Effects of hospital preference for endovascular repair on postoperative mortality after elective abdominal aortic aneurysm repair: analysis of the Dutch Surgical Aneurysm Audit.

BACKGROUND: Increased use of endovascular aneurysm repair (EVAR) and reduced open surgical repair (OSR), has decreased postoperative mortality after elective repair of abdominal aortic aneurysms (AAAs). The choice between EVAR or OSR depends on aneurysm anatomy, and the experience and preference of the vascular surgeon, and therefore differs between hospitals. The aim of this study was to investigate the current mortality risk difference (RD) between EVAR and OSR, and the effect of hospital preference for EVAR on overall mortality. METHODS: Primary elective infrarenal or juxtarenal aneurysm repairs registered in the Dutch Surgical Aneurysm Audit (2013-2017) were analysed. First, mortality in hospitals with a higher preference for EVAR (high-EVAR group) was compared with that in hospitals with a lower EVAR preference (low-EVAR group), divided by the median percentage of EVAR. Second, the mortality RD between EVAR and OSR was determined by unadjusted and adjusted linear regression and propensity-score (PS) analysis and then by instrumental-variable (IV) analysis, adjusting for unobserved confounders; percentage EVAR by hospital was used as the IV. RESULTS: A total of 11 997 patients were included. The median hospital rate of EVAR was 76.6 per cent. The overall mortality RD between high- and low-EVAR hospitals was 0.1 (95 per cent -0.5 to 0.4) per cent. The OSR mortality rate was significantly higher among high-EVAR hospitals than low-EVAR hospitals: 7.3 versus 4.0 per cent (RD 3.3 (1.4 to 5.3) per cent). The EVAR mortality rate was also higher in high-EVAR hospitals: 0.9 versus 0.7 per cent (RD 0.2 (-0.0 to 0.6) per cent). The RD following unadjusted, adjusted, and PS analysis was 4.2 (3.7 to 4.8), 4.4 (3.8 to 5.0), and 4.7 (4.1 to 5.3) per cent in favour of EVAR over OSR. However, the RD after IV analysis was not significant: 1.3 (-0.9 to 3.6) per cent. CONCLUSION: Even though EVAR has a lower mortality rate than OSR, the overall effect is offset by the high mortality rate after OSR in hospitals with a strong focus on EVAR.

Systematic approach towards reliable estimation of abdominal aortic aneurysm size by ultrasound imaging and CT.

BACKGROUND: The management of abdominal aortic aneurysm (AAA) is fully dictated by AAA size, but there are no uniform measurement guidelines, and systematic differences exist between ultrasound- and CT-based size estimation. The aim of this study was to devise a uniform ultrasound acquisition and measurement protocol, and to test whether harmonization of ultrasound and CT readings is feasible. METHODS: A literature review was undertaken to evaluate evidence for ultrasound-based measurement of AAA. A protocol for measuring AAA was then developed, and intraobserver and interobserver reproducibility was tested. Finally, agreement between ultrasound readings and CT-based AAA diameters was evaluated. This was an observational study of patients with a small AAA who participated in two pharmaceutical intervention trials. RESULTS: Based on a literature review, an ultrasound acquisition and reading protocol was devised. Evaluation of the protocol showed an intraobserver repeatability of 1.6 mm (2s.d.) and an interobserver intraclass correlation coefficient (ICC) of 0.97. Comparison of protocolled ultrasound readings and local CT readings indicated a good correlation (r = 0.81), but a systematic +4.1-mm difference for CT. Harmonized size readings for ultrasound imaging and CT increased the correlation (r = 0.91) and reduced the systematic difference to +1.8 mm by CT. Interobserver reproducibility of protocolized CT measurements showed an ICC of 0.94 for the inner-to-inner method and 0.96 for the outer-to-outer method. CONCLUSION: The absence of harmonized size acquisition and reading guidelines results in overtreatment and undertreatment of patients with AAA. This can be avoided by the implementation of standardized ultrasound acquisition and a harmonized reading protocol for ultrasound- and CT-based readings.

[Investigation into medical disciplinary law critically examined]. / Onderzoek naar medisch tuchtrecht onder de loep.

There is a suggestion that the medical disciplinary committees (MDC) in the Netherlands are making more severe rulings on medical professionals. In a 10-year analysis of MDC rulings, it appears that complaints made by patients are more frequently being judged to be well-founded, and that the measures being taken are more severe. The authors conclude that there is a numerical basis for the increasing severity of the rulings. However, a numerical trend as such does not constitute proof of this, as the way in which the ruling is arrived at is unknown. A more thorough analysis of the patient complaints, the ruling and the underlying arguments is necessary. The authors also make some other statements that can be refuted. The importance of the possible influence of the increasing complexity of health care as a factor in the increase in complaints to the MDC is not addressed.

A novel method for engineering autologous non-thrombogenic in situ tissue-engineered blood vessels for arteriovenous grafting.

The durability of prosthetic arteriovenous (AV) grafts for hemodialysis access is low, predominantly due to stenotic lesions in the venous outflow tract and infectious complications. Tissue engineered blood vessels (TEBVs) might offer a tailor-made autologous alternative for prosthetic grafts. We have designed a method in which TEBVs are grown in vivo, by utilizing the foreign body response to subcutaneously implanted polymeric rods in goats, resulting in the formation of an autologous fibrocellular tissue capsule (TC). One month after implantation, the polymeric rod is extracted, whereupon TCs (length 6 cm, diameter 6.8 mm) were grafted as arteriovenous conduit between the carotid artery and jugular vein of the same goats. At time of grafting, the TCs were shown to have sufficient mechanical strength in terms of bursting pressure (2382 ±â€¯129 mmHg), and suture retention strength (SRS: 1.97 ±â€¯0.49 N). The AV grafts were harvested at 1 or 2 months after grafting. In an ex vivo whole blood perfusion system, the lumen of the vascular grafts was shown to be less thrombogenic compared to the initial TCs and ePTFE grafts. At 8 weeks after grafting, the entire graft was covered with an endothelial layer and abundant elastin expression was present throughout the graft. Patency at 1 and 2 months was comparable with ePTFE AV-grafts. In conclusion, we demonstrate the remodeling capacity of cellularized in vivo engineered TEBVs, and their potential as autologous alternative for prosthetic vascular grafts.

Meta-analysis of long-term survival after elective endovascular or open repair of abdominal aortic aneurysm.

BACKGROUND: Endovascular aneurysm repair (EVAR) has become the preferred strategy for elective repair of abdominal aortic aneurysm (AAA) for many patients. However, the superiority of the endovascular procedure has recently been challenged by reports of impaired long-term survival in patients who underwent EVAR. A systematic review of long-term survival following AAA repair was therefore undertaken. METHODS: A systematic review was performed according to PRISMA guidelines. Articles reporting short- and/or long-term mortality of EVAR and open surgical repair (OSR) of AAA were identified. Pooled overall survival estimates (hazard ratios (HRs) with corresponding 95 per cent c.i. for EVAR versus OSR) were calculated using a random-effects model. Possible confounding owing to age differences between patients receiving EVAR or OSR was addressed by estimating relative survival. RESULTS: Some 53 studies were identified. The 30-day mortality rate was lower for EVAR compared with OSR: 1·16 (95 per cent c.i. 0·92 to 1·39) versus 3·27 (2·71 to 3·83) per cent. Long-term survival rates were similar for EVAR versus OSR (HRs 1·01, 1·00 and 0·98 for 3, 5 and 10 years respectively; P = 0·721, P = 0·912 and P = 0·777). Correction of age inequality by means of relative survival analysis showed equal long-term survival: 0·94, 0·91 and 0·76 at 3, 5 and 10 years for EVAR, and 0·96, 0·91 and 0·76 respectively for OSR. CONCLUSION: Long-term overall survival rates were similar for EVAR and OSR. Available data do not allow extension beyond the 10-year survival window or analysis of specific subgroups.

Migration of Aortic Occlusion Balloons in an in vitro model of the human circulation.

BACKGROUND: Aortic Occlusion Balloons (AOB) are used for hemorrhage control in hemodynamically unstable patients. Stability of an AOB is essential for reliable aortic occlusion. The primary aim of this study is to determine whether different types of AOB migrate after total, intermittent or partial occlusion in a porcine aorta positioned in an in vitro model. MATERIALS AND METHODS: A porcine thoracic aortic section was positioned in a model of the human circulation. Primary and secondary migration was tested in Cook Coda™ 2-9.0-35-120-32 and 2-10-35-140-46, Cook Medical, USA; Rescue balloon™ Tokai RB-167080-E, Tokai Medical Products, Japan; Reliant™ AB46, Medtronic, USA; Russian prototype AOB; ER-REBOA™, Prytime Medical Devices, USA; LeMaitre™ 28 and 45 Aortic Occlusion Catheter, LeMaitre Vascular, USA. These AOB were tested in hypotensive, normotensive and hypertensive scenarios. Migration in total occlusion, intermittent occlusion and partial occlusion was recorded for all AOB. RESULTS: Limited primary migration occurred in all AOB after total occlusion. The Cook Coda™ 2-9.0-35-120-32 balloon showed maximal migration in 1 test cycle. No migration occurred during intermittent occlusion. Kinking occurs in various degrees but does not seem to prevent a successful occlusion of the aorta. No migration occurred during partial occlusion except in the Russian prototype AOB. In a partial occlusion scenario, distal perfusion occurred only with 5 ml remaining in all balloon types. CONCLUSIONS: All AOB were successful in full aortic occlusion. Limited primary migration occurred in all AOB after total occlusion only the Cook Coda™ 2-9.0-35-120-32 balloon showed maximal migration once. No migration occurred during intermittent occlusion, during partial occlusion only the Russian prototype AOB migrated. Stiffness and size of the catheter are important factors in preventing migration and kinking.

Blockade of vascular endothelial growth factor receptor 2 inhibits intraplaque haemorrhage by normalization of plaque neovessels.

BACKGROUND: Plaque angiogenesis is associated with atherosclerotic lesion growth, plaque instability and negative clinical outcome. Plaque angiogenesis is a natural occurring process to fulfil the increasing demand of oxygen and nourishment of the vessel wall. However, inadequate formed, immature plaque neovessels are leaky and cause intraplaque haemorrhage. OBJECTIVE: Blockade of VEGFR2 normalizes the unbridled process of plaque neovessel formation and induces maturation of nascent vessels resulting in prevention of intraplaque haemorrhage and influx of inflammatory cells into the plaque and subsequently increases plaque stability. METHODS AND RESULTS: In human carotid and vein graft atherosclerotic lesions, leaky plaque neovessels and intraplaque haemorrhage co-localize with VEGF/VEGFR2 and angiopoietins. Using hypercholesterolaemic ApoE3*Leiden mice that received a donor caval vein interposition in the carotid artery, we demonstrate that atherosclerotic vein graft lesions at t28 are associated with hypoxia, Hif1α and Sdf1 up-regulation. Local VEGF administration results in increased plaque angiogenesis. VEGFR2 blockade in this model results in a significant 44% decrease in intraplaque haemorrhage and 80% less extravasated erythrocytes compared to controls. VEGFR2 blockade in vivo results in a 32% of reduction in vein graft size and more stable lesions with significantly reduced macrophage content (30%), and increased collagen (54%) and smooth muscle cell content (123%). Significant decreased VEGF, angiopoietin-2 and increased Connexin 40 expression levels demonstrate increased plaque neovessel maturation in the vein grafts. VEGFR2 blockade in an aortic ring assay showed increased pericyte coverage of the capillary sprouts. CONCLUSION: Inhibition of intraplaque haemorrhage by controlling neovessels maturation holds promise to improve plaque stability.

Vascular access training for REBOA placement: a feasibility study in a live tissue-simulator hybrid porcine model.

BACKGROUND: The use of resuscitative endovascular balloon occlusion of the aorta (REBOA) in patients with severe haemorrhagic shock is increasing. Obtaining vascular access is a necessary prerequisite for REBOA placement in these situations. METHODS: During the EVTM workshop (September 2017, Örebro, Sweden), 21 individuals participated in this study, 16 participants and five instructors. A formalised curriculum was constructed including basic anatomy of the femoral region and basic training in access materials for REBOA placement in zone 1. Key skills: (1) preparation of endovascular toolkit, (2) achieving vascular access in the model and (3) bleeding control with REBOA. Scoring ranged from 0 to 5 for non-anatomical skills. Identification of anatomical structures was either sufficient (score=1) or insufficient (score=0). Five consultants performed a second identical procedure as a post test. RESULTS: Consultants had significantly better overall technical skills in comparison with residents (p=0.005), while understanding of surgical anatomy showed no difference. Procedure times differed significantly (p<0.01), with residents having a median procedure time of 3 min and 24 s, consultants 2:33 and instructors 1:09. CONCLUSION: This comprehensive training model using a live tissue-simulator hybrid porcine model can be used for femoral access and REBOA placement training in medical personnel with different prior training levels. Higher levels of training are associated with faster procedure times. Further research in open and percutaneous access training is necessary to simulate real-life situations. This training method can be used in a multistep training programme, in combination with realistic moulage and perfused cadaver models.

The protective role of Toll-like receptor 3 and type-I interferons in the pathophysiology of vein graft disease.

BACKGROUND: Venous grafts are commonly used as conduits to bypass occluded arteries. Unfortunately, patency rates are limited by vein graft disease (VGD). Toll like receptors (TLRs) can be activated in vein grafts by endogenous ligands. This study aims to investigate the role of TLR3 in VGD. METHODS: Vein graft surgery was performed by donor caval vein interpositioning in the carotid artery of recipient Tlr2-/-, Tlr3-/-, Tlr4-/- and control mice. Vein grafts were harvested 7, 14 and 28d after surgery to perform immunohistochemical analysis. Expression of TLR-responsive genes in vein grafts was analysed using a RT2-profiler PCR Array. mRNA expression of type-I IFN inducible genes was measured with qPCR in bone marrow-derived macrophages (BMM). RESULTS: TLR2, TLR3 and TLR4 were observed on vein graft endothelial cells, smooth muscle cells and macrophages. Tlr3-/- vein grafts demonstrated no differences in vessel wall thickening after 7d, but after 14d a 2.0-fold increase (p = 0.02) and 28d a 1.8-fold increase (p = 0.009) compared to control vein grafts was observed, with an increased number of macrophages (p = 0.002) in the vein graft. Vessel wall thickening in Tlr4-/- decreased 0.6-fold (p = 0.04) and showed no differences in Tlr2-/- compared to control vein grafts. RT2-profiler array revealed a down-regulation of type-I IFN inducible genes in Tlr3-/- vein grafts. PolyI:C stimulated BMM of Tlr3-/- mice showed a reduction of Ifit1 (p = 0.003) and Mx1 (p < 0.0001) mRNA compared to control. CONCLUSIONS: We here demonstrate that TLR3 can play a protective role in VGD development, possibly regulated via type-I IFNs and a reduced inflammatory response.

The role of CD27-CD70-mediated T cell co-stimulation in vasculogenesis, arteriogenesis and angiogenesis.

BACKGROUND: T cells have a distinctive role in neovascularization, which consists of arteriogenesis and angiogenesis under pathological conditions and vasculogenesis under physiological conditions. However, the role of co-stimulation in T cell activation in neovascularization has yet to be established. The aim of this study was to investigate the role T cell co-stimulation and inhibition in angiogenesis, arteriogenesis and vasculogenesis. METHODS AND RESULTS: Hind limb ischemia was induced by double ligation of the left femoral artery in mice and blood flow recovery was measured with Laser Doppler Perfusion Imaging in control, CD70-/-, CD80/86-/-, CD70/80/86-/- and CTLA4+/- mice. Blood flow recovery was significantly impaired in mice lacking CD70 compared to control mice, but was similar in CD80/86-/-, CTLA4+/- and control mice. Mice lacking CD70 showed impaired vasculogenesis, since the number of pre-existing collaterals was reduced as observed in the pia mater compared to control mice. In vitro an impaired capability of vascular smooth muscle cells (VSMC) to activate T cells was observed in VSMC lacking CD70. Furthermore, CD70-/-, CD80/86-/- and CD70/80/86-/- mice showed reduced angiogenesis in the soleus muscle 10 days after ligation. Arteriogenesis was also decreased in CD70-/- compared to control mice 10 and 28 days after surgery. CONCLUSIONS: The present study is the first to describe an important role for T cell activation via co-stimulation in angiogenesis, arteriogenesis and vasculogenesis, where the CD27-CD70 T cell co-stimulation pathway appears to be the most important co-stimulation pathway in pre-existing collateral formation and post-ischemic blood flow recovery, by arteriogenesis and angiogenesis.

Systematic review of mortality risk prediction models in the era of endovascular abdominal aortic aneurysm surgery.

BACKGROUND: The introduction of endovascular aneurysm repair (EVAR) has reduced perioperative mortality after abdominal aortic aneurysm (AAA) surgery. The objective of this systematic review was to assess existing mortality risk prediction models, and identify which are most useful for patients undergoing AAA repair by either EVAR or open surgical repair. METHODS: A systematic search of the literature was conducted for perioperative mortality risk prediction models for patients with AAA published since 2006. PRISMA guidelines were used; quality was appraised, and data were extracted and interpreted following the CHARMS guidelines. RESULTS: Some 3903 studies were identified, of which 27 were selected. A total of 13 risk prediction models have been developed and directly validated. Most models were based on a UK or US population. The best performing models regarding both applicability and discrimination were the perioperative British Aneurysm Repair score (C-statistic 0·83) and the preoperative Vascular Biochemistry and Haematology Outcome Model (C-statistic 0·85), but both lacked substantial external validation. CONCLUSION: Mortality risk prediction in AAA surgery has been modelled extensively, but many of these models are weak methodologically and have highly variable performance across different populations. New models are unlikely to be helpful; instead case-mix correction should be modelled and adapted to the population of interest using the relevant mortality predictors.

The Consequences of Real Life Practice of Early Abdominal Aortic Aneurysm Repair: A Cost-Benefit Analysis.

BACKGROUND: The reported 54 mm median intervention diameter for endovascular aneurysm repair (EVAR) in the Vascular Quality Initiative and European data from the Pharmaceutical Aneurysm Stabilisation Trial (PHAST) implies that in real life the majority of abdominal aortic aneurysm (AAA) repairs occur at diameters smaller than the consensus intervention threshold of 55 mm. This study explores the potential consequences of this practice. METHODS: The differences between real life AAA repair and consensus based intervention threshold were explored in reported data from vascular quality initiatives and PHAST. The subsequent consequences of advancement of endovascular aneurysm repair (EVAR) were estimated using a multistate model based on life tables for the EVAR Medicare population. RESULTS: There appears an approximate 5 mm difference in AAA diameter between real life practice and consensus intervention threshold. Assuming a 2.5 mm annual growth rate, this results in an approximately 2 year advancement of AAA repair. According to the model used, early repair reduces overall small aneurysm patient mortality by 2.3%, it results in 21.9% more EVAR procedures, more EVAR related deaths, and 42.3% and 36.8% more open and endovascular re-interventions, respectively. Cost-benefit estimates imply 482 fewer AAA related deaths, but 140 extra EVAR related deaths for a population of more than 30,000 AAA patients, and a 300 million USD increase in health costs for the 8 year observation period in the Medicare population. CONCLUSIONS: In the real life situation a large proportion of EVAR procedures appear to occur before reaching the consensus threshold. Although this reduces mortality, it comes at a cost of approximately 1 million USD per prevented rupture related death.

[How we can learn better and more safely from serious incidents; translation of 'Just Culture' and 'Safety-II' into clinical practice]. / Hoe we beter en veilig kunnen leren van calamiteiten.

After a serious incident, all involved expect it will provide an opportunity to learn and that improvements will follow. However, 'safe' learning is often threatened due to a primary focus on accountability. Focus should, instead, be on the needs of both patients and care providers, with the goal of repairing damage and restoring trust in the wider sense - a culture of justice ('Just Culture'). Common daily practice is a more realistic focus for further investigation, with active involvement of healthcare professionals ('Safety-II'). This means that an event is no longer reduced to 'human failure' but that complex work processes and interdependencies are thoroughly investigated, as to understand how things mostly go well but sometimes also go wrong. Deeper insight into the context of a serious incident and its relation to daily practice could ensure that plans for improvement are more closely aligned with this daily practice. Primary focus on the needs of those involved, and appreciation of the complex context, can allow for a safe and realistic approach to learning from undesirable events, such as serious incidents.

Adjusted Hospital Outcomes of Abdominal Aortic Aneurysm Surgery Reported in the Dutch Surgical Aneurysm Audit.

OBJECTIVE/BACKGROUND: The Dutch Surgical Aneurysm Audit (DSAA) is mandatory for all patients with primary abdominal aortic aneurysms (AAAs) in the Netherlands. The aims are to present the observed outcomes of AAA surgery against the predicted outcomes by means of V-POSSUM (Vascular-Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity). Adjusted mortality was calculated by the original and re-estimated V(physiology)-POSSUM for hospital comparisons. METHODS: All patients operated on from January 2013 to December 2014 were included for analysis. Calibration and discrimination of V-POSSUM and V(p)-POSSUM was analysed. Mortality was benchmarked by means of the original V(p)-POSSUM formula and risk-adjusted by the re-estimated V(p)-POSSUM on the DSAA. RESULTS: In total, 5898 patients were included for analysis: 4579 with elective AAA (EAAA) and 1319 with acute abdominal aortic aneurysm (AAAA), acute symptomatic (SAAA; n = 371) or ruptured (RAAA; n = 948). The percentage of endovascular aneurysm repair (EVAR) varied between hospitals but showed no relation to hospital volume (EAAA: p = .12; AAAA: p = .07). EAAA, SAAA, and RAAA mortality was, respectively, 1.9%, 7.5%, and 28.7%. Elective mortality was 0.9% after EVAR and 5.0% after open surgical repair versus 15.6% and 27.4%, respectively, after AAAA. V-POSSUM overestimated mortality in most EAAA risk groups (p < .01). The discriminative ability of V-POSSUM in EAAA was moderate (C-statistic: .719) and poor for V(p)-POSSUM (C-statistic: .665). V-POSSUM in AAAA repair overestimated in high risk groups, and underestimated in low risk groups (p < .01). The discriminative ability in AAAA of V-POSSUM was moderate (.713) and of V(p)-POSSUM poor (.688). Risk adjustment by the re-estimated V(p)-POSSUM did not have any effect on hospital variation in EAAA but did in AAAA. CONCLUSION: Mortality in the DSAA was in line with the literature but is not discriminative for hospital comparisons in EAAA. Adjusting for V(p)-POSSUM, revealed no association between hospital volume and treatment or outcome. Risk adjustment for case mix by V(p)-POSSUM in patients with AAAA has been shown to be important.

[How does a surgeon decide that surgery is the best option?Assessing whether or not to operate]. / Hoe besluit de chirurg dat opereren het beste is?

All abdominal surgical procedures have a certain risk/benefit ratio. Recently, the way surgeons come to a decision whether to operate, or not, was discussed in the Annals of Surgery. First, the assessment of the decision for an operative versus a non-operative strategy was addressed on the basis of clinical vignettes. The perceptions concerning risk/benefit balance varied considerably between surgeons and these perceptions predicted the decision to operate. In a second paper, surgeons were randomized to either an arm in which they were exposed to a risk calculator or to a control arm. The decisions of the risk-calculator arm were less varied, but did not alter the likelihood of recommending an operation. Perhaps surgeons decide to operate or not rather intuitively, based on clinical and laboratory information. Alternatively, they may consider the statistically significant difference in risk/benefit to be less relevant. A better insight into surgeons' decision making and the way in which they weigh benefits against risks is very useful, but it is proving to be a considerable research challenge.

[Assessments during Medical Specialists Training: quantity or quality?] / Toetsen in de vervolgopleiding.

Structured assessments form a mandatory part of Dutch Medical Specialist Training, but create administrative workload for both the staff and supervisors. One could argue that the quality of the narrative feedback is more important than the extensive reporting in learning portfolios, and that the focus should be on continuous on-the-job coaching.

Editor's Choice - Pharmaceutical Management of Small Abdominal Aortic Aneurysms: A Systematic Review of the Clinical Evidence.

BACKGROUND: Management of abdominal aortic aneurysms (AAAs) relies on surgical repair of larger AAAs. Consequently medical interventions inhibiting AAA progression could greatly reduce the need for surgical repair. A spectrum of pharmaceutical strategies has been reported, albeit conclusions often appear contradictory. Given the longstanding interest in pharmaceutical AAA stabilization, a systematic review of the available literature is relevant. OBJECTIVES: The aim is to provide an up to date systematic review of the available data on pharmaceutical therapies for stabilizing or impeding AAA growth. METHODS: A search using Pubmed, Embase, Web of science, Cochrane, CINAHL, Academic Search Premier, and Science Direct identified 27 eligible papers that studied the clinical effect of the pharmaceutical therapy on AAA diameter growth. RESULTS: This review shows that there is currently no pharmaceutical strategy that reduces AAA growth. Most studies are of poor methodological quality. Initial promising reports are often not confirmed in subsequent larger studies, raising the possibility of selective reporting. CONCLUSION: There is currently no pharmaceutical means that halts AAA growth.

A change in inflammatory footprint precedes plaque instability: a systematic evaluation of cellular aspects of the adaptive immune response in human atherosclerosis.

BACKGROUND: Experimental studies characterize adaptive immune response as a critical factor in the progression and complications of atherosclerosis. Yet, it is unclear whether these observations translate to the human situation. This study systematically evaluates cellular components of the adaptive immune response in a biobank of human aortas covering the full spectrum of atherosclerotic disease. METHODS AND RESULTS: A systematic analysis was performed on 114 well-characterized perirenal aortic specimens with immunostaining for T-cell subsets (CD3/4/8/45RA/45RO/FoxP3) and the Th1/non-Th1/Th17 ratio (CD4(+)T-bet(+)/CD4(+)T-bet(-)/CD4(+)/interleukin-17(+) double staining). CD20 and CD138 were used to identify B cells and plasma cells, while B-cell maturation was evaluated by AID/CD21 staining and expression of lymphoid homeostatic CXCL13. Scattered CD4 and CD8 cells with a T memory subtype were found in normal aorta and early, nonprogressive lesions. The total number of T cells increases in progressive atherosclerotic lesions (≈1:5 CD4/CD8 T-cell ratio). A further increase in medial and adventitial T cells is found upon progression to vulnerable lesions.This critical stage is further hallmarked by de novo formation of adventitial lymphoidlike structures containing B cells and plasma cells, a process accompanied by transient expression of CXCL13. A dramatic reduction of T-cell subsets, disappearance of lymphoid structures, and loss of CXCL13 expression characterize postruptured lesions. FoxP3 and Th17 T cells were minimally present throughout the atherosclerotic process. CONCLUSIONS: Transient CXCL13 expression, restricted presence of B cells in human atherosclerosis, along with formation of nonfunctional extranodal lymphoid structures in the phase preceding plaque rupture, indicates a "critical" change in the inflammatory footprint before and during plaque destabilization.