Investigating the Link between Alpha-1 Antitrypsin Deficiency and Abdominal Aortic Aneurysms

Pini, Laura; Peroni, Michele; Zanotti, Cinzia; Pini, Alessandro; Bossoni, Erika; Bargagli, Elena; Perger, Elisa; Ferrarotti, Ilaria; Vizzardi, Enrico; Tiberio, Laura; Bonardelli, Stefano; Tantucci, Claudio

doi:10.1016/j.avsg.2021.05.064

Cited by 8 publications

(5 citation statements)

References 56 publications

(45 reference statements)

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“…At the beginning of the last decade, Pulinx et al 54 confirmed the presence of increased AAT serum levels in patients with AAA, although they did not find a direct correlation with the increase in aneurysmal diameter. Several years after, Pini et al 55 brought back the attention with a study involving 138 patients hospitalized for nontraumatic AAA rupture, documenting a higher prevalence of the S deficient AAT allele compared with the general Italian population, pointing to the AATD condition as a candidate risk factor for AAA development.…”

Section: Resultsmentioning

confidence: 99%

Alpha1-antitrypsin deficiency and cardiovascular disease: questions and issues of a debated relation

Pini

Ciarfaglia

Pini³

et al. 2022

Journal of Cardiovascular Medicine

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Section: Resultsmentioning

confidence: 99%

Alpha1-antitrypsin deficiency and cardiovascular disease: questions and issues of a debated relation

Pini

Ciarfaglia

Pini³

et al. 2022

Journal of Cardiovascular Medicine

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“…Thus, it started to emerge the hypothesis that local deficiency of AAT in large elastic arteries may contribute to the proteolytic damage of the arterial wall, thereby facilitating arterial enlargement and dissection [56]. Notably, various cardiovascular complications, such as aortic [57] and intracerebral aneurysms [58], descending aorta dissection [55], coronary and cervical artery dissection [59], and left ventricular pseudoaneurysm [54] have been observed in AATD patients.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Risk Associated with Alpha-1 Antitrypsin Deficiency (AATD) Genotypes: A Meta-Analysis with Meta-Regressions

Ambrosino,

Marcuccio,

Lombardi

et al. 2023

JCM

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Background. Alpha-1 antitrypsin deficiency (AATD) can result in severe liver and respiratory disorders. The uninhibited elastase activity on the elastic tissue of arterial walls suggests that AATD may also impact vascular health. Thus, we performed a meta-analysis of the studies evaluating cardiovascular risk in individuals with AATD and non-AATD controls. Methods. A systematic literature search was conducted in the main scientific databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Differences between cases and controls were expressed as odds ratios (OR) with 95% confidence intervals (95%CI). The protocol was registered on PROSPERO under the identification number CRD42023429756. Results. The analysis of eight studies showed that, with a prevented fraction of disease of 15.0% and a corresponding OR of 0.779 (95%CI: 0.665–0.912; p = 0.002), a total of 24,428 individuals with AATD exhibited a significantly lower risk of ischemic heart disease compared to 534,654 non-AATD controls. Accordingly, given a prevented fraction of disease of 19.5%, a lower risk of acute myocardial infarction was documented when analyzing four studies on 21,741 cases and 513,733 controls (OR: 0.774; 95%CI: 0.599–0.999; p = 0.049). Sensitivity and subgroup analyses substantially confirmed results. Meta-regression models suggested that these findings were not influenced by AATD genotypes or prevalence of chronic obstructive pulmonary disease (COPD) among cases and controls, while higher differences in the prevalence of male sex (Z-score: 3.40; p < 0.001), hypertension (Z-score: 2.31; p = 0.021), and diabetes (Z-score: 4.25; p < 0.001) were associated with a lower effect size. Conclusions. Individuals with AATD may exhibit a reduced risk of ischemic heart disease, even in the presence of mild deficiency of the serine protease inhibitor. Although caution is warranted due to the observational nature of the data, future pharmacological and rehabilitation strategies should also take this controversial relationship into account.

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“…A screening study revealed that patients with a ruptured AAA greater than 6 cm display increased levels of elastin-derived peptide, compared to those with small aneurysms that have not ruptured ( 29 ). The primary catabolic enzyme responsible of elastin degradation is elastase, a family of eight human genes including chymotrypsin (CTRC), neutrophil elastase (ELANE), and MMP-12 (also known as macrophage metalloelastase) ( 30 ), whose activity is inhibited by endogenous protease inhibitors such as alpha-1 anti-trypsin (A1AT) ( 31 ) and TIMP-3 ( 32 ). It has previously been shown that serum levels of A1AT are higher in AAA patients than those with aortic-occlusive disease, highlighting the role of elastin degradation during aneurysm progression and the response to alleviate increased elastase activity ( 1 ).…”

Section: Abdominal Aortic Aneurysmmentioning

confidence: 99%

The contribution of matrix metalloproteinases and their inhibitors to the development, progression, and rupture of abdominal aortic aneurysms

Atkinson,

Bianco,

Di Gregoli

et al. 2023

Front. Cardiovasc. Med.

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Abdominal aortic aneurysms (AAAs) account for up to 8% of deaths in men aged 65 years and over and 2.2% of women. Patients with AAAs often have atherosclerosis, and intimal atherosclerosis is generally present in AAAs. Accordingly, AAAs are considered a form of atherosclerosis and are frequently referred to as atherosclerotic aneurysms. Pathological observations advocate inflammatory cell infiltration alongside adverse extracellular matrix degradation as key contributing factors to the formation of human atherosclerotic AAAs. Therefore, macrophage production of proteolytic enzymes is deemed responsible for the damaging loss of ECM proteins, especially elastin and fibrillar collagens, which characterise AAA progression and rupture. Matrix metalloproteinases (MMPs) and their regulation by tissue inhibitors metalloproteinases (TIMPs) can orchestrate not only ECM remodelling, but also moderate the proliferation, migration, and apoptosis of resident aortic cells, alongside the recruitment and subsequent behaviour of inflammatory cells. Accordingly, MMPs are thought to play a central regulatory role in the development, progression, and eventual rupture of abdominal aortic aneurysms (AAAs). Together, clinical and animal studies have shed light on the complex and often diverse effects MMPs and TIMPs impart during the development of AAAs. This dichotomy is underlined from evidence utilising broad-spectrum MMP inhibition in animal models and clinical trials which have failed to provide consistent protection from AAA progression, although more encouraging results have been observed through deployment of selective inhibitors. This review provides a summary of the supporting evidence connecting the contribution of individual MMPs to AAA development, progression, and eventual rupture. Topics discussed include structural, functional, and cell-specific diversity of MMP members; evidence from animal models of AAA and comparisons with findings in humans; the dual role of MMPs and the requirement to selectively target individual MMPs; and the advances in identifying aberrant MMP activity. As evidenced, our developing understanding of the multifaceted roles individual MMPs perform during the progression and rupture of AAAs, should motivate clinical trials assessing the therapeutic potential of selective MMP inhibitors, which could restrict AAA-related morbidity and mortality worldwide.

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Investigating the Link between Alpha-1 Antitrypsin Deficiency and Abdominal Aortic Aneurysms

Cited by 8 publications

References 56 publications

Alpha1-antitrypsin deficiency and cardiovascular disease: questions and issues of a debated relation

Alpha1-antitrypsin deficiency and cardiovascular disease: questions and issues of a debated relation

Cardiovascular Risk Associated with Alpha-1 Antitrypsin Deficiency (AATD) Genotypes: A Meta-Analysis with Meta-Regressions

The contribution of matrix metalloproteinases and their inhibitors to the development, progression, and rupture of abdominal aortic aneurysms

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