S L I D E 1

Effect of statin therapy on the natural history of thoracic aortic aneurysms.

Louis H. Stein, Jessica Berger, Maryann Tranquilli, John A. Elefteriades. The Aortic Institute at Yale – New Haven Hospital

S L I D E 2

Bench top to bedside interaction

Medial Degeneration

ROS MMP -2 MMP -9

NADH / NADPH(VSM)

Statin

Beta blockers

ARB

S L I D E 3

Statin therapy and the Aorta

• Statins inhibit the progression of atherosclerosis.• In AAA, conflicting data on rate of aneurysm

expansion.1,2,3

• No specific data on TAA exists at present.

Does statin therapy impact the clinical course ofThoracic aortic aneurysms?

1. Karrowni W, et al “Statin therapy reduces growth of abdominal aortic aneurysms.”J Investig Med. 2011 Dec;59(8):1239-43.

2. Mosorin M, et al. “The use of statins and fate of small abdominal aortic aneurysms.” Interact Cardiovasc Thorac Surg. 2008 Aug;7(4):578-81.

3. Schlösser FJ, et al. “Growth predictors and prognosis of small abdominal aortic aneurysms.”J Vasc Surg. 2008 Jun;47(6):1127-33. Epub 2008 Apr 28.

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Baseline Characteristics

Characteristic No Statin Statin p - value n 1191 (76%) 369 (24%) Aneurysm Site Root 158 (13%) 46 (12%) NSArch 121 (10%) 40 (11%) NSAscending 595 (50%) 192 (52%) NSDescending 196 (16%) 66 (18%) NSTAA 121 (10%) 25 (7%) NSMedications  ACE 277 (23%) 103 (28%) NSAntiarrhythmia 26 (2%) 20 (5%) P=0.004ARB 78 (7%) 65 (17%) p<0.001Beta-blocker 520 (43%) 224 (61%) p<0.001CCB 252 (21%) 101 (27%) p = 0.038Insulin 12 (1%) 10 (3%) NSNSAID 38 (3%) 6 (2%) NS

S L I D E 5

Baseline Characteristics

Characteristic No Statin Statin p - value

HTN p < 0.0001None 332 (30%) 48 (14%) Mild 419 (39%) 133 (49%) Moderate 218 (20%) 111(33%) Severe 116 (11%) 44 (13%) CAD 216 (18%) 123 (33%) p< 0.0001 CHF 74 (6%) 19 (5%) NS AAA 168 (12%) 42 (10%) NS PVD 66 (5%) 22 (6%) NS Renal p < 0.0001None 960 (91%) 279 (87.7%)Mild 72 (6.8%) 19 (6.0%) Moderate 14 (1.3%) 1 (0.1%) Severe 9 (0.8%) 7 (2%)

Characteristic No Statin Statin p - value COPD NS None 818 (77%) 224 (69%)Mild 136 (13%) 57 (18%)

Moderate 78 (7%) 33 (10%)

Severe 36 (3%) 11 (4%)

Obesity 43 (3%) 1 (0.25%) p < 0.0039

Marfans 57 (5%) 2 (0.5%) p = 0.0009

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*

*

*

*

*

*

*

* - p <0.05

Percent of patients with and without statin therapy experiencing

dissection or rupture by aneurysm location

Percent of patients with and without statin therapy requiring surgical

intervention by aneurysm location

Percent of patients Percent of patients

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Kaplan-Meier freedom from aneurysm or rupture for ascending, arch, and descending aorta.

prob chi-squared = 0.0229

S L I D E 8

Kaplan-Meier freedom from surgery for ascending, arch, and descending aorta.

prob chi-squared < 0.001

Time (months)

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Does ARB therapy impact the protection provided by statins?

n - 1357 No Statin StatinNo ARB 962 267ARB 71 56

Laboratory data demonstrates a protective effect provided by ARBs in in vivo models.1

Clinical data has also demonstrated ARB slow the progression of thoracic aortic aneurysms in patients with Marfan’s Disease.2

Our data show an increased prevalence of ARB treatment among those treated with Statins.

1. Habashi TM, et al. Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science. 2011 Apr 15;332(6027):361-5.

2. Brooke BS, et al. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. N Engl J Med. 2008 Jun 26;358(26):2787-95.

S L I D E 10

Any thoracic aorta

Root

Ascending

Arch

Descending

Thoracoabdominal

0 5 10 15 20 25

ARBNo ARB

Percent of patients with and without ARB therapy experiencing

dissection or rupture by aneurysm location

Any thoracic aorta

Root

Ascending

Arch

Descending

Thoracoabdominal

0 10 20 30 40 50 60

ARBNo ARB

Percent of patients with and without ARB therapy requiring

surgical intervention by aneurysm location

Percent of patients Percent of patients

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Single logistic regression

Multiple Logistic Regression

Regression analysis of the effect of statin and ARB therapy on thoracic aortic aneurysm outcome

S L I D E 12

Conclusions

• Statin therapy has a protective effect against TAAA progressing to dissection, rupture, or surgery.

• This protective effect is seen in aneurysms of the ascending, arch, descending, and thoracoabdominal aorta.

• The protective effect is not demonstrated in aneurysms of the aortic root.

• These findings are in line with the current understanding of the physiology of the aorta – given the different embryologic derivation of different segments of the aorta.

• The effect on rupture or dissection is independent of ARB therapy.

• ARB therapy seem to help protect against requiring surgery.

• Effect of stain therapy on growth rate is currently under review.