Androgen aggravates aortic aneurysms via suppressing PD-1 in mice.

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and fatality rate in men than women. However, the mechanism by which androgen mediates aortic aneurysms is largely unknown. Herein, we found that male mice, not female mice, developed aortic aneurysms when exposed to aldosterone and high salt (Aldo-salt). We revealed that androgen and androgen receptors (AR) were crucial for this sexually dimorphic response to Aldo-salt. We identified programmed cell death protein 1 (PD-1), an immune checkpoint, as a key link between androgen and aortic aneurysms. We demonstrated that administration of anti-PD-1 Ab and adoptive PD-1 deficient T cell transfer reinstated Aldo-salt-induced aortic aneurysms in orchiectomized mice, and genetic deletion of PD-1 exacerbated aortic aneurysms induced by high-fat diet and angiotensin II (Ang II) in non-orchiectomized mice. Mechanistically, we discovered that AR bound to the PD-1 promoter to suppress its expression in the spleen. Thus, our study unveils a mechanism by which androgen aggravates aortic aneurysms by suppressing PD-1 expression in T cells. Moreover, our study suggests that some cancer patients might benefit from screenings for aortic aneurysms during immune checkpoint therapy.

Effect of Doxycycline on Progression of Arterial Calcification in the Noninvasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA(3)CT).

BACKGROUND: Doxycycline has been shown to prevent arterial calcification via attenuation of matrix metalloproteinases (MMP) in preclinical models. We assessed the effects of doxycycline on progression of arterial calcification in patients enrolled in the Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT). METHODS: Two hundred and sixty-one patients were randomized to 100 mg doxycycline twice daily or placebo. Arterial calcification was measured in abdominal vessels on noncontrast computed tomography scans. Patients with baseline computed tomography scan and 1 or more follow-up scans within the 2-year study were included for analysis. For individual arteries, mean change in iliofemoral artery calcification over time was calculated via linear regression. Serum MMP-3 and MMP-9 levels were measured at baseline and 6 months. RESULTS: Sixty-five patients in the doxycycline and 66 in the placebo arm were included in this analysis. Baseline characteristics between the groups were similar. The unadjusted mean change in iliofemoral calcium score per year trended toward higher values in patients treated with doxycycline compared with placebo (322 ± 399 units/year vs. 217 ± 307 units/year, P = 0.09). After 6 months, changes in serum MMP-3 and MMP-9 levels were not significantly different between study arms. CONCLUSIONS: In patients with small aortic aneurysm, treatment with doxycycline 100 mg twice daily did not decrease circulating levels of the matrix degrading enzymes MMP-3 and 9 or alter the progression of arterial calcification.

Androgen aggravates aortic aneurysms via suppressing PD-1 in mice.

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and mortality rate in men than women. However, the molecular mechanism by which androgen mediates aortic aneurysms is largely unknown. Here, we report that male but not female mice develop aortic aneurysms in response to aldosterone and high salt (Aldo-salt). We demonstrate that both androgen and androgen receptors (AR) are crucial for the sexually dimorphic response to Aldo-salt. We identify T cells expressing programmed cell death protein 1 (PD-1), an immune checkpoint molecule important in immunity and cancer immunotherapy, as a key link between androgen and aortic aneurysms. We show that intraperitoneal injection of anti-PD-1 antibody reinstates Aldo-salt-induced aortic aneurysms in orchiectomized mice. Mechanistically, we demonstrate that AR binds to the PD-1 promoter to suppress its expression in the spleen. Hence, our study reveals an important but unexplored mechanism by which androgen contributes to aortic aneurysms by suppressing PD-1 expression in T cells. Our study also suggests that cancer patients predisposed to the risk factors of aortic aneurysms may be advised to screen for aortic aneurysms during immune checkpoint therapy.

The effect of diabetes on abdominal aortic aneurysm growth over 2 years.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a common progressive disease and a significant cause of morbidity and mortality. Prior investigations have shown that diabetes mellitus (DM) may be relatively protective of AAA incidence and growth. The Non-invasive Treatment of Aortic Aneurysm Clinical Trial (N-TA3CT) is a contemporary study of small AAA growth that provides a unique opportunity to validate and explore the effect of DM on AAA. Confirming the effect of DM on AAA growth in this study may present opportunities to explore for clues to potential biologic mechanisms as well as inform current patient management. METHODS: This is a secondary analysis examining the association of diabetes and aneurysm growth within N-TA3CT: a placebo-controlled multicenter trial of doxycycline in 261 patients with AAA maximum transverse diameters (MTDs) between 3.5 and 5 cm. The primary outcome is the change in the MTD from baseline as determined by computed tomography (CT) scans obtained during the trial. Secondary outcome is the growth pattern of the AAA. Baseline characteristics and growth patterns were assessed with t tests (continuous) or χ2 tests (categorical). Unadjusted and adjusted longitudinal analyses were performed with a repeated measures linear mixed model to compare AAA growth rates between patients with and without diabetes. RESULTS: Of 261 patients, 250 subjects had sufficient imaging and were included in this study. There were 56 patients (22.4%) with diabetes and 194 (77.6%) without. Diabetes was associated with higher body mass index and increased rates of hypercholesterolemia and coronary artery disease (P < .05). Diabetes was also associated with increased frequency of treatment for atherosclerosis and hypertension including treatment with statin, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, anti-platelet, and diuretic therapy (P < .05). Baseline MTD was not significantly different between those with (4.32 cm) and without DM (4.30 cm). Median growth rate for patients with diabetes was 0.12 cm/y (interquartile range, 0.07-0.22 cm/y) and 0.19 cm/y (interquartile range, 0.12-0.27 cm/y) in patients without DM, which was significantly different on unadjusted analysis (P < .0001). Diabetes remained significantly associated with AAA growth after adjustment for other relevant clinical factors (coef, -0.057; P < .0001). CONCLUSIONS: Patients with diabetes have more than a 35% reduction in the median growth rates of AAA despite more severe concomitant vascular comorbidities and similar initial sizes of aneurysms. This effect persists and remains robust after adjusted analysis; and slower growth rates may delay the time to reach repair threshold. Rapid growth (>0.5 cm/y) is infrequent in patients with DM.

Role of volume in small abdominal aortic aneurysm surveillance.

OBJECTIVE: Current management of small abdominal aortic aneurysms (AAAs) primarily involves serial imaging surveillance of maximum transverse diameter (MTD) to estimate rupture risk. Other measurements, such as volume and tortuosity, are less well-studied and may help characterize and predict AAA progression. This study evaluated predictors of AAA volume growth and discusses the role of volume in clinical practice. METHODS: Subjects from the Non-invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (baseline AAA MTD, 3.5-5.0 cm) with ≥2 computed tomography scans were included in this study (n = 250). Computed tomography scans were conducted approximately every 6 months over 2 years. MTD, volume, and tortuosity were used to model growth. Univariable and multivariable backwards elimination least squares regressions assessed associations with volume growth. RESULTS: Baseline MTD accounted for 43% of baseline volume variance (P < .0001). Mean volume growth rate was 10.4 cm3/year (standard deviation, 8.8 cm3/year) (mean volume change +10.4%). Baseline volume accounted for 30% of volume growth variance; MTD accounted for 13% of volume growth variance. More tortuous aneurysms at baseline had significantly larger volume growth rates (difference, 32.8 cm3/year; P < .0001). Univariable analysis identified angiotensin II receptor blocker use (difference, -3.4 cm3/year; P = .02) and history of diabetes mellitus (difference, -2.8 cm3/year; P = .04) to be associated with lower rates of volume growth. Baseline volume, tortuosity index, current tobacco use, and absence of diabetes mellitus remained significantly associated with volume growth in multivariable analysis. AAAs that reached the MTD threshold for repair had a wide range of volumes: 102 cm3 to 142 cm3 in female patients (n = 5) and 105 cm3 to 229 cm3 in male patients (n = 20). CONCLUSIONS: Baseline AAA volume and MTD were found to be moderately correlated. On average, AAA volume grows about 10% annually. Baseline volume, tortuosity, MTD, current tobacco use, angiotensin II receptor blocker use, and history of diabetes mellitus were predictive of volume growth over time.

Evaluating Growth Patterns of Abdominal Aortic Aneurysm Diameter With Serial Computed Tomography Surveillance.

Importance: Small abdominal aortic aneurysms (AAAs) are common in the elderly population. Their growth rates and patterns, which drive clinical surveillance, are widely disputed. Objective: To assess the growth patterns and rates of AAAs as documented on serial computed tomography (CT) scans. Design, Setting, and Participants: Cohort study and secondary analysis of the Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT), a randomized, double-blind placebo-controlled clinical trial conducted from 2013 to 2018, with CT imaging every 6 months for 2 years. The trial was a multicenter, observational secondary analysis, not related to treatment hypotheses of data collected in the N-TA3CT. Participants included 254 patients with baseline AAA diameter between 3.5 and 5.0 cm. Exposures: Patients received serial CT scan measurements, analyzed for maximum transverse diameter, at 6-month intervals. Main Outcomes and Measures: The primary study outcome was AAA annual growth rate. Secondary analyses included characterizing AAA growth patterns, assessing likelihood of AAA diameter to exceed sex-specific intervention thresholds over 2 years. Results: A total of 254 patients, 35 women with baseline AAA diameter 3.5 to 4.5 cm and 219 men with baseline diameter 3.5 to 5.0 cm, were included. Yearly growth rates of AAA diameters were a median of 0.17 cm/y (interquartile range [IQR], 0.16) and a mean (SD), 0.19 (0.14) cm/y. Ten percent of AAAs displayed minimal to no growth (<0.05 cm/y), 62% displayed low growth (0.05-0.25 cm/y), and 28% displayed high growth (>0.25 cm/y). Baseline AAA diameter accounted for 5.4% of variance of growth rate (P < .001; R2, 0.054). Most AAAs displayed linear growth (70%); large variations in interval growth rates occurred infrequently (3% staccato growth and 4% exponential growth); and some patients' growth patterns were not clearly classifiable (23% indeterminate). No patients with a maximum transverse diameter less than 4.25 cm exceeded sex-specific repair thresholds at 2 years (men, 0 of 92; 95% CI, 0.00-0.055; women, 0 of 25 ; 95% CI, 0.00-0.247). Twenty-six percent of patients with a maximum transverse diameter of at least 4.25 cm exceeded sex-specific repair thresholds at 2 years (n = 12 of 83 men with diameter ranging from 4.25 to <4.75 cm; 95% CI, 0.091-0.264; n = 21 of 44 men with diameter ranging from 4.75-5.0 cm; 95% CI, 0.362-0.669; n = 3 of 10 women with diameter ≥4.25 cm; 95% CI, 0.093-0.726). Conclusions and Relevance: Most small AAAs showed linear growth; large intrapatient variations in interval growth rates were infrequently observed over 2 years. Linear growth modeling of AAAs in individual patients suggests smaller AAAs (<4.25 cm) can be followed up with a CT scan in at least 2 years with little chance of exceeding interventional thresholds. Trial Registration: ClinicalTrials.gov Identifier: NCT01756833.

Pneumothorax, pneumomediastinum, and dysphonia complicating awake transcarotid artery revascularization.

A 59-year-old woman presented with advanced, symptomatic carotid artery stenosis in the setting of severe medical comorbidities including coronary artery disease, congestive heart failure with recent admission for exacerbation, and diabetes mellitus. She underwent awake transcarotid artery revascularization because of her medically high-risk status. Postoperatively, she was noted to have developed pneumothorax, pneumomediastinum, and dysphonia, thought to be secondary to entrained air during the course of low neck dissection for carotid artery exposure in the setting of partial airway obstruction and high negative intrathoracic pressures during the procedure. After conservative treatment, she ultimately enjoyed complete clinical resolution. This case demonstrates an unusual complication of awake transcarotid artery revascularization.

Follow-up imaging of traumatic vertebral artery dissections is unnecessary in asymptomatic patients.

OBJECTIVE: Routine computed tomography (CT) imaging in trauma patients has led to increased recognition of blunt vertebral artery injuries (BVIs). We sought to determine the prevalence of strokes, injury progression, and need for intervention in patients with BVI. METHODS: Consecutive patients presenting with BVI during 2 years were identified from the institutional trauma registry. Inpatient records, imaging studies, and follow-up data were reviewed in detail from the electronic medical record. RESULTS: There were 76 BVIs identified in 70 patients (64% male; mean age, 47 ± 19 years); bilateral injuries occurred in 6 patients. Five patients who arrived at the hospital intubated had evidence of posterior circulation infarcts on admission CT, whereas one additional patient had evidence of a posterior circulation infarct attributed to complications of late spinal surgery. Four of the five patients with infarcts on admission CT survived to discharge, but only one had residual stroke symptoms. Minor (grade 1 or grade 2) injuries occurred in 25 (36%) patients; severe (grade 3 or grade 4) injuries occurred in 45 (64%). Twelve patients died of associated injuries (eight with severe BVI, four with minor BVI). Stepwise logistic regression analysis selected age (odds ratio, 1.14; confidence interval, 1.04-1.25; P < .001) and intubation on arrival (odds ratio, 450.4; confidence interval, 17.41-1645.51; P < .001) as independent predictors of hospital stroke and death. Of the 58 surviving to discharge, 31 (53%) returned for follow-up CT scans. Six of 10 (60%) patients with minor injuries had resolution or improvement compared with 3 of 21 (14%) with severe injuries (P = .027). One patient (10%) with a minor BVI and two patients (10%) with severe BVI had radiologic progression, but none were clinically significant. During a mean follow-up of 15 ± 13 months, none of the study patients had treatment (surgical or interventional) for BVI, and there were no delayed strokes. Only five patients in this series had vertebral pseudoaneurysms, which limits conclusions about this type of BVI. CONCLUSIONS: These data suggest that BVI-related strokes are present at the time of admission and do not have clinical sequelae. No late strokes occurred in this series, and no surgical or interventional treatments were required even in the presence of radiographic worsening. The relatively few cases of vertebral pseudoaneurysms in this series limit any conclusions about these specific lesions. However, these data indicate that follow-up imaging of nonaneurysmal BVI is not necessary in adults who are found to be asymptomatic on follow-up.

LNK deficiency promotes acute aortic dissection and rupture.

Aortic dissection (AD) is a life-threatening vascular disease with limited treatment strategies. Here, we show that loss of the GWAS-identified SH2B3 gene, encoding lymphocyte adaptor protein LNK, markedly increases susceptibility to acute AD and rupture in response to angiotensin (Ang) II infusion. As early as day 3 following Ang II infusion, prior to the development of AD, Lnk-/- aortas display altered mechanical properties, increased elastin breaks, collagen thinning, enhanced neutrophil accumulation, and increased MMP-9 activity compared with WT mice. Adoptive transfer of Lnk-/- leukocytes into Rag1-/- mice induces AD and rupture in response to Ang II, demonstrating that LNK deficiency in hematopoietic cells plays a key role in this disease. Interestingly, treatment with doxycycline prevents the early accumulation of aortic neutrophils and significantly reduces the incidence of AD and rupture. PrediXcan analysis in a biobank of more than 23,000 individuals reveals that decreased expression of SH2B3 is significantly associated with increased frequency of AD-related phenotypes (odds ratio 0.81). Thus, we identified a role for LNK in the pathology of AD in experimental animals and humans and describe a new model that can be used to inform both inherited and acquired forms of this disease.

Initial and intermediate-term treatment of the phantom thrombus (primary non-occlusive mural thrombus on normal arteries).

An embolic event originating from thrombus on an otherwise un-diseased or minimally diseased proximal artery (Phantom Thrombus) is a rare but significant clinical challenge. All patients from a single center with an imaging defined luminal thrombus with a focal mural attachment site on an artery were evaluated retrospectively. We excluded all patients with underlying anatomic abnormalities of the vessel at the attachment site. Six patients with a mean age of 62.5 years were identified over a 2.5-year period. All patients had completed treatment for or had a current diagnosis of malignancy and none were on antiplatelets or other anticoagulants. Four thrombi originated in the aorta proximal to the renal arteries and one originated distal. One thrombus was found in the common carotid artery and one was in an arterialized vein graft. Mean follow-up was 22 months. None of the patients underwent removal or exclusion of the embolic source. With systemic anticoagulation, four of the phantom thrombi were resolved on imaging within 8 weeks, one resolved after 72 weeks. One phantom thrombus reoccurred after 6 months on reduced anticoagulant dosing. There was one acute and one death in follow-up (26 months). One patient required a partial foot amputation secondary to tissue necrosis from the initial thromboembolic event. Arterial thrombi forming on otherwise normal vessels are a distinct clinical entity. In patients with a phantom thrombus, a strategy of therapeutic anticoagulation for management of the embolic source seems to be safe and effective over both the short and intermediate-term.

Aortic arch involvement worsens the prognosis of type B aortic dissections.

OBJECTIVE: Medical management of acute aortic dissections limited to the descending thoracic aorta (AD-desc) is associated with acceptable outcomes. Uncertainty remains about whether acute type B aortic dissections involving the aortic arch (AD-arch) have an increased risk of retrograde extension into the ascending aorta or other dissection-related complications. This study compared outcomes of AD-arch with AD-desc managed medically. METHODS: Consecutive patients admitted from 2005 to 2014 with acute aortic dissections not involving the ascending aorta were retrospectively analyzed. Primary end points included dissection-related death and operative intervention. RESULTS: The study included 99 patients (63% men; mean age, 60 ± 14 years) with acute aortic dissections. Dissections were limited to the aorta distal to the left subclavian artery (AD-desc) in 79 patients (80%), and 20 (20%) had involvement of the left subclavian (n = 16), left common carotid (n = 1), or innominate (n = 3) arteries (AD-arch). Dissections ended proximal to the celiac artery in 30 patients (30%), between the celiac artery and aortic bifurcation in 36 (36%), and distal to the aortic bifurcation in 33 (33%). During medical management, further proximal extension into the arch occurred in two AD-arch patients and one AD-desc patient (P < .05), but proximal dissection into the ascending aorta occurred in only one AD-arch patient with Marfan disease. Compared with patients with AD-desc, those with AD-arch were younger (53 ± 12.5 vs 62 ± 16 years; P < .01) and had more frequent early interventions (40% vs 19%; P = .047), cardiac complications (35% vs 11%; P < .01), and neurologic events (25% vs 6%; P < .01). Seven AD-arch patients (35%) and nine AD-desc patients (11%) died of dissection-related causes (P < .01). Among survivors, late interventions were performed in four of eight AD-arch patients (50%) and in six of 58 AD-desc patients (10%; P = .02). Medical treatment without intervention was successful in four AD-arch patients (20%) and in 52 AD-desc patients (66%; P < .001). Multivariate logistic regression retained arch involvement as the sole predictor of dissection-related death (odds ratio, 4.2; 95% confidence interval, 1.3-13.4) and failure of medical treatment (odds ratio, 7.7; 95% confidence interval, 2.5-29). The distal extent of dissection had no bearing on outcome. CONCLUSIONS: AD-arch dissections are associated with a higher risk of cardiac and neurologic events, need for early intervention, and dissection-related death than AD-desc dissections. Because further proximal dissections into the ascending aorta were rare in this study, medical management appears to be safe as the initial treatment of AD-arch dissections. However, surgeons should be aware of the increased risk of complications and the potential need for urgent interventions in these patients.

Inclusion bodies enriched for p62 and polyubiquitinated proteins in macrophages protect against atherosclerosis.

Autophagy is a catabolic cellular mechanism that degrades dysfunctional proteins and organelles. Atherosclerotic plaque formation is enhanced in mice with macrophages deficient for the critical autophagy protein ATG5. We showed that exposure of macrophages to lipids that promote atherosclerosis increased the abundance of the autophagy chaperone p62 and that p62 colocalized with polyubiquitinated proteins in cytoplasmic inclusions, which are characterized by insoluble protein aggregates. ATG5-null macrophages developed further p62 accumulation at the sites of large cytoplasmic ubiquitin-positive inclusion bodies. Aortas from atherosclerotic mice and plaques from human endarterectomy samples showed increased abundance of p62 and polyubiquitinated proteins that colocalized with plaque macrophages, suggesting that p62-enriched protein aggregates were characteristic of atherosclerosis. The formation of the cytoplasmic inclusions depended on p62 because lipid-loaded p62-null macrophages accumulated polyubiquitinated proteins in a diffuse cytoplasmic pattern. Lipid-loaded p62-null macrophages also exhibited increased secretion of interleukin-1ß (IL-1ß) and had an increased tendency to undergo apoptosis, which depended on the p62 ubiquitin-binding domain and at least partly involved p62-mediated clearance of NLRP3 inflammasomes. Consistent with our in vitro observations, p62-deficient mice formed greater numbers of more complex atherosclerotic plaques, and p62 deficiency further increased atherosclerotic plaque burden in mice with a macrophage-specific ablation of ATG5. Together, these data suggested that sequestration of cytotoxic ubiquitinated proteins by p62 protects against atherogenesis, a condition in which the clearance of protein aggregates is disrupted.

Periadventitial adipose-derived stem cell treatment halts elastase-induced abdominal aortic aneurysm progression.

AIM: Demonstrate that periadventitial delivery of adipose-derived mesenchymal stem cells (ADMSCs) slows aneurysm progression in an established murine elastase-perfusion model of abdominal aortic aneurysm (AAA). MATERIALS & METHODS: AAAs were induced in C57BL/6 mice using porcine elastase. During elastase perfusion, a delivery device consisting of a subcutaneous port, tubing and porous scaffold was implanted. Five days after elastase perfusion, 100,000 ADMSCs were delivered through the port to the aorta. After sacrifice at day 14, analyzed metrics included aortic diameter and structure of aortic elastin. RESULTS: ADMSC treated aneurysms had a smaller diameter and less fragmented elastin versus saline controls. CONCLUSION: Periadventitial stem cell delivery prevented the expansion of an established aneurysm between days 5 and 14 after elastase perfusion.

Smooth muscle cells from abdominal aortic aneurysms are unique and can independently and synergistically degrade insoluble elastin.

BACKGROUND: The purpose of this study was to further elucidate the role of the vascular smooth muscle cells (SMCs) in abdominal aortic aneurysm (AAA) disease. We hypothesized that that AAA SMCs are unique and actively participate in the process of degrading the aortic matrix. METHODS: Whole-genome expression profiles of SMCs from AAAs, nondilated abdominal aorta (NAA), and carotid endarterectomy (CEA) were compared. We quantified elastolytic activity by culturing SMCs in [(3)H]elastin-coated plates and measuring solubilized tritium in the media after 7 days. Matrix metalloproteinase (MMP)-2 and MMP-9 production was assessed using real-time polymerase chain reaction, zymography, and Western blotting. RESULTS: Each SMC type exhibited a unique gene expression pattern. AAA SMCs had greater elastolytic activity than NAA-SMCs (+68%; P < .001) and CEA-SMCs (+45%; P < .001). Zymography showed an increase of active MMP-2 (62 kD) in media from AAA SMCs. AAA SMCs demonstrated twofold greater expression of MMP-2 messenger (m)RNA (P < .05) and 7.3-fold greater MMP-9 expression (P < .01) than NAA-SMCs. Culture with U937 monocytes caused a synergistic increase of elastolysis by AAA SMCs (41%; P < .001) but not NAA-SMCs or CEA-SMCs (P = .99). Coculture with U937 caused a large increase in MMP-9 mRNA in AAA-SMCs and NAA-SMCs (P < .001). MMP-2 mRNA expression was not affected. Western blots of culture media showed a fourfold increase of MMP-9 (92 kD) protein only in AAA-SMCs/U937 but not in NAA-SMCs/U937 (P < .001) and a large increase in active-MMP2 (62 kD), which was less apparent in NAA-SMCs/U937 media (P < .01). CONCLUSIONS: AAA-SMCs have a unique gene expression profile and a proelastolytic phenotype that is augmented by macrophages. This may occur by a failure of post-transcriptional control of MMP-9 synthesis.

Understanding the effects of tobacco smoke on the pathogenesis of aortic aneurysm.

Aneurysmal arterial disease is a vascular degenerative condition that is distinct from atherosclerotic and other occlusive arterial diseases. There is regionalization of the predisposition to aneurysm formation within the vascular tree, and the pathological process varies with location. Infrarenal abdominal aortic aneurysm (AAA) is the most common manifestation of aneurysmal disease, and smoking is the dominant risk factor. Smoking is a much greater risk factor for AAA than for atherosclerosis. In addition to playing a role in the pathogenesis of AAA, smoking also increases the rate of expansion and risk of rupture of established AAA. The mechanistic relationship between AAA and smoking is being established by the use of enhanced animal models that are dependent on smoke or smoke components. The mechanisms seem to involve durable alterations in vascular smooth muscle cell and inflammatory cell function. This review examines the clinical, epidemiological, and mechanistic evidence implicating smoking as a cause of aneurysms, focusing on AAA.