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Q: Dr. Cassis, you published a very fascinating paper on a pathophysiological link between obesity and AAA in ATVB this month. Would you mind giving us a brief synopsis of your work and findings?
A: We found that obesity, whether from high fat feeding or from leptin deficiency, increased the incidence of angiotensin II (AngII)-induced abdominal aortic aneurysms (AAAs) in male mice. Our studies also demonstrated that white adipocytes surrounding the abdominal aorta of obese mice were inflamed, which may have contributed to higher AAA incidence.
Q: This is really intriguing. Could you elaborate some more on the different predisposition to aneurysm formation between thoracic and abdominal aorta? Is this due to regional differences of the adipocytes and their interaction with macrophages?
A: The aorta is surrounded by adipose tissue along its length. The function of this periaortic adipose tissue has not been extensively defined. We found that adipose tissue surrounding the thoracic aorta is composed of primarily multi-locular brown adipocytes, while in the abdominal region there is a preponderance of white adipocytes. Periaortic adipose tissue surrounding the abdominal, but not the thoracic aorta became inflamed with obesity. Our data would suggest that the type of adipocytes may contribute to localized inflammation in periaortic adipose tissue, and through this mechanism influence the closely adjacent aorta.
Q: There was no difference in diet-induced and genetically induced obesity in the interaction with AngII to induce AAA - is this correct? What is the common pathomechanistic factor of obesity then?
A: We consider it an important finding that both diet-induced obesity, as well as obesity from leptin deficiency (without a high fat diet as the obesity stimulus), both enhanced AAA formation. These results suggest that it is obesity, and not the high fat diet, that is the primary stimulus for higher AAA incidence. Our results basically ruled out several factors from obesity as mechanisms, such as high fat diet, hypercholesterolemia, leptin, and even diabetes. We hypothesize that it is adipose inflammation, particularly periaortic adipose inflammation with macrophage infiltration, that is the common factor enhancing AAA formation with obesity.
Q: Seemingly, AAAs were induced by the combination of obesity and AngII infusion – would obesity by itself be sufficient or is it “simply a primer” for AAA formation?
A: We have previously published that obesity promotes the systemic concentrations of angiotensin II in mice. However, in the experimental design of our studies in this paper, we did not see AAAs in mice that were not infused with AngII, suggesting that endogenous levels of AngII were insufficient to initiate AAA formation. Based on our results to date, obesity is more of a primer for AAA formation. Obesity may also impact the progression of an AAA.
Q: This work is seemingly built on excellent prior studies on AngII and AAA. Is the current concept that obesity generates the macrophages that are recruited to the periaortic area and under the influence of AngII lead to the structural changes of the aorta?
A: That is an accurate summary of our current findings.
Q: Could substances released from the abdominal adipose tissue be involved as well? What is your opinion on the role of local versus systemic factors for AAA?
A: Our results demonstrate that obese mice infused with AngII exhibited an increase in plasma concentrations of resistin (both models of obesity), leptin (high fat fed) and insulin (leptin deficient). We cannot exclude the possibility that any of these changes in systemic factors released from adipocytes contributed to enhanced AAA formation.
Q: Intriguingly, mice with genetic obesity had features of the metabolic syndrome. Is insulin resistance a pathomechanistic factor, especially as it impairs the eNOS pathway?
A: Our data shows that leptin deficient obese mice infused with AngII exhibited improved glucose tolerance, despite elevated AAA formation. While we did not directly measure insulin resistance, improvements in glucose tolerance make it unlikely that the obese mice were insulin resistance. However, we have not explored this interesting possibility, or examined the eNOS pathway in the effects of obesity.
Q: How do you explain the fact that mice with genetic obesity had a greater incidence of aortic rupture? Are the AAAs induced by obesity as vulnerable as AAA induced by other mechanisms?
A: The AngII model of AAAs typically exhibits around 10-20% rupture, depending on the mouse background. C57BL/6 mice, the strain used in these studies, exhibits low AAA incidence and rupture. We have no data defining mechanisms of increased rupture in obese mice. A hypothesis would be that increase physical pressure from large amounts of adjacent adipose tissue may influence aneurismal rupture.
Q: Taking the findings of the current study further into the clinical arena, would patients with obesity and hypertension or particular components of the metabolic syndrome be at higher risk of AAA formation than obesity without those additional features?
A: I can only speak to findings using the AngII model of AAAs. From this perspective, we have previously found that hypertension is not a primary contributor to AAA formation. However, based on results from other investigators and on the knowledge that apolipoprotein E deficient hypercholesterolemic mice readily develop AAAs even without high fat feeding, cholesterol levels, and potentially types of cholesterol, may contribute to AAA risk.
Q: Would you anticipate that obese people who smoke are at even greater risk of AAA formation and/or rupture?
A: Definitely, as smoking is the primary risk factor for AAA formation even in the absence of obesity.
Q: Even in the presence of a normal BMI, visceral obesity can be present. Do these patients have a similar amount of perivascular adipose tissue formation and activity?
A: Recently published studies in humans have demonstrated that waist to hip ratios are an independent risk factor for AAAs. However, these patients were obese by BMI. Other than these data, it is not known if visceral adiposity in the absence of obesity (by BMI) influences perivascular adipose tissue.
Q: While exposed to same systemic factors not all patients develop AAA. Hence, there seems to be a genetic predisposition. Could this predisposition related to pathways stimulated by obesity?
A: This seems reasonable.
Q: Obesity is not in the list of qualifying factors in the current recommendations for AAA screening. Would your findings suggest that it should be?
A: They would suggest so, but further clinical studies would need to be performed to define obesity as a clinical qualifying factor in AAA screening.
Q: What should be the next step in the line of investigations?
A: We are currently examining effects of weight loss in obese mice on the progression of established AAAs. Since there are no medical treatments for AAAs, we believe that this lifestyle modification may be important in mitigating any potential effects of obesity in this disease.
Q: Dr. Cassis, thank you so much for your time and for sharing your expertise. We are looking forward to more studies in this area. Again, congratulations on a superb study. As a final question, may our readers contact you by E-mail if they wish to pursue further discussions?
A: Yes, but I hope that they are limited contacts!
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