FG, Ikonomidis JS. Regional heterogeneity within the aorta: Relevance to aneurysm disease. The Journal of Thoracic and Cardiovascular Surgery 2008;136:1123-1130

Lindsay ME, Dietz HC. The genetic basis of aortic aneurysm. Cold Spring Harbor

TE D

6.

Perspectives in Medicine 2014;4:a015909 7.

Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time.

8.

EP

Controlled Clinical Trials 1996;17:343-346 Weintraub NL. Understanding abdominal aortic aneurysm. N Engl J Med

9.

AC C

2009;361:1114-1116

Hagan PG, Nienaber CA, Isselbacher EM, Bruckman D, Karavite DJ, Russman PL,

Evangelista A, Fattori R, Suzuki T, Oh JK, Moore AG, Malouf JF, Pape LA, Gaca C,

Sechtem U, Lenferink S, Deutsch HJ, Diedrichs H, Marcos y Robles J, Llovet A, Gilon D,

Das SK, Armstrong WF, Deeb GM, Eagle KA. The international registry of acute aortic dissection (irad): New insights into an old disease. JAMA 2000;283:897-903 10.

Pape LA, Tsai TT, Isselbacher EM, Oh JK, O'Gara P T, Evangelista A, Fattori R, Meinhardt G, Trimarchi S, Bossone E, Suzuki T, Cooper JV, Froehlich JB, Nienaber CA,

10

ACCEPTED MANUSCRIPT

Eagle KA, International Registry of Acute Aortic Dissection I. Aortic diameter >or = 5.5 cm is not a good predictor of type a aortic dissection: Observations from the international registry of acute aortic dissection (irad). Circulation 2007;116:1120-1127 Trimarchi S, Jonker FH, Hutchison S, Isselbacher EM, Pape LA, Patel HJ, Froehlich JB,

RI PT

11.

Muhs BE, Rampoldi V, Grassi V, Evangelista A, Meinhardt G, Beckman J, Myrmel T, Pyeritz RE, Hirsch AT, Sundt TM, 3rd, Nienaber CA, Eagle KA. Descending aortic

SC

diameter of 5.5 cm or greater is not an accurate predictor of acute type b aortic

dissection. The Journal of Thoracic and Cardiovascular Surgery 2011;142:e101-107 Coady MA, Rizzo JA, Hammond GL, Mandapati D, Darr U, Kopf GS, Elefteriades JA.

M AN U

12.

What is the appropriate size criterion for resection of thoracic aortic aneurysms? The Journal of Thoracic and Cardiovascular Surgery 1997;113:476-491; discussion 489-491 13.

Larsson E, Vishnevskaya L, Kalin B, Granath F, Swedenborg J, Hultgren R. High frequency of thoracic aneurysms in patients with abdominal aortic aneurysms. Annals of

14.

TE D

Surgery 2011;253:180-184

Haimovici H, Maier N, Strauss L. Fate of aortic homografts in experimental canine atherosclerosis; study of fresh thoracic implants into abdominal aorta. A.M.A. Archives of

15.

EP

Surgery 1958;76:282-288

Haimovici H, Maier N. Fate of aortic homografts in canine atherosclerosis. 3. Study of

AC C

fresh abdominal and thoracic aortic implants into thoracic aorta: Role of tissue susceptibility in atherogenesis. Archives of Surgery 1964;89:961-969

16.

Meissner I, Khandheria BK, Sheps SG, Schwartz GL, Wiebers DO, Whisnant JP, Covalt

JL, Petterson TM, Christianson TJ, Agmon Y. Atherosclerosis of the aorta: Risk factor, risk marker, or innocent bystander? A prospective population-based transesophageal echocardiography study. Journal of the American College of Cardiology 2004;44:1018-

1024

11

ACCEPTED MANUSCRIPT

17.

Bown MJ, Jones GT, Harrison SC, Wright BJ, Bumpstead S, Baas AF, Gretarsdottir S, Badger SA, Bradley DT, Burnand K, Child AH, Clough RE, Cockerill G, Hafez H, Scott DJ, Futers S, Johnson A, Sohrabi S, Smith A, Thompson MM, van Bockxmeer FM,

RI PT

Waltham M, Matthiasson SE, Thorleifsson G, Thorsteinsdottir U, Blankensteijn JD, Teijink JA, Wijmenga C, de Graaf J, Kiemeney LA, Assimes TL, McPherson R,

Consortium CA, Global BC, Consortium D, Consortium V, Folkersen L, Franco-

SC

Cereceda A, Palmen J, Smith AJ, Sylvius N, Wild JB, Refstrup M, Edkins S, Gwilliam R, Hunt SE, Potter S, Lindholt JS, Frikke-Schmidt R, Tybjaerg-Hansen A, Hughes AE,

M AN U

Golledge J, Norman PE, van Rij A, Powell JT, Eriksson P, Stefansson K, Thompson JR, Humphries SE, Sayers RD, Deloukas P, Samani NJ. Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1. American Journal of Human Genetics 2011;89:619-627 18.

Bradley DT, Hughes AE, Badger SA, Jones GT, Harrison SC, Wright BJ, Bumpstead S,

TE D

Baas AF, Gretarsdottir S, Burnand K, Child AH, Clough RE, Cockerill G, Hafez H, Scott DJ, Ariens RA, Johnson A, Sohrabi S, Smith A, Thompson MM, van Bockxmeer FM, Waltham M, Matthiasson SE, Thorleifsson G, Thorsteinsdottir U, Blankensteijn JD,

EP

Teijink JA, Wijmenga C, de Graaf J, Kiemeney LA, Wild JB, Edkins S, Gwilliam R, Hunt SE, Potter S, Lindholt JS, Golledge J, Norman PE, van Rij A, Powell JT, Eriksson P,

AC C

Stefansson K, Thompson JR, Humphries SE, Sayers RD, Deloukas P, Samani NJ, Bown MJ. A variant in ldlr is associated with abdominal aortic aneurysm. Circulation. Cardiovascular Genetics. 2013;6:498-504

19.

Helgadottir A, Thorleifsson G, Magnusson KP, Gretarsdottir S, Steinthorsdottir V,

Manolescu A, Jones GT, Rinkel GJ, Blankensteijn JD, Ronkainen A, Jaaskelainen JE, Kyo Y, Lenk GM, Sakalihasan N, Kostulas K, Gottsater A, Flex A, Stefansson H, Hansen T, Andersen G, Weinsheimer S, Borch-Johnsen K, Jorgensen T, Shah SH, Quyyumi AA, Granger CB, Reilly MP, Austin H, Levey AI, Vaccarino V, Palsdottir E, Walters GB,

12

ACCEPTED MANUSCRIPT

Jonsdottir T, Snorradottir S, Magnusdottir D, Gudmundsson G, Ferrell RE, Sveinbjornsdottir S, Hernesniemi J, Niemela M, Limet R, Andersen K, Sigurdsson G, Benediktsson R, Verhoeven EL, Teijink JA, Grobbee DE, Rader DJ, Collier DA,

RI PT

Pedersen O, Pola R, Hillert J, Lindblad B, Valdimarsson EM, Magnadottir HB, Wijmenga C, Tromp G, Baas AF, Ruigrok YM, van Rij AM, Kuivaniemi H, Powell JT, Matthiasson SE, Gulcher JR, Thorgeirsson G, Kong A, Thorsteinsdottir U, Stefansson K. The same

SC

sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet 2008;40:217-224

Jones GT, Bown MJ, Gretarsdottir S, Romaine SP, Helgadottir A, Yu G, Tromp G,

M AN U

20.

Norman PE, Jin C, Baas AF, Blankensteijn JD, Kullo IJ, Phillips LV, Williams MJ, Topless R, Merriman TR, Vasudevan TM, Lewis DR, Blair RD, Hill AA, Sayers RD, Powell JT, Deloukas P, Thorleifsson G, Matthiasson SE, Thorsteinsdottir U, Golledge J, Ariens RA, Johnson A, Sohrabi S, Scott DJ, Carey DJ, Erdman R, Elmore JR,

TE D

Kuivaniemi H, Samani NJ, Stefansson K, van Rij AM. A sequence variant associated with sortilin-1 (sort1) on 1p13.3 is independently associated with abdominal aortic aneurysm. Hum Mol Genet 2013;22:2941-2947 Lemaire SA, McDonald ML, Guo DC, Russell L, Miller CC, 3rd, Johnson RJ, Bekheirnia

EP

21.

MR, Franco LM, Nguyen M, Pyeritz RE, Bavaria JE, Devereux R, Maslen C, Holmes

AC C

KW, Eagle K, Body SC, Seidman C, Seidman JG, Isselbacher EM, Bray M, Coselli JS, Estrera AL, Safi HJ, Belmont JW, Leal SM, Milewicz DM. Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning fbn1 at 15q21.1. Nat Genet 2011

22.

Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, Puffenberger EG, Hamosh A, Nanthakumar EJ, Curristin SM, Stetten G, Meyers DA, Francomano CA. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991;352:337-339

13

ACCEPTED MANUSCRIPT

23.

Majesky MW. Developmental basis of vascular smooth muscle diversity. Arteriosclerosis, Thrombosis, and Vascular biology 2007;27:1248-1258

24.

Lindsay ME, Dietz HC. Lessons on the pathogenesis of aneurysm from heritable

25.

RI PT

conditions. Nature 2011;473:308-316 Appelbaum A, Karp RB, Kirklin JW. Ascending vs descending aortic dissections. Annals of Surgery 1976;183:296-300

Albini PT, Segura AM, Liu G, Minard CG, Coselli JS, Milewicz DM, Shen YH, LeMaire

SC

26.

SA. Advanced atherosclerosis is associated with increased medial degeneration in

27.

M AN U

sporadic ascending aortic aneurysms. Atherosclerosis 2014;232:361-368 Daugherty A, Manning MW, Cassis LA. Angiotensin ii promotes atherosclerotic lesions and aneurysms in apolipoprotein e-deficient mice. J Clin Inves 2000;105:1605-1612 28.

Saraff K, Babamusta F, Cassis LA, Daugherty A. Aortic dissection precedes formation of aneurysms and atherosclerosis in angiotensin ii-infused, apolipoprotein e-deficient mice.

Cambria RP, Brewster DC, Moncure AC, Steinberg FL, Abbott WM. Spontaneous aortic dissection in the presence of coexistent or previously repaired atherosclerotic aortic

EP

aneurysm. Annals of Surgery 1988;208:619-624

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29.

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Arteriosclerosis, Thrombosis, and Vascular Biology 2003;23:1621-1626

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Figure Legends: Figure 1. Ascertainment strategy for ascending, descending, and mixed aneurysm cohorts with

Figure 2. Distribution of aneurysm size by patient groups.

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representative aortic imaging (white bar = 2 cm).

Figure 3. Kaplan-Meier curves stratified by AA vs. DTA groups: A) freedom from thoracic aortic repair; B) freedom from all cause mortality; non-aortic mortality included 6 unknown, 3 cancer, 2

freedom from aortic events during all follow-up.

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respiratory arrests, and 1 mesenteric infarction. C) freedom from aortic events at one year; D)

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Figure 4. Kaplan-Meier curves showing freedom aortic events based on: A) maximal diameter of the thoracic aorta; and (B) the presence or absence of aortic atherosclerosis. Figure 5. Ascending thoracic aortic aneurysm (AA) occurs more commonly in younger patients and suggests a genetic etiology. Descending thoracic aortic aneurysm (DTA) is a disease

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dominated by hypertension and atherosclerosis.

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Table 1.

Baseline Demographics of Thoracic Aortic Aneurysm Patients

74.0 ± 9.1

AA vs. DTA P value <0.001

DTA vs. MTA P value 0.2

AA vs. MTA P value <0.001

25.5 ± 5.4

26.8 ± 7.3

<0.001

0.2

0.2

2.0 ± 0.3

1.8 ± 0.2

1.9 ± 0.2

<0.001

<0.001

<0.001

188 (30%)

79 (61%)

43 (50%)

<0.001

0.1

<0.001

192 (31%)

0

5 (1%)

<0.001

<0.05

<0.001

0

0

<0.05

N/A

0.2

371 (59%)

106 (82%)

69 (80%)

<0.001

0.8

<0.001

Diabetes Mellitus

32 (5%)

16 (12%)

11 (13%)

<0.001

0.8

<0.001

Smoking history

279 (44%)

92 (71%)

67 (78%)

<0.001

0.1

<0.001

Area* (m2 ± SD) Female Bicuspid Aortic Valve TGFβ vasculopathies Hypertension

Coronary Artery Bypass Grafting Abdominal Aortic Aneurysm Aortic Arch

Aortic Arch

22 (4%)

62 (10%)

19 (15%)

19 (22%)

0.1

<0.001

<0.001

5 (1%)

87 (67%)

44 (51%)

<0.001

<0.001

<0.001

29 ± 5.0

34 ± 5.1

<0.003

<0.001

<0.001

2%

9%

0.3

0.1

0.3

31 ± 5.0

AC C

Diameter (mm)

28.0 ± 5.5

Diameter >40mm

RI PT

Body Surface

72.0 ± 11.1

SC

(kg/m2 ± SD)

60.3 ± 13.4

M AN U

Body Mass Index*

MTA n=86

TE D

Age (years ± SD)

DTA n=130

EP

Variable

AA n=628

5%

* note that data available on the following subsets of patients AA n=491, DTA n=87, MTA n=41.

Age (years ± SD) Body Surface Area* (m2 ± SD)

74.3 ± 8.0

AA vs. DTA P value <0.001

DTA vs. MTA P value 0.1

AA vs. MTA P value <0.001

1.9 ± 0.2

<0.001

<0.05

0.1

AA n=416

DTA n=130

MTA n=81

64.0 ± 12.6

72.1 ± 11.1

2.0 ± 0.3

1.8 ± 0.2

SC

Variable

Baseline Demographics After Removal of Overt GeneticallyTriggered Aortic Conditions

M AN U

Table 2. -

RI PT

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137 (33%)

79 (61%)

42 (52%)

<0.001

0.2

<0.001

Hypertension

267 (64%)

106 (82%)

65 (80%)

<0.001

0.8

<0.001

Diabetes Mellitus

23 (6%)

16 (12%)

11 (14%)

<0.05

0.7

<0.05

Smoking History

196 (47%)

92 (71%)

64 (79%)

<0.001

0.1

<0.001

Coronary Artery Bypass Grafting

Aneurysm

38 (9%)

19 (15%)

17 (21%)

0.1

0.2

<0.05

4 (1%)

87 (67%)

42 (52%)

<0.001

<0.05

<0.001

EP

Abdominal Aortic

TE D

Female

AC C

* note that data available on the following subsets of patients AA n=311, DTA n=60, MTA n=35.

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Table 3. – CT or MRI Imaging Characteristics of Thoracic Aortic Aneurysms

DTA (n=216)

47±5

55±9

Atheroma

58 (9%)

190 (88%)

<0.001

Calcium

50 (8%)

173 (80%)

<0.001

Mean of each patient's maximum thoracic aortic

P value

RI PT

AA (n=628)

Variable

<0.001

AC C

EP

TE D

M AN U

SC

diameter (mm ± SD)

1

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Aortic Surgical Procedures in Study Groups

DTA (n=138)

Ascending Aortic Graft

115 (69%)

10 (7%)

Arch Replacement

41 (24%)

7 (5%)

Thoracoabdominal Aortic Aneurysm Surgery

1* (1%)

Thoracic Endovascular Aortic Aneurysm Repair

2 (1%)

57 (41%)

Valve Sparing Root Repair

18 (11%)

0

63 (46%)

TE D

Composite Valve Repair

SC

AA (n=168)

M AN U

Surgical Procedure

RI PT

Table 4.

58 (35%)

6 (4%)

AC C

EP

*A Descending Thoracic Aneurysm developed in this patient after index scan.

1

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Characteristics of Adverse Aortic Events

RI PT

Table 5.

AA (n=628)

DTA (n=216)

Aortic Dissection or Rupture in Ascending Aorta

7 (1%)

0

Aortic Dissection or Rupture in Descending Aorta Fatal

0

4 (1%)

AC C

EP

TE D

Surgical Treatment of Aortic Event

17 (8%)

7 (3%)

M AN U

5 (1%)

SC

Variable

11 (5%)

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Risk factors

Univariable HR

Multivariable

95% CI

P value

<0.001

HR

95% CI

P value

6.04

0.80-45.34

0.080

1.11

1.06-1.15

Hypertension

13.98

1.89-103.20

0.010

Aneurysm location (DTA vs. AA)

9.83

4.22-22.90

<0.001

0.15

0.02-1.14

0.067

13.76

5.16-36.72

<0.001

5.72

2.02-16.15

<0.001

1.15

1.11-1.19

<0.001

1.12

1.07-1.16

<0.001

Bicuspid aortic valve Atherosclerosis (atheroma ± calcification) in aneurysm

TE D

Maximal aortic diameter (by 1 mm increment)

SC

Age (by 1 yr increment)

M AN U

Definite event

RI PT

Table 6. Univariable and Multivariable Cox-Regression Analyses for Adverse Aortic Events

AC C

EP

For multivariable analyses, variables with a P value of 0.20 or less in univariable analyses were candidates for the multivariable Cox models. Multivariable analyses involved a backward elimination technique and only variables with a P value of less than 0.10 were used in the final model. Final models were validated in 999 bootstrap samples. Variables not reaching a P value of 0.20 or less in univariable analyses included Female Gender, BMI, Diabetes Mellitus, Smoking, Beta Blocker, Calcium Channel Blocker, Angiotensin converting enzyme inhibitor (or Angiotensin type-1 receptor blocker), Alpha Blocker, Diuretics, Prior Stroke, Creatinine Level, Coronary Disease, and Dyslipidemia.

AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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