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Medical treatment of small abdominal aortic aneurysms
Abstract
Screening for abdominal aortic aneurysm (AAA) in selected groups is now performed in England, the USA and Sweden. Patients with aneurysms over 55 mm in diameter are generally considered for elective surgical repair. Patients with aneurysm diameters below or equal to 55 mm (termed 'small AAAs') are managed with aneurysm surveillance as there is currently insufficient evidence to recommend surgery in these cases. As more patients are screened, there will be an increasing number of small AAAs identified. There is interest in pharmaceutical interventions (for example angiotensin converting enzyme (ACE) inhibitors, antibiotics, beta-blockers, statins) which could be given to such patients to delay or reverse aneurysm expansion and reduce the need for elective surgical repair.
To assess the effects of medical treatment on the expansion rate of small abdominal aortic aneurysms.
The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (May 2012) and CENTRAL (2012, Issue 5). Clinical trials databases were searched for details of ongoing or unpublished studies. The reference lists of articles retrieved by electronic searches were searched for additional citations.
We selected randomised trials in which patients with small AAAs allocated to medical treatment with the intention of retarding aneurysm expansion were compared to patients allocated to a placebo treatment, alternative medical treatment, a different regimen of the same drug or imaging surveillance alone.
Two authors independently extracted the data and assessed the risk of bias in the trials. Meta-analyses were used when heterogeneity was considered low. The two primary outcomes were the mean difference (MD) in aneurysm diameter and the odds ratio (OR) calculated to compare the number of individuals referred to AAA surgery in each group over the trial period.
Seven trials involving 1558 participants were included in this review; 457 were involved in four trials of antibiotic medication, and 1101 were involved in three trials of beta-blocker medication. Five of the studies were rated at a high risk of bias.Individually, all of the included trials reported non-significant differences in AAA expansion rates between their intervention and control groups.The two major drug groups were then analysed separately. For AAA expansion it was only possible to combine two of the antibiotic trials in a meta-analysis. This demonstrated that roxithromycin had a small but significant protective effect (MD -0.86 mm; 95% confidence interval (CI) -1.57 to -0.14). When referral to AAA surgery was compared (including all four antibiotic trials in the meta-analysis), non-significantly fewer patients were referred in the intervention groups (OR 0.96; 95% CI 0.59 to 1.57) than the control groups. When only the trials reporting actual elective surgery were included in a subgroup analysis, the result remained statistically non-significant (OR 1.17; 95% CI 0.57 to 2.42).For the beta-blocker trials, when all were combined in a meta-analysis, there was a very small, non-significant protective effect for propranolol on AAA expansion (MD -0.08 mm; 95% CI -0.25 to 0.10), and non-significantly fewer patients were referred to AAA surgery in the propranolol group (OR 0.74; 95% CI 0.52 to 1.05). Bronchospasm and shortness of breath were the main adverse effects from the beta-blockers. In one trial the adverse effects were reportedly so severe that the trial was stopped early after two years.
There is some limited evidence that antibiotic medication may have a slight protective effect in retarding the expansion rates of small AAAs. The quality of the evidence makes it unclear whether this translates into fewer referrals to AAA surgery, owing mainly to the small sample sizes of the studies.Antibiotics were generally well tolerated with minimal adverse effects. Propranolol was poorly tolerated by patients in all of the beta-blocker trials and demonstrated only minimal and non-significant protective effects. Further research on beta-blockers for AAA needs to consider the use of drugs other than propranolol.In general, there is surprisingly little high quality evidence on medical treatment for small AAAs, especially in relation to the use of newer beta-blockers, ACE inhibitors and statins.
... An abdominal aortic aneurysm (AAA) is an abnormal dilation of the abdominal aorta and is associated with a mortality rate of >50% in the event it ruptures. AAAs are characterized by an increase of ³50% in aortic diameter compared with the normal diameter or a maximum infrarenal aortic diameter ≥30 mm (1). The prevalence of AAA increases with age and ~4% of men >55 years have an AAA (1) and AAAs cause ~1% of all deaths in developed countries (2). ...
... AAAs are characterized by an increase of ³50% in aortic diameter compared with the normal diameter or a maximum infrarenal aortic diameter ≥30 mm (1). The prevalence of AAA increases with age and ~4% of men >55 years have an AAA (1) and AAAs cause ~1% of all deaths in developed countries (2). ...
... Therapeutic options for AAA are currently limited to surgical or interventional repair to prevent rupture which can be effective for several decades; however, no pharmacologic therapy has been reported to have a significant effect in humans (1,3,4). A delay in the development of AAA treatments is partly due to the absence of an AAA animal model of human AAA (3) and because human AAA tissue can only be obtained during surgical repair, investigation of AAA with human tissue is limited (5). ...
The present study established a novel and reproducible animal model to study abdominal aortic aneurysms. In total, 22 adult Lewis rats underwent a procedure to produce mechanical injuries at the infrarenal aorta which was opened temporarily. The aortas were injured 6 times and repaired. Those rats were divided into 2 groups and the aortic aneurysm tissue was harvested after 42 (6-week group) or 63 (9-week group) days and evaluated for the progression of aortic aneurysms. In the 6-week group, changes in the aneurysm were observed in 6/10 (60%) rats and the mean maximum diameter of the aorta demonstrated a 119% increase in size from the baseline measurement. In the 9-week group, changes in the aneurysm were observed in 8/11 (88%) rats and the mean maximum diameter of aorta demonstrated a 133% increase in size. Additional findings from the aortic aneurysm tissue were found microscopically, including the destruction of the tunica media and the elastic fiber. The present study demonstrated that this novel animal model for the development of abdominal aortic aneurysms (AAAs) produced by mechanical injury may have high reproducibility and similar gross and microscopic morphology to humans. This model could be helpful to investigate the treatment of AAAs.
... Abdominal aortic aneurysm (AAA) usually occurs in the infrarenal part of the aorta, and is usually accompanied by a variety of risks for rupture and sudden death [1][2][3]. AAA generally happens and forms below the aortic hiatus of the diaphragm to the point of bifurcation [1]. Its formation closely associates with chronic aortic inflammation, increased local expression of proteinase, and degradation of connective tissue protein [4]. ...
... Abdominal aortic aneurysm (AAA) usually occurs in the infrarenal part of the aorta, and is usually accompanied by a variety of risks for rupture and sudden death [1][2][3]. AAA generally happens and forms below the aortic hiatus of the diaphragm to the point of bifurcation [1]. Its formation closely associates with chronic aortic inflammation, increased local expression of proteinase, and degradation of connective tissue protein [4]. ...
Objective
The purpose of this meta-analysis was to evaluate the effect of exercise training intervention in patients with abdominal aortic aneurysm (AAA).
Methods
Eight randomized controlled trials (RCTs) that recruited 588 AAA patients were extracted using 4 databases (PubMed, Embase, Wanfang Data, and Cochrane Library). Physiological and biochemistry parameters that included in this study are high-sensitivity C-reactive protein (hs-CRP), respiratory peak oxygen uptake rate (VO2peak), triglyceride (TG), total cholesterol (TC), anaerobic threshold (AT), the diameter of AAA, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), and matrix metalloproteinase-9 (MMP-9). Standard mean difference (SMD) was used to assess the between group effect.
Results
This meta-analysis was synthesized with findings from RCTs and found that hs-CRP (SMD, − 0.56 mg/dL; 95% CI: − 0.90 to 0.22; P = 0.001), VO2peak (SMD, 0.4 mL/kg/min; 95% CI, 0.21 to 0.60; P < 0.001), TG (SMD, − 0.39 mg/dL; 95% CI: − 0.02 to 0.77; P = 0.04), and AT (SMD, 0.75 mL/kg/min; 95% CI, 0.54 to 0.96; P < 0.001) were significantly improved in the exercise groups, while the size of AAA (SMD, − 0.15; 95% CI: − 0.36 to 0.06; P = 0.15), TC (SMD, 0.16 mg/dL; 95% CI: − 0.10 to 0.42; P = 0.23), HDL/LDL ratio (SMD, − 0.06; 95% CI: − 0.32 to 0.20; P = 0.64), HDL (SMD, − 0.09; 95% CI: − 0.39 to 0.20; P = 0.54), LDL (SMD, 0.08; 95% CI: − 0.21 to 0.38; P = 0.59), and MMP-9 (SMD, − 0.23 mg/dL; 95% CI: − 0.53 to 0.06; P = 0.12) did not differ in the exercise groups compared with the controls.
Conclusion
Exercise intervention improved some of the CVD risk factors but not all, hs-CRP, VO2peak and AT were significantly improved after exercise intervention, while, changes of MMP-9, the size of AAA, and the overall lipids profile were not. Exercise intervention provides an additional solution for improving cardiorespiratory capacity and health status among AAA patients, and might lead to a delay of AAA progression.
... Patients with large aneurysms (aneurysms with a diameter of 5.0 to 5.5 cm) are at high risk for rupture and are recommended to undergo open or interventional repair 5 . AAAs smaller than 5.5 cm in diameter are termed "small AAAs" 6 . Lifestyle changes and close observation are recommended for patients with small aneurysms due to the lack of effective pharmacotherapy options 6 . ...
... AAAs smaller than 5.5 cm in diameter are termed "small AAAs" 6 . Lifestyle changes and close observation are recommended for patients with small aneurysms due to the lack of effective pharmacotherapy options 6 . Therapeutic targets for AAAs have long been sought; thus, we aimed to elucidate the pathogenesis of the disease. ...
Vascular smooth muscle cell (VSMC) phenotypic switching plays a critical role in the formation of abdominal aortic aneurysms (AAAs). FoxO3a is a key suppressor of VSMC homeostasis. We found that in human and animal AAA tissues, FoxO3a was upregulated, SM22α and α-smooth muscle actin (α-SMA) proteins were downregulated and synthetic phenotypic markers were upregulated, indicating that VSMC phenotypic switching occurred in these diseased tissues. In addition, in cultured VSMCs, significant enhancement of FoxO3a expression was found during angiotensin II (Ang II)-induced VSMC phenotypic switching. In vivo, FoxO3a overexpression in C57BL/6J mice treated with Ang II increased the formation of AAAs, whereas FoxO3a knockdown exerted an inhibitory effect on AAA formation in ApoE−/− mice infused with Ang II. Mechanistically, FoxO3a overexpression significantly inhibited the expression of differentiated smooth muscle cell (SMC) markers, activated autophagy, the essential repressor of VSMC homeostasis, and promoted AAA formation. Our study revealed that FoxO3a promotes VSMC phenotypic switching to accelerate AAA formation through the P62/LC3BII autophagy signaling pathway and that therapeutic approaches that decrease FoxO3a expression may prevent AAA formation.
... The rupture of AAA represents a significant clinical event, having a mortality rate of 90% [4,5], and e.g. in the case of AAA sizes greater than 50% of the normal artery diameter, approximately 15,000 people died a year in the United States [6,7]. The risk assessment of rupture, determining aneurysm examination and if surgery is required is to age related, smoking, hypertension, high blood pressure, size and growth rate over 5 years after diagnosis, and family history of aneurysm [8][9][10][11][12][13]. Recently, many guidelines have been issued by the European Society of Cardiology (ESC) as well as other societies and organizations [14]. ...
... Furthermore, the curve becomes steeper with age. Because of the timedependent function, the mathematical expression that defines the stiffness of the artery is complex, so several equations have been proposed [4,[6][7][8][9]. ...
The shape and size of aneurysms were quantified using an ellipsoidal equation and a new procedure was proposed to evaluate the mechanical stress associated with changes in the wall thickness due to aneurysm dilation and blood pressure. The aneurysm rupture risk (ARR) can be assessed quantitatively from stiffness and strength of the patient using changes in diameter of the common carotid artery (CCA) with ultrasonic imaging. APR can also be derived from the natural frequency of brachial artery wall oscillations or the external ear canal side of the superficial temporal artery (STA) with the pulsation. By using this method of digitizing the risk of aneurysm rupture and its related information, it is possible to save clinical data around the world as big data and obtain optimal diagnostic solutions by the application of statistics and probability based AI techniques. Therefore, hospitals around the world will always be able to obtain the highest level of objective diagnostic information, regardless of country or region.
... [18][19][20] The effects of statins on AAA-related outcomes have previously been summarized. [21][22][23][24][25][26][27][28][29][30][31][32][33] However, only a minority of these studies 26,28,[31][32][33] conducted meta-analyses, none of them analyzed AAA rupture risk, and considerable amounts of new data have emerged since their publication. The aims of this systematic review and meta-analysis are to summarize and mathematically synthesize the available medical literature regarding the effects of statins on AAA growth, rupture, and elective perioperative mortality. ...
... The effect of statin pharmacotherapy on AAA-related outcomes has been the subject of several previous systematic reviews dating back to 2008. [21][22][23][24][25][26][27][28][29][30][31][32][33] Seven of these review articles conducted meta-analyses. Two of them evaluated the effect of statin therapy on long-term survival following AAA repair, 21 Adjusted for baseline aneurysm diameter, aneurysm length, age, sex, weight, hypertension, diabetes mellitus, cerebrovascular disease, hyperlipidemia, and chronic kidney disease. ...
Background
There are no recognized pharmacological treatments for abdominal aortic aneurysms (AAA), although statins are suggested to be beneficial. We sought to summarize the literature regarding the effects of statins on human AAA growth, rupture, and 30‐day mortality.
Methods and Results
We conducted a systematic review and meta‐analysis of randomized and observational studies using the Cochrane CENTRAL database, MEDLINE, and EMBASE up to June 15, 2018. Review, abstraction, and quality assessment were conducted by 2 independent reviewers, and a third author resolved discrepancies. Pooled mean differences and odds ratios with 95% confidence intervals were calculated using random effects models. Heterogeneity was quantified using the I² statistic, and publication bias was assessed using funnel plots. Our search yielded 911 articles. One case‐control and 21 cohort studies involving 80 428 patients were included. The risk of bias was low to moderate. Statin use was associated with a mean AAA growth rate reduction of 0.82 mm/y (95% confidence interval 0.33, 1.32, P=0.001, I²=86%). Statins were also associated with a lower rupture risk (odds ratio 0.63, 95% confidence interval 0.51, 0.78, P<0.0001, I²=27%), and preoperative statin use was associated with a lower 30‐day mortality following elective AAA repair (odds ratio 0.55, 95% confidence interval 0.36, 0.83, P=0.005, I²=57%).
Conclusions
Statin therapy may be associated with reduction in AAA progression, rupture, and lower rates of perioperative mortality following elective AAA repair. These data argue for widespread statin use in AAA patients.
Clinical Trial Registration
URL: http://www.crd.york.ac.uk. Unique identifier: CRD42017056480.
... Although animal studies have suggested a protective effect of beta blockade on aneurysm expansion and rupture, randomized clinical trial data have not replicated such findings [53]. Other antihypertensive agents, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, also are of unclear benefit based on limited available data [1,60,94]. Insufficient data also limit any recommendation on antibiotic therapy in the management of AAA despite weak evidence supporting the inhibition of inflammation and protease activity by roxithromycin and doxycycline [63, 94,95]. Screening for AAA is recommended for first degree relatives of all patients with an AAA [1]. ...
... Other antihypertensive agents, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, also are of unclear benefit based on limited available data [1,60,94]. Insufficient data also limit any recommendation on antibiotic therapy in the management of AAA despite weak evidence supporting the inhibition of inflammation and protease activity by roxithromycin and doxycycline [63, 94,95]. Screening for AAA is recommended for first degree relatives of all patients with an AAA [1]. ...
Abdominal aortic aneurysm (AAA) is most commonly defined as a maximal diameter of the abdominal aorta in excess of 3 cm in either anterior-posterior or transverse planes or, alternatively, as a focal dilation ≥ 1.5 times the diameter of the normal adjacent arterial segment. Risk factors for the development of AAA include age > 60, tobacco use, male gender, Caucasian race, and family history of AAA. Aneurysm growth and rupture risk appear to be associated with persistent tobacco use, female gender, and chronic pulmonary disease. The majority of AAAs are asymptomatic and detected incidentally on various imaging studies, including abdominal ultrasound, and computed tomographic angiography. Symptoms associated with AAA may include abdominal or back pain, thromboembolization, atheroembolization, aortic rupture, or development of an arteriovenous or aortoenteric fistula. The Screening Abdominal Aortic Aneurysms Efficiently (SAAAVE) Act provides coverage for a one-time screening abdominal ultrasound at age 65 for men who have smoked at least 100 cigarettes and women who have family history of AAA disease. Medical management is recommended for asymptomatic patients with AAAs < 5 cm in diameter and focuses on modifiable risk factors, including smoking cessation and blood pressure control. Primary indications for intervention in patients with AAA include development of symptoms, rupture, rapid aneurysm growth (> 5 mm/6 months), or presence of a fusiform aneurysm with maximum diameter of 5.5 cm or greater. Intervention for AAA includes conventional open surgical repair and endovascular aortic stent graft repair.
... A recent meta-analysis and a previous Cochrane review highlighted the absence of any single pharmacological agent that can be used to arrest or slow AAA growth 5,36 . These reviews, however, synthesized primary studies with considerable methodological limitations, including small study populations, retrospective design, and limited follow-up. ...
Background
There is a clinical need for treatments that can slow or prevent the growth of an abdominal aortic aneurysm, not only to reduce the need for surgery, but to provide a means to treat those who cannot undergo surgery.
Methods
Analysis of the UK Aneurysm Growth Study (UKAGS) prospective cohort was conducted to test for an association between cardiometabolic medications and the growth of an abdominal aortic aneurysm above 30 mm in diameter, using linear mixed-effect models.
Results
A total of 3670 male participants with data available on abdominal aortic aneurysm growth, smoking status, co-morbidities, and medication history were included. The mean age at recruitment was 69.5 years, the median number of surveillance scans was 6, and the mean(s.e.) unadjusted abdominal aortic aneurysm growth rate was 1.75(0.03) mm/year. In a multivariate linear mixed-effect model, smoking (mean(s.e.) +0.305(0.07) mm/year, P = 0.00003) and antiplatelet use (mean(s.e.) +0.235(0.06) mm/year, P = 0.00018) were found to be associated with more rapid abdominal aortic aneurysm growth, whilst metformin was strongly associated with slower abdominal aortic aneurysm growth (mean(s.e.) −0.38(0.1) mm/year, P = 0.00019), as were angiotensin-converting enzyme inhibitors (mean(s.e.) −0.243(0.07) mm/year, P = 0.0004), angiotensin II receptor antagonists (mean(s.e.) −0.253(0.08) mm/year, P = 0.00255), and thiazides/related diuretics (mean(s.e.) −0.307(0.09) mm/year, P = 0.00078).
Conclusion
The strong association of metformin with slower abdominal aortic aneurysm growth highlights the importance of the ongoing clinical trials assessing the effectiveness of metformin with regard to the prevention of abdominal aortic aneurysm growth and/or rupture. The association of angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and diuretics with slower abdominal aortic aneurysm growth points to the possibility that optimization of cardiovascular risk management as part of abdominal aortic aneurysm surveillance may have the secondary benefit of also reducing abdominal aortic aneurysm growth rates.
... In case of smaller AAAs (<5.5 cm diameter), the conservative management along with regular imaging tests is advised (40). Currently, no medical therapy has been proven to decrease the expansion rate of AAA (41,42). ...
Patients with abdominal aortic aneurysm (AAA) have a higher risk of cardiovascular (CV) events, which seems to be associated with disturbed platelet (PLT) function. Endovascular aneurysm repair (EVAR) is an emerging, less-invasive treatment alternative to surgical AAA repair. Both platelet function abnormalities in patients with AAA and the effect of EVAR on platelet function are poorly understood. In this review, we aim to fill the gap regarding the effect of EVAR on PLT function in AAA patients by discussing PLT function disturbances in patients with AAA, PLT function changes after EVAR, evidence from clinical studies regarding PLT function before and after EVAR, and antiplatelet or and antithrombotic treatment in patients undergoing EVAR. The goal of our review is to summarize the contemporary knowledge and initiate further studies to better understand PLT function changes in patients undergoing EVAR, optimize the pharmacotherapy before and after EVAR and further improve outcomes in this group of patients.
... Originally, beta-blockers (mainly atenolol and propranolol) were thought to slow AAA growth in rats and humans [127][128][129][130]. More recent analyses have provided counter-evidence to the previous conclusion [131,132]. Pertinent clinical studies outside of Clinicaltrials.gov suggest no effect of propranolol on halting AAA growth rates [133][134][135]. ...
The cardiovascular field is still searching for a treatment for abdominal aortic aneurysms (AAA). This inflammatory disease often goes undiagnosed until a late stage and associated rupture has a high mortality rate. No pharmacological treatment options are available. Three hallmark factors of AAA pathology include inflammation, extracellular matrix remodeling, and vascular smooth muscle dysfunction. Here we discuss drugs for AAA treatment that have been studied in clinical trials by examining the drug targets and data present for each drug’s ability to regulate the aforementioned three hallmark pathways in AAA progression. Historically, drugs that were examined in interventional clinical trials for treatment of AAA were repurposed therapeutics. Novel treatments (biologics, small-molecule compounds etc.) have not been able to reach the clinic, stalling out in pre-clinical studies. Here we discuss the backgrounds of previous investigational drugs in hopes of better informing future development of potential therapeutics. Overall, the highlighted themes discussed here stress the importance of both centralized anti-inflammatory drug targets and rigor of translatability. Exceedingly few murine studies have examined an intervention-based drug treatment in halting further growth of an established AAA despite interventional treatment being the therapeutic approach taken to treat AAA in a clinical setting. Additionally, data suggest that a potentially successful drug target may be a central inflammatory biomarker. Specifically, one that can effectively modulate all three hallmark factors of AAA formation, not just inflammation. It is suggested that inhibiting PGE2 formation with an mPGES-1 inhibitor is a leading drug target for AAA treatment to this end.
... However, only using these measurements as biomarkers is not high accuracy (3). Continuous monitoring of AAA biological activity is important for reducing mortality and morbidity associated with rupture; however, there is no effective predictive biomarker of AAA diameter (4) or treatment that prevents AAA from growing or rupturing (5,6). Therefore, it is critical that we elucidate the underlying mechanisms of AAA progression to accurately identify appropriate therapeutic targets. ...
Identifying biomarkers for abdominal aortic aneurysms (AAA) is key to understanding their pathogenesis, developing novel targeted therapeutics, and possibly improving patients outcomes and risk of rupture. Here, we identified AAA biomarkers from public databases using single-cell RNA-sequencing, weighted co-expression network (WGCNA), and differential expression analyses. Additionally, we used the multiple machine learning methods to identify biomarkers that differentiated large AAA from small AAA. Biomarkers were validated using GEO datasets. CIBERSORT was used to assess immune cell infiltration into AAA tissues and investigate the relationship between biomarkers and infiltrating immune cells. Therefore, 288 differentially expressed genes (DEGs) were screened for AAA and normal samples. The identified DEGs were mostly related to inflammatory responses, lipids, and atherosclerosis. For the large and small AAA samples, 17 DEGs, mostly related to necroptosis, were screened. As biomarkers for AAA, G0/G1 switch 2 (G0S2) (Area under the curve [AUC] = 0.861, 0.875, and 0.911, in GSE57691, GSE47472, and GSE7284, respectively) and for large AAA, heparinase (HPSE) (AUC = 0.669 and 0.754, in GSE57691 and GSE98278, respectively) were identified and further verified by qRT-PCR. Immune cell infiltration analysis revealed that the AAA process may be mediated by T follicular helper (Tfh) cells and the large AAA process may also be mediated by Tfh cells, M1, and M2 macrophages. Additionally, G0S2 expression was associated with neutrophils, activated and resting mast cells, M0 and M1 macrophages, regulatory T cells (Tregs), resting dendritic cells, and resting CD4 memory T cells. Moreover, HPSE expression was associated with M0 and M1 macrophages, activated and resting mast cells, Tregs, and resting CD4 memory T cells. Additional, G0S2 may be an effective diagnostic biomarker for AAA, whereas HPSE may be used to confer risk of rupture in large AAAs. Immune cells play a role in the onset and progression of AAA, which may improve its diagnosis and treatment.
... Bu amaçla etkin olduğuna dair kuvvetli veriler bulunan en önemli ilaç betablokerlerdir. (43)(44)(45) AAA tanısı konan hastalarda risk faktörlerinin düzenlenmesi gerekir. Bu amaçla antihipertansif tedavi verilmesi, anti-lipidemik tedavi verilmesi, sigaranın bırakılması, kilo kontrolü sağlanması gibi yaşam tarzı değişiklikleri önemlidir. ...
... Two studies by Vammen et al. 14 and Høgh et al. 11 recruited patients from the same Viborg County study for screening AAAs, but they are considered as separate studies because they applied different treatment regimens, as was the case in Cochrane database systematic review and meta-analysis. 17 The overall risk of bias was low (online Supplemental Figure 2). ...
Background
Pharmacotherapy for undersized abdominal aortic aneurysm (AAA) is a clinical unmet need. Randomized controlled trials (RCTs) have failed to show effectiveness despite countless promising data in preclinical studies. We aimed to identify the population with undersized AAAs (30–54 mm) who potentially benefit from pharmacotherapy.
Methods
In accordance with the PRISMA statement, we conducted a systematic review and meta-analysis of placebo-controlled RCTs. The primary outcome was mean difference (MD) in annual growth rate (< 0 favors pharmacotherapy), and the secondary outcome was aneurysm-related events (diameters ⩾ 55 mm, ruptures, or referral to surgery).
Results
Our search strategy identified eight RCTs (six trials on antibiotics [ABx], two on renin-angiotensin system inhibitors [RAS-I]) with a total of 1325 patients. The mean of baseline diameters ranged from 33.1 mm to 43.1 mm. Neither ABx nor RAS-I showed significant differences in MD. Multivariable random-effects restricted maximum likelihood meta-regression revealed a statistically significant linear relationship between baseline diameter and MD (coefficient 0.15 [95% CI 0.0011, 0.30], p = 0.049) but not for the follow-up period ( p = 0.28) and duration of treatment ( p = 0.11). In line with this result, ABx with baseline diameter < 40 mm significantly reduced MD (−1.03 mm/year [95% CI −1.64, −0.42], p = 0.001) and a borderline significant difference in aneurysm-related events (HR 0.53 [95% CI 0.28, 1.00], p = 0.05), whereas the other groups ⩾ 40 mm never demonstrated effectiveness. Fixed-effect models did not change the results. No evidence of publication bias was detected.
Conclusion
Undersized AAAs < 40 mm can potentially benefit from pharmacotherapy. Future RCTs should consider preferentially including undersized AAA with smaller diameters.
... È stato dimostrato che queste MMP sono localizzate prevalentemente in prossimità della giunzione medio-avventiziale della lesione aneurismatica, dove accelerano i processi infiammatori e la degradazione del collagene, favorendo quindi anche la rottura dell'aneurisma (10). L'utilizzo del beta-bloccante propanololo nel ridurre l'espansione degli aneurismi dell'aorta addominale è stato associato ad un ampio numero di eventi avversi che hanno complessivamente portato a bassa aderenza alla terapia e a risultati di scarsa efficacia (11). Le statine, così come l'acido acetil salicilico, esercitano un effetto antinfiammatorio ed il loro utilizzo è stato associato ad un rallentamento della crescita degli aneurismi (12). ...
An aortic aneurysm is a ruinous condition that compromises the aortic wall. If inaccurately monitored, it could evolve in an extensive dilatation of the vessel and eventually in the aorta's devastating rupture with low survival rates. The recent attempts to increase clinical remission and disease clearance have only partially alleviated the disease-related poor prognosis. Indeed, aortic aneurysm events annually increase their impact on the National Health Systems of industrialized countries. In recent years, liquid biopsy tests have gained attention as a valuable alternative to traditional diagnostics. Classified as small extracellular vesicles of endosomal origin, exosomes are 30-150 nm diameter vesicles, which are physiologically produced by all cell types and secreted through an exocytosis process in blood, urine, cerebrospinal fluid, and other body fluids. Representing the molecular footprint of the cells of origin, exosomes have been recently considered to design a reliable liquid biopsy for non-invasive monitoring of disease evolution and a valuable tool to monitor the therapy response. Metalloproteinases have been reported as specific markers of aortic aneurysm in terms of disease staging and progression. Of interest, it has been demonstrated a specular metalloproteinase expression in the extracellular vesicles of patients, thus constituting a personal "barcode" of disease progression. This evidence could potentially allow the definition of innovative liquid biopsy approaches for monitoring the disease together with a comprehensive aortic aneurysm-derived exosomes molecular characterization and trapping.
... Currently, surgery is the only effective clinical management for abdominal aortic aneurysms (AAAs). Gene expression analysis showed that HDAC is deregulated in human AAA, and treatment of an AAA mouse model with MS-275 (class I HDACi) or MC-1568 (class IIa HDACi), which decreases lymphocyte and macrophage infiltration, limited aneurysm expansion [151]. HDACi is a promising pharmacotherapy for overcoming human aneurysm progression [84]. ...
Genetic changes are difficult to reverse; thus, epigenetic aberrations, including changes in DNA methylation, histone modifications, and noncoding RNAs, with potential reversibility, have attracted attention as pharmaceutical targets. The current paradigm is that histone deacetylases (HDACs) regulate gene expression via deacetylation of histone and nonhistone proteins or by forming corepressor complexes with transcription factors. The emergence of epigenetic tools related to HDACs can be used as diagnostic and therapeutic markers. HDAC inhibitors that block specific or a series of HDACs have proven to be a powerful therapeutic treatment for immune-related diseases. Here, we summarize the various roles of HDACs and HDAC inhibitors in the development and function of innate and adaptive immune cells and their implications for various diseases and therapies.
... For patients with small AAAs or those who are not eligible for AAA repair, close aneurysm surveillance and adjuvant therapy are recommended [5]. So far, no effective pharmacological treatments have been developed to prevent AAA growth or rupture [7,8]. Hence, there is a need to elucidate the possible mechanisms of AAA progression and explore corresponding pharmaceutical treatments. ...
Abdominal aortic aneurysm (AAA) is a prevalent aortic disease that causes high mortality due to asymptomatic gradual expansion and sudden rupture. The underlying molecular mechanisms and effective pharmaceutical therapy for preventing AAA progression have not been fully identified. In this study, we identified the key modules and hub genes involved in AAA growth from the GSE17901 dataset in the Gene Expression Omnibus (GEO) database through the weighted gene co-expression network analysis (WGCNA). Key genes were further selected and validated in the mouse dataset (GSE12591) and human datasets (GSE7084, GSE47472, and GSE57691). Finally, we predicted drug candidates targeting key genes using the Drug–Gene Interaction database. Overall, we identified key modules enriched in the mitotic cell cycle, GTPase activity, and several metabolic processes. Seven key genes (CCR5, ADCY5, ADCY3, ACACB, LPIN1, ACSL1, UCP3) related to AAA progression were identified. A total of 35 drugs/compounds targeting the key genes were predicted, which may have the potential to prevent AAA progression.
... The techniques to repair AAA include surgical repair and endovascular repair [2,3]. In both guidelines, no specific drug has been found to be effective in slowing the expansion rate of an abdominal aortic aneurysm; thus, no specific medical therapy has been recommended [4][5][6][7][8]. Therefore, in the clinic, when the diameter of the AAA does not meet the treatment threshold, physicians do not have a better strategy to control or to decrease the growth rate of small AAAs, which causes a dilemma for both patients and physicians. ...
Objectives
Aneurysms are generally the result of dilation of all 3 layers of the vessel wall, and pseudoaneurysms are the result of localized extravasation of blood that is contained by surrounding tissue. Since there is still no recommended protocol to decrease aneurysm formation and progression, we hypothesised that intramural delivery of TGF β1 hydrogel can decrease aneurysm and pseudoaneurysm formation and progression.
Materials
Male C57BL/6 J mice (12–14 wk), SD rats (200 g) and pig abdominal aortas were used, and hydrogels were fabricated by the interaction of sodium alginate (SA), hyaluronic acid (HA) and CaCO3.
Methods
A CaCl2 adventitial incubation model in mice and a decellularized human great saphenous vein patch angioplasty model in rats were used. TGF β1 hydrogel was intramurally delivered after CaCl2 incubation in mice; at day 7, the abdomen in some mice was reopened, and TGF β1 hydrogel was injected intramurally into the aorta. In rats, TGF β1 hydrogel was delivered intramurally after patch angioplasty completion. Tissues were harvested at day 14 and analysed by histology and immunohistochemistry staining. The pig aorta was also intramurally injected with hydrogel.
Results
In mice, rhodamine hydrogel was still found between the medium and adventitia at day 14. In the mouse aneurysm model, there was a thicker wall and smaller amount of elastin breaks in the TGF β1 hydrogel-delivered groups both at day 0 and day 7 after CaCl2 incubation, and there were larger numbers of p-smad2- and TAK1-positive cells in the TGF β1 hydrogel-injected groups. In the rat decellularized human saphenous vein patch pseudoaneurysm model, there was a higher incidence of pseudoaneurysm formation when the patch was decellularized using 3% SDS, and delivery of TGF β1 hydrogel could effectively decrease the formation of pseudoaneurysm formation and increase p-smad2 and TAK1 expression. In pig aortas, hydrogels can be delivered between the medium and adventitia easily and successfully.
Conclusions
Intramural delivery of TGF β1 hydrogel can effectively decease aneurysm and pseudoaneurysm formation and progression in both mice and rats, and pig aortas can also be successfully intramurally injected with hydrogel. This technique may be a promising drug delivery method and therapeutic choice to decrease aneurysm and pseudoaneurysm formation and progression in the clinic.
... However, these results have not translated to humans. 13 Studies of the effects of propranolol have not demonstrated statistically significant results and have been further complicated by poor tolerance in patients. 13 ...
Introduction:
Abdominal aortic aneurysms (AAA) more commonly affect men than women and are estimated to affect 4% to 8% of men older that age 60 years. Mortality because of a ruptured AAA is high, but elective repair is an effective and relatively safe intervention.
Case presentation:
A 79-year-old man came to the Emergency Department because of worsening back pain. Workup revealed a previously unknown, 10-cm aneurysm that had ruptured. Unfortunately, the patient died during emergency surgery.
Discussion:
A literature review of proper screening, referral timeframe, the most common surgical techniques, potential complications, and postoperative surveillance was conducted. Early detection, referral to vascular surgery, and possible open or endovascular repair are key to limiting the morbidity and mortality associated with AAA.
... Pharmacological approaches to limit progression of small AAA (30-50 mm) using anti-inflammatory drugs have not been successful 3,4 . Surgical interventions for the large AAAs (>50 mm) are associated with a significant financial burden and do not provide long-term survival advantages for the small AAAs (≥30-50 mm) [5][6][7] . These limited options for treatment of AAA highlight the need for innovative research to halt the progression of the disease. ...
Abdominal aortic aneurysm (AAA) is characterized by transmural infiltration of myeloid cells at the vascular injury site. Previously, we reported preventive effects of Notch deficiency on the development of AAA by reduction of infiltrating myeloid cells. In this study, we examined if Notch inhibition attenuates the progression of pre-established AAA and potential implications. Pharmacological Notch inhibitor (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester; DAPT) was administered subcutaneously three times a week starting at day 28 of angiotensin II (AngII) infusion. Progressive increase in pulse wave velocity (PWV), maximal intra-luminal diameter (MILD) and maximal external aortic diameter (MEAD) were observed at day 56 of the AngII. DAPT prevented such increase in MILD, PWV and MEAD (P < 0.01). Histologically, the aortae of DAPT-treated Apoe−/− mice had significant reduction in inflammatory response and elastin fragmentation. Naked collagen microfibrils and weaker banded structure observed in the aortae of Apoe−/− mice in response to AngII, were substantially diminished by DAPT. A significant decrease in the proteolytic activity in the aneurysmal tissues and vascular smooth muscle cells (vSMCs) was observed with DAPT (P < 0.01). In human and mouse AAA tissues, increased immunoreactivity of activated Notch signaling correlated strongly with CD38 expression (R2 = 0.61). Collectively, we propose inhibition of Notch signaling as a potential therapeutic target for AAA progression.
... A Cochrane review published in 2012 and a systematic review published in 2015 have summarized prior clinical trials testing drug therapies for AAA but are out of date [44,45]. In order to update these reviews, we performed a search of the PubMed database, Clinical Trials Registers and reference lists of prior reviews. ...
Abdominal aortic aneurysm (AAA) rupture is a common cause of death in adults. Current AAA treatment is by open surgical or endovascular aneurysm repair. Rodent model and human epidemiology, genetic and observational studies over the last few decades have highlighted the potential of a number of drug therapies, including medications that lower blood pressure, correct dyslipidemia, or inhibit thrombosis, inflammation or matrix remodeling, as approaches to managing small AAA. This review summarizes prior AAA pathogenesis data from animal and human studies aimed at identifying targets for the development of drug therapies. The review also systematically assesses past randomized placebo‐controlled drug trials in patients with small AAAs. Eleven previously published randomized‐controlled clinical trials testing different drug therapies aimed at slowing AAA progression were identified. Five of the trials tested antibiotics and three trials assessed medications that lower blood pressure. Meta‐analyses of these trials suggested that neither of these approaches limit AAA growth. Allocation to blood pressure lowering medication was associated with a small reduction in AAA rupture or repair, compared to placebo (relative risk 0.94, 95% confidence intervals 0.89, 1.00, p=0.047). Three further trials assessed the effect of a mast cell inhibitor, fibrate or platelet inhibition and reported no effect on AAA growth or clinical events. Past trials were noted to have a number of design issues, particularly small sample sizes and limited follow‐up. Much larger trials are needed to properly test potential therapeutic approaches if a convincingly effective medical therapy for AAA is to be identified. This article is protected by copyright. All rights reserved.
... Several different classes of drugs have been assessed for their ability to reduce the rate of small aneurysm growth in randomised trials. To date, no class of drug has been shown to be effective, including doxycycline, beta blockers, angiotensin converting enzyme inhibitors, and statins 109,[172][173][174] and other trials are still ongoing. ...
... Some studies including clinical trials in which patients with small aneurysms allocated to medical treatment with the intention of retarding aneurysm expansion were treated with doxycycline and other antibiotics. These studies showed that there is potentially promising evidence for antibiotics reducing the growth rates of small aneurysms 40,41 . However, more research is needed to develop strategies to regulate specific MMPs and TIMPs, in a particular disease without affecting other metalloproteinases that are vital for maintaining normal physiological functions. ...
... Several different classes of drugs have been assessed for their ability to reduce the rate of small aneurysm growth in randomised trials. To date, no class of drug has been shown to be effective, including doxycycline, beta blockers, angiotensin converting enzyme inhibitors, and statins 63,352,469,591 and other trials are still ongoing. ...
This article describes the ESVS practice guidelines for abdominal aortic and iliac aneurysms.
... These recommendation are based on four randomized, controlled trials that reported no advantage of either early elective open or endovascular surgery over monitoring and delayed surgery if the AAA became symptomatic or grew to >55 mm in maximum diameter 15,16,21,22,28 . No drug therapy has been convincingly shown to limit AAA growth or rupture [29][30][31] . The absence of a drug based therapy means that patients with small AAAs or those deemed unfit for AAA repair have no active treatment options. ...
Abdominal aortic aneurysm (AAA) rupture is an important cause of death in adults. Currently, the only treatment for AAA is open or endovascular surgical repair. In most parts of the developed world, AAAs can be identified at an early stage as a result of incidental imaging and screening programmes. Randomized clinical trials have demonstrated that early elective surgical repair of these small AAAs is not beneficial, and an unmet clinical need exists to develop medical therapies for small AAAs that limit or prevent the progressive expansion and rupture of the aneurysm. A large amount of research is currently being performed to increase the understanding of AAA pathogenesis and ultimately lead to the development of medical therapies, such as drug-based and cell-based strategies for this disease. This Review summarizes the latest research findings and current theories on AAA pathogenesis, including discussion of the pros and cons of current rodent models of AAA, and highlights potential medical therapies for AAA, summarizing previous, ongoing and potential clinical trials of medical interventions for small AAAs. This expanding volume of research on AAA is expected to result in a range of novel medical therapies for AAA within the next decade.
... A systematic review of the literature revealed that hypertension is associated with the presence of AAA but there is no evidence that the AAA expansion rate is higher in hypertensive patients [4]. Accordingly, there is no evidence supporting a beneficial effect of beta blockers on AAA expansion rate [5]. ...
In this article a brief version of the newly developed S3 guidelines on screening, diagnosis, therapy and follow-up of abdominal aortic aneurysms (AAA), which was developed under the auspices of the German Society of Vascular Surgery and VascularMedicine (DGG) is presented. In addition to the DGG, participating professional societies were the German Radiological Society (DRG), German Society for Angiology/Society for Vascular Medicine (DGA), German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI), German Society for Ultrasound in Medicine (DEGUM), German Vascular League e.V., German Society for Interventional Radiology (DEGIR), German Society for Anesthesiology and Intensive Care Medicine (DGAI), German Society for Thoracic and Cardiovascular Surgery (DGTHG) and the German Society of Surgery (DGCH). The guidelines are based on a systematic literature search in Medline (PubMed) for the period from 1 January 2000 to 1 January 2017. Important publications from 2017 were also considered. The selection of evidence was made by a multilevel screening process. In addition to the evidence, other criteria were included in the assessment of the recommendation level, such as the consistency of the study results, the clinical relevance of the endpoints and effect sizes, the benefit–risk balance, the applicability of the study results to the patient target group and the care system, the feasibility of the recommendations in everyday life, patient preferences and ethical and legal considerations. All recommendations/findings were approved with strong consensus (approval of >95% of the participating professional societies/associations). Thus, the present text version of the S3 guidelines on AAA represents the view of all participating societies.
... Doxycycline has been investigated as a molecule to inhibit matrix metalloproteinase activity since the 1990s, 1,11 and pooled results from several trials on doxycycline suggest this antibiotic may slow aneurysm growth. 12 In contrast to doxycycline, fluoroquinolones may potentiate aneurysm growth and rupture. Preclinical work from LeMaire and colleagues, demonstrating that increased matrix metalloproteinase activity is one of several effects of ciprofloxacin, 13 provides an important piece of evidence that makes the association of ciprofloxacin and aneurysm rupture 14 more compelling. ...
... While statins and ACEI are well tolerated, a recent meta-analysis on the available data concluded that these drug classes or anti-inflammatory therapies did not influence AAA progression [97]. Although animal studies have demonstrated that beta receptor blockers can inhibit the growth and rupture of aneurysms by influencing hemodynamics, which is beneficial to delay AAA expansion [98], there was no clinical evidence for a beneficial effect of such strategies on AAA progression. On the contrary, evidence was found for growth acceleration in patients taking doxycycline, a MMP inhibitor [99]. ...
Abdominal aortic aneurysm (AAA) was previously ascribed to weaken defective medial arterial/adventitial layers, for example, smooth muscle/fibroblast cells. Therefore, besides surgical repair, medications targeting the medial layer to strengthen the aortic wall are the most feasible treatment strategy for AAA. However, so far, it is unclear whether such drugs have any beneficial effect on AAA prognosis, rate of aneurysm growth, rupture, or survival. Notably, clinical studies have shown that AAA is highly associated with endothelial dysfunction in the aged population. Additionally, animal models of endothelial dysfunction and endothelial nitric oxide synthase (eNOS) uncoupling had a very high rate of AAA formation, indicating there is crucial involvement of the endothelium and a possible pharmacological solution targeting the endothelium in AAA treatment. Endothelial cells have been found to trigger vascular wall remodeling by releasing proteases, or recruiting macrophages along with other neutrophils, into the medial layer. Moreover, inflammation and oxidative stress of the arterial wall were induced by endothelial dysfunction. Interestingly, there is a paradoxical differential correlation between diabetes and aneurysm formation in retinal capillaries and the aorta. Deciphering the significance of such a difference may explain current unsuccessful AAA medications and offer a solution to this treatment challenge. It is now believed that AAA and atherosclerosis are two separate but related diseases, based on their different clinical patterns which have further complicated the puzzle. Therefore, a thorough investigation of the interaction between endothelium and medial/adventitial layer may provide us a better understanding and new perspective on AAA formation, especially after taking into account the importance of endothelium in the development of AAA. Moreover, a novel medication strategy replacing the currently used, but suboptimal treatments for AAA, could be informed with this analysis.
... Die medizinische Behandlung besteht idealerweise in der Überwachung des Blutdrucks, Senkung des Cholesterinspiegels, Rauchstopp und einer Behandlung mit Thrombozytenaggregationshemmern. Die tatsächliche Wirksamkeit von Statinen, Betablockern und ACE-Hemmern konnte in einer kürzlich veröffentlichten Meta-Analyse nicht mit einem hohen Evidenzniveau belegt werden[3]. Ist die Indikation zur Operation gestellt, ist eine Untersuchung des Patienten erforderlich, um das Operationsrisiko zu evaluieren und die bestmögliche Behandlung auszuwählen. Die präoperative Untersuchung dient zudem der etwaigen Entdeckung weiterer Aneurysmen, insbesondere im thorakalen und peripheren Bereich. ...
... Le traitement médical idéal devrait permettre le contrôle de la pression artérielle, une réduction du taux de cholestérol, un arrêt du tabac et un traitement anti-aggrégant. L'efficacité réelle des statines, des béta-bloquants ou de l'inhibiteur de l'enzyme de conversion n'a pas pu être démontrée avec un niveau d'évidence élevé dans une récente méta-analyse [3]. priée. ...
... A number of studies have assessed the efficacy of anti-hypertensive agents (β-adrenoceptor antagonists, angiotensin converting enzyme (ACE) inhibitors, diuretics, Ca 2+ channel blockers), antibiotics (macrolides, tetracyclines), lipid lowering drugs (statins) and anti-platelet agents (non-steroidal anti-inflammatory drugs) for reducing AAA expansion rate. However, following evaluation of randomized clinical trials, no statistically significant reduction in AAA growth was observed for patients who were treated with the anti-hypertensive agents [27,28]. An association study that adjusted for variables that affect AAA growth showed no effect of statin therapy on small AAA expansion [29]. ...
Abdominal aortic aneurysm (AAA) is an inflammatory disease associated with macrophage accumulation in the adventitia, oxidative stress, medial elastin degradation and aortic dilation. Progression of AAA is linked to increased risk of rupture, which carries a high mortality rate. Drug therapies trialled to date lack efficacy and although aneurysm repair is available for patients with large aneurysm, peri-surgical morbidity and mortality have been widely reported. Recent studies using rodent models of AAA suggest that long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFAs) and their metabolites can moderate inflammation and oxidative stress perpetuated by infiltrating macrophages and intervene in the destruction of medial elastin. This review examines evidence from these animal studies and related reports of inhibition of inflammation and arrest of aneurysm development following prophylactic supplementation with LC n-3 PUFAs. The efficacy of LC n-3 PUFAs for management of existing aneurysm is unclear and further investigations involving human clinical trials are warranted.
Objectives
The mortality rate of abdominal aortic aneurysm (AAA) is extremely high in the older population. This study aimed to identify potential biomarkers of AAA and aortic rupture and analyze infiltration of immune cells in stable and ruptured AAA samples.
Methods
Raw data of GSE47472, GSE57691, and GSE98278 were downloaded. After data processing, the co-expression gene networks were constructed. Gene Ontology and pathway enrichment analysis of AAA- and aortic rupture-related gene modules were conducted using the Database for Annotation, Visualization, and Integrated Discovery. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were used for further enrichment analysis. The CIBERSORT tool was used to analyze the relative abundance of immune cells in samples. Differentially expressed immune-related genes were analyzed between different samples. Predictive models were constructed via extreme gradient boosting, and hub genes were identified according to feature importance.
Results
Blue and yellow modules were significantly related to AAA, and genes in these modules were associated with the aortic wall and immune response, respectively. In terms of aortic rupture, the most relevant module was significantly enriched in the inflammatory response. The results of GSEA and GSVA suggested that immune cells and the inflammatory response were involved in the development of AAA and aortic rupture. There were significant differences in the infiltration of immune cells and expression levels of immune-related genes among different samples. NFKB1 might be an important transcription factor mediating the inflammatory response of AAA and aortic rupture. After the construction of a predictive model, CD19 , SELL , and CCR7 were selected as hub genes for AAA whereas OAS3 , IFIT1 , and IFI44L were identified as hub genes for aortic rupture.
Conclusion
Weakening of the aortic wall and the immune response both contributed to the development of AAA, and the inflammatory response was closely associated with aortic rupture. The infiltration of immune cells was significantly different between different samples. NFKB1 might be an important transcription factor in AAA and aortic rupture. CD19 , SELL , and CCR7 had potential diagnostic value for AAA. OAS3 , IFIT1 , and IFI44L might be predictive factors for aortic rupture.
Abdominal aortic aneurysm (AAA) is a progressive focal dilatation and weakening of the abdominal aorta, causing 1.3% of all deaths among men aged 65–85 years worldwide. The formation of AAA is a complex process with multiple risk factors. Therefore, this study aimed to determine the relationship of disease severity and physiological factors, and gut microbiota structures in AAA patients. Physiological indicators and fecal 16S rRNA gene sequences from healthy controls and patients with AAA were collected. The correlations between the diameter of the AAA and clinical parameters, and gut microbiota composition were then analyzed separately using multivariable analysis. The diameter of AAA was extremely positively correlated with smoking index, alkaline phosphatase, blood glucose, and blood triglycerides and negatively correlated with prealbumin and Cystatin C. As the diameter of AAA increased, the α-diversity, including Chao 1, Shannon, and Simpson indices, of the gut microbiota decreased and presented a negative linear relationship. Patients with AAA with more severe disease had significantly increased relative abundance of Enterobacteriaceae and decreased relative abundance of Veillonellaceae. A strong correlation was observed between the diameter and physiological data, as well as between diameter and gut microbiota composition. This study could improve the understanding of AAA, and gut microbiota may be a potential target to prevent and treat this deadly disease.
Background:
An abdominal aortic aneurysm (AAA) is an abnormal dilation in the diameter of the abdominal aorta of 50% or more of the normal diameter or greater than 3 cm in total. The risk of rupture increases with the diameter of the aneurysm, particularly above a diameter of approximately 5.5 cm. Perioperative and postoperative morbidity is common following elective repair in people with AAA. Prehabilitation or preoperative exercise is the process of enhancing an individual's functional capacity before surgery to improve postoperative outcomes. Studies have evaluated exercise interventions for people waiting for AAA repair, but the results of these studies are conflicting.
Objectives:
To assess the effects of exercise programmes on perioperative and postoperative morbidity and mortality associated with elective abdominal aortic aneurysm repair.
Search methods:
We searched the Cochrane Vascular Specialised register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and Physiotherapy Evidence Database (PEDro) databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 6 July 2020. We also examined the included study reports' bibliographies to identify other relevant articles.
Selection criteria:
We considered randomised controlled trials (RCTs) examining exercise interventions compared with usual care (no exercise; participants maintained normal physical activity) for people waiting for AAA repair.
Data collection and analysis:
Two review authors independently selected studies for inclusion, assessed the included studies, extracted data and resolved disagreements by discussion. We assessed the methodological quality of studies using the Cochrane risk of bias tool and collected results related to the outcomes of interest: post-AAA repair mortality; perioperative and postoperative complications; length of intensive care unit (ICU) stay; length of hospital stay; number of days on a ventilator; change in aneurysm size pre- and post-exercise; and quality of life. We used GRADE to evaluate certainty of the evidence. For dichotomous outcomes, we calculated the risk ratio (RR) with the corresponding 95% confidence interval (CI).
Main results:
This review identified four RCTs with a total of 232 participants with clinically diagnosed AAA deemed suitable for elective intervention, comparing prehabilitation exercise therapy with usual care (no exercise). The prehabilitation exercise therapy was supervised and hospital-based in three of the four included trials, and in the remaining trial the first session was supervised in hospital, but subsequent sessions were completed unsupervised in the participants' homes. The dose and schedule of the prehabilitation exercise therapy varied across the trials with three to six sessions per week and a duration of one hour per session for a period of one to six weeks. The types of exercise therapy included circuit training, moderate-intensity continuous exercise and high-intensity interval training. All trials were at a high risk of bias. The certainty of the evidence for each of our outcomes was low to very low. We downgraded the certainty of the evidence because of risk of bias and imprecision (small sample sizes). Overall, we are uncertain whether prehabilitation exercise compared to usual care (no exercise) reduces the occurrence of 30-day (or longer if reported) mortality post-AAA repair (RR 1.33, 95% CI 0.31 to 5.77; 3 trials, 192 participants; very low-certainty evidence). Compared to usual care (no exercise), prehabilitation exercise may decrease the occurrence of cardiac complications (RR 0.36, 95% CI 0.14 to 0.92; 1 trial, 124 participants; low-certainty evidence) and the occurrence of renal complications (RR 0.31, 95% CI 0.11 to 0.88; 1 trial, 124 participants; low-certainty evidence). We are uncertain whether prehabilitation exercise, compared to usual care (no exercise), decreases the occurrence of pulmonary complications (RR 0.49, 95% 0.26 to 0.92; 2 trials, 144 participants; very low-certainty evidence), decreases the need for re-intervention (RR 1.29, 95% 0.33 to 4.96; 2 trials, 144 participants; very low-certainty evidence) or decreases postoperative bleeding (RR 0.57, 95% CI 0.18 to 1.80; 1 trial, 124 participants; very low-certainty evidence). There was little or no difference between the exercise and usual care (no exercise) groups in length of ICU stay, length of hospital stay and quality of life. None of the studies reported data for the number of days on a ventilator and change in aneurysm size pre- and post-exercise outcomes.
Authors' conclusions:
Due to very low-certainty evidence, we are uncertain whether prehabilitation exercise therapy reduces 30-day mortality, pulmonary complications, need for re-intervention or postoperative bleeding. Prehabilitation exercise therapy might slightly reduce cardiac and renal complications compared with usual care (no exercise). More RCTs of high methodological quality, with large sample sizes and long-term follow-up, are needed. Important questions should include the type and cost-effectiveness of exercise programmes, the minimum number of sessions and programme duration needed to effect clinically important benefits, and which groups of participants and types of repair benefit most.
Objective
Aortic diameter (AD), used traditionally for abdominal aortic aneurysm (AAA) screening may have a role in assessing cardiovascular risk. Unfortunately, AD estimates for those without AAA are underutilised, whilst cardiovascular risk is sub-optimally managed in those with AAA. Our objective was to examine the association between AD measurements and future cardiovascular risk.
Methods
Retrospective analysis of three databases of male participants screened for aortic aneurysm disease. Imaging and clinical data were obtained from three independent sources: 1) the Multi-centre Aneurysm Screening Study (MASS) trial (n = 26 882 men); 2) the 2013/14 cohort of the English NHS AAA Screening Programme (NAAASP) (n = 237 441 men) linked with NHS hospital admission and death registry data; and 3) the Framingham Heart Study (FHS) offspring cohort (n = 649). Associations between maximal aortic diameter, as measured on ultrasound or computed tomography, and cardiovascular outcomes were examined.
Results
Cardiovascular mortality in the MASS trial, was higher in men with AAA at 13 years of follow up, compared to those without (Hazard Ratio [HR] 2.22, 95% CI 1.97–2.50, p < .001). Contemporary risk of major adverse cardiovascular events in the NAAASP was highest in those with an AAA (HR 2.91, 95% CI 2.00–4.25), whilst, extremes of aortic diameter were associated with increased risk for cardiovascular events. Aortic diameter was an independent risk factor for cardiovascular events in the FHS dataset.
Conclusion
Irrespective of the diagnosis of AAA, men attending for AAA screening who are found to have an abnormal aortic diameter are at high risk of future cardiovascular events. This currently unutilised data from AAA screening programmes has the potential to improve preventative management of cardiovascular risk.
Aims
Phenotypic switching of vascular smooth muscle cells (VSMCs) is essential for the formation of abdominal aortic aneurysms (AAAs). MicroRNA-23b (miR-23b) has recently been shown to play a vital role in maintaining the VSMC contractile phenotype; however, little is known about the role of miR-23b in the formation of AAAs. Here, we investigated whether miR-23b prevents AAA formation by inhibiting VSMC phenotypic switching.
Materials and methods
We administered angiotensin II (Ang II, 1000 ng/kg/min) or vehicle to 10–12-week-old male apolipoprotein E knockout (ApoE−/−) or C57BL/6J mice via subcutaneous osmotic minipumps for 4 weeks.
Key findings
The expression of miR-23b was significantly reduced in the aorta during the early onset of AAA in angiotensin II-treated ApoE−/− mice and in human AAA samples. In vitro experiments showed that the suppression of SMC contractile marker gene expression induced by Ang II was accelerated by miR-23b inhibitors but inhibited by mimics. In vivo studies revealed that miR-23b deficiency in Ang II-treated C57BL/6J mice aggravated the formation of AAAs in these mice compared with control mice; the opposite results were observed in miR-23b-overexpressing mice. Mechanistically, miR-23b knockdown significantly increased the expression of the transcription factor forkhead box O4 (FoxO4) during VSMC phenotypic switching induced by Ang II. In addition, a luciferase reporter assay showed that FoxO4 is a target of miR-23b in VSMCs.
Significance
Our study revealed a pivotal role for miR-23b in protecting against aortic aneurysm formation by maintaining the VSMC contractile phenotype.
Important positive and negative recommendations for the treatment of abdominal aortic aneurysms (AAA) are presented based on the guidelines of the German Society for Vascular Surgery and Vascular Medicine (DGG) and the guidelines of the European Society for Vascular and Endovascular Surgery (ESVS). Positive recommendations relate to AAA screening, monitoring of small aneurysms, quitting smoking, the indications for asymptomatic AAA repair, the choice of treatment for intact and ruptured AAA, and the follow-up after endovascular AAA repair (EVAR). Drug therapy for AAA, prophylactic carotid interventions in asymptomatic carotid stenosis prior to AAA treatment and initiation of treatment with beta blockers prior to the procedure are not recommended. Elective AAA repair in patients with limited life expectancy and treatment in centers with less than 20 AAA repairs/year are also rejected. Routine use of secondary antibiotic prophylaxis during dental procedures after preceding AAA repair is not recommended. The statements emphasize some of the recommendations of the guidelines but are not intended to replace their study.
Aortic aneurysm is a cardiovascular disease that has a great deal of notoriety all over the world. If the diagnosis is postponed, there is a strong risk
for rupture, leading to 90% mortality even before the patient arrives to the hospital. Treatment of aortic aneurysm is usually surgery in the form of
open surgery or endovascular grafting. However, this type of surgery still has some disadvantages, including the safety profile and the risk of failure.
Nanorobot surgery is a potential approach as a standard treatment for aortic aneurysm. The existence as a precision surgery will provide a better
method of delivery. A combination with canonical Particle Swarm Optimization (PSO) and bionanocomposite could improve its effectiveness,
operation and stability, creating a better nanorobot for aortic aneurysm therapy.
Background:
Aortic aneurysms are worrisome because of their predisposition to dissection and rupture. Beta-blockers are considered first line therapy for aortic aneurysms. The following meta-analysis assess if beta-blockers diminish aortic aneurysm growth.
Methods:
A literature search was performed to collect information on clinical trials that have assessed aortic aneurysm growth between beta-blockers and placebo. The primary endpoint was aortic aneurysm growth rate per year. A forest plot with a random effects model was used for analysis.
Results:
Eight clinical trials were included in the analysis. Beta-blockers showed a statistically non-significant effect on aortic aneurysm growth (standard mean difference -0.44; 95% CI [-0.44, 0.00]).
Conclusion:
Beta-blockers do not significantly influence aortic aneurysm growth. Further studies are required to find a suitable medical therapy to reduce growth rates.
Objective There is currently no medical treatment proven to limit abdominal aortic aneurysm (AAA) progression. The aim of this systematic review and meta-analysis was to pool data from previous randomised controlled trials assessing the efficacy of blood pressure-lowering and antibiotic medications in limiting AAA growth and AAA-related events, that is, rupture or repair.
Methods A systematic literature search was performed to identify randomised controlled trials that examined the efficacy of blood pressure-lowering medications or antibiotics in reducing AAA growth and AAA-related events. AAA growth (mm/year) was measured by ultrasound or computed tomography imaging. Meta-analyses were performed using random effects models. A subanalysis was conducted including trials that investigated tetracycline or macrolide antibiotics.
Results Ten randomised controlled trials including 2045 participants with an asymptomatic AAA were included. Follow-up was between 18 and 63 months. Neither blood pressure-lowering medications (mean growth±SD 2.0±2.4 vs 2.3±2.7 mm/year; standardised mean difference (SMD) −0.07, 95% CI −0.19 to 0.06; p=0.288) or antibiotics (mean growth±SD 2.6±2.1 vs 2.6±2.5 mm/year; SMD −0.11, 95% CI −0.38 to 0.16; p=0.418) reduced AAA growth or AAA-related events (blood pressure-lowering medications: 92 vs 95 events; risk ratio (RR) 0.86, 95% CI 0.66 to 1.11; p=0.244; and antibiotics: 69 vs 73 events; RR 0.93, 95% CI 0.69 to 1.25; p=0.614). The subanalysis of antibiotics showed similar results.
Conclusions This meta-analysis suggests that neither blood pressure-lowering medications or antibiotics limit growth or clinically relevant events in people with AAAs.
Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults due to aortic rupture. Surgical repair (either by endovascular or open surgery) is the only treatment for AAA. However, large randomized controlled trials have demonstrated that elective repair of small (<55 mm) AAAs does not reduce all-cause mortality. Most AAAs detected through screening programs or incidental imaging are too small to warrant immediate surgical repair. Such patients are managed conservatively with repeated imaging to monitor AAA diameter. Nonetheless, 60–70% of AAAs managed in this way eventually grow to a size warranting elective surgery. Discovery of a drug therapy which effectively slows the growth of small AAAs has significant potential to improve patient welfare and reduce the number of individuals requiring elective surgery. This chapter reviews the current understanding of AAA pathogenesis gained through assessment of animal models and clinical samples. Previous AAA drug trials are also discussed. Finally, the challenges in developing AAA drugs are outlined.
Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. To assess the effects of exercise programmes on perioperative and postoperative morbidity and mortality associated with abdominal aortic aneurysm repair. Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Aortic structure and function are controlled by the coordinated actions of different aortic cells and the extracellular matrix. Several pathways have been identified that control the aortic wall in a cell-type-specific manner and play diverse roles in various phases of aortic injury, repair, and remodeling. This complexity of signaling in the aortic wall poses challenges to the development of therapeutic strategies for treating aortic aneurysms and dissections. Here, in part II of this Recent Highlights series on aortic aneurysms and dissections, we will summarize recent studies published in Arteriosclerosis, Thrombosis, and Vascular Biology that have contributed to our knowledge of the signaling pathway-related mechanisms of aortic aneurysms and dissections.
Zusammenfassung
Aneurysmen der Extremitätenarterien haben eine geringe Inzidenz und manifestieren sich häufig durch Komplikationen. Schwerste Komplikationen sind die Ruptur und die extremitätenbedrohende Ischämie. Beide sind diagnoseführend. Eine absolute Therapieindikation besteht bei symptomatischen Aneurysmen und bei asymptomatischen ab einer Größe von 2,0 cm. Goldstandard ist extrailiakal das Interponat oder der Bypass mit venösem Graftmaterial. Endovaskuläre Methoden sind inoperablen Patienten vorbehalten und klinische Einzelfallentscheidungen. Im Gegensatz dazu sind komplexe endovaskukläre Techniken beim isolierten Iliakalaneurysma etabliert und haben die Behandlungsmöglichkeiten deutlich verbessert. Ihre Realisierung ist an die Existenz einer geeigneten Landungszone gebunden. Diese ist Grundlage einer neuen Klassifikation des isolierten Iliakalaneurysmas. Anhand morphologischer Subtypen ist mit dieser Klassifikation eine standardisierte Prozedurplanung zum Perfusionserhalt der A. iliaca interna möglich. Die vorliegende Arbeit gibt eine Übersicht über die aktuelle Behandlungsstrategie der Extremitätenarterienaneurysmen. Gemeinsamkeiten und regionale Unterschiede in der Therapie werden diskutiert.
Der vorliegende Artikel stellt eine Zusammenfassung der 2018 neuerarbeiteten S3 Leitlinie zu Screening, Diagnostik, Therapie und Nachsorge des Bauchaortenaneurysmas (AAA) aus anästhesiologischer Sicht dar. Es ist die einzig interdisziplinär erstellte Leitlinie, die insbesondere auch das perioperative anästhesiologische und intensivmedizinische Management beschreibt.
Background:
Identification of a safe and effective medical therapy for abdominal aortic aneurysm (AAA) disease remains a significant unmet medical need. Recent small cohort studies indicate that metformin, the world's most commonly prescribed oral hypoglycemic agent, may limit AAA enlargement. We sought to validate these preliminary observations in a larger cohort.
Methods:
All patients with asymptomatic AAA disease managed in the Veterans Affairs Health Care System between 2003 and 2013 were identified by International Classification of Diseases, Ninth Revision codes. Those with a concomitant diagnosis of diabetes mellitus who also received two or more abdominal imaging studies (computed tomography, magnetic resonance imaging, or ultrasound) documenting the presence and size of an AAA, separated by at least 1 year, were included for review. Maximal AAA diameters were determined from radiologic reports. Further data acquisition was censored after surgical AAA repair, when performed. Comorbidities, active smoking status, and outpatient medication records (within 6 months of AAA diagnosis) were also queried. Yearly AAA enlargement rates, as a function of metformin treatment status, were compared using two statistical models expressed in millimeters per year: a multivariate linear regression (model 1) and a multivariate mixed-effects model with random intercept and random slope (model 2).
Results:
A total of 13,834 patients with 58,833 radiographic records were included in the analysis, with radiology imaging follow-up of 4.2 ± 2.6 years (mean ± standard deviation). The average age of the patients at AAA diagnosis was 69.8 ± 7.8 years, and 39.7% had a metformin prescription within ±6 months of AAA. The mean growth rate for AAAs in the entire cohort was 1.4 ± 2.0 mm/y by model 1 analysis and 1.3 ± 1.6 mm/y by model 2 analysis. The unadjusted mean rate of AAA growth was 1.2 ± 1.9 mm/y for patients prescribed metformin compared with 1.5 ± 2.2 mm/y for those without (P < .001), a 20% decrease. This effect remained significant when adjusted for variables relevant on AAA progression: metformin prescription was associated with a reduction in yearly AAA growth rate of -0.23 mm (95% confidence interval, -0.35 to -0.16; P < .001) by model 1 analysis and 0.20 mm/y (95% confidence interval, -0.26 to -0.14; P < .001) by model 2 analysis. A subset analysis of 7462 patients with baseline AAA size of 35 to 49 mm showed a similar inhibitory effect (1.4 ± 2.0 mm/y to 1.7 ± 2.2 mm/y; P < .001). Patients' factors associated with an increased yearly AAA growth rate were baseline AAA size, metastatic solid tumors, active smoking, chronic obstructive pulmonary disease, and chronic renal disease. Factors associated with decreased yearly AAA growth rates included prescriptions for angiotensin II type 1 receptor blockers or sulfonylureas and the presence of diabetes-related complications.
Conclusions:
In a nationwide analysis of diabetic Veterans Affairs patients, prescription for metformin was associated with decreased AAA enlargement. These findings provide further support for the conduct of prospective clinical trials to test the ability of metformin to limit progression of early AAA disease.
Abdominal and thoracoabdominal aortic aneurysms are life-threatening diseases that are a frequent cause of death throughout the world. The etiology, risk factors, and indications for treatment are discussed. The history and outstanding results achieved with open surgical treatment utilizing modern practices are reviewed. The indications, techniques, outcomes, and complications of endovascular therapy, which has radically transformed the treatment approach to aortic disease, are evaluated in detail. Finally, novel approaches, including combined hybrid surgical and endovascular treatment, and new technologies, including branched and fenestrated stent grafts for the treatment of complex aortic pathology, are examined.
Background
Short-term survival benefits of endovascular aneurysm repair (EVAR) compared with open repair (OR) of intact abdominal aortic aneurysms have been shown in randomised trials, but this early survival benefit is soon lost. Survival benefit of EVAR was unclear at follow-up to 10 years.
Objective
To assess the long-term efficacy of EVAR against OR in patients deemed fit and suitable for both procedures (EVAR trial 1; EVAR-1); and against no intervention in patients unfit for OR (EVAR trial 2; EVAR-2). To appraise the long-term significance of type II endoleak and define criteria for intervention.
Design
Two national, multicentre randomised controlled trials: EVAR-1 and EVAR-2.
Setting
Patients were recruited from 37 hospitals in the UK between 1 September 1999 and 31 August 2004.
Participants
Men and women aged ≥ 60 years with an aneurysm of ≥ 5.5 cm (as identified by computed tomography scanning), anatomically suitable and fit for OR were randomly assigned 1 : 1 to either EVAR ( n = 626) or OR ( n = 626) in EVAR-1 using computer-generated sequences at the trial hub. Patients considered unfit were randomly assigned to EVAR ( n = 197) or no intervention ( n = 207) in EVAR-2. There was no blinding.
Interventions
EVAR, OR or no intervention.
Main outcome measures
The primary end points were total and aneurysm-related mortality until mid-2015 for both trials. Secondary outcomes for EVAR-1 were reinterventions, costs and cost-effectiveness.
Results
In EVAR-1, over a mean of 12.7 years (standard deviation 1.5 years; maximum 15.8 years), we recorded 9.3 deaths per 100 person-years in the EVAR group and 8.9 deaths per 100 person-years in the OR group [adjusted hazard ratio (HR) 1.11, 95% confidence interval (CI) 0.97 to 1.27; p = 0.14]. At 0–6 months after randomisation, patients in the EVAR group had a lower mortality (adjusted HR 0.61, 95% CI 0.37 to 1.02 for total mortality; HR 0.47, 95% CI 0.23 to 0.93 for aneurysm-related mortality; p = 0.031), but beyond 8 years of follow-up patients in the OR group had a significantly lower mortality (adjusted HR 1.25, 95% CI 1.00 to 1.56, p = 0.048 for total mortality; HR 5.82, 95% CI 1.64 to 20.65, p = 0.0064 for aneurysm-related mortality). The increased aneurysm-related mortality in the EVAR group after 8 years was mainly attributable to secondary aneurysm sac rupture, with increased cancer mortality also observed in the EVAR group. Overall, aneurysm reintervention rates were higher in the EVAR group than in the OR group, 4.1 and 1.7 per 100 person-years, respectively ( p < 0.001), with reinterventions occurring throughout follow-up. The mean difference in costs over 14 years was £3798 (95% CI £2338 to £5258). Economic modelling based on the outcomes of the EVAR-1 trial showed that the cost per quality-adjusted life-year gained over the patient’s lifetime exceeds conventional thresholds used in the UK. In EVAR-2, patients died at the same rate in both groups, but there was suggestion of lower aneurysm mortality in those who actually underwent EVAR. Type II endoleak itself is not associated with a higher rate of mortality.
Limitations
Devices used were implanted between 1999 and 2004. Newer devices might have better results. Later follow-up imaging declined, particularly for OR patients. Methodology to capture reinterventions changed mainly to record linkage through the Hospital Episode Statistics administrative data set from 2009.
Conclusions
EVAR has an early survival benefit but an inferior late survival benefit compared with OR, which needs to be addressed by lifelong surveillance of EVAR and reintervention if necessary. EVAR does not prolong life in patients unfit for OR. Type II endoleak alone is relatively benign.
Future work
To find easier ways to monitor sac expansion to trigger timely reintervention.
Trial registration
Current Controlled Trials ISRCTN55703451.
Funding
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and the results will be published in full in Health Technology Assessment ; Vol. 22, No. 5. See the NIHR Journals Library website for further project information.
Background:
Marfan syndrome is a hereditary disorder affecting the connective tissue and is caused by a mutation of the fibrillin-1 (FBN1) gene. It affects multiple systems of the body, most notably the cardiovascular, ocular, skeletal, dural and pulmonary systems. Aortic root dilatation is the most frequent cardiovascular manifestation and its complications, including aortic regurgitation, dissection and rupture are the main cause of morbidity and mortality.
Objectives:
To assess the long-term efficacy and safety of beta-blocker therapy as compared to placebo, no treatment or surveillance only in people with Marfan syndrome.
Search methods:
We searched the following databases on 28 June 2017; CENTRAL, MEDLINE, Embase, Science Citation Index Expanded and the Conference Proceeding Citation Index - Science in the Web of Science Core Collection. We also searched the Online Metabolic and Molecular Bases of Inherited Disease (OMMBID), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 30 June 2017. We did not impose any restriction on language of publication.
Selection criteria:
All randomised controlled trials (RCTs) of at least one year in duration assessing the effects of beta-blocker monotherapy compared with placebo, no treatment or surveillance only, in people of all ages with a confirmed diagnosis of Marfan syndrome were eligible for inclusion.
Data collection and analysis:
Two review authors independently screened titles and abstracts for inclusion, extracted data and assessed trial quality. Trial authors were contacted to obtain missing data. Dichotomous outcomes will be reported as relative risk and continuous outcomes as mean differences with 95% confidence intervals. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Main results:
One open-label, randomised, single-centre trial including 70 participants with Marfan syndrome (aged 12 to 50 years old) met the inclusion criteria. Participants were randomly assigned to propranolol (N = 32) or no treatment (N = 38) for an average duration of 9.3 years in the control group and 10.7 years in the treatment group. The initial dose of propranolol was 10 mg four times daily and the optimal dose was reached when the heart rate remained below 100 beats per minute during exercise or the systolic time interval increased by 30%. The mean (± standard error (SE)) optimal dose of propranolol was 212 ± 68 mg given in four divided doses daily.Beta-blocker therapy did not reduce the incidence of all-cause mortality (RR 0.24, 95% CI 0.01 to 4.75; participants = 70; low-quality evidence). Mortality attributed to Marfan syndrome was not reported. Non-fatal serious adverse events were also not reported. However, study authors report on pre-defined, non-fatal clinical endpoints, which include aortic dissection, aortic regurgitation, cardiovascular surgery and congestive heart failure. Their analysis showed no difference between the treatment and control groups in these outcomes (RR 0.79, 95% CI 0.37 to 1.69; participants = 70; low-quality evidence).Beta-blocker therapy did not reduce the incidence of aortic dissection (RR 0.59, 95% CI 0.12 to 3.03), aortic regurgitation (RR 1.19, 95% CI 0.18 to 7.96), congestive heart failure (RR 1.19, 95% CI 0.18 to 7.96) or cardiovascular surgery, (RR 0.59, 95% CI 0.12 to 3.03); participants = 70; low-quality evidence.The study reports a reduced rate of aortic dilatation measured by M-mode echocardiography in the treatment group (aortic ratio mean slope: 0.084 (control) vs 0.023 (treatment), P < 0.001). The change in systolic and diastolic blood pressure, total adverse events and withdrawal due to adverse events were not reported in the treatment or control group at study end point.We judged this study to be at high risk of selection (allocation concealment) bias, performance bias, detection bias, attrition bias and selective reporting bias. The overall quality of evidence was low. We do not know whether a statistically significant reduced rate of aortic dilatation translates into clinical benefit in terms of aortic dissection or mortality.
Authors' conclusions:
Based on only one, low-quality RCT comparing long-term propranolol to no treatment in people with Marfan syndrome, we could draw no definitive conclusions for clinical practice. High-quality, randomised trials are needed to evaluate the long-term efficacy of beta-blocker treatment in people with Marfan syndrome. Future trials should report on all clinically relevant end points and adverse events to evaluate benefit versus harm of therapy.
Objective:
Recent evidence suggests an important role for angiotensin-converting enzyme 2 (ACE2) in limiting abdominal aortic aneurysm (AAA). This study examined the effect of ACE2 deficiency on AAA development and the efficacy of resveratrol to upregulate ACE2 in experimental AAA. APPROACH AND RESULTS: Ace2 deletion in apolipoprotein-deficient mice (ApoE(-/)(-)Ace2(-/y) ) resulted in increased aortic diameter and spontaneous aneurysm of the suprarenal aorta associated with increased expression of inflammation and proteolytic enzyme markers. In humans, serum ACE2 activity was negatively associated with AAA diagnosis. ACE2 expression was lower in infrarenal biopsies of patients with AAA than organ donors. AAA was more severe in ApoE(-/-)Ace2(-/y) mice compared with controls in 2 experimental models. Resveratrol (0.05/100-g chow) inhibited growth of pre-established AAAs in ApoE(-/-) mice fed high-fat chow and infused with angiotensin II continuously for 56 days. Reduced suprarenal aorta dilatation in mice receiving resveratrol was associated with elevated serum ACE2 and increased suprarenal aorta tissue levels of ACE2 and sirtuin 1 activity. In addition, the relative phosphorylation of Akt and ERK (extracellular signal-regulated kinase) 1/2 within suprarenal aorta tissue and gene expression for nuclear factor of kappa light polypeptide gene enhancer in B cells 1, angiotensin type-1 receptor, and metallopeptidase 2 and 9 were significantly reduced. Upregulation of ACE2 in human aortic smooth muscle cells by resveratrol in vitro was sirtuin 1-dependent.
Conclusions:
This study provides experimental evidence of an important role for ACE2 in limiting AAA development and growth. Resveratrol upregulated ACE2 and inhibited AAA growth in a mouse model.
Hypoxia-inducible factor (HIF)-1α is a transcription factor that regulates various genes responding to hypoxic conditions. We previously reported that myeloid-specific activation of HIF-1α had protective effects on hypertensive cardiovascular remodeling in mice. However the role of myeloid lineage HIF-1α in the development of abdominal aortic aneurysm (AAA) has not been determined. Myeloid-specific HIF-1α knockout (HIF-1KO) mice were created using a Cre-lox recombination system in the background of apolipoprotein E-deficient mice. HIF-1KO and control mice were fed high-fat diet (HFD) and infused with angiotensin II (Ang II, 1800 ng/kg/min) by an osmotic mini pump for 4 weeks to induce AAA formation. Deletion of HIF-1α increased aortic external diameter (2.47±0.21 mm, vs. 1.80±0.28 mm in control, P=0.035). AAA formation rate (94.4% in HIF-1KO vs. 81.8% in control) was not statistically significant. Elastic lamina degradation grade determined by Elastica van Gieson staining was deteriorated in HIF-1KO mice (3.91±0.08, vs. 3.25±0.31 in control, P=0.013). The number of infiltrated macrophages into the abdominal aorta was increased in HIF-1KO mice. Expression of tissue inhibitors of metalloproteinases (TIMPs) was suppressed in the aorta and peritoneal macrophages from HIF-1KO mice compared with control mice. HIF-1α in myeloid lineage cells may have a protective role against AAA formation induced by Ang II and HFD in apolipoprotein E-deficient mice.
An abdominal aortic aneurysm (AAA) is an abnormal ballooning of the major abdominal artery. Some AAAs present as emergencies and require surgery; others remain asymptomatic. Treatment of asymptomatic AAAs depends on many factors but an important one is size of the aneurysm, as risk of rupture increases with aneurysm size. Large asymptomatic AAAs (> 5.5 cm in diameter) are usually operated on; very small AAAs (< 4.0 cm diameter) are monitored with ultrasonography. The optimal timing of surgery would benefit from further evidence.
This review compared long-term survival in patients with AAAs of diameter 4.0 to 5.5 cm who received immediate repair versus routine ultrasound surveillance.
For this update the Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (February 2012) and CENTRAL (2012, Issue 1). Reference lists of relevant articles were checked for additional studies and the searches were supplemented by handsearches of recent conference proceedings and information from experts in the field.
Randomised controlled trials in which men and women with asymptomatic AAAs of diameter 4.0 to 5.5 cm were randomly allocated to immediate repair or imaging-based surveillance at least every six months. Outcomes had to include mortality or survival.
Two authors (GF, MAMM) abstracted the data, which were cross-checked by the other authors (DJB, JTP). Due to the small number of trials, formal tests of heterogeneity and sensitivity analyses were not conducted.
Four trials with a combined total of 3314 patients, the UK Small Aneurysm Trial (UKSAT), the Aneurysm Detection and Management (ADAM) trial, the Comparison of Surveillance Versus Aortic Endografting for Small Aneurysm Repair (CAESAR), and the Positive Impact of Endovascular Options for treating Aneurysms Early (PIVOTAL) fulfilled the inclusion criteria. The four trials showed an early survival benefit in the surveillance group (due to 30-day operative mortality with surgery) but no significant differences in long-term survival (adjusted hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.75 to 1.02, mean follow up 10 years (UKSAT); HR 1.21, 95% CI 0.95 to 1.54, mean follow up 4.9 years (ADAM); HR 0.76, 95% CI 0.30 to 1.93, median follow up 32.4 months (CAESAR); HR 1.01, 95% CI 0.49 to 2.07, mean follow up 20 months (PIVOTAL)). The meta analyses of mortality at one year (CAESAR and PIVOTAL only) and six years (UKSAT and ADAM only) revealed a non-significant association (Peto odds ratio at one year 1.15, 95% CI 0.59 to 2.25; Peto odds ratio at six years 1.11, 95% CI 0.91 to 1.34).
The results from the four trials to date demonstrate no advantage to early repair (via open or endovascular surgery) for small AAA (4.0 to 5.5 cm) and suggest that 'best care' for these patients favours surveillance. Furthermore, the more recent trials focused on the efficacy of endovascular aneurysm repair and still failed to show benefit. Thus, both open and endovascular repair of small AAAs are not supported by currently available evidence.
Patients with abdominal aortic aneurysms (AAA) represent a high-risk surgical group. Despite medical optimization and radiological stenting interventions, mortality remains high and it is difficult to improve fitness. The aim of this pilot study was to evaluate the effect of a 6 week, supervised exercise programme (30 min continuous moderate intensity cycle ergometry, twice weekly) on anaerobic threshold (AT) in subjects with AAA.
Thirty participants with an AAA under surveillance were randomized to either the supervised exercise intervention (n=20) or a usual care control group (n=10). AT was measured using cardiopulmonary exercise testing, at baseline (AT1), week 5 (AT2), and week 7 (AT3). The change in AT (AT3-AT1) between the groups was compared using a mixed model ancova, providing the mean effect together with the standard deviation (sd) for individual patient responses to the intervention. The minimum clinically important difference (MCID) was defined as an improvement in AT of 2 ml O(2) kg(-1) min(-1).
Of the 30 participants recruited, 17 of 20 (exercise) and eight of 10 (control) completed the study. The AT in the intervention group increased by 10% (equivalent to 1.1 ml O(2) kg(-1) min(-1)) compared with the control (90% confidence interval 4-16%; P=0.007). The sd for the individual patient responses to the intervention was 8%. The estimated number needed to treat (NNT) for benefit was 5 patients.
The small mean benefit was lower than the MCID. However, the marked variability in the individual patient responses revealed that a proportion of patients did benefit clinically, with an estimated NNT of 5.
Abdominal aortic aneurysm (AAA) is a common degenerative condition with high mortality in older men. Elective surgical or endovascular repair is performed to prevent rupture of large AAAs. In contrast, despite gradual expansion, small AAAs have a low risk of rupture, and there is currently no well-defined treatment strategy for them. Therefore, a pharmacological approach for AAA is expected in the clinical setting. Indeed, several therapeutic effects of pharmacological agents have been reported in experimental models, and some agents have undergone clinical trials. Treatment with statins, angiotensin-converting enzyme-inhibitors, antibiotics, and anti-inflammatory agents appears to inhibit the growth rate of AAA in humans. However, as the sample size and follow-up period were limited in these studies, a large randomized study with long-term follow-up of small AAA should be performed to clarify the effect of these agents. Recently, the regression of AAA using molecular pharmacological approaches was reported in experimental studies. The characteristics of these strategies are the regulation of multiple molecular mediators and the signalling networks associated with AAA formation. On the basis of the results of these investigations, it may be possible to repair the injured aortic wall and obtain the remission of AAA using pharmacological therapy.
We previously reported the prevalence and associations of abdominal aortic aneurysm (AAA) in 73451 veterans aged 50 to 79 years who underwent ultrasound screening.
To understand the prevalence of and principal positive and negative risk factors for AAA, and to assess reproducibility of our previous findings.
In the new cohort of veterans undergoing screening, 52 745 subjects aged 50 to 79 without history of AAA underwent successful ultrasound screening for AAA, after completing a questionnaire on demographics and potential risk factors.
We detected AAA of 4.0 cm or larger in 613 participants (1.2%; compared with 1.4% in the earlier cohort). The direction and magnitude of the important associations reported in the first cohort were confirmed. Respective odds ratios for the major associations with AAA for the second and for the combined cohorts were as follows: 1.81 and 1.71 for age (per 7 years), 0.12 and 0. 18 for female sex, 0.59 and 0.53 for black race, 1.94 and 1.94 for family history of AAA, 4.45 and 5.07 for smoking, 0.50 and 0.52 for diabetes, and 1.60 and 1.66 for atherosclerotic diseases. The excess prevalence associated with smoking accounted for 75% of all AAAs of 4.0 cm or larger in the total population of 126 196. Associations for AAA of 3.0 to 3.9 cm were similar but tended to be somewhat weaker.
Our findings confirm our previous cohort findings. Age, smoking, family history of AAA, and atherosclerotic diseases remained the principal positive associations with AAA, and female sex, diabetes, and black race remained the principal negative associations.
In a population-based study of 6,386 men and women aged 25--84 years in Tromsø, Norway, in 1994--1995, the authors assessed the age- and sex-specific distribution of the abdominal aortic diameter and the prevalence of and risk factors for abdominal aortic aneurysm. Renal and infrarenal aortic diameters were measured with ultrasound. The mean infrarenal aortic diameter increased with age. The increase was more pronounced in men than in women. The age-related increase in the median diameter was less than that in the mean diameter. An aneurysm was present in 263 (8.9%) men and 74 (2.2%) women (p < 0.001). The prevalence of abdominal aortic aneurysm increased with age. No person aged less than 48 years was found with an abdominal aortic aneurysm. Persons who had smoked for more than 40 years had an odds ratio of 8.0 for abdominal aortic aneurysm (95% confidence interval: 5.0, 12.6) compared with never smokers. Low serum high density lipoprotein cholesterol was associated with an increased risk for abdominal aortic aneurysm. Other factors associated with abdominal aortic aneurysm were a high level of plasma fibrinogen and a low blood platelet count. Antihypertensive medication (ever use) was significantly associated with abdominal aortic aneurysm, but high systolic blood pressure was a risk factor in women only. This study indicates that risk factors for atherosclerosis are also associated with increased risk for abdominal aortic aneurysm.
Whether elective surgical repair of small abdominal aortic aneurysms improves survival remains controversial.
We randomly assigned patients 50 to 79 years old with abdominal aortic aneurysms of 4.0 to 5.4 cm in diameter who did not have high surgical risk to undergo immediate open surgical repair of the aneurysm or to undergo surveillance by means of ultrasonography or computed tomography every six months with repair reserved for aneurysms that became symptomatic or enlarged to 5.5 cm. Follow-up ranged from 3.5 to 8.0 years (mean, 4.9).
A total of 569 patients were randomly assigned to immediate repair and 567 to surveillance. By the end of the study, aneurysm repair had been performed in 92.6 percent of the patients in the immediate-repair group and 61.6 percent of those in the surveillance group. The rate of death from any cause, the primary outcome, was not significantly different in the two groups (relative risk in the immediate-repair group as compared with the surveillance group, 1.21; 95 percent confidence interval, 0.95 to 1.54). Trends in survival did not favor immediate repair in any of the prespecified subgroups defined by age or diameter of aneurysm at entry. These findings were obtained despite a low total operative mortality of 2.7 percent in the immediate-repair group. There was also no reduction in the rate of death related to abdominal aortic aneurysm in the immediate-repair group (3.0 percent) as compared with the surveillance group (2.6 percent). Eleven patients in the surveillance group had rupture of abdominal aortic aneurysms (0.6 percent per year), resulting in seven deaths. The rate of hospitalization related to abdominal aortic aneurysm was 39 percent lower in the surveillance group.
Survival is not improved by elective repair of abdominal aortic aneurysms smaller than 5.5 cm, even when operative mortality is low.
Abdominal aortic aneurysm (AAA) ruptures cause 16,000 deaths a year. Randomized clinical trials on AAA screening in Europe demonstrated ultrasonography significantly reduces AAA-related mortality. As a result, AAA screening programs were developed to prevent AAA ruptures by identifying and treating patients with AAA. An AAA is defined as an aortic diameter about 1.5 times greater than a normal aortic diameter, typically ≥3.0 cm in diameter. Based on current screening data, the diagnosis of AAA is made in 4-8% of males 65-75 years of age. Much research has been invested into determining the causes of AAA development and expansion, so that screening yield of patients and management protocols for patients with AAA can be improved. This chapter discusses the screening parameters for the diagnosis of AAA, the evolution of AAA screening from the randomized screening trials to current AAA screening programs, as well as new research improving AAA screening yield and diagnosis.
Purpose:
Animal and human studies have suggested that beta-blockade may decrease the growth rate of aneurysms. We investigated whether propranolol decreases the growth rate of small abdominal aortic aneurysms (AAAs).
Methods:
We randomly assigned patients with an asymptomatic AAA between 3.0 and 5.0 cm to receive either a placebo (n = 272) or propranolol (n = 276) in a double-blind fashion. Patients were observed for a mean of 2.5 years. The primary end point was the mean annual growth rate as determined by means of ultrasound scanning performed every 6 months. Secondary outcomes were death, surgery, withdrawal from study medication, and quality of life measured by means of the Short-form Health Survey (SF-36). The main analyses were performed by means of intention to treat.
Results:
The two groups were similar at baseline: 84% were men with a mean age of 69 years and a mean AAA size of 3.8 cm. Fewer patients in the placebo group stopped their study medication (26.8% vs 42.4%; P =.0002). The annual growth rate was similar in the two groups (placebo, 0.26 cm/y vs propranolol 0.22 cm/y; P =.11). There was a trend toward more elective surgery in the placebo group (26.5% vs 20.3%; P =.11), but there was no difference in death rate (placebo, 9% vs propranolol, 12%; P =.36). Patients in the propranolol group had significantly poorer quality of life scores in the physical functioning, physical role, and vitality dimensions of the SF-36.
Conclusion:
Patients with AAAs do not tolerate propranolol well, and the drug did not significantly affect the growth rate of small AAAs.
Background
We previously reported the prevalence and associations of abdominal aortic aneurysm (AAA) in 73,451 veterans aged 50 to 79 years who underwent ultrasound screening.
Objective
To understand the prevalence of and principal positive and negative risk factors for AAA, and to assess reproducibility of our previous findings.
Methods
In the new cohort of veterans undergoing screening, 52,745 subjects aged 50 to 79 without history of AAA underwent successful ultrasound screening for AAA, after completing a questionnaire on demographics and potential risk factors.
Results
We detected AAA of 4.0 cm or larger in 613 participants (1.2%; compared with 1.4% in the earlier cohort). The direction and magnitude of the important associations reported in the first cohort were confirmed. Respective odds ratios for the major associations with AAA for the second and for the combined cohorts were as follows: 1.81 and 1.71 for age (per 7 years), 0.12 and 0.18 for female sex, 0.59 and 0.53 for black race, 1.94 and 1.94 for family history of AAA, 4.45 and 5.07 for smoking, 0.50 and 0.52 for diabetes, and 1.60 and 1.66 for atherosclerotic diseases. The excess prevalence associated with smoking accounted for 75% of all AAAs of 4.0 cm or larger in the total population of 126,196. Associations for AAA of 3.0 to 3.9 cm were similar but tended to be somewhat weaker.
Conclusions
Our findings confirm our previous cohort findings. Age, smoking, family history of AAA, and atherosclerotic diseases remained the principal positive associations with AAA, and female sex, diabetes, and black race remained the principal negative associations.
This study investigated whether propanolol reduces the growth rate of small screen-detected abdominal aortic aneurysms (AAAs).
This was a prospective blinded randomized study of men with an aneurysm between 3 and 4·5 cm detected in a community-based screening programme.
Some 477 patients were randomized: 256 to take propanolol 40 mg and 221 controls. The mean growth rate in the propanolol group was 0·06 (95 per cent confidence interval 0–0·14) versus 0·1 (0·02–0·19) mm in the control group (P = 0·48). Propanolol decreased growth in 59 patients with an AAA larger than 3·9 cm (0·13 (0–0·31) versus 0·43 (0·26–0·60) mm in controls; P = 0·02). Compliance with propanolol treatment was poor: 31 per cent of the active treatment group were on beta blockers compared with 15 per cent in the control group. The growth in patients actually taking beta blockers was 0·24 (0·11–0·38) versus 0·25 (0·17–0·33) mm (P = 0·91). Stiffness measurements did not differ significantly between patients taking beta blockers and controls. Subgroup analysis showed an increased stiffness in the patients on beta blockers (mean(s.d.) 31·1(4·2) versus 23·4(1·9) in controls in aortas larger than 3·4 cm; P = 0·057).
Propanolol is not associated with a significant reduction in the growth of small aneurysms. Propanolol reduces the growth of aneurysms larger than 4 cm. Compliance with propanolol treatment for small aneurysms is low. Treatment of small screen-detected aneurysms with propanolol cannot be recommended. © 2000 British Journal of Surgery Society Ltd
Objective:
Eradication of Chlamydia pneumoniae infection and inhibition of elastolytic matrix metalloproteinases with doxycycline have been suggested to reduce the growth rates of small abdominal aortic aneurysms (AAA). We designed a study to investigate the efficacy of doxycycline in reducing the expansion of small AAAs.
Subjects and methods:
This was a prospective, double-blind, randomized, placebo-controlled study that was set in a university referral hospital. The study group consisted of 32 of 34 initially eligible patients who had an AAA diameter perpendicular to the aortic axis of 30 mm or more in size or a ratio of infrarenal to suprarenal aortic diameter of 1.2 or more and a diameter less than 55 mm. Patients were randomly assigned to receive either doxycycline (150 mg daily) or placebo during a 3-month period and underwent ultrasound surveillance during an 18-month period. Outcome measures included aneurysm expansion rates, the number of patients who had AAA rupture or repair, C pneumoniae antibody titers, and serum concentrations of C-reactive protein.
Results:
The aneurysm expansion rate in the doxycycline group was significantly lower than that in the placebo group during the 6- to 12-month (P = .01) and the 12- to 18-month periods (P =.01). Five patients (41%) in the placebo group and 1 patient (7%) in the doxycycline group had an overall expansion of the aneurysm of 5 mm or more during the 18-month follow-up. Among the placebo group patients, a higher expansion rate was observed in those with enhanced C pneumoniae immunoglobulin G antibody titers (> 128) than in those with lower titers (P = .03). Doxycycline treatment had no clear effect on antibody titers. However, at 6-month follow-up, C-reactive protein levels in the doxycycline group were significantly lower than the baseline levels (P = .01).
Conclusions:
The results of this small pilot study suggest that doxycycline may favorably alter the outcome of patients with small AAA. However, because of the small size of this randomized study and of the potentially confounding effect of pretreatment risk factors, doxycycline-based treatment cannot be justified only on the ground of the current results. Because of the high prevalence of this disorder and its clinical, social, and economic relevance, a multicenter study should be performed to further investigate whether there is any place for medical treatment of small AAAs.
Screening elderly men with ultrasound is an established method to reduce mortality from ruptured abdominal aortic aneurysm (AAA; Evidence Level 1a). Such programs are being implemented and generally consist of a single scan at 65 years of age. We report the results from screening 65-year-old men for AAA in middle Sweden.
All 65-year-old men (n=26,256), identified through the National Population Registry, were invited to an ultrasound examination. An AAA was defined as a maximum infrarenal aortic diameter of ≥30 mm. In total, 22 187 (85%) accepted, and 373 AAAs were detected (1.7%; 95% confidence interval, 1.5 to 1.9). With 127 previously known AAAs (repaired/under surveillance) included, the total prevalence of the disease in the population was 2.2% (95% confidence interval, 2.0 to 2.4). Self-reported smoking (odds ratio, 3.4; P<0.001), coronary artery disease (odds ratio, 2.0; P<0.001), and hypertension (odds ratio, 1.6; P=0.001) were independently associated with AAA in a multivariate logistic regression model. Thirteen percent of the entire population reported to be current smokers, one third of the frequency reported in the 1980s. The observed low prevalence of AAA was explained mainly by this change in smoking habits.
On the basis of the observed reduced exposure to risk factors, lower-than-expected prevalence of AAA among 65-year-old men, unchanged AAA repair rate, and significantly improved longevity of the elderly population, the current generally agreed-on AAA screening model can be questioned. Important issues to address are the threshold diameter for follow-up, the possible need for rescreening at a higher age, and selective screening among smokers.
Small abdominal aortic aneurysms are usually asymptomatic and managed safely in ultrasound surveillance programmes until they grow to a diameter threshold where intervention is considered. The aim of this study was to synthesize systematically the published data on growth rates for small aneurysms to investigate the evidence basis for surveillance intervals.
This was a systematic review of the literature published before January 2010, which identified 61 potentially eligible reports. Detailed review yielded 15 studies providing growth rates for aneurysms 3·0-5·5 cm in diameter (14 in millimetres per year, 1 as percentage change per year). These studies included 7630 people (predominantly men) enrolled during 1976-2005.
The pooled mean growth rate was 2·32 (95 per cent confidence interval 1·95 to 2·70) mm/year but there was very high heterogeneity between studies; the growth rate ranged from - 0·33 to + 3·95 mm/year. Six studies reported growth rates by 5-mm diameter bands, which showed the trend for growth rate to increase with aneurysm diameter. Simple methods to determine growth rate were associated with higher estimates. Meta-regression analysis showed that a 10-mm increase in aneurysm diameter was associated with a mean(s.e.m.) 1·62(0·20) mm/year increase in growth rate. Neither mean age nor percentage of women in each study had a significant effect. On average, a 3·5-cm aneurysm would take 6·2 years to reach 5·5 cm, whereas a 4·5-cm aneurysm would take only 2·3 years.
There was considerable variation in the reported growth rates of small aneurysms beyond that explained by aneurysm diameter. Fuller evidence on which to base surveillance intervals for patients in screening programmes requires a meta-analysis based on individual patient data.
A double-blind, randomized controlled trial was carried out to study the effects of statins on matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in areas of peak and low abdominal aortic aneurysm (AAA) wall stress.
A total of 40 patients undergoing elective open AAA repair were randomized to receive either atorvastatin 80 mg (n = 20) or placebo (n = 20) for 4 weeks preoperatively. Finite element analysis was used to determine AAA wall stress distribution. Full thickness aortic samples were obtained at surgery from areas of low and peak wall stress, snap-frozen, and stored at -80°C for subsequent MMP-2, -8, and -9 and TIMP-1 and -2 analyses. Statistical analysis was performed using SPSS 16.0 (SPSS Inc, Chicago, IL).
Both groups were well matched (p > 0.05) regarding age, gender, comorbidities, and duration of hospital stay. There were no statistically significant differences in levels of MMPs and TIMPs between the statin and placebo group and between areas of low and peak AAA wall stress.
The short-term use of statins is not associated in reducing levels of MMP 2, 8, and 9 and TIMP-1 and -2 in areas of low and peak wall stress in patients with AAA.
No effective medical therapy exists for early abdominal aortic aneurysm (AAA) disease. Lower extremity exercise improves aortic hemodynamics and reduces inflammation, but the safety and efficacy of exercise training in AAA disease is unknown. As an interim analysis of our prospective, randomized, longitudinal trial of exercise for AAA suppression, we investigated whether subjects with early disease could safely achieve target metabolic and hemodynamic goals.
One hundred eight participants were randomized to exercise training (EX) or usual care (UC). EX subjects participated in a combination of in-house and home exercise training, with efforts directed toward moderate daily exercise participation. Comparisons were made between EX and UC subjects who completed 1 year of follow-up (n = 26 and 31, respectively, mean age 72 ± 8 years). EX and UC groups were compared for safety, cardiopulmonary exercise test responses, weekly energy expenditure, and biometric indices.
No paradoxical increase in AAA growth rate or adverse clinical events occurred as a consequence of exercise training. EX participants expended an average of 2269 ± 1207 kcal/wk and increased exercise capacity (42% increase in treadmill time, 24% increase in estimated metabolic equivalents, P = .01 and .08 between groups, respectively). EX participants demonstrated a significant reduction in C-reactive protein and tended to reduce waist circumference and waist-to-hip ratio (P = .06 and .07, respectively).
Preliminary analyses suggest that exercise training is well tolerated and sustainable in small AAA subjects over 1 year. Despite age and comorbidities, exercising AAA subjects achieve meaningful exercise targets and significantly modify activity-dependent variables.
Abdominal aortic aneurysm is a common-but preventable-cause of death in elderly men; 4% of men at the age of 65 years have an aorta >3 cm in diameter. Continued expansion runs the risk of aneurysm rupture, a condition that is fatal in all but 15% of individuals. A national screening programme has commenced that aims to reduce the number of deaths from aneurysm rupture by 50%. The programme will detect a large number of men with a small aneurysm who are not in imminent danger of rupture, but who will join a regular ultrasound programme of surveillance. If the aneurysm expansion rate could be reduced, fewer men would be at risk of aneurysm rupture, and fewer would need elective aneurysm repair. A considerable amount is known about the pathophysiology of aneurysm growth. Exploring pharmacological means to delay or reduce aneurysm growth could make a considerable contribution to any screening programme. A number of case control studies have suggested that some antihypertensive drugs, non-steroidal anti-inflammatory drugs, antibiotics, and statins may reduce aneurysm growth rates. Data from controlled studies have provided less secure conclusions. Use of these medications, together with lifestyle modification such as stopping smoking, could become standard advice to men with a small aortic aneurysm. Further studies of novel agents and larger controlled trials of existing drugs are warranted.
Atherosclerotic plaques are a feature of abdominal aortic aneurysms (AAAs). Atherosclerosis and AAA appear to share similar risk factors. These observations have led to the conclusion that AAAs are a consequence of advanced atherosclerosis.
This review explores current theories regarding the pathogenesis of AAA and their implications for treatment.
A systematic literature search was conducted using the search terms abdominal aortic aneurysm, atherosclerosis, pathogenesis, and systemic disease. Articles were categorized according to the association of AAAs with atherosclerosis, arteriomegaly, peripheral aneurysm, systemic expression, genetics, autoimmunity, oxidative stress, and systemic disease. Twenty-nine articles reporting changes in the systemic vasculature associated with AAA and 12 articles examining the shared risk factor hypothesis were identified.
There is insufficient evidence to confirm that AAAs are the result of advanced atherosclerosis. The bulk of evidence points to AAA disease being a systemic disease of the vasculature, with a predetermined genetic susceptibility leading to a phenotype governed by environmental factors.
Abdominal aortic aneurysm (AAA) is a common and life-threatening disease characterized by progressive dilatation and rupture, and has a mortality rate of up to 90%. Surgical repair is recommended for large aneurysms, whereas small aneurysms are managed by 'watchful waiting'. The recently introduced AAA screening programs reduce aneurysm-related mortality; however, aneurysm detection leads to psychological problems and a reduced quality of life of patients. The success of pharmacological therapy for AAA in small animals continues to provide insights into the pathogenetic mechanisms of this disease. As a result, medications, such as doxycycline, roxithromycin and statins, have been used to limit the growth of AAAs in small human studies with promising results. However, randomized trials with large numbers of patients and long follow-ups are required for the thorough investigation of safe and effective medical therapies. Control of cardiovascular risk factors, particularly smoking cessation, may result in a reduced growth of the AAA and improve overall patient care.
Antibodies against Chlamydia pneumoniae are associated with an increased rate of expansion of small abdominal aortic aneurysms (AAAs). Short-term follow-up trials have shown a transient reduction AAA growth rate, in macrolide treated compared with placebo. Therefore we analysed the influence of intermittent, long-term roxithromycin treatment on AAA expansion and referral for surgery.
Eighty-four patients with small AAAs were randomized to either an annual 4 weeks' treatment with roxithromycin or placebo, and followed prospectively.
Intermittent, long-term Roxithromycin-treatment reduced mean annual growth rate by 36% compared with placebo after adjustment for potential confounders. Long-term roxithromycin-treated patients had a 29% lower risk of being referred for surgical evaluation, increasing to 57% after adjusting for potential confounders.
Annual 4 week treatment with 300 mg roxithromycin daily may reduce the progression of small AAAs, and later need for surgical repair. However, more robust studies are needed for confirmation.
The aim of the study was to evaluate the effect of azithromycin on the expansion rate of small abdominal aortic aneurysms (AAAs), and to determine whether or not a correlation exists between serological markers for Chlamydophilia pneumonia (Cpn) infection and AAA expansion.
Nine vascular centers were included and 259 patients were invited to participate. Ten patients declined and 2 patients had chronic kidney failure, leaving a total of 247 patients. Inclusion criteria were: AAA 35-49 mm and age <80 years. Patients were randomized to receive either azithromycin (Azithromax, Pfizer Inc, New York, NY) 600 mg once daily for 3 days and then 600 mg once weekly for 15 weeks, or placebo in identical tablets. The ultrasound scans were performed in a standardized way within a month before inclusion and every 6 months for a minimum follow-up time of 18 months. Cpn serology was analyzed in blood samples taken at inclusion and 6 months later. Serum was analyzed for Cpn IgA and IgG antibodies by microimmunofluorescence (MIF). Computed tomography (CT) scans were done in 66 patients at inclusion and at 1 year for volume calculations.
Thirty-four patients were excluded, ie, could not be followed for 18 months, 20 in the placebo group and 16 in the active treatment group. A total of 211 patients had at least two measurements and all were analyzed in an intention-to-treat analysis. Detectable IgA against Cpn was found in 115 patients and detectable IgG against Cpn in 160 patients. No statistically significant differences were found between the groups regarding median expansion rate measured by ultrasound scan (0.22 cm/year, interquartile range [IQR]: 0.09 to 0.34 in the placebo group vs 0.22, IQR: 0.12 to 0.36 in the treatment group, P = .85). Volume calculation did not change that outcome (10.4 cm(3)/year in the placebo group vs 15.9 cm(3)/year in the treatment group, P = .61). No correlation was found between serological markers for Cpn infection and the expansion rate. Patients taking statins in combination with acetylsalicylic acid (ASA) had significantly reduced expansion rate compared to patients who did not take statins or ASA, 0.14 cm/year vs 0.27 cm/year, P < .001.
Azithromycin did not have any effect on AAA expansion. No correlation was found between serological markers for Cpn and AAA expansion, indicating no clinical relevance for Cpn testing in AAA surveillance. However, a significant reduction in AAA expansion rate was found in patients treated with a combination of ASA and statins.
Abdominal aortic aneurysm (AAA) accumulates features of a chronic inflammatory disorder and irreversible destruction of connective tissue. A recent experimental study identified c-Jun N terminal kinase (JNK) as a proximal signaling molecule in the pathogenesis of AAA and vascular dendritic cells as key players in the inflammatory reaction and degradation of the extracellular matrix. Statins can inhibit cell proliferation and vascular inflammation, which might help prevent AAA progression. However, supporting clinical data from human studies are lacking. We hypothesized that atorvastatin might inhibit JNK and dendritic cells, resulting in suppression of inflammatory cells and matrix metalloproteinases (MMPs) in human tissue of AAA.
Patients with AAA were randomized to atorvastatin (20mg/day, n=10) and non-treated (n=10) groups. After treatment for 4 weeks, patients underwent abdominal aorta replacement, tissue specimens were obtained, and tissue composition was assessed using immunohistochemistry with quantitative image analysis.
Atorvastatin significantly reduced expression of JNK (1.1% vs. 8.1%, P=0.0002) and dendritic cells (3.2 vs. 7.2, P=0.003) compared to controls. T cells (142 vs. 315, P=0.008), macrophages (13 vs. 24, P=0.048) and immunoreactivity to MMP-2 (7.8% vs. 21%, P=0.049) and MMP-9 (13% vs. 24%, P=0.028) were also suppressed in the atorvastatin group. Serum low-density lipoprotein cholesterol level was decreased by 40% in the atorvastatin group.
Atorvastatin treatment acutely reduces JNK expression and dendritic cells, resulting in reduced inflammatory cell content and expression of MMPs in the AAA wall.
Using MRI, we reported plaque regression in thoracic aorta and retardation of plaque progression in abdominal aorta by 1-year atorvastatin. However, association between serial plaque changes and LDL-cholesterol levels was not fully elucidated.
A prospective, randomized, open-label trial.
We investigated the long-term effect of 20 versus 5-mg atorvastatin on thoracic and abdominal plaques and the association between plaque progression and on-treatment LDL-cholesterol levels in 36 hypercholesterolemic patients. MRI was performed at baseline and 1 and 2 years of treatment. Vessel wall area change was evaluated.
The 20-mg dose markedly reduced LDL-cholesterol levels (-47%) versus 5-mg (-35%) dose. After 2 years of treatment, regression of thoracic plaques was found in the 20-mg group (-15% vessel wall area reduction), but not in the 5-mg group (+7%). Although the 20-mg dose induced plaque regression (-14%) from baseline to 1 year, no further regression was seen from 1 to 2 years of treatment (-1%). Regarding abdominal plaques, progression was found in the 5-mg group (+10%), but not in the 20-mg group (+2%). Plaque progression in the 5-mg group was found from baseline to 1 year (+8%), but not from 1 to 2 years (+2%). The degree of thoracic plaque regression correlated with LDL-cholesterol reduction (r = 0.61), whereas thoracic plaque change from 1 to 2 years correlated with on-treatment LDL-cholesterol levels (r = 0.64).
Twenty milligrams of atorvastatin regressed thoracic plaques. However, maintaining low LDL-cholesterol levels was needed to prevent plaque progression. In abdominal aorta, only retardation of plaque progression was found after 2 years of 20-mg treatment.
A study of 150 patients examined by ultrasonography is described. It was designed specifically to diagnose and investigate abdominal aortic aneurysms. Sixty-four aneurysms were found. Ultrasonography was useful in distinguishing aneurysms from other conditions and there was a high degree of correlation between size measured by scanning and operative size. In addition to the demonstration of rupture it was possible to perform serial measurements. The technique is simple and quick and causes minimal disturbance to the patient.
The literature on arterial aneurysms is subject to potential misinterpretation because of inconsistencies in reporting standards. The joint councils of the Society for Vascular Surgery and the North American Chapter of the International Society for Cardiovascular Surgery appointed an ad hoc committee to address this issue. This communication, prepared in response to the need for standardized reporting, defines and classifies arterial aneurysms and recommends standards for describing the causes, manifestations, treatment, and outcome criteria that are important when publishing data on aneurysmal disease.
To assess the age- and sex-specific prevalence and risk factors for aneurysms of the abdominal aorta, the authors performed a population-based study in 5,419 subjects (42% men, 58% women) aged 55 years and over. The proximal and distal diameter of the abdominal aorta were measured by ultrasound. An aneurysm was defined as a distal aortic diameter of 35 mm or more or a dilatation of the distal part of the the abdominal aorta of 50% or more. The mean distal and proximal aortic diameter increased 0.7 mm and 0.3 mm, respectively, with every 10 years of age. In 2.1% (95% confidence interval (CI) 1.7-2.5) of the study population, an aneurysm was present, or in 4.1% (95% CI 3.2-4.9) of the men and 0.7% (95% CI 0.4-1.0) of the women. Subjects with an abdominal aneurysm were more likely to be smokers and they had higher serum cholesterol levels and higher prevalence of cardiovascular disease compared with subjects without an aneurysm. The authors conclude that the ultrasound diameter of the abdominal aorta clearly increases with age in both men and women and that the prevalence of aneurysms of the abdominal aorta in older adults in relatively high, especially in men.
Increased local production of matrix metalloproteinases (MMPs) is a potential mechanism underlying structural protein degradation in abdominal aortic aneurysms (AAA). With an elastase-induced rodent model of AAA, we determined whether pharmacologic treatment with an MMP-inhibiting tetracycline might limit the development of experimental AAA in vivo.
Forty-eight Wistar rats underwent a 2-hour perfusion of the abdominal aorta with 50 U porcine pancreatic elastase and were then treated with either subcutaneous doxycycline (25 mg/day; n=24) or saline solution vehicle (n=24). Aortic diameter was measured before and after elastase perfusion was performed and before the rats were killed at 0, 2, 7, or 14 days, and AAAs were defined as an increase in aortic diameter to at least twice that before perfusion. At death the aortic tissues were either perfusion-fixed for histologic evaluation or extracted for substrate zymographic evaluation.
Aortic diameter was not different between groups at 0 or 2 days, but it was significantly less in animals treated with doxycycline at both 7 and 14 days (mean+/-SEM, p<0.01). After day 2 the incidence of AAA was reduced from 83% (10 of 12 rats treated with saline solution) to 8% (1 of 12 animals treated with doxycycline). By histologic assessment doxycycline prevented the structural deterioration of aortic elastin without decreasing the influx of inflammatory cells. Increased aortic wall production of 92 kD gelatinase observed in a saline solution-treated control group was markedly suppressed in animals treated with doxycycline.
Treatment with an MMP-inhibiting tetracycline inhibits the development of experimental AAA in vivo. This inhibition may be due to selective blockade of elastolytic MMP expression in infiltrating inflammatory cells. Additional experiments, however, are necessitated to fully delineate this process.
To investigate features of the smoking habit and other cardiovascular risk factors associated with the development of abdominal aortic aneurysm in smokers.
Case control study of smokers recruited, between 1989 and 1992, in a London teaching hospital.
Consecutive smokers referred with abdominal aortic aneurysm (cases n=44) and 244 age and sex-matched smokers attending Dermatology, Orthopaedic and Urology clinics (controls).
Hypertension was more common amongst the patients with aneurysm (30%) than the controls (19%). Measured systolic and diastolic blood pressures were significantly higher in the aneurysm patients. The relative risk of having an abdominal aortic aneurysm increased 3.4-fold (95% CI 1.06-10.89) for those with a diastolic blood pressure of >90mmHg, p=0.035 and 4.1-fold (95% CI 1.27-13.16) for those with a mean arterial pressure > or = 100mmHg, p=0.009. Plasma lipids, fibrinogen and cotinine were similar amongst patients with aneurysm and controls. The cumulative smoking exposure was similar in the patients with aneurysm and controls, median 49 and 44 pack-years respectively. The relative risk of developing an aneurysm increased with the number of cigarettes currently smoked, p=0.008, and with increasing depth of inhalation, p=0.025, but was not associated with the tar or nicotine yield of current cigarettes.
In smokers, the risk of developing an abdominal aortic aneurysm increases with increasing mean arterial and diastolic blood pressure and two aspects of current smoking habit: the number of cigarettes currently smoked and the depth of inhalation.
To study the propranolol treatment of small abdominal aortic aneurysms (AAA) concerning intention to treat, side effects, and inhibition of expansion.
Two-year lasting prospective randomised double-blinded intervention trial.
Hospital-based mass screening for AAA with annual ambulatory control of small AAA.
Of 122 screening-diagnosed small AAA, 51 (42%) were excluded because of contraindications or present beta-blockage, and 17 refused participation. Thus, 54 (44.3%) were included.
Participants were randomised to 40 mg propranolol twice a day or placebo.
The same observed was used to follow-up AAA-expansion, side effects, quality of life (QL), branchial and ankle blood pressure (ABI), and pulmonary function (FEV1 and FVC).
Sixty percent in the propranolol group, and 25% in the placebo group dropped out, mainly caused by dyspnoea in the propranolol group (RR=1.74, 95% C.I.: 1.06-2.86). Five (16.7%) died in the propranolol group, while 1 (4.2%) died in the placebo group (RR=1.6 (1.02-2.51)). Furthermore, decreased pulmonary function, ABI, and QL was noticed in the propranolol group. Consequently, the trial was stopped after two years. Ninety-five percent of the measurements of the AAA were measured within 2 mm variation. If expansion was defined as above 2 mm annually, the relative risk of expansion in the placebo group was 1.17 (0.74-1.85), and 2.44 (0.88-6.77) among the non-drop-outs.
Only 22% of small screenings-diagnosed AAA were treatable with propranolol for two years. Consequently, only large scale studies are capable of showing potential minor inhibition of expansion by propranolol. However, whether such treatment ever becomes ethically acceptable is debatable.
Abdominal aortic aneurysms (AAAs) have historically been considered to be a manifestation of atherosclerosis. However, there are epidemiologic and biochemical differences between occlusive atherosclerotic disease and aneurysmal disease of the aorta. A case-control study was performed to investigate risk factors for AAA at the two tertiary care hospitals in Winnipeg, Manitoba, Canada, between June 1992 and December 1995 to investigate risk factors for AAA. Newly diagnosed cases of AAA (n = 98) were compared with non-AAA controls (n = 102), who underwent ultrasound for indications similar to those of the cases. Compared with that for never smokers, the adjusted odds ratio (OR) was 2.75 (95% confidence interval (CI): 0.85, 8.91) for 1-19 pack-years, 7.31 (95% CI: 2.44, 21.9) for 20-34 pack-years, 7.35 (95% CI: 2.40, 22.5) for 35-49 pack-years, and 9.55 (95% CI: 2.81, 32.5) for 50 or more pack-years. Other factors significantly associated with AAA were male gender (OR = 2.68, 95% CI: 1.26, 5.73), diastolic blood pressure (OR per 10 mmHg = 1.88, 95% CI: 1.31, 2.69), and family history of AAA (OR = 4.77, 95% CI: 1.26, 18.1). There was an inverse association between diabetes mellitus and AAA (OR = 0.32, 95% CI: 0.12, 0.88). Neither clinical hypercholesterolemia nor serum levels of total cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol was associated with AAA. The results of this study suggest that the risk factors for AAA differ from those for atherosclerosis and that atherosclerosis per se is not an adequate explanation as the cause of AAAs.
Persons with abdominal aortic aneurysm are more likely to have a higher prevalence of risk factors for and clinical manifestations of cardiovascular disease. It is unknown whether these factors explain the high mortality rate associated with abdominal aortic aneurysm.
To describe the risk for mortality, cardiovascular mortality, and cardiovascular morbidity in persons screened for abdominal aortic aneurysm.
Longitudinal cohort study.
Four communities in the United States.
4734 men and women older than 65 years of age recruited from Medicare eligibility lists.
Abdominal ultrasonography was used to measure the aortic diameter and the ratio of infrarenal to suprarenal measurement of aortic diameter in 1992-1993. Abdominal aortic aneurysm was defined as aortic diameter of 3 cm or greater or infrarenal-to-suprarenal ratio of 1.2 or greater. Mortality, cardiovascular disease mortality, incident cardiovascular disease, and repair or rupture were assessed after 4.5 years.
The prevalence of aneurysm was 8.8%, and 87.7% of aneurysms were 3.5 cm or less in diameter. Rates of total mortality (65.1 vs. 32.8 per 1000 person-years), cardiovascular mortality (34.3 vs. 13.8 per 1000 person-years), and incident cardiovascular disease (47.3 vs. 31.0 per 1000 person-years) were higher in participants with aneurysm than in those without aneurysm; after adjustment for age, risk factors, and presence of other cardiovascular disease, the respective relative risks were 1.32, 1.36, and 1.57. Rates of repair and rupture were low.
Rates of total mortality, cardiovascular disease mortality, and incident cardiovascular disease were higher in participants with abdominal aortic aneurysm than in those without aneurysm, independent of age, sex, other clinical cardiovascular disease, and extent of atherosclerosis detected by noninvasive testing. Persons with smaller aneurysms detected by ultrasonography should be advised to modify risk factors for cardiovascular disease while under surveillance for increase in the size of the aneurysm.
Macrolide treatment has been reported to lower the risk of recurrent ischaemic heart disease. The influence of macrolides on the expansion rate of abdominal aortic aneurysms (AAAs) remains unknown. The aim was to investigate the effect of roxithromycin on the expansion rate of small AAAs.
A total of 92 subjects with a small AAA were recruited from two populations. One population consisted of 6339 men aged 65-73 years who were offered a hospital-based mass screening programme for AAA. From this population 66 subjects were recruited. The remaining 26 men were recruited from among 49 subjects diagnosed at interval screening for an initial aortic diameter between 25 and 29 mm. Subjects were randomized to receive either oral roxithromycin 300 mg once daily for 28 days or matching placebo, and followed for a mean of 1.5 years.
During the first year the mean annual expansion rate of AAAs was reduced by 44 [corrected] per cent in the intervention group (1.56 mm per year), compared with 2.80 mm per year following placebo (P = 0.02). During the second year the difference was only 5 per cent [corrected]. Multiple linear regression analysis showed that roxithromycin treatment and initial AAA size were significantly related to AAA expansion when adjusted for smoking, diastolic blood pressure and immunoglobulin A level of 20 or more [corrected]. Logistic regression analysis confirmed a significant difference in expansion rates above 2 mm annually between the intervention and placebo groups: odds ratio = 0.09 (95 per cent confidence interval 0.01-0.83) [corrected].
In comparison to placebo, roxithromycin 300 mg daily for 4 weeks reduced the expansion rate of AAAs.
Objective: Eradication of Chlamydia pneumoniae infection and inhibition of elastolytic matrix metalloproteinases with doxycycline have been suggested to reduce the growth rates of small abdominal aortic aneurysms (AAA). We designed a study to investigate the efficacy of doxycycline in reducing the expansion of small AAAs. Subjects and Methods: This was a prospective, double-blind, randomized, placebo-controlled study that was set in a university referral hospital. The study group consisted of 32 of 34 initially eligible patients who had an AAA diameter perpendicular to the aortic axis of 30 mm or more in size or a ratio of infrarenal to suprarenal aortic diameter of 1.2 or more and a diameter less than 55 mm. Patients were randomly assigned to receive either doxycycline (150 mg daily) or placebo during a 3-month period and underwent ultrasound surveillance during an 18-month period. Outcome measures included aneurysm expansion rates, the number of patients who had AAA rupture or repair, C pneumoniae antibody titers, and serum concentrations of C-reactive protein. Results: The aneurysm expansion rate in the doxycycline group was significantly lower than that in the placebo group during the 6- to 12-month (P = .01) and the 12- to 18-month periods (P = .01). Five patients (41%) in the placebo group and 1 patient (7%) in the doxycycline group had an overall expansion of the aneurysm of 5 mm or more during the 18-month follow-up. Among the placebo group patients, a higher expansion rate was observed in those with enhanced C pneumoniae immunoglobulin G antibody titers (> 128) than in those with lower titers (P = .03). Doxycycline treatment had no clear effect on antibody titers. However, at 6-month follow-up, C-reactive protein levels in the doxycycline group were significantly lower than the baseline levels (P = .01). Conclusions: The results of this small pilot study suggest that doxycycline may favorably alter the outcome of patients with small AAA. However, because of the small size of this randomized study and of the potentially confounding effect of pretreatment risk factors, doxycycline-based treatment cannot be justified only on the ground of the current results. Because of the high prevalence of this disorder and its clinical, social, and economic relevance, a multicenter study should be performed to further investigate whether there is any place for medical treatment of small AAAs. (J Vasc Surg 2001;34:606-10.)
Doxycycline has been shown to inhibit aneurysm formation in a rodent model of abdominal aortic aneurysm (AAA). The doses necessary for this inhibition (6 mg/kg) are much higher than the standard antibiotic doses (1 to 1.5 mg/kg) used in humans. Because the side effects associated with doxycycline are dose related, whether patients would tolerate doses that are four to six times higher than normal is unclear. Also unclear is whether the serum levels necessary in these animal models can be safely achieved in patients. The purposes of this study were to determine the serum concentrations necessary to inhibit aneurysm formation in a mouse model of AAA and to compare them with the plasma concentrations in patients with AAA with a standard dose of doxycycline.
Four groups of 10 mice of C57BL/6 strain were given doxycycline (0, 10, 50, and 100 mg/kg) beginning at 7 weeks of age. At 8 weeks of age, the mice underwent AAA induction through bathing periadventitial aortic tissue with 0.25 mol/L CaCl(2). Blood samples were taken 10 weeks after surgery to assess the levels of doxycycline. Aortic size was measured at AAA induction and at death with a videomicrometer. Fourteen patients with diagnosed AAA were given 100 mg of doxycycline twice a day for at least 3 months. Blood samples to determine the plasma levels of the drug were taken at 3 or 6 months. The circulating levels of doxycycline for mice and humans were assessed with high-performance liquid chromatography.
The changes in aortic size and circulating levels of doxycycline in the AAA murine model are reported. Doses of 10, 50, and 100 mg/kg accounted for a 33%, 44%, and 66% reduction of the aneurysmal growth in the mice, respectively. In patients, the circulating doxycycline levels ranged from 1.8 to 9.42 microg/mL (mean, 4.14 +/- 0.557), values similar to those obtained in mice.
The circulating doxycycline levels of the patients are comparable with those achieved in mice. Doxycycline accounts for an inhibition of 33% to 66% of the aortic growth. The findings suggest that standard doxycycline doses could inhibit AAA growth in humans.
to test the hypothesis that the presence of Chlamydia pneumoniae (C. pneumoniae) in the wall of abdominal aortic aneurysms (AAA) is associated with increased activity of matrix metalloproteinase (MMP)-2 and/or MMP-9.
case-control study.
in a series of 40 patients with AAA > or =5cm in maximal cross-sectional diameter, C. pneumoniae-DNA was identified in the aneurysm wall by nested PCR in 14 (35%) patients. Another 14 C. pneumoniae-DNA-negative AAA patients from the same series, matched for gender and aneurysm diameter, were used as controls. In each group there were 7 asymptomatic (aAAA) and 7 ruptured (rAAA) aneurysms. MMP-2 and -9 activity was estimated in AAA wall biopsies by gelatin zymography.
patients with a C. pneumoniae-DNA-positive aneurysm wall specimen showed an over-all lower activity of MMP-2 and MMP-9 (pro- and active enzyme) compared to the C. pneumoniae-DNA negative patients. However, there were no statistically significant differences in MMP activity between the two groups of patients with aAAA. Among patients with rAAA both pro-MMP-9 (p=0,026) and active-MMP-9 (p=0.007) were significantly lower in C. pneumoniae-DNA-positive patients compared to C. pneumoniae-DNA-negative patients, whereas there were no significant differences in pro-MMP-2 or active-MMP-2.
this preliminary study does not support the hypothesis that the presence of C. pneumoniae in the AAA wall is associated with increased activity of MMP-2 and MMP-9.
Macrolide treatment has been reported to reduce the risk of recurrent ischaemic heart disease. The influence of a macrolide on the expansion rate of small abdominal aortic aneurysms (AAA) is unknown at present. The aim of this study was to investigate the effect of roxithromycin on the expansion rate of small AAA.
A total of 92 patients with a small AAA were recruited from two populations. One population consisted of 6.339 men aged 65-73 years who were offered participation in a mass screening programme for AAA at the local hospital. From this population 66 subjects were recruited. The remaining 26 were recruited from among 49 subjects diagnosed at interval screening for an initial aortic diameter between 25 mm and 29 mm. The patients were randomized to receive either oral roxithromycin 300 mg once daily for 28 days or matching placebo, and followed for a mean of 1.5 years.
During the first year the mean annual expansion rate of AAA was reduced by 44% in the macrolid group (1.56 mm/year) compared to 2.80 mm/year after placebo (p = 0.02). During the second year the difference was only 5%. Multiple linear regression analysis showed that roxithromycin treatment and initial AAA size were significantly related to AAA expansion when adjusted for smoking, diastolic blood pressure, and IgA level > or = 20. The logistic regression analysis confirmed a significant difference in expansion rates above 2 mm annually between the intervention and placebo groups, OR = 0.09 (95% CI: 0.01-0.83).
In comparison to placebo, roxithromycin 300 mg daily for four weeks reduced the expansion rate of AAA.
Ruptured abdominal aortoiliac aneurysms, when treated with open surgical repair, have high morbidity and mortality rates. Since 1994, the authors have used endovascular approaches to treat this entity. Patients with presumed ruptured aortoiliac aneurysms were treated with restricted fluid resuscitation (hypotensive hemostasis), transport to the operating room, placement under local anesthesia of a brachial or femoral guide wire into the supraceliac aorta, and arteriography. If aortoiliac anatomy was suitable, an endovascular graft (stent-graft) repair was performed. If the anatomy was unfavorable, standard open repair was performed. Only if circulatory collapse occurred was a supraceliac balloon placed and inflated using the previously positioned guidewire. Of 35 patients treated in this manner, 29 underwent endovascular graft repair, and 6 required open repair. Four patients died within 30 days (operative mortality rate, 11%). Only 10 patients required supraceliac balloon control. Endovascular grafts, when combined with hypotensive hemostasis and other endovascular techniques including proximal balloon control, may improve treatment outcomes with ruptured abdominal aortoiliac aneurysms. The authors believe these techniques will become widely used for the treatment of ruptured aneurysms.
We sought to elucidate the effects of 20-mg versus 5-mg atorvastatin on thoracic and abdominal aortic plaques.
Regression of thoracic aortic plaques by simvastatin was demonstrated using magnetic resonance imaging (MRI). However, the effects of different doses of statin have not been assessed.
Using MRI, we investigated the effects of 20-mg versus 5-mg atorvastatin on thoracic and abdominal aortic plaques in 40 hypercholesterolemic patients who were randomized to receive either dose. Treatment effects were evaluated as changes in vessel wall thickness (VWT) and vessel wall area (VWA) of atherosclerotic lesions from baseline to 12 months of treatment.
The 20-mg dose induced a greater low-density lipoprotein (LDL) cholesterol reduction than did the 5-mg dose (-47% vs. -34%, p < 0.001). Although 20 mg and 5 mg reduced C-reactive protein (CRP) levels (-47% and -28%), the degree of CRP reduction did not differ between the two doses. The 20-mg dose reduced VWT and VWA of thoracic aortic plaques (-12% and -18%, p < 0.001), whereas 5 mg did not (+1% and +4%). Regarding abdominal aortic plaques, even 20 mg could not reduce VWT or VWA (-1% and +3%), but instead progression was observed with 5-mg treatment (+5% and +12%, p < 0.01). Notably, the degree of plaque regression in thoracic aorta correlated with LDL cholesterol (r = 0.64) and CRP (r = 0.49) reductions. Although changes in abdominal aortic plaques only weakly correlated with LDL cholesterol reduction (r = 0.34), they correlated with age (r = 0.41).
One-year 20-mg atorvastatin treatment induced regression of thoracic aortic plaques with marked LDL cholesterol reduction, whereas it resulted in only retardation of plaque progression in abdominal aorta. Thoracic and abdominal aortic plaques may have different susceptibilities to lipid lowering.
The aim of our study was to assess the presence of Chlmydia pneumoniae infection in AAA patients and to evaluate its association with clinical symptoms and histological signs of inflammation in the aortal wall. Fifty-two AAA patients participated in the research. Thirty healthy controls took part in serological examination. C. pneumoniae was detected by PCR and immunofluorescence in situ reaction in aorta samples of 84.6% and 86.54% of the patients, respectively. Serological markers of chronic C. pneumoniae infection were detected in 86.5% of AAA patients and in 33.3% of healthy controls. High titers of specific IgG and IgA were found in 37.8% of AAA patients with serologically defined chronic infection. All patients in "high serology" group had symptomatic aneurysm and inflammatory infiltrations in their aortal wall samples. AAA patients infected with C. pneumoniae are not a homogenous group. "High serology" group is much more prone to have symptomatic aneurysm than the remaining of AAA patients. Serology can be very useful in predicting the risk of AAA rupture. Inter-laboratory standardization of direct and indirect detection methods of C. pneumoniae infection is required to elucidate the role of these bacteria in AAA development.
To assess the mid-term outcomes up to 5 years following endovascular repair of abdominal aortic aneurysms (EVAR), following its initial introduction into practice in the UK.
A prospective voluntary Registry of Endovascular Treatment of Aneurysms (RETA) collected demographic and risk factor data, short term (30 day) outcomes and follow up outcomes up to 5 years from the 41 centres that initially undertook EVAR in the UK.
Short term outcomes (30 days): 90.4% of aneurysms were successfully excluded, 6.1% had persistent endoleaks and 5.8% of patients had died. Follow up was obtained from 30 days up to 5 years (mean 3.1 years). Returns rates for requested follow up data were 87% at 1 year and 77, 65, 52 and 51% at 2, 3, 4 and 5 years, respectively. Ninety percent of deaths at follow up were unrelated to the stent-graft or aneurysm. Persistent proximal type I endoleak was associated with significant mortality both from attempted open repair or from rupture if untreated. Other endoleaks were more benign. Complications related to the aneurysm or device occurred at an average rate of 15% per annum. The most common complications were secondary endoleaks or graft migration. Endovascular treatment was preferred if treatment was necessary for graft complications. The cumulative freedom from secondary procedure (Kaplan-Meier) were 87, 77, 70, 65 and 62% at 1, 2, 3, 4 and 5 years of follow up, respectively.
Registry data provides useful information to guide the design of more formal trials. Collecting follow up from voluntarily submitted data is difficult. The registry data remains well ahead of the trial data, but indicate that long term follow up is required in these trials, because of the high rate of complications seen at follow up.
Endovascular abdominal aortic aneurysm repair (EVAR), when compared with conventional open surgical repair, has been shown to reduce perioperative morbidity and mortality. We performed a retrospective cohort study with prospectively collected data from the Department of Veterans Affairs to examine outcomes after elective aneurysm repair.
We studied 30-day mortality, 1-year survival, and postoperative complications in 1,904 patients who underwent elective abdominal aortic aneurysm repair (EVAR n=717 [37.7%]; open n=1,187 [62.3%]) at 123 Department of Veterans Affairs hospitals between May 1, 2001 and September 30, 2003. We investigated the influence of patient, operative, and hospital variables on outcomes.
Patients undergoing EVAR had significantly lower 30-day (3.1% versus 5.6%, p=0.01) and 1- year mortality rates (8.7% versus 12.1%, p=0.018) than patients having open repair. EVAR was associated with a decrease in 30-day postoperative mortality (adjusted odds ratio[OR]=0.59; 95% CI=0.36, 0.99; p=0.04). The risk of perioperative complications was much less after EVAR (15.5% versus 27.7%; p<0.001; unadjusted OR 0.48; 95% CI=0.38, 0.61; p<0.001). Patients operated on at low volume hospitals (25% of entire cohort) were more likely to have had open repair (31.3% compared with 15.9% EVAR; p<0.001) and a nearly two-fold increase in adjusted 30-day mortality risk (OR=1.9; 95% CI=1.19, 2.98; p=0.006).
In routine daily practice, veterans who undergo elective EVAR have substantially lower perioperative mortality and morbidity rates compared with patients having open repair. The benefits of a minimally invasive approach were readily apparent in this cohort, but we recommend using caution in choosing EVAR for all elective abdominal aortic aneurysm repairs until longer-term data on device durability are available.
Patients with manifest vascular disease are at high risk of a new vascular event or death. Modification of classical risk factors is often not successful. We determined whether the extra care of a nurse practitioner could be beneficial to the cardiovascular risk profile of high-risk patients.
We conducted a randomized, controlled trial based on the Zelen design.
Two hundred and thirty-six patients with manifestations of a vascular disease and who had two or more modifiable vascular risk factors were pre-randomized to receive treatment by a nurse practitioner plus usual care or usual care alone. After 1 year, risk factors were remeasured. The primary endpoint was achievement of treatment goals for blood pressure, lipid, glucose and homocysteine levels, body mass index, and smoking.
Of the pre-randomized patients, 95 of 119 (80%) in the intervention group and 80 of 117 (68%) in the control group participated in the study. After a mean follow-up of 14 months, the patients in the intervention group achieved significantly more treatment goals than did the patients in the control group (systolic blood pressure 63 versus 37%, total cholesterol 79 versus 61%, low density lipoprotein-cholesterol 88 versus 67%, and body mass index 38 versus 24%). Medication use was increased in both groups and no differences were found in patients' quality of life (SF-36) at follow-up.
Treatment delivered by nurse practitioners, in addition to a vascular risk factor screening and prevention program, resulted in a better management of vascular risk factors than usual care alone in vascular patients after 1-year follow-up.
Current efforts to limit the mortality from abdominal aortic aneurysm (AAA) are dependent on detection and elective repair. Even by conservative estimates, there are more than 300,000 undetected AAAs in the United States, most of which are small and would not require immediate intervention. Current practice following detection of a small AAA includes education, risk factor management, and serial observation. This approach, based on the statistical probability of death from rupture compared to the morbidity and mortality of repair, can be unsettling to patients and lead to a decline in perceived quality of life. While the pathophysiology of AAA is not completely understood, observations from human tissues and animal studies have identified a number of potential targets for inhibiting aneurysm expansion. It is clear that the prominent inflammatory response identified in aneurysm tissue has a role in promoting aortic expansion. This inflammatory response is thought to account for increased expression of proteolytic enzymes. Recent work has suggested a unifying hypothesis centered on the MAP kinase family affecting both the regulation of matrix synthesis and the expression of proteolytic enzymes. The tetracycline antibiotics and antihypertensive medications that affect the angiotensin-converting enzyme system can inhibit proteolysis. There are adequate preliminary data to support a large prospective randomized trial of doxycycline to prevent aneurysm expansion.