1. S L I D E 0 Intracranial Aneurysm Patients May Harbor Thoracic Aortic Aneurysms 1 Yale University School of Medicine, New Haven, CT 2 Department of Neurosurgery, Yale-New Haven Hospital, New Haven CT 3 Aortic Institute at Yale-New Haven Hospital, New Haven, CT Gregory A. Kuzmik 1, Murat Gunel 2, Ketan Bulsara 2, Maryann Tranquilli 3, John A. Elefteriades 3

2. S L I D E 1 Background Thoracic aortic aneurysm (TAA) and intracranial aneurysm (ICA) share common pathogenic mediators (Koullias 2004, Kim 1997) There is increasing evidence of a common genetic basis for TAA and ICA (Ruigrok 2008, Regalado 2011[Am.J.Med.Genet.A.], Regalado 2011 [Circ.Res.])

3. S L I D E 2 Background Patients with TAA have a 9% rate of concurrent ICA (Kuzmik 2010) –9-fold higher ICA prevalence than the general population

4. S L I D E 3 Objective To determine the prevalence of concurrent thoracic aortic aneurysms (TAA) in patients with intracranial aneurysms (ICA).

5. S L I D E 4 Methods Retrospective review of all patients presenting within the past 6 years for evaluation or treatment of ruptured or unruptured ICA Radiographic records reviewed for recent thoracic imaging –Obtained for pre-operative work-up ( 64%) or unrelated reasons ( 36%) such as trauma or cancer screening TAA defined by official radiology reports documenting focal aortic dilation relative to the adjacent vessel rather than arbitrary size cut-offs

6. S L I D E 5 Results 1,224 patients with ICA 1,224 patients with ICA 359 with thoracic imaging 359 with thoracic imaging 4.7% (17) with concurrent TAA 4.7% (17) with concurrent TAA

7. S L I D E 6 Patient Characteristics All patients (n = 359) Thoracic Imaging CT: 146 (41%) Echo: 212 (59%) MRI: 1 (< 1%) Mean Age58.4 years Gender64.1% Female Ethnicity68.5% Caucasian; 16.4% African American; 13.1% Hispanic; 1.4% Asian; 0.6% Other Blood Pressure 57% Hypertensive Smoking56% Smokers ICA Presentation 64% Ruptured; 36% Unruptured Mean ICA Size6.54 mm ICA Location (75 patients with multiple ICA; 472 Total ICA) 34 ACA (7%) 94 Acom (20%) 30 Basilar (6%) 106 ICA (22%) 110 MCA (23%) 3 PCA (<1%) 66 Pcom (14%) 4 PICA (1%) 8 SCA (2%) 13 Vert (3%) 4 Other (1%) TAA patients (n = 17) Thoracic Imaging CT: 9 (53%) Echo: 8 (47%) Mean Age67.1 years Gender53% Female Ethnicity65% Caucasian 29% African American 6% Hispanic Blood Pressure 76% Hypertensive Smoking38% Smokers ICA Presentation 59% Ruptured; 41% Unruptured Mean ICA Size7.23 mm ICA Location (2 patients with multiple ICA; 19 Total ICA) 1 ACA (5%) 6 Acom (32%) 2 ICA (11%) 5 MCA (26%) 2 Pcom (11%) 2 Vert (11%) 1 Other (5%) (anterior spinal artery) ACA = anterior cerebral artery; Acom = anterior communicating artery; ICA = internal carotid artery; MCA = middle cerebral artery; PCA = posterior cerebral artery; Pcom = posterior communicating artery; PICA = posterior inferior cerebellar artery; SCA = superior cerebellar artery; Vert = vertebral artery

8. S L I D E 7 Results TAA Location: –Root/Ascending: 14 (82%) (mean 4.4 cm, range 3.6 – 6.3 cm) –Arch: 2 (12%) (mean 5.4 cm, range 4.8 – 6.0 cm) –Descending: 3 (18%) (mean 3.5 cm, range 2.9 – 4.3 cm ) (2 patients had multiple TAAs) 1,224 patients with ICA 1,224 patients with ICA 359 with thoracic imaging 359 with thoracic imaging 4.7% (17) with concurrent TAA 4.7% (17) with concurrent TAA

9. S L I D E 8 Results Patients with ICA > 4.0 mm had 6.4% rate of concurrent TAA and a significantly increased risk of TAA (p = 0.03) Patients > 70 years-old had 10.8% rate of concurrent TAA and a significantly increased risk of TAA (p = 0.01) Rate of Concurrent TAA Patients with ICA * * p = 0.03 p = 0.01

10. S L I D E 9 Results Gender, race, hypertension, and smoking status did not significantly affect risk of concurrent TAA Rate of Concurrent TAA Patients with ICA

11. S L I D E 10 Conclusions ICA patients have approximately a 5% rate of concurrent TAA Patients with ICA > 4.0 mm and > 70 years-old have an even higher risk of concurrent TAA We suggest that ICA patients be screened for silent TAA, which could jeopardize their longevity even after successful treatment of ICA

12. S L I D E 11 References 1. Koullias GJ, Ravichandran P, Korkolis DP, Rimm DL, Elefteriades JA. Increased tissue microarray matrix metalloproteinase expression favors proteolysis in thoracic aortic aneurysms and dissections, Ann Thorac Surg 2004;78:2106-10; discussion 2110-1. 2. Kim SC, Singh M, Huang J, Prestigiacomo CJ, Winfree CJ, Solomon RA, Connolly ES,Jr. Matrix metalloproteinase- 9 in cerebral aneurysms, Neurosurgery 1997;41:642-66; discussion 646-7. 3. Ruigrok YM, Elias R, Wijmenga C, Rinkel GJ. A comparison of genetic chromosomal loci for intracranial, thoracic aortic, and abdominal aortic aneurysms in search of common genetic risk factors, Cardiovasc Pathol 2008;17:40-47. 4. Regalado E, Medrek S, Tran-Fadulu V, Guo DC, Pannu H, Golabbakhsh H, Smart S, Chen JH, Shete S, Kim DH, Stern R, Braverman AC, Milewicz DM. Autosomal dominant inheritance of a predisposition to thoracic aortic aneurysms and dissections and intracranial saccular aneurysms, Am J Med Genet A 2011;155A:2125-2130. 5. Regalado ES, Guo DC, Villamizar C, Avidan N, Gilchrist D, McGillivray B, Clarke L, Bernier F, Santos-Cortez RL, Leal SM, Bertoli-Avella AM, Shendure J, Rieder MJ, Nickerson DA, NHLBI GO Exome Sequencing Project, Milewicz DM. Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms, Circ Res 2011;109:680-686. 6. Kuzmik GA, Feldman M, Tranquilli M, Rizzo JA, Johnson M, Elefteriades JA. Concurrent intracranial and thoracic aortic aneurysms, Am J Cardiol 2010;105:417-420.