ACE DD Genotype: A Predisposing Factor for Abdominal Aortic Aneurysm

Fatini, Cinzia; Pratesi, Giovanni; Sofi, Francesco; Gensini, Francesca; Sticchi, Elena; Lari, Barbara; Pulli, Raffaele; Dorigo, Walter; Azas, Leonidas; Pratesi, Carlo Alberto; Gensini, Gian Franco; Abbate, Rosanna

doi:10.1016/j.ejvs.2004.12.018

Cited by 58 publications

(77 citation statements)

References 33 publications

(24 reference statements)

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“…In animal models, angiotensin II infusion leads to increased matrix metalloproteinase activity in the vasculature, resulting in vascular smooth muscle cell apoptosis and aneurysm formation (15). In addition, higher ACE levels occurring in the setting of an ACE gene variant (DD genotype polymorphism) are associated with a greater propensity for aortic aneurysm (16).…”

Section: Discussionmentioning

confidence: 99%

The prevalence and clinical impact of obesity in adults with Marfan syndrome

Yetman

McCrindle

2010

Canadian Journal of Cardiology

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Despite improvement in survival noted throughout the past few decades (1), patients with Marfan syndrome remain at risk for premature death secondary to the cardiovascular complications of aortic dilation and dissection (2). Risk factors for such complications remain poorly defined, thereby impeding attempts at risk stratification for the individual patient. Family history of aortic dissection (3) and spontaneous genetic mutations (4) have been identified as risk factors but, currently, no potentially modifiable risk factors have been elucidated.The underlying biomechanical abnormalities in Marfan syndrome have been well described. Patients with Marfan syndrome have reduced aortic distensibility, which becomes progressively more abnormal with increasing age (5). These biomechanical abnormalities precede the vascular complication of aortic dilation and dissection, and may reflect both endothelial and vascular smooth muscle cell abnormalities of the aortic wall (6-8).The current obesity epidemic has been the subject of much lay and scientific attention. Obesity, hyperlipidemia, smoking and hypertension have been established as clear risk factors for atherosclerotic arterial disease (9). These risk factors predispose to impaired vascular endothelial function, thereby increasing the risk of vascular complications including coronary arterial obstructive disease and stroke (10). Marfan syndrome is characteristically associated with an asthenic body habitus; as a result, these patients have been considered to be exempt from the current obesity epidemic.We sought to determine the prevalence of obesity and overweight in an adult cohort of patients with Marfan syndrome, to assess the prevalence of other cardiovascular risk factors among this patient group -namely smoking, hyperlipidemia, diabetes and hypertensionand to determine what, if any, clinical impact such risk factors had on outcome in this patient cohort. BACKGROUND:Patients with Marfan syndrome characteristically have an asthenic body habitus and are considered to be exempt from the obesity epidemic. OBJECTIVE: To examine the prevalence and clinical impact of obesity in a cohort of adults with Marfan syndrome. METHODS: Fifty outpatients (30 female) with a mean (± SD) age of 38±13 years were studied. Demographic variables including previously identified risk factors for aortic dissection were recorded. Body mass index (BMI) was determined and patients were classified as normal (BMI less than 25 kg/m 2 ), overweight (BMI 25 kg/m 2 to 29.9 kg/m 2 ) or obese (BMI 30 kg/m 2 or greater). Other cardiovascular risk factors were examined. An adverse clinical outcome was defined as either the attainment of surgical criteria for aortic root replacement or the presence of aortic dissection. RESULTS: A family history of aortic dissection was present in 13 (26%) patients. In 23 (46%) patients, there was no known family history of Marfan syndrome. Mean BMI was 25.4±7.4 kg/m 2 , with 18 (36%) patients having an elevated BMI. Positive smoking status was present in 15 (30%), hyp...

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Section: Discussionmentioning

confidence: 99%

The prevalence and clinical impact of obesity in adults with Marfan syndrome

Yetman

McCrindle

2010

Canadian Journal of Cardiology

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“…In this regard, it is noteworthy that recent studies suggested a significant association between AT1 receptor gene polymorphism and AAA in at least 3 independent cohorts (19). The ACE DD genotype has also been shown to be associated with AAA (20). Interestingly, while genetic polymorphisms in the main TGF-β receptors could not be linked to AAA in humans (47,48), a recent study has shown that the association of ACE DD and TGBR1 6A polymorphisms greatly and synergistically increased the predisposition to AAA (48).…”

Section: Figurementioning

confidence: 95%

“…Moreover, Ang II type I receptor and angiotensin-converting enzyme (ACE) DD polymorphisms are associated with AAA in humans (19,20). Therefore, this model was appropriate for testing the role of TGF-β activity in AAA formation.…”

Section: Introductionmentioning

confidence: 99%

TGF-β activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II–infused mice

Wang¹,

Ait‐Oufella²,

Herbin³

et al. 2010

J. Clin. Invest.

360

365

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Complicated abdominal aortic aneurysm (AAA) is a major cause of mortality in elderly men. Ang II-dependent TGF-β activity promotes aortic aneurysm progression in experimental Marfan syndrome. However, the role of TGF-β in experimental models of AAA has not been comprehensively assessed. Here, we show that systemic neutralization of TGF-β activity breaks the resistance of normocholesterolemic C57BL/6 mice to Ang II-induced AAA formation and markedly increases their susceptibility to the disease. These aneurysms displayed a large spectrum of complications on echography, including fissuration, double channel formation, and rupture, leading to death from aneurysm complications. The disease was refractory to inhibition of IFN-γ, IL-4, IL-6, or TNF-α signaling. Genetic deletion of T and B cells or inhibition of the CX3CR1 pathway resulted in partial protection. Interestingly, neutralization of TGF-β activity enhanced monocyte invasiveness, and monocyte depletion markedly inhibited aneurysm progression and complications. Finally, TGF-β neutralization increased MMP-12 activity, and MMP-12 deficiency prevented aneurysm rupture. These results clearly identify a critical role for TGF-β in the taming of the innate immune response and the preservation of vessel integrity in C57BL/6 mice, which contrasts with its reported pathogenic role in Marfan syndrome.

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“…Such link has on the other hand been identified by others. [3][4][5] Previous experimental studies lend support to the suggestion that ACE has a role in aneurysm formation. 28,29 Accumulation of ACE has been reported in the abdominal aortic wall in patients with aneurysm, 28 and angiotensin II infusion induces AAA in mice.…”

Section: Multiple Regression Analysesmentioning

confidence: 77%

“…1,2 In addition, this polymorphism has been associated with abdominal aortic aneurysm (AAA), [3][4][5] although this association has been questioned. 6 The abdominal aorta is of particular interest as age-and gender-related changes are more pronounced at this site than other arteries 7 and as the abdominal aorta is particularly prone to aneurysm formation.…”

Section: Introductionmentioning

confidence: 99%