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Abdominal aortic aneurysms (AAA) are the most frequent aortic dilation, with considerable morbidity and mortality. Inflammatory (infl) and IgG4-positive AAAs represent specific subtypes of unclear incidence and clinical significance. Here, histologic and serologic analyses with retrospective clinical data acquisition are investigated via detailed histology, including morphologic (HE, EvG: inflammatory subtype, angiogenesis, and fibrosis) and immunhistochemic analyses (IgG and IgG4). In addition, complement factors C3/C4 and immunoglobulins IgG, IgG2, IgG4 and IgE were measured in serum samples and clinical data uses patients’ metrics, as well as through semi-automated morphometric analysis (diameter, volume, angulation and vessel tortuosity). A total of 101 eligible patients showed five (5%) IgG4 positive (all scored 1) and seven (7%) inflammatory AAAs. An increased degree of inflammation was seen in IgG4 positive and inflAAA, respectively. However, serologic analysis revealed no increased levels of IgG or IgG4. The operative procedure time was not different for those cases and the short-term clinical outcomes were equal for the entire AAA cohort. Overall, the incidence of inflammatory and IgG4-positive AAA samples seems very low based on histologic and serum analyses. Both entities must be considered distinct disease phenotypes. Short-term operative outcomes were not different for both sub-cohorts.

Background While numerous interventions effectively interfered with abdominal aortic aneurysm (AAA) formation/progression in preclinical models, none of the successes translated into clinical success. Hence, a systematic exploration of parallel and divergent processes in clinical AAA disease and its 2 primary models (the porcine pancreatic elastase and angiotensin‐II infusion [AngII] murine model) was performed to identify mechanisms relevant for aneurysm disease. Methods and Results This study combines Movat staining and pathway analysis for histological and genomic comparisons between clinical disease and its models. The impact of a notable genomic signal for metabolic reprogramming was tested in a rescue trial (AngII model) evaluating the impact of 1‐(4‐pyridinyl)‐3‐(2‐quinolinyl)‐2‐propen‐1‐one (PFK15)‐mediated interference with main glycolytic switch PFKFB3. Histological evaluation characterized the AngII model as a dissection model that is accompanied by adventitial fibrosis. The porcine pancreatic elastase model showed a transient inflammatory response and aortic dilatation, followed by stabilization and fibrosis. Normalization of the genomic responses at day 14 confirmed the self‐limiting nature of the porcine pancreatic elastase model. Clear parallel genomic responses with activated adaptive immune responses, and particularly strong signals for metabolic switching were observed in human AAA and the AngII model. Rescue intervention with the glycolysis inhibitor PFK15 in the AngII model showed that interference with the glycolytic switching quenches aneurysm formation. Conclusions Despite clear morphological contrasts, remarkable genomic parallels exist for clinical AAA disease and the AngII model. The metabolic response appears causatively involved in AAA progression and provides a novel therapeutic target. The clear transient genomic response classifies the porcine pancreatic elastase model as a disease initiation model.

BACKGROUND The German quality assurance guideline on abdominal aortic aneurysm (AAA) was implemented by the Joint Federal Committee (Gemeinsamer Bundesausschuss, G-BA) in 2008. The aims of this study were to verify the association between hospital case volume and outcome and to assess the hypothetical effect of minimum caseload requirements. METHODS The German diagnosis-related groups statistics for the years 2012 to 2016 were scrutinized for AAA (ICD-10 GM I71.3/4) with procedure codes for endo - vascular or open surgical treatment. The primary endpoint was in-hospital mortality. Logistic regression models were used for risk adjustment, and odds ratios (OR) were calculated as a function of the annual hospital-level case volume of AAA. In a hypo - thetical approach, the linear distances for various minimum caseloads (MC) were evaluated to assess accessibility. RESULTS The mortality of intact AAA (iAAA) was 2.7% (men [M] 2.4%, women [W] 4.2%); ruptured AAA (rAAA), 36.9% (M 36.9%, F 37.5%). An inverse relationship between annual hospital case volume of AAA and mortality was confirmed (iAAA/rAAA: from 3.9%/51% [

Introduction Abdominal aortic aneurysm (AAA) is a condition that has considerable socioeconomic impact and an eventual rupture is associated with high mortality and morbidity. Despite decades of research, surgical repair remains the treatment of choice and no medical therapy is currently available. Animal models and, in particular, murine models, of AAA are a vital tool for experimental in vivo research. However, each of the different models has individual limitations and provide only partial mimicry of human disease. This narrative review addresses the translational potential of the available mouse models, highlighting unanswered questions from a clinical perspective. It is based on a thorough presentation of the available literature and more than a decade of personal experience, with most of the available models in experimental and translational AAA research. Results From all the models published, only the four inducible models, namely the angiotensin II model (AngII), the porcine pancreatic elastase perfusion model (PPE), the external periadventitial elastase application (ePPE), and the CaCl2 model have been widely used by different independent research groups. Although the angiotensin II model provides features of dissection and aneurysm formation, the PPE model shows reliable features of human AAA, especially beyond day 7 after induction, but remains technically challenging. The translational value of ePPE as a model and the combination with β-aminopropionitrile to induce rupture and intraluminal thrombus formation is promising, but warrants further mechanistic insights. Finally, the external CaCl2 application is known to produce inflammatory vascular wall thickening. Unmet translational research questions include the origin of AAA development, monitoring aneurysm growth, gender issues, and novel surgical therapies as well as novel nonsurgical therapies. Conclusion New imaging techniques, experimental therapeutic alternatives, and endovascular treatment options provide a plethora of research topics to strengthen the individual features of currently available mouse models, creating the possibility of shedding new light on translational research questions.

Collecting biological tissue samples in a biobank grants a unique opportunity to validate diagnostic and therapeutic strategies for translational and clinical research. In the present work, we provide our long-standing experience in establishing and maintaining a biobank of vascular tissue samples, including the evaluation of tissue quality, especially in formalin-fixed paraffin-embedded specimens (FFPE). Our Munich Vascular Biobank includes, thus far, vascular biomaterial from patients with high-grade carotid artery stenosis (n = 1567), peripheral arterial disease (n = 703), and abdominal aortic aneurysm (n = 481) from our Department of Vascular and Endovascular Surgery (January 2004⁻December 2018). Vascular tissue samples are continuously processed and characterized to assess tissue morphology, histological quality, cellular composition, inflammation, calcification, neovascularization, and the content of elastin and collagen fibers. Atherosclerotic plaques are further classified in accordance with the American Heart Association (AHA), and plaque stability is determined. In order to assess the quality of RNA from FFPE tissue samples over time (2009⁻2018), RNA integrity number (RIN) and the extent of RNA fragmentation were evaluated. Expression analysis was performed with two housekeeping genes—glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and beta-actin (ACTB)—using TaqMan-based quantitative reverse-transcription polymerase chain reaction (qRT)-PCR. FFPE biospecimens demonstrated unaltered RNA stability over time for up to 10 years. Furthermore, we provide a protocol for processing tissue samples in our Munich Vascular Biobank. In this work, we demonstrate that biobanking is an important tool not only for scientific research but also for clinical usage and personalized medicine.

Reduced lower-limb blood flow has been shown to lead to asymmetrical abdominal aortic aneurysms (AAAs) but the mechanism of action is not fully understood. Therefore, small animal ultrasound (Vevo2100, FUJIFILM VisualSonics) was used to longitudinally study mice that underwent standard porcine pancreatic elastase (PPE) infusion (n = 5), and PPE infusion with modified 20% iliac artery stenosis in the left (n = 4) and right (n = 5) iliac arteries. Human AAA computed tomography images were obtained from patients with normal (n = 9) or stenosed left (n = 2), right (n = 1), and bilateral (n = 1) iliac arteries. We observed rapid early growth and rightward expansion (8/9 mice) in the modified PPE groups (p < 0.05), leading to slightly larger and asymmetric AAAs compared to the standard PPE group. Further examination showed a significant increase in TGFβ1 (p < 0.05) and cellular infiltration (p < 0.05) in the modified PPE group versus standard PPE mice. Congruent, yet variable, observations were made in human AAA patients with reduced iliac outflow compared to those with normal iliac outflow. Our results suggest that arterial stenosis at the time of aneurysm induction leads to faster AAA growth with aneurysm asymmetry and increased vascular inflammation after 8 weeks, indicating that moderate iliac stenosis may have upstream effects on AAA progression.

Background: Long noncoding RNAs have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize long noncoding RNAs as potential mediators in abdominal aortic aneurysm development. Methods: We profiled RNA transcript expression in 2 murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in apolipoprotein E–deficient ( ApoE −/− ) mice (n=8) and porcine pancreatic elastase instillation in C57BL/6 wild-type mice (n=12). The long noncoding RNA H19 was identified as 1 of the most highly upregulated transcripts in both mouse aneurysm models compared with sham-operated controls. This was confirmed by quantitative reverse transcription–polymerase chain reaction and in situ hybridization. Results: Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human abdominal aortic aneurysm tissue samples, and in a novel preclinical LDLR −/− (low-density lipoprotein receptor) Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, whereas overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1α as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and hypoxia-inducible factor 1α and sequential p53 stabilization. Additionally, H19 induced transcription of hypoxia-inducible factor 1α via recruiting the transcription factor specificity protein 1 to the promoter region. Conclusions: The long noncoding RNA H19 is a novel regulator of SMC survival in abdominal aortic aneurysm development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.

Background Abdominal aortic aneurysm (AAA) has an age-dependent prevalence of 2% to 11% and is a leading cause of death in men aged >65 years if not treated surgically. Today, endovascular aneurysm repair (EVAR) is performed in up to 80% of elective cases and 60% of ruptured cases. Although EVAR improves perioperative, early, and midterm outcomes, it is associated with specific complications, especially endoleaks (ELs). Type II EL occurs in up to 30% of procedures; however, aneurysm sac expansion and rupture are rare, and currently nothing is known about the morphologic changes in this condition. In this study, we investigate the aneurysm wall morphology in secondary expanding human AAA samples after EVAR with persistent type II EL in comparison to nonaneurysmatic control aortic and AAA samples. Methods Samples were acquired from the aneurysm sac during retroperitoneal feeder vessel ligation in a cohort of 10 patients with secondary expansion after EVAR and type II EL diagnosed by computed tomography and contrast-enhanced ultrasound. Control tissues included 42 AAAs and 13 control aortae published previously. Hematoxylin and eosin staining and immunohistochemistry for CD3/4/31/68 and Ki67 were performed for morphologic analysis. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) assays allowed quantification of apoptosis. Reverse transcription-polymerase chain reaction was used to quantify gene expression and Western blot to quantify collagen expression. Results Secondary expansion of 33.8% ± 30% during 5 years was seen after EVAR before reoperation. The aneurysm wall after expansion shows significant thinning of the intima-media layer accompanied by a scarcity of cells, with only a little chronic inflammation left compared with AAA samples. Macrophages are seen in abundance, and matrix metalloproteinase expression is significantly upregulated. Relevant apoptosis is not noticed. Fibrous tissue is reduced, and a collagen turnover to different subtypes is noted in comparison to nonaneurysmatic control aorta and AAA. In addition, the transcription factors vascular endothelial growth factor, Kruppel-like factor 4, and BCL2, elevated in AAA, are significantly reduced after secondary expansion. Conclusions The aneurysm sac morphology after EVAR with persistent type II EL is characterized by atrophy and proteolysis suggestive of structural weakening. These results should be considered for the follow-up schedule as well as for the potential treatment of this most frequent EVAR complication.

Introduction: Abdominal aortic aneurysm (AAA) is a major challenge in vascular surgery practice due to high morbidity and mortality, especially in case of rupture. Despite open surgery or endovascular stent implantation, no therapeutic option remains to clinicians. Micro-RNAs (miR) have emerged as novel therapeutic targets in the cardiovascular field. For translational research, animal models mimicking human disease are crucial, however, most often a compromise between size, cost and features similar to human disease limits the translational value. Material and Methods: We used the homozygote low-density lipoprotein receptor (LDLR) knockout (KO) Yucatan mini-pig to create a human-relevant animal model for AAA. Local application of porcine pancreatic elastase was applied to the infrarenal aorta for aneurysm inductions. Vascular ultrasound and CT was used for follow-up examination. 8 days after induction, catheter-guided anti-miR-29b coated balloon angioplasty was performed. Animals were sacrificed after 30 days. PCR and immunohistochemistry were used for further characterization of the model. Results: The LDLR KO is hypercholesterolemic and shows severe atherosclerosis in the infrarenal aorta. Aneurysms can be induced by local elastase application for 10 minutes and the aortic diameter increases by 60% over the course of four weeks. Despite atherosclerosis, the aneurysmatic vessel wall shows many features of human disease such as inflammation, extracellular matrix remodeling, angiogenesis and vascular smooth muscle cell phenotype switch. Targeted delivery by balloon angioplasty is feasible and anti-miR-29b penetrates through all layers of the aortic wall, eventually inducing local matrix remodeling. Anti-miR-29b treated animals had significantly smaller AAAs, while not showing any signs of off-target effects. Conclusion: Elastase perfusion in atherosclerosis-prone pigs is a feasible pre-clinical AAA model with many features similar to human disease. Locally balloon-delivered anti-miR-29b induces a pro-fibrotic response, halting aneurysm growth.

Long noncoding RNAs (lncRNAs) have been shown as crucial molecular regulators in various biological processes and diseases. Recently we demonstrated that lncRNA H19 is highly upregulated during abdominal aortic aneurysm (AAA) development and progression in murine models (Angiotensin II in ApoE-/- mice; porcine pancreatic elastase model (PPE) in C57BL/6 mice). Experimental H19 knock-down using specific antisense LNA oligonucleotides showed a significant reduction in AAA growth in both models. Aim of this current study was to utilize genetically mutated H19-depleted mice (H19-/-) vs. wildtype littermate controls, to assess their behavior upon experimental AAA induction using PPE. In addition, we studied the proliferation rates of smooth muscle cells, originating from either H19-/- or H19+/+ mice in a kinetic live-cell imaging system. H19-/- on a C57BL/6J background were exposed to PPE. The aortic diameter in H19-/- mice was compared to WT littermate controls (upon PPE-AAA induction) at baseline, and then consecutively at days 7, 14, and 28. Primary mouse aortic smooth muscle cells were isolated from wild type or H19-depleted aortas, and cultured and monitored in the IncuCyte live cell imaging system for 48 hours, in an effort to study their proliferation rate. H19-/- mice upon PPE-AAA induction displayed significantly lower diameters throughout the study compared to WT controls. Primary aortic smooth muscle cells from H19-depleted mice showed greatly increased proliferation rates (based on cell confluency detection) in our kinetic live-cell imaging system in comparison to WT control cells. In conclusion, our study in H19-depleted mice supports our previously presented efforts, that H19 is an important contributor to experimental AAA development and progression. Further mechanistic studies will have to reveal the molecular properties of this long non-coding RNA in smooth muscle cell survival and proliferation.

Background: Long noncoding RNAs (lncRNAs) have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize lncRNAs as potential mediators in abdominal aortic aneurysm (AAA) development. Methods and results: We profiled RNA transcript expression in two murine AAA models, Angiotensin II (ANGII) infusion in ApoE-/- mice ( n =10) and porcine pancreatic elastase (PPE) instillation in C57BL/6 wildtype mice ( n =12). The lncRNA H19 was identified as one of the most highly up-regulated transcripts in both mouse aneurysm models compared to sham-operated controls. This was confirmed by qRT-PCR and in situ hybridization. Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo , significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human AAA tissue samples, and in a novel preclinical LDLR-/- Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, while overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1-alpha (HIF1α) as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and HIF1α and sequential p53 stabilization. Additionally, H19 induced transcription of HIF1α via recruiting specificity protein 1 (Sp1) transcription factor to the promoter region. Conclusions: The lncRNA H19 is a novel regulator of SMC survival in AAA development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.

Significance Cysteinyl-leukotrienes (cys-LTs) are lipid mediators involved in human inflammatory diseases, in particular asthma. We have previously identified cys-LTs in tissue specimens of human abdominal aortic aneurysm (AAA) and linked these mediators to increased metalloproteinase activity. Here we show in vivo that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against aneurysm in three mouse models of AAA at doses comparable to human medical practice. Together, these data support the role of cys-LTs in AAA and indicate a new potential therapeutic approach for treatment of this clinically silent and highly lethal disease., Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (>50% increase = aneurysm) in a mouse model of CaCl2-induced AAA at a dose comparable to human medical practice. Analysis of tissue extracts revealed that montelukast reduces the levels of matrix metalloproteinase-9 (MMP-9) and macrophage inflammatory protein-1α (MIP-1α) in the aortic wall. Furthermore, aneurysm progression was specifically mediated through CysLT1 signaling since a selective CysLT2 antagonist was without effect. A significantly reduced vessel dilatation is also observed when treatment with montelukast is started days after aneurysm induction, suggesting that the drug not only prevents but also stops and possibly reverts an already ongoing degenerative process. Moreover, montelukast reduced the incidence of aortic rupture and attenuated the AAA development in two additional independent models, i.e., angiotensin II- and porcine pancreatic elastase-induced AAA, respectively. Our results indicate that cys-LTs are involved in the pathogenesis of AAA and that antagonism of the CysLT1 receptor is a promising strategy for preventive and therapeutic treatment of this clinically silent and highly lethal disease.

Objective/Background Abdominal aortic aneurysm (AAA) is an individual and socioeconomic burden in today's ageing society. Treatment relies on surgical exclusion of the dilated aorta by open or endovascular repair. For research purposes, animal models are necessary and the elastase induced aneurysm model closely mimics end stage human aneurysm disease. To improve the translational value of this model, four modifications to the classic elastase perfusion procedure (PPE) in relation to human aneurysm morphology were conducted. Methods In ten week old male C57BL/6J wild type mice the PPE procedure was modified in four ways using two different techniques. Flow alteration was simulated by partial ligation of the common iliac artery or the distal aorta. Additionally, careful exploration of the abdominal aortic branches allowed PPE induction at the suprarenal and iliac level. Molecular biology, ultrasound, and immunohistochemistry were used to evaluate these pilot results. Results Two aortic outflow obstructions simulating distal aortic or iliac stenosis significantly increase murine AAA diameter (p = .046), and affect local vascular wall remodelling. Suprarenal aortic dissection allows a juxtarenal aneurysm to be induced, similar to the angiotensin II induced aneurysm model. A separate investigation for canonical activation of transforming growth factor β in the two embryonically distinct juxtarenal and infrarenal segments showed no distinct difference. Creating an aortoiliac bifurcated aneurysm completes the mimicry of human aneurysm morphology. Conclusion The alteration of the classic PPE aneurysm by outflow modulation and further elastase perfusion to the juxtarenal and aortoiliac segment modifies morphology and diameter, and thus increases the translational value in future research.

Background: Long noncoding RNAs (lncRNAs) have emerged as critical epigenetic regulators in various biological processes and diseases. Here we sought to identify and functionally characterize the lncRNA H19 as a novel regulator in abdominal aortic aneurysm development. Methods and Results: We profiled RNA transcript expression in two murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in ApoE-/- mice and porcine pancreatic elastase (PPE) instillation in C57BL/6 wildtype mice. The lncRNA H19 was identified as one of the most highly up-regulated transcripts in both mouse aneurysm models compared to sham-operated controls. This was confirmed by qRT-PCR and in situ hybridization. Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo , significantly limited aneurysm growth in both models. Upregulated H19 correlated well with smooth muscle cell (SMC) content and its apoptosis in progressing aneurysms. Of importance, a similar pattern could be observed in human AAA tissue samples, and in a novel preclinical LDLR-/- Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, while overexpression of H19 had the opposite effect. Interestingly, H19-dependent cell fate decisions in SMCs appeared independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array and proteomic analysis revealed the hypoxia-inducible factor 1-alpha (HIF1A) and interleukin 1 receptor-like 2 (IL1RL2) as the main downstream effectors being regulated via H19. Conclusion: The lncRNA H19 is a novel regulator of SMC survival and aortic inflammation in AAA development and progression. Ultimately inhibition of H19 expression might serve as a novel molecular therapeutic target for aneurysm disease. Key words: Long noncoding RNAs (lncRNAs); abdominal aortic aneurysm; smooth muscle cells (SMCs); Inflammation

Introduction: Abdominal aortic aneurysm (AAA) is an individual and socioeconomic burden in the aging society. Treatment relies on surgical exclusion of the dilated aorta by open or endovascular repair only. For research purposes, animal models are necessary and the elastase induced aneurysm model (PPE) has gained much attention for it closely mimics endstage human aneurysm disease. However, to improve the translational value of this model we conducted a couple of modifications in relation to human aneurysm morphology. Materials and Methods: In 10-week-old male C57BL/6J wild-type mice the classic PPE procedure with local perfusion of porcine pancreatic elastase in order to induce aneurysm was modified using flow alteration by partial ligation of the iliac artery or the aorta. Additionally, careful exploration of the abdominal aortic branches allowed PPE induction at the suprarenal and iliac level. Molecular biology, ultrasound and immunistochemistry were used to evaluate the results. Results: Aortic blood flow restriction (PPE 2.0) significantly increases murine AAA diameter and affects the localization of vascular wall remodeling. Suprarenal aortic dissection allows inducing a more proximal aneurysm (PPE 3.0) similar to the angiotensin II induced aneurysm model. Separate investigation for canonical activation of transforming growth factor ß in these two embryologically distinct segments shows no difference. Creating an aorto-iliac bifurcated aneurysm (PPE 4.0) completes the mimicry of human aneurysm morphologies. Conclusion: PPE is the most important model for AAA research and the ß-versions PPE 2.0, 3.0 and 4.0 modifying its morphology further increase the translational value.

Aneurysm formation occurs most frequently as abdominal aortic aneurysm (AAA), but is also seen in other localizations like thoracic or peripheral aneurysm. While initial mechanisms for aneurysm induction remain elusive, observations from AAA samples show transmural inflammation with proteolytic imbalance and repair mechanisms triggered by the innate immune system. However, limited knowledge exists about aneurysm pathology, especially for others than AAA. We compared 42 AAA, 15 popliteal, 3 ascending aortic, five iliac, two femoral, two brachial, one visceral and two secondary aneurysms to non-aneurysmatic controls by histologic analysis, immunohistochemistry and cytokine expression. Muscular and elastic type arteries show a uniform way of aneurysm formation. All samples show similar morphology. The changes compared to controls are distinct and include matrix remodeling with smooth muscle cell phenotype switch and angiogenesis, adventitial lymphoid cell accumulation and M1 macrophage homing together with neutrophil inflammation. Inflammatory cytokines are up-regulated accordingly. Comparative analysis of different disease entities can identify characteristic pathomechanisms. The phenotype of human advanced aneurysm disease is observed for elastic and muscular type arteries, does not differ between disease localizations and might, thus, be a unique response of the vasculature to the still unknown trigger of aneurysm formation.

Introduction: Aneurysm disease occurs throughout the arterial tree, abdominal aortic aneurysm (AAA) and popliteal artery aneurysm (PAA) being the most frequent ones. The pathology is best examined, yet little understood, for AAA. Aneurysm disease has distinct features like angiogenesis and phenotype switch of vascular smooth muscle cells (VSMC). However, little is known about these characteristics in other than AAA. Material and Methods: From a surgical biobank we compared 42 AAA, 15 PAA, 3 ascending aortic, 5 iliac, 3 femoral, 2 brachial, 1 visceral and 1 carotid artery aneurysm on morphologic, protein and mRNA-expression levels. Two multi-stage mouse models of aneurysm disease were applied to test response to aneurysm induction at different arterial locations. Results: AAAs show a varying histomorphologic appearance, not seen in PAA, which, in turn, has a high proliferation rate in the aneurysm sac, making other than surgical interventions appealing. All entities show VSMC phenotype switch, angiogenesis, matrix remodeling and T-cell/macrophage inflammation. AAA and PAA have similar alterations in TGFß-signaling. To further investigate these conditions in mouse models, we applied the PPE procedure to a juxtarenal aorta and the EPA model to a thoracic, abdominal and femoral location. Conclusion: Despite different arterial morphogenesis, advanced aneurysm disease from human intraoperative specimen shows similar characteristics of end-stage disease.

Objective Abdominal aortic aneurysm (AAA) is a frequent, potentially life-threatening, disease that can only be treated by surgical means such as open surgery or endovascular repair. No alternative treatment is currently available, and despite expanding knowledge about the pathomechanism, clinical trials on medical aneurysm abrogation have led to inconclusive results. The heterogeneity of human AAA based on histologic examination is thereby generally neglected. In this study we aimed to further elucidate the role of these differences in aneurysm disease. Methods Tissue samples from AAA and popliteal artery aneurysm patients were examined by histomorphologic analysis, immunohistochemistry, Western blot, and polymerase chain reaction. The results were correlated with clinical data such as aneurysm diameter and laboratory results. Results The morphology of human AAA vessel wall probes varies tremendously based on the grade of inflammation. This correlates with increasing intima/media thickness and upregulation of the vascular endothelial growth factor cascade but not with any clinical parameter or the aneurysm diameter. The phenotypic switch of vascular smooth muscle cells occurred regardless of the inflammatory state and expressional changes of the transcription factors Kruppel-like factor-4 and transforming growth factor-β lead to differential protein localization in aneurysmal compared with control arteries. These changes were in similar manner also observed in samples from popliteal artery aneurysms, which, however, showed a more homogenous phenotype. Conclusions Heterogeneity of AAA vessel walls based on inflammatory morphology does not correlate with AAA diameter yet harbors specific implications for basic research and possible aneurysm detection.