Introduction: Previous clinical studies have found an association between the serum protein, haptoglobin (Hp), and the formation of abdominal aneurysms, but no studies have investigated this association in a physiologically relevant, preclinical model of aneurysm formation. We investigated the size of aneurysms in wild-type Hp1-1 and pro-inflammatory Hp2-2 mice and found the Hp2-2 genotype to be associated with increased aneurysm size and increased numbers of macrophages infiltrating the vessel wall.
Methods: Carotid artery aneurysms (CCA) were induced in the left CCA of wild-type Hp1-1 mice and transgenic Hp2-2 mice using a physiologically relevant aneurysm model that involves administration of elastase to cause vessel wall destruction and angiotensin II to cause hypertension. There were four experimental groups, (1) sham surgery (n=11); (2) angiotensin II only (n=10); (3) elastase only (n=20); and (4) elastase + angiotensin II (n=20). The size of all aneurysms was determined by measuring the outer circumference and luminal circumference. Macrophages that infiltrated the aneurysm wall were quantified by immunohistochemistry. All results were analyzed using a two-way ANOVA with a Bonferroni post-test.
Results: Concomitant administration of elastase and angiotensin II resulted in a significant increase in aneurysm size as compared to all other treatment groups. Using this model, we found that aneurysms in Hp-2-2 mice were significantly larger than aneurysms in Hp1-1 mice (p=0.02 for outer circumference, p=0.0006 for inner circumference)(Figure 1 and Figure 2). Finally, the number of infiltrating macrophages was significantly increased in aneurysms in Hp2-2 mice in the setting of vessel wall destruction and hypertension (p=0.0001) (Figure 3).
Conclusions: Hp2-2 mice formed aneurysms that were significantly larger and had a significantly increased number of macrophages in the aneurysm wall as compared to Hp1-1 mice. This suggests that the Hp protein is involved in aneurysm formation and that Hp genotype may be a useful biomarker in predicting aneurysm progression.
Patient Care: Currently there is no biomarker to follow or predict aneurysm growth. Our data suggests that a patients' haptoglobin genotype, specifically the Hp2-2 genotype, is associated with increased aneurysm growth which may alter treatment decisions.
Learning Objectives: By the conclusion of this session, participants should be able to: (1) discuss the factors involved in aneurysm formation; (2) describe the importance of a pro-inflammatory state on aneurysm formation and; (3) discuss the possibility of the haptoglobin protein as a biomarker for increased aneurysm growth.
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2. Wiernicki I, Safranow K, Baranowska-Bosiacka I, Piatek J, Gutowski P. Haptoglobin 2-1 phenotype predicts rapid growth of abdominal aortic aneurysms. J Vasc Surg. Sep 2010;52(3):691-696.
3. Kadirvel R, Ding YH, Dai D, Lewis DA, Kallmes DF. Differential expression of genes in elastase-induced saccular aneurysms with high and low aspect ratios. Neurosurgery. Mar 2010;66(3):578-584; discussion 584.
4. Wiernicki I, Safranow K, Baranowska-Bosiacka I, Piatek J, Gutowski P. Haptoglobin 2-1 phenotype predicts rapid growth of abdominal aortic aneurysms. J Vasc Surg. Sep 2010;52(3):691-696.