Hypercholesterolemia and type 2 diabetes mellitus (DM) are well-established risk factors for atherosclerotic occlusive disease. However, of the 2, only the former is a risk factor for abdominal aortic aneurysm (AAA). In this editorial, we point out the principal epidemiologic and pathobiologic differences between the effects of hypercholesterolemia and DM on AAA growth, lessons learned related to these mechanisms from nonhuman studies including preventative effects of experimental phototherapy by low-level laser, and implications for novel mechanism–based treatment approaches.
Epidemiology
The positive association between hypercholesterolemia and aneurysm progression is exemplified in the 7-year prospective Tromso Study of >4,000 subjects. Patients with high total serum cholesterol were >2 times more likely to have AAA than those with lower total cholesterol ( Table 1 ). In addition, those with low-serum high-density lipoprotein were >3 times more likely to develop AAA than those with high-serum high-density lipoprotein ( Table 1 ). In the RESCAN study that looked at >15,000 patients with AAA from 18 studies, statins reduced the overall progression of AAA by <1 mm/y (maximum diameter) which was the best result of any of the other “cardioprotective” drugs studied including angiotensin-converting enzyme inhibitors and other antihypertensives ( Table 1 ). The role of hypercholesterolemia in aneurysm formation has also been emphasized in small and large experimental animal models.
| Effect on Abdominal Aortic Aneurysm | |
|---|---|
| Serum cholesterol >290 vs < 226 mg/dl | 2-fold increase in prevalence |
| Serum HDL < 48 vs >70 mg/dl | 3-fold increase in prevalence |
| Statins | slightly reduced progression |
In contrast, epidemiologic studies, including the Aneurysm Detection and Management study of >73,000 patients, have shown that those with DM have a decreased overall prevalence, and slower rate of progression, of AAA than those without DM ( Table 2 ). Conversely, a meta-analysis of 11 studies showed that the prevalence of DM in patients “without” AAA ranged from 17% to 36%, but its prevalence in patients “with” AAA was only 6% to 14%. The RESCAN study also showed that the strongest predictors of aneurysmal growth are current smoking and diabetes—but in opposite ways. Whereas the 2.21 mm/y mean aneurysmal growth across all studies was increased in smokers by 0.35 ± 0.07 mm, AAA growth in those with diabetes was “decreased” by 0.51 ± 0.1 mm ( Table 2 ). They also found that although rupture rates were significantly higher in older patients, hypertensives, current smokers, and in women versus men, “no association was found with diabetes.” Moreover, in the study of Kang et al that included patients from the Aneurysm Detection and Management Study and others, it was found that the prevalence of AAA >4.0 cm diameter in patients with >50% carotid stenosis was much less in diabetic patients than in nondiabetic patients ( Table 2 ).
| Variable | Diabetes Mellitus | |
|---|---|---|
| No | Yes | |
| Patients with AAA >4.0 cm | 19% | 12% |
| Growth of AAA (mm/year) | 2.21 (all subjects) | 1.70 |
| Patients with AAA among those with >50% carotid stenosis | 10.2% | 2.8% |
Mechanisms
Hypercholesterolemia is associated with markedly increased infiltration of a variety of inflammatory cells including neutrophils, a variety of antigenic types of lymphocytes, and monocyte macrophages whose proteolytic activity has been shown not only to destabilize “vulnerable” plaques but also facilitate aneurysm progression by weakening the extracellular matrix of the aortic wall. Hypercholesterolemia has been shown to upregulate the expression of intercellular adhesion molecule-1 (cluster of differentiation 54) and vascular cell adhesion molecule-1 (cluster of differentiation 106), thereby facilitating inflammatory cell infiltration and increasing the expression and secretion by these cells of proteolytic enzymes, such as matrix metalloproteinase (MMP)-2, MMP-9, and MMP-12 (shown primarily in monocyte/macrophages), that break down collagen, elastin, and other matrix proteins. The disturbance of the balance between matrix protein formation and degradation results in progressive weakening of the aortic wall that facilitates aneurysmal dilatation and eventual rupture.
Elevated glucose in patients with DM increases glycation of protein precursors of the extracellular matrix resulting in increased synthesis and increased formation of advanced glycation end products. These end products are thought to increase smooth muscle cell proliferation, the principal source of matrix proteins of the aortic wall, and facilitate covalent cross-linking, for example, during collagen formation, resulting in stiffening of the extracellular matrix, rendering it less prone to proteolysis, and reducing the likelihood of aneurysmal expansion and rupture. It has also been reported that patients with DM have reduced levels of MMP-2 and MMP-9, thus limiting the breakdown and remodeling of the extracellular matrix proteins in the aortic wall. Hyperglycemia and its associated effect on extracellular matrix has also been shown to limit AAA formation in mice including the pancreatic elastase infusion and the angiotensin-II–infused, apolipoprotein-E–deficient (Apo-E −/− ) models.
Mechanisms
Hypercholesterolemia is associated with markedly increased infiltration of a variety of inflammatory cells including neutrophils, a variety of antigenic types of lymphocytes, and monocyte macrophages whose proteolytic activity has been shown not only to destabilize “vulnerable” plaques but also facilitate aneurysm progression by weakening the extracellular matrix of the aortic wall. Hypercholesterolemia has been shown to upregulate the expression of intercellular adhesion molecule-1 (cluster of differentiation 54) and vascular cell adhesion molecule-1 (cluster of differentiation 106), thereby facilitating inflammatory cell infiltration and increasing the expression and secretion by these cells of proteolytic enzymes, such as matrix metalloproteinase (MMP)-2, MMP-9, and MMP-12 (shown primarily in monocyte/macrophages), that break down collagen, elastin, and other matrix proteins. The disturbance of the balance between matrix protein formation and degradation results in progressive weakening of the aortic wall that facilitates aneurysmal dilatation and eventual rupture.
Elevated glucose in patients with DM increases glycation of protein precursors of the extracellular matrix resulting in increased synthesis and increased formation of advanced glycation end products. These end products are thought to increase smooth muscle cell proliferation, the principal source of matrix proteins of the aortic wall, and facilitate covalent cross-linking, for example, during collagen formation, resulting in stiffening of the extracellular matrix, rendering it less prone to proteolysis, and reducing the likelihood of aneurysmal expansion and rupture. It has also been reported that patients with DM have reduced levels of MMP-2 and MMP-9, thus limiting the breakdown and remodeling of the extracellular matrix proteins in the aortic wall. Hyperglycemia and its associated effect on extracellular matrix has also been shown to limit AAA formation in mice including the pancreatic elastase infusion and the angiotensin-II–infused, apolipoprotein-E–deficient (Apo-E −/− ) models.
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