Meeting Abstracts

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AORTA, October 2016, Volume 4, Issue 5:185-218
DOI: 10.12945/j.aorta.2016.16.500

5th International Meeting on Aortic Diseases: New Insights into an Old Problem

Natzi Sakalihasan, MD, PhD (course director)

Notes

[1] Note from the Editors: The unedited abstracts from the 5th International Meeting on Aortic Disease are reproduced herein, as supplied by the organizers.


EXTRA-AORTIC CARDIOVASCULAR FEATURES IN MARFAN SYNDROME - RELEVANCE AND MANAGEMENT

Backer Julie De

Marfan syndrome (MFS), caused by mutations in the fibrillin 1 gene has been the leading disease model for the study of genetic aortic aneurysms and dissections. Aortic root aneurysm formation at the level of the sinus of Valsalva occurs in the vast majority of patients and aortic dissection is still one of the leading causes of death in patients with MFS. With better medical and surgical management, MFS patients grow older nowadays and other cardiovascular features are now emerging and gaining more attention. Mitral valve prolapse (MVP) has been recognized as a key feature in MFS and still plays a role in the diagnostic setting. Being a benign disease in the majority of non-MFS cases, the outcome of MVP in MFS is quite different and needs careful follow-up. Timely and appropriate surgical intervention needs to be carefully considered. Heart failure in MFS has been recognized as a major cause of mortality in surgical series for several decades now, but the understanding of the pathogenesis of myocardial dysfunction is still not entirely elucidated. Related to myocardial dysfunction to some extent, arrhythmias are more frequently documented in MFS patients and sudden arrhythmic death occurs more common than in the general population. Managing these extra-aortic features in MFS requires adequate knowledge and a specific approach in some cases. These issues will be discussed in this presentation.

References

  1.  
    Hoffmann, B. A. et al. Prospective risk stratification of sudden cardiac death in Marfan’s syndrome. Int J Cardiol 1–7 (2012). DOI:10.1016/j.ijcard.2012.06.036
  2.  
    Rybczynski, M. et al. Predictors of outcome of mitral valve prolapse in patients with the Marfan syndrome. Am J Cardiol 107, 268–274 (2011).
  3.  
    Helder, M. R. K. et al. Management of mitral regurgitation in Marfan syndrome: Outcomes of valve repair versus replacement and comparison with myxomatous mitral valve disease. The Journal of Thoracic and Cardiovascular Surgery 148, 1020–1024 (2014).
  4.  
    Kunkala, M. R. et al. Mitral valve disease in patients with marfan syndrome undergoing aortic root replacement. Circulation 128, S243–7 (2013).
  5.  
    Cook, J. R. et al. Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome. Journal of Clinical Investigation (2014). DOI:10.1172/JCI71059DS1
  6.  
    Campens, L. et al. Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1(C1039G/+) model and longitudinal findings in humans. Pediatr Res 78, 256–263 (2015).

COMBINING MENDELIAN GENETICS AND GENETIC EPIDEMIOLOGY FOR AAA

Albuisson Juliette

The pace of new genes discovery in the field of Mendelian disorders has been dramatically accelerated by the availability of the human genome sequence in the 2000s, and the next-generation sequencing technologies in the 2010s. However, a majority of the elucidated conditions so far correspond to relatively simplified situations, where the prevalence and the penetrance of the condition are high and the genetic heterogeneity is low. Nowadays, geneticists meet more and more situations where gene identification in unknown disorders can be tricky. Heritable conditions that are very rare, heterogenous or with imperfect Mendelian transmission can only be elucidated using large cohorts of patients, with a very well-characterized phenotype. Generally, using exome sequencing alone is not efficient enough to elucidate these types of conditions. On the other hand, common conditions like cardiovascular disorders have been long studied using whole genome association studies and genotyping, or sequencing tools. The efficiency of these approaches to identify strong genetic effects is globally low, and odds-ratios do not generally reach 2. The concept of hidden heritability raised from these observations, pointing to the implication of other types of variants like rare or very rare variants, in common disorders. The power of recently developed strategies comes from combining exome or genome sequencing with recently developed genetic association analysis tools, allowing for the identification of rare variants with stronger effects. These latter have been specifically developed in the context of rare, heterogenous, or polygenic disorders. We employed exome sequencing in the identification of genetic components of abdominal aortic aneurysm. This common cardiovascular disorder has a strong hereditary component and rare situations of fully penetrant, dominant inheritance. Exome sequencing was performed in a large family showing dominant inheritance, identifying only one strong candidate gene. Rare and very rare variants association analysis of the identified candidate gene was performed in a large cohort of 2500 sporadic and 500 familial AAA cases, using a recently developed association tool called SKAT-O. This combined approach allowed to characterize genetic effect of rare and very rare variants at the level of a single gene, with deleterious and protecting effect depending on the identified variants. Functional analysis of the variants and the role of the candidate gene is ongoing in cellular models.


WHOLE BLOOD DNA METHYLATION ANALYSIS IN AAA; AN EPIGENOME-WIDE ASSOCIATION STUDY

Jones Gregory T.

Abdominal aortic aneurysm (AAA) is a complex disease, with several well-established genetic and environmental risk factors having been identified, nevertheless, much remains to be understood regarding its aetiology. It is becoming increasingly clear that there are interactions between genetic and environmental risk factors. Such interactions can be detected by alterations in epigenetic markers, such as the methylation of DNA CpG sites. An epigenome-wide approach was therefore applied to an AAA case control cohort in order to identify novel disease biomarkers.

Study Design and Methods

Whole blood methylation status of over 450,000 CpG sites was assessed in each of 961 males (488 cases and 473 AAA-free controls; mean age 72 years) using the Illumina Human Methylation450 bead chip array. Normalised methylation values were corrected for participant age and prior history of occlusive vascular disease. Results were filtered for CpGs known to be strongly associated with white blood cell composition.

Results

In total 50 gene loci (most with multiple CpG sites) were significantly (adjusted P<5x10-8) differentially methylated in AAA. Importantly, 18 (36%) of these loci matched those previously reported as being significantly associated with smoking. These included the strongest smoking associations reproducibly reported in the AHRR, F2RL3, ALPI and IER3 genes. Approximately half of the CpG sites were also strongly associated with white blood cell composition. A pathway-based analysis implicated biological mechanisms such as interleukin signaling, vascular inflammation, T & B cell activation and blood coagulation. Protein expression of some of the genes associated with differentially expressed CpG sites was examined in aortic tissue. One such gene, YWHAQ, encodes for the 14-3-3 theta protein that was found to be significantly overexpressed within AAA-associated adventitial T-cell aggregates.

Conclusion

Whole blood epigenome-wide association analysis identified a set of genes whose differential DNA methylation appears to be consistent with known environmental risk factors and biologically causal pathways in AAA. A large proportion of the differentially methylated signal also appeared to be strong white cell markers, suggesting that a proportion of the observed signature may be a surrogate of blood cell composition. This study demonstrates the potential utility of whole blood epigenetic studies to identify novel disease biomarkers.


NEW INSIGHTS ON GENETIC ASPECT OF AORTIC DISEASE

Elefteriades John A.

Background

Hereditary factors play an important etiologic role in thoracic aortic aneurysm and dissection (TAAD), with a number of genes proven to predispose to this condition. We initiated a clinical program for routine genetic testing of individuals for TAAD via whole exome sequencing (WES). Here we present our initial results.

Methods

WES was performed in 102 patients (mean age 56.8 years, range 13-83, 70 males (68.6%)) with TAAD. The following 21-gene panel was tested via WES: ACTA2, ADAMTS10, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, ELN, FBLN4, FLNA, FBN1, FBN2, MYH11, MYLK, NOTCH1, PRKG1, SLC2A10, SMAD3, TGFB2, TGFBR1, TGFBR2.

Results

Seventy-four patients (72.5%) had no medically important genetic alterations. Four patients (3.9%) had a deleterious mutation identified in the FBN1, COL5A1, MYLK, and FLNA genes. Twenty-two (21.6%) previously unreported suspicious variants of unknown significance were identified in one or more of these genes: FBN1 (n=5), MYH11 (n=4), ACTA2 (n=2), COL1A1 (n=2), TGFBR1 (n=2), COL3A1 (n=1), COL5A1 (n=1), COL5A2 (n=1), FLNA (n=1), NOTCH1 (n=1), PRKG1 (n=1), and TGFBR3 (n=1). Identified mutations had implications for clinical management.

Conclusions

Routine genetic screening of patients with TAAD provides information that enables genetically personalized care and permits identification of novel mutations responsible for aortic pathology. Analysis of large data sets of variants of unknown significance that include associated clinical features will help define the mutational spectrum of known genes underlying this phenotype and potential identify new candidate loci.


IS RISK-FACTOR TARGETED AAA SCREENING THE FUTURE? DATA FROM THE OXFORD VASCULAR STUDY

Howard Dominic

Background

Current abdominal aortic aneurysm (AAA) screening in men aged 65 might have limited impact on overall AAA-death rates if incidence is moving to older ages. Up-to-date population-based data of age-specific incidence and outcome of acute abdominal aortic aneurysm (AAA) events are needed to understand the impact of risk factor modification and demographic change, and to inform screening policy.

Methods

In a prospective population-based study (Oxfordshire, UK, 2002-2014), event rates, incidence, early case fatality, and long-term outcome of all acute AAA events were determined, both overall and in relation to the four main risk factors (smoking, hypertension, male gender and age).

Results

Over the 12 year period, 103 incident acute AAA events occurred in the study population of 92,728 (male 72.8%, 59·2% 30-day case-fatality). Incidence/100,000/year was 55 in men aged 65-74 years, but increased to 112 at 75-85 and 298 at ≥85, with 66.0% of all events occurring at age ≥75yrs. Incidence at 65-74 was highest in male smokers (274), with 96.4% of events in men aged<75 years occurring in ever-smokers. Mean age (SD) (yrs) at event was lowest in current smokers (72.2 (7.2)), compared to ex-smokers (81.2 (7.0)) and never-smokers (83.7 (7.9)) (p<0.0001). Hypertension was the predominant risk factor in women (diagnosed in 92.9%) with 54.8% of all events in women occurring in hypertensives aged 75 and over. Extrapolating rates to the UK population, using trial evidence of screening efficacy, the current UK screening programme would prevent 5.6% of aneurysm-related deaths (315,200 scans/year: 1426/death prevented, 121/year-of-life saved). Screening only male smokers aged 65 and then all men at age 75 would prevent 21.1% of deaths (247,900 scans/year; 297/death prevented, 34/year-of-life saved).

Conclusions

Two-thirds of acute AAA events occurred at age ≥75yrs and over 25% of events occurred in women. Screening non-smokers at age 65 is likely to have very little impact on AAA event rates. Risk-factor targeted screening may prevent more deaths than current strategies.


MORPHOLOGY OF RUPTURED VERSUS UNRUPTURED ABDOMINAL AORTIC ANEURYSMS

Powell Janet T.

Currently the best metric to assess the risk of aortic aneurysm rupture is the maximum aortic diameter. Recently aneurysm volume also has been investigated. However, other morphological characteristics, readily obtainable from 3D CT reconstructions, have largely been ignored as potential prognostic indicators.

The core laboratory for admission CT scans for IMPROVE trial patients provided an opportunity to compare the morphology of ruptured and unruptured aneurysms. These have been separated into abdominal aortic and common iliac aneurysms. Proximal aneurysm neck length, diameter and angle, maximum aortic diameter, iliac bifurcation angle and iliac artery diameter were measured according to protocol, with quality control for intra- and inter-observer variability of measurements.

For abdominal aortic aneurysms we have compared 294 confirmed cases of rupture with 907 elective cases according to a prespecified analysis plan, adjusting for sex. For common iliac aneurysms the cases are fewer (and all male) and we have compared 9 cases of iliac rupture with 10 elective cases and these data will be presented.

For both types of aneurysm, the angle of the iliac bifurcation appears to be the most influential measurement after maximum aneurysm diameter which distinguishes ruptured from intact aneurysms.


AAA RUPTURE IN STOCKHOLM

Zommorodi Sayid1, Roy Joy1, 3, Hultgren Rebecka1, 2

This population based investigation includes all patients admitted to the any of the seven emergency departments within Stockholm County diagnosed with rAAA 2009-2013. A total of 283 patients were identified, 30 % (n = 85) had a previously detected AAA. Men were in majority (76% vs 24%), and four years younger than women. A majority of patients admitted to an emergency department were treated (212/283, 75%), a similar proportion of women and men. Treated patients were younger (77 vs 84 years, p<0.001). One third were treated with EVAR was 27%, they were older than OR treated (79 vs 76 years, p=0.043). Patients with a previous diagnosis of AAA, before rupture occurred, had a higher mortality, partly due to a lower intervention rate (59 % versus 82 %, P < .001). Reasons for non-treatment when diagnosed with AAA were; denied elective surgery (36 %), patient choice (18 %), size-related (13 %) and surveillance deficiency (31 %). The majority of patients missed in surveillance were treated at rupture (85 %). Overall; 47% of patients admitted with rAAA survived 30 days, and 62% of treated patients survived 30 days, similar mortality for women and men. Our results and other contemporary series show a shift towards a higher rate of patients with rAAA being treated, increasing use of EVAR and continuously improving outcomes, similarly for women and men. Improved patient-specific protocols to reduce the surveillance gaps and new methods of determining rupture risk in each individual case of AAA could be two possible future strategies to reduce the incidence of rupture, in the previously diagnosed group. Data for patients treated 2014-2015 will also be included in the presentation.

References

  1.  
    High proportion of known abdominal aortic aneurysm in patients with rupture indicates surveillance deficiency, Zommorodi Sayid, Roy Joy, Steuer Johnny, Hultgren Rebecka, In press, JVS 2016.

AUSTRALIAN TRIALS TO IDENTIFY TREATMENTS TO SLOW AAA GROWTH

Golledge Jonathan

Background

Currently there is no treatment for small abdominal aortic aneurysms (AAAs). Fenofibrate has been shown to limit AAA development in two studies in mouse models associated with reduction in aortic concentration of the matrix protein osteopontin and reduced aortic inflammation. Fenofibrate has also been shown to have a number of other effects which may favourably modify AAA pathology including raising high density lipoprotein and reducing matrix metalloproteinase.

Methods

Fenofibrate in the mangement of AAA (FAME-2) is a multi-centre, prospective, randomised, placebo-controlled trial to assess the effect of 24 weeks oral therapy of 145mg of fenofibrate on pathological markers of AAA. The primary endpoints are circulating biomarkers of AAA, including osteopontin. Secondary outcomes include maximum diameter assessed on ultrasound. FAME-2 is a collaboration conducted from three vascular centres in Australia.

Discussion

Currently, no medication has been demonstrated to limit abdominal aortic aneurysm progression. FAME-2 is a pilot study to examine whether promising results in a rodent model can be confirmed in patients.

References

  1.  
    Golledge J, et al Peroxisome proliferator-activated receptor ligands reduce aortic dilatation in a mouse model of aortic aneurysm. Atherosclerosis. 2010;210(1):51-6.
  2.  
    Krishna SM, et al Fenofibrate increases high-density lipoprotein and sphingosine 1 phosphate concentrations limiting abdominal aortic aneurysm progression in a mouse model. Am J Pathol. 2012;181(2):706-18.

AAA MEASUREMENT AND ENLARGEMENT

Lederle Frank A.

Background

No effective treatment is currently available to prevent progression of small and medium-sized abdominal aortic aneurysms (AAAs). Identification of drugs with sufficient promise to justify large expensive randomized trials remains challenging. One potentially useful strategy is to look for associations between commonly used drugs and AAA enlargement in appropriately adjusted observational studies.

Methods

Potential AAA measurements were identified from abdominal imaging reports in the electronic data files of three medical centres from 1995 to 2010. AAA measurements were extracted manually and patients with an aneurysm of 3 cm or larger, who had at least two measurements over an interval of at least 6 months, were identified. Other data were obtained from the electronic data files (demographics, co-morbidities, smoking status, drug use) to conduct a propensity analysis of the associations of drugs and other factors with AAA enlargement.

Results

From 52 962 abdominal imaging studies, 5362 patients with an AAA of 3 cm or more were identified, of whom 2428 had at least two measurements over at least 6months. Mean AAA follow-up was 3•4 years and the mean AAA enlargement rate was 2•0mm per year. Propensity analysis demonstrated no significant association of AAA enlargement with statins, beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Diabetes was associated with a reduction in AAA enlargement of 1•2mm per year (P =0•008), and chronic obstructive pulmonary disease was associated with increased enlargement (0•5mm per year; P =0•050). Moderate AAA measurement variation and substantial terminal digit preference were also observed, but the digit preference became less pronounced after 2000.

Conclusion

This study confirms the negative association of diabetes with AAA progression. There was no evidence that commonly used cardiovascular drugs affect AAA enlargement.


CIRCULATING MIRNA ASSOCIATED WITH INSTABLE ABDOMINAL AORTIC ANEURYSM PET POSITIVE

Courtois Audrey1, Nusgens Betty1, Hustinx Roland2, Defraigne Jean-Olivier2, Colige Alain1, Sakalihasan Natzi2

Background

Prediction of abdominal aortic aneurysm (AAA) rupture is a challenging issue. Small non-coding RNAs (miRNAs) are potent regulators of gene expression and are considered as valuable circulating biomarkers. Recently, 18F-FDG uptake detected by PET in AAA was correlated with cellular and molecular alterations presaging wall instability and its potential rupture. Our study aims at identifying circulating miRNAs correlated with a positive PET that could help discriminating patients at higher risk of rupture.

Methods

The levels of 372 miRNAs were evaluated by PCR array in plasma from 35 AAA patients displaying no FDG uptake (A0) and 22 patients with a positive PET (A+). The level of modulated miRNAs was validated by qPCR and was also measured in aneurysmal tissues.

Results

Six miRNAs were found significantly modulated in A+ vs A0 patients. They were significantly correlated between them and with PET-positivity but only two of them were also correlated with the AAA diameter. These miRNAs displayed significant discriminating power (ROC curve) between the A+ and A0 groups. Three down-regulated circulating miRNAs, miR-99b-5p, miR-125b-5p and miR-204-5p, were also significantly reduced in the aneurysmal tissue at the FDG-uptake site compared to a negative zone in the same aneurysm and as compared to A0 aneurysms. They were further significantly inversely correlated with the expression, at the positive uptake site, of some of their potential gene targets, most notably MMP13.

Conclusions

Six miRNAs were identified as potential new circulating biomarkers of PET+ AAA at high risk of rupture, three of them being similarly modulated in the metabolically active aneurysmal wall and might be directly involved in AAA instability


FOCAL ADHESION KINASE IS A NOVEL TARGET FOR PHARMACOTHERAPY OF ABDOMINAL AORTIC ANEURYSM

Yoshimura Koichi1, 2, Harada Takasuke1, Hamano Kimikazu1

Abdominal aortic aneurysm (AAA) is characterized by chronic inflammatory cell infiltration and progressive destruction of the extracellular matrix by proteolytic enzymes. However, the molecular mechanisms that regulate chronic inflammation in AAA remain largely unknown. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays critical roles in integrin-mediated signal transduction. We previously demonstrated in vitro that FAK is involved in inflammatory responses to mechanical strain in vascular smooth muscle cells. These findings led to the hypothesis that FAK might promote AAA progression by maintaining and enhancing inflammatory responses. In this study, we found that FAK was highly activated in human AAA wall specimens compared with non-AAA walls. Activated FAK was mostly localized to macrophages within AAA tissues. FAK inhibitor, PF573228, significantly reduced secretion of monocyte chemoattractant protein-1 and matrix metalloproteinase-9 from cultured macrophages after stimulation with tumor necrosis factor-alpha. Furthermore, we created the mouse model of AAA by periaortic application of calcium chloride. Treatment of mice with PF573228 over the entire experimental period (from weeks 0 to 6 after calcium application) significantly reduced inflammatory cell infiltration and disruption of the elastic lamellae, and prevented the development of AAA. Importantly, delayed treatment with PF573228 (only from weeks 3 to 6) blocked increases in cellular infiltration and elastin disruption in aortic walls, and significantly inhibited further progression of AAA. Our findings uncover a critical role of FAK in the development and progression of AAA, indicating that FAK represents a novel therapeutic target for the treatment of AAA.


TELMISARTAN IN THE MANAGEMENT OF ABDOMINAL AORTIC ANEURYSM (TEDY): THE STUDY PROTOCOL FOR A RANDOMIZED CONTROLLED TRIAL

Golledge Jonathan

Background

Experimental studies suggest that angiotensin II plays a central role in the pathogenesis of abdominal aortic aneurysm. This trial aims to evaluate the efficacy of the angiotensin receptor blocker telmisartan in limiting the progression of abdominal aortic aneurysm.

Methods/Design

Telmisartan in the management of abdominal aortic aneurysm (TEDY) is a multicentre, parallel-design, randomised, double-blind, placebo-controlled trial with an intention-to-treat analysis. We aim to randomly assign 300 participants with small abdominal aortic aneurysm to either 40 mg of telmisartan or identical placebo and follow patients over 2 years. The primary endpoint will be abdominal aortic aneurysm growth as measured by 1) maximum infra-renal aortic volume on computed tomographic angiography, 2) maximum orthogonal diameter on computed tomographic angiography, and 3) maximum diameter on ultrasound. Secondary endpoints include change in resting brachial blood pressure, abdominal aortic aneurysm biomarker profile and health-related quality of life. TEDY is an international collaboration conducted from major vascular centres in Australia, the United States and the Netherlands.

Discussion

Currently, no medication has been convincingly demonstrated to limit abdominal aortic aneurysm progression. TEDY will examine the potential of a promising treatment strategy for patients with small abdominal aortic aneurysms.

References

  1.  
    Morris DR, et al. TElmisartan in the management of abDominal aortic aneurYsm (TEDY): The study protocol for a randomized controlled trial.Trials. 2015;16:274.

THE EFFECT OF METFORMIN ON AAA

Dalman Ronald

Diabetes mellitus is negatively associated with the prevalence and progression of abdominal aortic aneurysm (AAA) disease. We investigated the possibility that the oral hypoglycemic agent metformin (Glucophage) may influence the progression of AAA disease.

Methods

Preoperative AAA patients also noted to have diabetes were identified from an institutional database. Following assessment of individual cardiovascular and demographic risk factors and prescription drug regimens, odds ratios for categorical influences on annual AAA enlargement were calculated through nominal logistic regression. Experimental AAAs were created in normoglycemic mice to validate the database-derived observations as well to identify potential mechanisms of metformin-induced aneurysm suppression.

Results

Fifty eight patients met criteria for study inclusion. Of 11 distinct classes of medications considered, only metformin use was negatively associated with AAA enlargement. This association remained significant after controlling for gender, age, cigarette smoking status and obesity. The median enlargement AAA enlargement rate in patients not taking oral diabetic medication was 1.5 mm/y; by nominal logistic regression, metformin, hyperlipidemia and age ≥ 70 years were associated wtih below-median enlargement, whereas sulfonylurea therapy, initial aortic diameter ≥ 40 mm, and statin use were associated with above-median enlargement. In experimental modeling, metformin dramatically suppressed the formation of AAA, with medial elastin and smooth muscle preservation and reduced aortic mural macrophage, CD8 T cell, and neovessel density.

Conclusions

Epidemiologic evidence of AAA suppression in diabetes may be attributable to concurrent therapy with the oral hypoglycemic agent metformin.

Figure 1.

Mechanisms of experimental AAA suppression by metformin

media/vol4/issue5/images/aorta-04-185-g001.jpg

References

  1.  
    Fujimora N, Xiong Jiang, Kettler EB, Xuan H, Glover KJ, Mell MW, Xu B, Dalman RL. Metformin treatment status and abdominal aortic aneurysm disease progression. Journal of Vascular Surgery 2016 epub before press.

WHAT DO WE KNOW ABOUT AAA AND DIABETES AND DOES IT MATTER

Norman Paul

Diabetes is generally considered to increase the risk of most manifestations of cardiovascular disease, particularly coronary heart disease and peripheral arterial disease. In contrast with occlusive arterial disease, there is a negative association between diabetes and abdominal aortic aneurysm (AAA). Several large cross-sectional studies have shown that the prevalence of AAA is 30% lower in the presence of diabetes. Cohort studies have shown that the incidence of new AAA is reduced by 60% and the expansion of existing AAAs is about 50% lower in diabetes. The underlying mechanisms for the negative association are still unclear. Whilst animal model studies and clinical observations suggest the importance of hyperglycaemia, there is also evidence that drugs used to treat diabetes, such as metformin, may play a role. One of the consequences of chronic hyperglycaemia is the increased formation of Advanced Glycation Endproducts (AGEs) due to non-enzymatic reactions between sugar metabolites and both proteins and lipids. The deposition of AGEs may result in complex changes in extra-cellular matrix, including fibrosis and resistance to proteolysis, which are compatible with reduction in AAA formation. On the other hand, binding of AGEs to a cell surface receptor (RAGE) can increase oxidative stress and inflammation – both associated with increased AAA formation. The association between AGE formation and AAAs can be assessed indirectly via biomarkers of the glycation pathway. The relationship between four of these biomarkers (glyoxal, methylglyoxal, carboxymethyllysine, and the soluble RAGE) and both aortic diameter and AAA presence in a cohort of ~900 men screened for AAA will be reported.


IMAGING ALTERNATIVES IN ORDER TO PREVENT RUPTURE (VOLUME VS DIAMETER)

Gasser T. Christian

Background

The diagnosis and management of abdominal aortic aneurysms (AAA) currently relies on the aortic maximal diameter, which, however, is the subject of increasing discussion. Specifically, the threshold diameter criterion lacks a sound patient-individual assessment, is already about 20 years old, and may no longer adequately reflect current treatment options. Most important, AAA rupture is a complex event and a better understanding requires a multi-disciplinary approach [1].

Methods

All AAA patients at Karolinska University Hospital, Stockholm, Sweden who had undergone two Computed Tomography Angiographies (CTA) with roughly one year’s interval (8-17 months) were retrospectively identified. Forty-one patients (9 female, 32 male) were included and digital three-dimensional reproductions of the aneurysms were segmented and analyzed from the 82 CTAs (A4clinics Research Edition, VASCOPS GmbH, Austria). Specifically, AAA diameter, AAA volume were measured from 3D reconstructions, while Peak Wall Rupture Index (PWRI) was calculated based on a Finite Element Analysis (FEA) [2].

Results

Diameter growth rate did not correlate with baseline diameter (r=0.15, p=0.34) or with increasing PWRI (r=0.17, p=0.30). Volume growth rate correlated with baseline volume (r=0.56, p=0.0001) and volume growth rate higher than or equal to the sample median could be predicted with 90% sensitivity and 85% specificity, see Figure 1. Volume growth rate correlated with increasing PWRI (r=0.75, p=0.0001) and further results are reported elsewhere [3].

Figure 1.

Baseline diameter versus baseline volume as growth predictor

media/vol4/issue5/images/aorta-04-185-g002.jpg

Conclusion

Our study clearly demonstrated that aneurysm volume, compared to its maximum diameter, better predicts aneurysm growth rate and correlates stronger with increasing biomechanical rupture risk. Our results support the notion of monitoring all three dimensions of an AAA.

Receiver Operator Characteristics (ROC) curves for baseline diameter (left) and baseline volume (right) to predict Abdominal Aortic Aneurysms diameter growth. Data is based on following-up 41 patients over approximately one year and demonstrates that aneurysm diameter growth can be reasonably predicted by baseline volume but not by baseline diameter. Dashed line in the left image represents flipping a coin, i.e. represents the ROC curve of no predictive information at all.

References

  1.  
    T.C. Gasser , Aorta, (in press).
  2.  
    T.C. Gasser, A. Nchimi, J. Swedenborg, J. Roy, N. Sakalihasan, D. BöcklerA. Hyhlik-Dürr, Eur J Vasc Endovasc Surg. 2014; 47:288-295.
  3.  
    M.L. Liljeqvist, R. HultgrenGasser, J T.C., Roy. Journal of Vascular Surgery 2016; 63:1434–1442.e3.

IS THE RISK DIFFERENT FOR FEMALE OR MALE FDRS TO AAA PATIENTS?

Linne Anneli1, Hultgren Rebecka1, 2

Although family history is well known as a risk factor for development of AAA, the problem is not systematically addressed in clinical practice. The prevalence of AAA is higher in persons with a family history than in smokers. Guidelines suggest selective screening of First Degree Relatives (FDRs) (regardless of sex) in the US at one time, and the ESVS guidelines at age 50-55 years, although the level of evidence is low. Male relatives, but not female, will however be invited within the population-based screening programs for elderly men in Sweden and the UK. Previous studies have reported contradictory findings regarding prevalence of AAA in FDRs, but most reports show an increased prevalence, approximately 10%. The prevalence in female FDRs is always lower, but this mainly reflects the lower prevalence overall in women in the population as compared to men (0.5-1% vs 1.5-4%). The risk for a male FDR (brothers) to develop an AAA is 20% compared to 6% in a female FDR, as reported from the Liege AAA Family study. In the Swedish Sibling study; 17% vs 6% prevalence in brothers and sisters was found; however this should be compared with the prevalence in the population, which gives a 12 times increased prevalence in female FDRs compared to women in the population, and 8-9 times in male. The age at which screening of FDRs could be adequate, has recently been investigated in our Swedish Sibling cohort. Our results, and others support a selective screening program for all FDRs (male and female at 50 and 55 years) supporting the ESVS guidelines. The population based screening at 65 could be too late for all FDRs, a finding supported by several reports on the increased diameter at diagnosis, growth rate and rupture risk in patients with AAA and a family history compared to non-familial AAA. The risk for the FDR to develop disease if the proband is a male or female has also been investigated, and quite contradictory findings from an increased risk to a similar risk are found (Darling, Mejnert, Larsson, Blanchard).

In conclusion, the risk for all FDRs to develop AAA is high compared to the population, even when smokers are analyzed separately. One should possibly compare the AAA prevalence in female FDRs with that of women in the population, rather than with male FDRs when developing selective screening programs. The male FDRs also have an increased chance of detection due to the ongoing population based screening programs.

References

  1.  
    Abdominal Aortic Diameter Is Increased in Males with a Family History of Abdominal Aortic Aneurysms: Results from the Danish VIVA-trial¨, T.M.M. Joergensen a,*, K. Houlind a, A. Green b, J.S. Lindholt, Eur J Vasc Endovasc Surg (2014) 48, 669e675
  2.  
    Family history of aortic aneurysm is an independent risk factor for more rapid growth of small abdominal aortic aneurysms in Japan, Atsushi Akai, Yoshiko Watanabe, Katsuyuki Hoshina, Yukio Obitsu, Juno Deguchi, Osamu Sato, Kunihiro Shigematsu, and Tetsuro Miyata, J Vasc Surg 2015;61:287-90.
  3.  
    Family Members of Patients with Abdominal Aortic Aneurysms Are at Increased Risk for Aneurysms: Analysis of 618 Probands and Their Families from the Liège AAA Family Study, Natzi Sakalihasan, Jean-Olivier Defraigne, Marie-Ange KerstenneJean-Paul Cheramy-Bien, Diane T. Smelser, Gerard Tromp, Helena Kuivaniemi, Annals of Vascular Surgery, Volume 28, Issue 4, May 2014, Pages 787–797
  4.  
    Risk Factors for Abdominal Aortic Aneurysm: Results of a Case-Control Study. James F. Blanchard,u Haroutune K. Armenian,3 and Pamela Poulter Friesen4 American Journal of Epidemiology, 2000 Vol. 151, No. 6
  5.  
    A population-based case-control study of the familial risk of abdominal aortic aneurysm. E. Larsson, F. Granath, J. Swedenborg and R. Hultgren, J Vasc Surg 2009;49:47-51. PMID: 19028058
  6.  
    Genetic and Environmental Contributions to Abdominal Aortic Aneurysm Development in a Twin Population. C. Wahlgren, P. Magnusson, E. Larsson, R. Hultgren, and J. Swedenborg, J Vasc Surg 2010;51:3-8. PMID: 19939604
  7.  
    Age at Detection of AAA in Siblings to Patients with Abdominal Aortic Aneurysms in Sweden, Linné A, Forsberg J, Lindström D, Ideskog E, Hultgren. R, J Vasc Surg. 2016 Apr;63(4):883-7. DOI: 10.1016/j.jvs.2015.10.057. Epub 2016 Jan 26, PMID: 10.1016/j.jvs.2015.10.057

LESSONS LEARNED FROM THE IMPROVE TRIAL

Powell Janet T.

The Immediate Management of the Patient with Rupture: Open Versus Endovascular repair (IMPROVE) trial randomised 613 patients with an in hospital diagnosis of ruptured abdominal aortic aneurysm to either a strategy of endovascular first (with open repair as the default) versus open repair between 2009 and 2013.

The trial reported its primary outcome, 30-day mortality, early in 2014 [1] and 1-year outcomes in Spring 2015 [2] and now is poised to complete analysis of the final 3 year follow up. There was no difference in either 30-day or 1-year mortality between the randomised groups, although subgroup analyses at both timepoints were consistent with women having a survival advantage from an endovascular strategy. The 1-year results also reported quality of life, costs and cost-effectiveness, which were all better in the endovascular first strategy group [2].

Since this is perhaps the largest prospective series of patients with ruptured abdominal aortic aneurysm, we have been able to learn about other important aspects too, including the impact of pre-operative blood pressure, type of anaesthesia, aortic morphology and abdominal compartment syndrome [3, 4]. We also have collaborated with 2 smaller European trials to publish individual patient data meta-analyses, which strengthen all the main observations of the IMPROVE trial [5].

References

  1.  
    Endovascular or open repair strategy for ruptured abdominal aortic aneurysm: 30 day outcomes from IMPROVE randomised trial. IMPROVE Trial Investigators. Powell JT, Sweeting MJ, Thompson MM, Ashleigh R, Bell R, Gomes M, Greenhalgh RM, Grieve R, Heatley F, Hinchliffe RJ, Thompson SG, Ulug P. BMJ. 2014 Jan 13;348:f7661.
  2.  
    Endovascular strategy or open repair for ruptured abdominal aortic aneurysms: 1 year outcomes from the IMPROVE randomized trial. IMPROVE trial investigators. Eur Heart J. 2015;36:2061-9.
  3.  
    Observations from the IMPROVE trial concerning the clinical care of patients with ruptured abdominal aortic aneurysm. IMPROVE trial investigators, Powell JT, Hinchliffe RJ, Thompson MM, Sweeting MJ, Ashleigh R, Bell R, Gomes M, Greenhalgh RM, Grieve RJ, Heatley F, Thompson SG, Ulug P. Br J Surg. 2014;101:216-24
  4.  
    The effect of aortic morphology on peri-operative mortality in patients with ruptured abdominal aortic aneurysm. IMPROVE trial investigators. Eur Heart J 2015;36:1328-34
  5.  
    Individual patient meta-analysis of 3 randomized trials comparing endovascular versus open repair for ruptured abdominal aortic aneurysm. Sweeting MJ, Balm R, Desgranges P, Ulug P, Powell JT; Ruptured Aneurysm Trialists. Br J Surg. 2015 Sep;102:1229-39.

DIAGNOSTIC ALGORITHM FOR ACUTE AORTIC DISSECTION – IMAGING AND BIOMARKERS

Suzuki Toru

Diagnosis of acute aortic dissection still remains a challenge. Effective use of available diagnostic technologies including imaging and biomarkers is critical for immediate decision making. Recent developments in biomarkers such as D-dimer have established a potential role for biomarker-assisted diagnosis. Coupled with rapid imaging such as a triple rule-out CT would provide for a diagnostic algorithm of acute aortic dissection. Protocol-based diagnostic algorithms are helpful in the emergency setting and integration with available pathways such as for STEMI will be a topic that needs to be addressed. Current thinking on diagnostic algorithms based on biomarkers and imaging will be discussed.


INDIVIDUALIZED RISK ASSESSMENT IN TYPE B AORTIC DISSECTION

Clough Rachel1, 2

Thoracic endovascular aortic repair is considered to be the first-line treatment for patients with complicated type B aortic dissection. Decision making is often based on physician experience and subjective clinical judgment and therefore the management of type B aortic dissection is complex. The long-term benefits of endovascular repair to prevent aortic-related mortality has been demonstrated in randomised controlled trials however recently attention has been turned to whether endovascular repair should be performed in uncomplicated cases. Pre-emptive surgery may not be the solution for all patients because of the occurrence of adverse events such death, stroke and paraplegia. A number of groups have undertaken studies to investigate morphological and false lumen characteristics that may be able to identify patients with uncomplicated type B aortic dissection at high risk of complications that would benefit from early endovascular intervention. Characteristics investigated include aortic diameter, the position, size and number of entry tears and false lumen thrombus volume. Functional imaging methods such as magnetic resonance and echocardiography are able to provide clinically relevant structural, hemodynamic and biomechanical information, which could be used for risk stratification of individual patients. A patient-specific approach designed to intervene only in patients that are at high risk of developing complications should improve the long-term outcome of these patients.


CAN WE PREDICT AORTIC SIZE PRIOR TO DISSECTION? YES!

Elefteriades John A.

Objectives

Multiple studies have quantified the relationship between aortic size and risk of dissection. However, these studies estimated the risk of dissection without accounting for any increase in aortic size from the dissection process itself. This study aims to compare aortic size before and after dissection and to evaluate the change in size consequent to the dissection itself.

Methods

Fifty-five consecutive patients (29 Type-A; 26 Type-B) with aortic dissection (AoD) and incidental imaging studies prior to dissection were identified and compared to a control group of aneurysm patients (n=205). Average time between measurement at and prior to dissection was 1.7±1.9years (1.9±2.0years mean inter-image time in control group). A multivariate regression model controlling for growth rate, age and gender was created to estimate the effect of dissection itself on aortic size.

Results

Mean aortic sizes at and prior to dissection were 54.2±7.0mm and 45.1±5.7mm for the ascending (AA), and 47.1±13.8mm and 39.5±13.1mm for the descending aorta (DA), respectively. Multivariable analysis revealed a significant impact by the dissection itself (p<.001) and estimated an increase in size by 7.65mm (AA) and 6.38mm (DA). Thus, a proportional estimate of 82.8% (AA) and 80.8% (DA) dissect at a size lower than the guideline recommended threshold (55mm).

Conclusions

Aortic diameter increases substantially due to aortic dissection itself and thus, aortas are dissecting at clinically meaningfully smaller sizes than natural history analyses have previously suggested. These findings have important implications regarding at what size to intervene surgically (suggesting a shift toward smaller aortic sizes).


INITIAL EXPERIENCE IN DISSECTION OF AORTA IN NEPAL

Kumar Yadav, Bhatta Deo, Rajbanshi Vijoy, Timila Ravindra

Introduction

Interventional cardiology including cardiovascular surgery is in its early phase of development in Nepal. Sahid Gangalal National Heart Centre is the only cardiology dedicated government hospital in Nepal and therefore, the main tertiary cardiac patient referral centre for the whole country. Surgery for aortic dissection has recently started in the country. We present our early experience with aortic dissection cases in the hospital.

Method

We did a retrospective descriptive analysis of aortic dissection cases requiring surgery over a period of 26 months between February 2014 and April 2016.

Results

Altogether 20 cases of dissection of aorta were operated during the period. Thirteen (65 %) patients were males. Average age of the patients was 54 years (range: 25 to 81 years). Eighteen cases (90%) were of type A dissection: 17 with acute and 1 with chronic dissection, while the remaining two (10%) had type B dissection and required surgery because of complications like leak or rupture. Of the 18 type A dissection cases, two-third (12/18) underwent M Bentall’s procedure while 3 underwent Bentall’s with hemi arch replacement, 2 underwent ascending aortic replacement, and 1 underwent Bentall’s with proximal arch replacement. In addition, one of these patients had right coronary artery unroofing while another one had coronary artery bypass graft. Five of these 18 patients (27.8%) died. The two cases of type B dissection underwent surgery in an emergency basis due to ongoing leak and both expired post-operatively.

Conclusion

Our early experience with aortic dissection management shows a success rate of 65%. Studies that look into details of patient characteristics and health-provider related parameters can help improve success rate, and reduce mortality.


POSITIVE FAMILY HISTORY OF AORTIC DISSECTION DRAMATICALLY INCREASES DISSECTION RISK IN FAMILY MEMBERS

Elefteriades John A.

Objective

Although family members of patients with aortic dissection (AoD) are believed to be at higher risk of aortic dissection, the prognostic value of a positive family history (FH) of aortic dissection (FHAD) in family members of patients with AoD has not been studied rigorously. We seek to examine how much a positive family history of aortic dissection may increase the risk of developing new aortic dissection among first-degree family members.

Methods

Patients with AoD treated at our institution between 1983 and 2015 were contacted to complete a questionnaire on FHAD. A family history was considered positive if AoD occurred in the index patient and one or more family members. The age at AoD, exposure years in adulthood before AoD, and annual probability of AoD among first-degree relatives were compared between patients with negative and positive FHADs.

Results

A total of 100 patients with AoD were identified. Mean age at dissection was 59.9 ± 14.7 years. FHAD was positive in 32 patients and negative in 68. Compared to patients with negative FHAD, patients with positive FHAD dissected at significantly younger age (54.7 ± 16.8 vs 62.4 ± 13.0 years, P = 0.013), had more AoD events in first-degree relatives (2.3 ± 0.6 vs 1.0 ± 0.0, P < 0.001), and shorter exposure years per AoD event (18.3 ± 6.7 vs 43.1 ± 8.5, P < 0.001). The annual probability of AoD per first-degree relative was 2.77 times higher in patients with positive than negative FHADs (0.0100 ± 0.0057 vs 0.0036 ± 0.0014, P < 0.001).

Conclusions

A positive FHAD confers a significantly increased risk of developing AD on family members.


OPEN SURGICAL CONVERSION AFTER TEVAR: INCIDENCE AND TREATMENT OPTIONS

Melissano Germano1, Tshomba Yamume1, Mascia Daniele1, Baccellieri Domenico1, Kahlberg Andrea1, Bertoglio Luca1, Nardelli Pasquale1, Negri Giampiero2, Chiesa Roberto1

Background

To analyze indications, describe different approaches and report outcomes of patients undergoing late open conversion (LOC) after thoracic endovascular aortic repair (TEVAR).

Methods

From to 1999 to 2015, 65 patients at our Institution underwent redo procedures after TEVAR. Thirty of them underwent LOC. Average time from the index TEVAR to LOC was 57 months (range 2-98 months), indication to LOC was progression of distal aortic disease in nine patients (30%), stent-graft infection/fistulization in 10 (33.3%), retrograde dissection in 6 (20%), endoleak in 3 (10%), device migration/failure in 2 (6.7%). In 17 patients (56.6%) thoracic stent-graft was only partially removed and the proximal anastomosis was performed including native aorta, stent-graft and surgical graft. Left heart bypass and cerebrospinal fluid drainage were used in 22 (73.3%) and 16 (53.3%) cases, respectively. Biological flap coverage with intercostal muscle flap was used 6 six of infected cases.

Results

Overall perioperative mortality rate was 16.6% (5 patients) – 20% in the subgroup of patients with stent-graft infection/fistulization (2 patients) and 33% in the subgroup with retrograde dissection (2 patients). The most common postoperative complication was respiratory failure with seven cases (23.3%). Paraplegia was observed in 1 patient (3.3%). During a mean follow-up of 19 months (range, 5-63) was registered only one aortic-related death for aorto-esophageal fistula.

Conclusions

Open conversion after TEVAR is a technically demanding procedure but feasible leaving in site the proximal segment of thoracic stent-graft in most of the cases. Morbidity and mortality rates were higher in case of infection, fistula and retrograde dissection.


NEUROMONITORING USING MOTOR AND SOMATOSENSORY EVOKED POTENTIALS IN AORTIC SURGERY

Elefteriades John A.

Background

Motor evoked potentials (MEP) and somatosensory evoked potentials (SSEP) are established methods of neuromonitoring aimed at preventing paraplegia after descending or thoracoabdominal aortic repair. However, their predictive impact remains controversial. The aim of this study was to evaluate our single center experience using this monitoring technique.

Methods

Between 2009 and 2014, 78 patients (mean age 66 ± 12, 53% male) underwent either descending or thoracoabdominal aortic repairs. Of these, 60% had an aortic aneurysm, 30% dissection and 10% other etiologies. Intraoperatively, MEPs and SSEPs were monitored and, if necessary, clinical parameters (blood pressure, hematocrit, oxygenation) were adjusted in response to neuromonitoring signals. This analysis is focused on the neurological outcome (paraplegia, stroke) after the use of intraoperative neuromonitoring.

Results

Thirty-day mortality was 10 (12.8%). All patients with continuously stable signals or signals that returned after signal loss developed no spinal cord injury, whereas 2/6 of the evaluable patients with signal loss (without return) during the procedure suffered from postoperative paraplegia (one transient and one permanent). Sensitivity and specificity of use of MEP and SSEP were 100% and 94.20% regarding paraplegia, respectively.

Conclusions

(1) Preservation of signals or return of signals is an excellent prognostic indicator for spinal cord function. (2) Intraoperative modifications in direct response to the signal change may have averted permanent paralysis in the patients with signal loss without neurologic injury. We have found MEP and SSEP neuromonitoring to be instrumental in the prevention of paraplegia.


RADIATION PROTECTION FOR PATIENT AND STAFF DURING ROUTINE EVAR AND TEVAR PROCEDURES

Matsagkas Miltiadis, Kouvelos George

Endovascular aortic aneurysm repair require extended fluoroscopy guidance for the manipulation of endovascular devices, which is associated with biological risks for both physicians and patients. Potential consequences range from skin injuries to the development of solid cancers and leukemia. There is no absolutely safe amount of ionizing radiation and protection must be a priority for the endovascular therapist. When following good practices it is possible to keep the risks as low as reasonably achievable to commensurate with the medical purpose. Radiation protection can be achieved with the use of appropriate protective equipment and the reduction of the radiation dose. The use of shielding devices (lead aprons, thyroid shields, table suspended lead shields) is mandatory. The use of tables with a carbon fiber top instead of regular surgical tables is preferable. The distance between the patient’s body and the image receptor should always be minimized to avoid beam energy dispersion and the screen should always be collimated vertically and horizontally to the area of interest. Radiation dose reduction requires a strict application of the “as low as reasonably achievable” principle. The x-ray system should be by default set to low dose program and pulsed mode, while the pedal should be engaged only when information is required. Magnification should be avoided, while digital subtraction angiography should be replaced by fluoroscopy runs in most instances possible. Extreme angulations of the x-ray equipment should be avoided. Image fusion can facilitate endovascular navigation and reduce the dose needed, although have not been widely applicable. All interventionists should receive appropriate radiation protection training and always audit and review the outcomes of each procedure. The application of specific regulation of radiation protection during routine EVAR and TEVAR is mandatory. Optimized set-up of the fluoroscopy system, adherence to good clinical practice and adequate training are key points to ensure safety for both the patients and the staff during the procedure.


PATIENTS’ COMPLIANCE WITH POST-EVAR FOLLOW-UP AND ITS IMPACT ON THE OUTCOME

Giannoukas Athanasios

Lifelong follow-up after Endovascular Aortic Aneurysm repair (EVAR) is recommended to monitor the effectiveness and durability of the treatment. Nevertheless, patients’ compliance with follow-up protocol is an important element that may be related to the outcome. We conducted a study to assess patients’ compliance with the follow-up imaging protocol, the presence of any factors associated with the patients’ compliance and the potential influence of imaging-protocol adherence on outcomes. This study was a systematic review of the existing literature by searching the MEDLINE, CENTRAL, and Cochrane databases and the related keys references.

One randomized control and nine retrospective studies were identified reporting on post-EVAR follow-up compliance. The studies included 36,119 patients with mean age of 76±3.1 years and the mean follow-up ranged from 25 to 73 months. Most of the patients were males (51%-89%), white (51%-97.7%) and the majority of them were living <100 miles from the treatment center. The data were too heterogeneous to perform a meta-analysis. Incomplete follow-up and complete loss of follow-up were ranging from 15% to 65% and 22% to 56%, respectively. Advanced age, symptomatic or ruptured aneurysm, history of chronic diseases, and social-economic issues were associated with poor follow-up compliance. Five of these studies suggested that complete follow-up did not offer any survival benefit, while only one study suggested that incomplete follow-up was associated with higher fatal complication rates.

Patients’ compliance with a post-EVAR follow-up imaging protocol is poor while patients’ age, social-economic issues, chronic comorbidities and operation undertaken as emergency appear to be factors associated with poor patients’ compliance. However, there is lack of solid evidence to show that this poor compliance results in worse outcomes. Prospective studies focused on the impact of follow up adherence on the EVAR outcomes are needed.


EARLY AND LONG-TERM OUTCOMES AFTER OPEN OR ENDOVASCULAR REPAIR FOR ABDOMINAL AORTIC ANEURYSMS IN HIGH-RISK PATIENTS

Palombo Domenico, Bessone Carlo, Perfumo Maria Cecilia, Pane Bianca, Ferrero Cesare, Mambrini Simone, Spinella Giovanni

Introduction

The aim of this study was to evaluate the short and long term results of surgical or endovascular treatment for abdominal aortic aneurysms (AAA), stratifying patients according to preoperative risk.

Methods

A retrospective, observational study was performed. Data on preoperative risk factors were analyzed to stratify patients according to the SVS / ISCVS score. The patients were then classified in two groups according to the surgical risk (Group A SVS score 0-10, Group B SVS score 11-22). In the two groups of patients were evaluated postoperative complications, 30-day mortality and survival during follow-up.

Results

From July 2011 to November 2014 at our unit were treated electively 374 patients with AAA. The analysis of the results was carried out only in 212 cases (24 females and 188 males) in which it was possible to collect clinical data. The mean age was 76.5 years (range 56-93 years); 135 (63.7%) patients underwent OR treatment, 77 (36.3%) underwent EVAR. The medium follow-up was 685 days (0-1420 days range). Open repair performed out in 75 and 60 patients in group A and B respectively. EVAR was done in 43 and 34 of the group A and B respectively. Mortality at 30 days was 1.7% and 3.2% in group A and B respectively. During follow-up the median survival was 91.9% for patients in the OR group, and 98.3% for patients undergoing EVAR in group A and 98.3% for patients subjected to OR and 79.4% for patients undergoing EVAR.

Conclusions

The results of our study showed a lower 30-day mortality in high-risk patients undergoing surgical or endovascular treatment. Analysis of the results showed that survival in high-risk patients during follow-up does not seem to be affected by the type of treatment and in fact was higher in patients undergoing OR compared with patients undergoing EVAR.


RENAL FUNCTION IS THE MAIN PREDICTOR OF ACUTE KIDNEY INJURY AFTER ENDOVASCULAR ABDOMINAL AORTIC ANEURYSM REPAIR

Saratzis Athanasios, Sidloff David, Bown Matthew

Background

Postoperative acute kidney injury (AKI) may occur in up to 20% of elective endovascular abdominal aortic aneurysm repairs (EVAR) (1-3) and has been associated with poor outcome (1-4); however, it is not clear which patients are at highest risk, to target renoprotection effectively. We sought to determine the predictive factors of AKI after elective EVAR.

Methods

Overall, 947 patients undergoing elective EVAR between January 2004 and December 2014 were analyzed, using prospectively collected data. Postoperative AKI was defined by serum creatinine change within 48 hours, using the latest validated criteria (Acute Kidney Injury Network and Kidney Disease Improving Global Outcomes). Cardiovascular and kidney-disease risk factors were entered in univariate and multivariate analyses to assess influence on AKI development. Associations between AKI and long-term mortality, morbidity and cardiovascular events were sought using multivariate models.

Results

Overall, 167 (17.6%) patients developed AKI but only 2 patients required dialysis perioperatively. At multivariate analysis, adjusted for established AKI-risk factors and parameters that differed between groups at baseline, preoperative estimated glomerular filtration rate (eGFR; as per the chronic kidney disease epidemiology [CKD] formula); odds ratio (OR): 1.02 (per unit decrease); 95% confidence interval (CI): 1.003-1.041; P = 0.025; and chronic kidney disease (CKD) stage > 2 (OR: 1.28; 95% CI: 1.249-2.531, P = 0.001) were associated with development of AKI. During a median follow-up of 62 months, AKI was associated with CV events on adjusted analyses [Hazard Ratio (HR): 1.73, 95% CI 1.06-3.39, p=0.03] and mortality (HR: 1.84, 95% CI 1.01-4.22, p=0.01).

Conclusions

AKI was common after elective infrarenal EVAR and preoperative renal function was the main predictor. Patients with a low eGFR need to be targeted with more aggressive renal protection, since AKI development is associated with poor outcomes.

References

  1.  
    Saratzis A, Melas N, Sarafidis P. Incidence of Acute Kidney Injury (AKI) after Endovascular Abdominal Aortic Aneurysm Repair (EVAR) and Impact on Outcome. European Journal of Vascular and Endovascular Surgery 2015; 49:534-40.
  2.  
    Saratzis A, Goodyear S, Sur H, Mahmood A. Acute kidney injury after endovascular repair of abdominal aortic aneurysm. Journal of Endovascular Therapy 2013; 20:315-30
  3.  
    Saratzis A, Bath M, Sayers R, Bown M. Impact of Fenestrated Endovascular Abdominal Aortic Aneurysm Repair on Renal Function; Journal of Endovascular Therapy 2015; 22:889-96.
  4.  
    Saratzis A, Bath MF, Harrison S, Sayers RD, Mahmood A, Sarafidis P, Bown MJ. Intervention Associated Acute Kidney Injury and Long-Term Cardiovascular Outcomes. American Journal of Nephrology 2015; 42:285-294

STRUCTURAL FINITE ELEMENT MODELLING OF THE BICUSPID ROOT TO UNDERSTAND DISEASE PROGRESSION

Votta Emiliano1, Presicce Marica1, Corte Alessandro Della2, Dellegrottaglie Santo3, 4, Bancone Ciro2, Sturla Francesco1, Redaelli Alberto1

Bicuspid aortic valve (BAV) is a congenital aortic valve disease where two out of the three leaflets are fused together. BAV is a recognized risk factor for pathologies affecting the aortic valve and the ascending aorta. Despite the genetic origin of BAV, the associated alterations in aortic root structural mechanics and fluid dynamics may play a relevant role in the progression of the mentioned degenerative processes, and hence in the timing for surgery. Currently, the evaluation of the progression of the disease, and hence prognosis and decision for surgery, largely rely on purely geometrical criteria, i.e. on the measurement of some key dimensions of the aortic root (AR) from clinical images. These criteria are empirical and sub-optimal; complementing them with new and biomechanically-driven ones could allow for more reliable prognosis and aid the decisional process. On this basis, we developed computational tools to assess the in vivo fluid dynamics and structural mechanics of the AR, aimed to the quantification of the biomechanical anomalies characterizing BAV disease. Here we focus on the finite element analysis of AR structural mechanics in presence of BAV through a novel approach that exploits the anatomical information yielded by magnetic resonance imaging and that allows for consistency between the image-based AR geometry and the pressure loads acting on it. We simulated AR function throughout the cardiac cycle for two preliminary cohorts of healthy volunteers (n=4) and BAV patients with normo-functional valves (n=3), and compared the corresponding biomechanical variables. Namely, we analyzed two features of potential clinical relevance in BAV patients. First, the increase in diastolic leaflet strains and stresses characterizing the abnormal closed valve configuration, which may impact on the differentiation of valvular interstitial cells (VICs) and promote aortic valve calcification. Second, the increase in systolic aortic wall stresses in BAV patients in the tubular ascending aorta, which may be linked to aortic wall remodeling and to an increased risk for wall dilation and coarctation. Despite the inter-subject variability within each cohort, differences were evident between healthy ARs and BAV-affected ones. When compared to healthy ARs, BAV-affected ones were characterized by i) altered diastolic leaflet stretches, which were notably reduced in the commissure-commissure direction and increased in the annulus-to-free margin direction, ii) increased diastolic leaflet stresses, and iii) aortic wall regions affected by elevated stresses in systole, which run from to sino-tubular junction to the convex side of the ascending aorta. When applied to a sufficiently wide and statistically robust population of subjects undergoing proper follow-up, our approach may yield detailed biomechanical data whose prognostic value could be evaluated, paving the way towards sounder criteria for the prognosis of BAV disease.


IDENTIFYING CIRCULATING BIOMARKERS OF BAV AORTOPATHY RISK

Corte Alessandro Della

The current knowledge of bicuspid aortic valve (BAV)-related aortopathy is recognized to be inadequate [1], especially in its pathogenetic and prognostic aspects. Patients are usually operated on electively, to prevent the risk of acute aortic events, namely aortic rupture and aortic dissection, on the basis of “dimensional” criteria of indication, i.e. aortic diameter and size progression rate [2]. However, it is now understood that dimensional criteria alone are not enough to adequately manage such a heterogeneous disease as BAV aortopathy, especially in terms of prognosis [3]: thus additional “non-dimensional” criteria for risk stratification are needed to the purpose of developing personalized medicine strategies [4, 5]. The search for putative risk markers of BAV aortopathy is particularly lively, however most studies have addressed imaging-based markers [6], while only few focused on the identification of biochemical markers [7-9]. Indeed, a biomarker of aortopathy should have pathogenetic significance, and ideally it should have limited correlation with aortic diameter, to provide additional information for prognostic stratification alongside this parameter. The issue of identifying possible biomarkers of BAV aortopathy has been addressed by few studies, with different approaches. Tzemos et al. previously reported higher MMP-2 serum concentration in BAV patients with aortopathy than in BAV patients without aortopathy (defined by aortic diameter >40mm and <35mm respectively) [10]. Later on, unique profiles of plasma MMPs, tissue inhibitors of MMPs and microRNAs were revealed in TAV versus BAV patients with aortic aneurysm [7], showing the possibility to predict the presence of specific etiologic subtypes (i.e. TAV or BAV) of aneurysm disease using a plasma multi-analyte regression strategy. Others [8] reported significant correlation between serum levels of the receptor for advanced glycation end-products (sRAGE) and its tissue expression, that was in turn associated with disrupted elastin and proteoglycan deposition, irrespective of the diameter. Hillebrand et al.[11] recently assessed the serum levels of TGF-ß1 in an etiologically heterogeneous population, also including BAV patients: total serum TGF-β1 was higher in patients with aortic dilatation, however the only independent predictor in multivariable analysis was the presence of a genetic syndrome, and non-syndromic BAV patients had lower serum levels of TGF-β1 compared to the reference controls. The growing body of information on this topic will be systematically reviewed in this presentation and the unmet needs in the search for prognostically relevant biomarkers in BAV aortopathy will be appraised.

References

  1.  
    Della Corte A, Body SC, Booher AM, et al; BAVCon Investigators. (2014) Surgical treatment of bicuspid aortic valve disease: knowledge gaps and research perspectives. J Thorac Cardiovasc Surg 2014;147:1749-1757.
  2.  
    Hardikar AA, Marwick TH. Surgical thresholds for bicuspid aortic valve associated aortopathy. JACC Cardiovasc Imaging 2013;6:1311-1320.
  3.  
    Detaint D, Michelena HI, Nkomo VT, Vahanian A, Jondeau G, Sarano ME. Aortic dilatation patterns and rates in adults with bicuspid aortic valves: a comparative study with Marfan syndrome and degenerative aortopathy. Heart 2014;100:126-134.
  4.  
    Della Corte A. Phenotypic heterogeneity of bicuspid aortopathy: a potential key to decode the prognosis? Heart 2014;100:96-97.
  5.  
    Fedak PW, Verma S. Bicuspid aortopathy and the development of individualized resection strategies. J Thorac Cardiovasc 2014;148:2080-2081.
  6.  
    Bissell MM, Hess AT, Biasiolli L, Glaze SJ, Loudon M, Pitcher A, Davis A, Prendergast B, Markl M, Barker AJ, Neubauer S, Myerson SG. Aortic dilation in bicuspid aortic valve disease: flow pattern is a major contributor and differs with valve fusion type. Circ Cardiovasc Imaging 2013;6:499-507.
  7.  
    Ikonomidis JS, Ivey CR, Wheeler JB, Akerman AW, Rice A, Patel RK, Stroud RE, Shah AA, Hughes CG, Ferrari G, Mukherjee R, Jones JA. Plasma biomarkers for distinguishing etiologic subtypes of thoracic aortic aneurysm disease. J Thorac Cardiovasc Surg 2013;145:1326-1333.
  8.  
    Branchetti E, Bavaria JE, Grau JB, Shaw RE, Poggio P, Lai EK, Desai ND, Gorman JH, Gorman RC, Ferrari G. Circulating soluble receptor for advanced glycation end product identifies patients with bicuspid aortic valve and associated aortopathies. Arterioscler Thromb Vasc Biol 2014;34:2349-2355.
  9.  
    Wang Y, Wu B, Dong L, Wang C, Wang X, Shu X. Circulating matrix metalloproteinase patterns in association with aortic dilatation in bicuspid aortic valve patients with isolated severe aortic stenosis. Heart Vessels 2016;31(2):189-197.
  10.  
    Tzemos N, Lyseggen E, Silversides C, Jamorski M, Tong JH, Harvey P, Floras J, Siu S. Endothelial function, carotid-femoral stiffness, and plasma matrix metalloproteinase-2 in men with bicuspid aortic valve and dilated aorta. J Am Coll Cardiol 2010;55:660-668.
  11.  
    Hillebrand M, Millot N, Sheikhzadeh S, et al. Total serum transforming growth factor-beta1 is elevated in the entire spectrum of genetic aortic syndromes. Clin Cardiol 2014;37:672-679.

HOW TO INTEGRATE IMAGING AND BIOCHEMISTRY INTO RISK STRATIFICATION OF BICUSPID AORTOPATHY

Fedak Paul W.M.1, Guzzardi David1, Barker Alex2

Efforts over the past few years have focused on defining individual risk factors for disease progression in patients with bicuspid aortic valve (BAV) and aortopathy. The risks associated with BAV aortopathy may be less than previously believed. This statement is based on contemporary natural history studies and key comparisons to those with tricuspid aortic valve disease and genetic connective tissue aortopathies. More conservative and selective approaches to prophylactic aortic resection may be indicated, particularly in patients with BAV stenosis.

Using newer state-of-the-art imaging modalities (4D-flow MRI) with tissue correlation of molecular biomarkers, novel data supports valve-mediated hemodynamics as a critical mediator of disease progression in BAV aortopathy. Recent studies by us and others indicate that altered aortic hemodynamics in BAV patients are directly associated with regional degradation of the aortic wall and the BAV aortopathy phenotype. Findings based on 4D flow MRI, which allows for the in-vivo measurement of aortic blood flow with full volumetric coverage of the aorta, have documented changes in transvalvular blood flow and their downstream impact on regional aortic wall shear stress (WSS) even for BAVs without valve dysfunction. WSS is a known stimulus for arterial mechanotransduction and can alter endothelial cell function resulting in outward vascular remodeling (e.g. dilation). A recent study from our group provides strong evidence for this proposed mechanism via the use of in-vivo 4D flow MRI and aortic tissue resection in BAV patients undergoing aortic repair. Correlation of aortic 4D flow MRI hemodynamics with resected aortic tissue histopathology showed that regionally elevated WSS patterns were closely associated with the severity of aortopathy.

There remains a substantial gap in knowledge with respect to BAV aortopathy in the pathophysiology and molecular mechanisms of disease progression. There is a critical need to develop individualized risk assessments beyond size and growth criteria to offer more precise and individualized strategies for surgical resection of the aorta in BAV patients. The integration of novel imaging and biomolecular markers of BAV aortic disease progression and severity may improve our management of individual patients who need prophylatic aortic resection.

References

  1.  
    Michelena HI, Corte AD, Prakash SK, Milewicz DM, Evangelista A, Enriquez-Sarano M. Bicuspid aortic valve aortopathy in adults: Incidence, etiology, and clinical significance. Int J Cardiol 2015;201:400-407.
  2.  
    Della Corte A, Body SC, Booher AM et al. Surgical treatment of bicuspid aortic valve disease: Knowledge gaps and research perspectives. J Thorac Cardiovasc Surg 2014;147(6):1749-1757, 1757 e1741.
  3.  
    Hardikar AA, Marwick TH. The natural history of guidelines: The case of aortopathy related to bicuspid aortic valves. Int J Cardiol 2015;199:150-153.
  4.  
    Della Corte A, Bancone C, Dialetto G et al. Towards an individualized approach to bicuspid aortopathy: Different valve types have unique determinants of aortic dilatation. Eur J Cardiothorac Surg 2014;45(4):e118-124; discussion e124.
  5.  
    Itagaki S, Chikwe JP, Chiang YP, Egorova NN, Adams DH. Long-term risk for aortic complications after aortic valve replacement in patients with bicuspid aortic valve versus marfan syndrome. J Am Coll Cardiol 2015;65(22):2363-2369.
  6.  
    Guzzardi DG, Barker AJ, van Ooij P et al. Valve-related hemodynamics mediate human bicuspid aortopathy: Insights from wall shear stress mapping. J Am Coll Cardiol 2015;66(8):892-900.

TWENTY-FIVE YEAR OUTCOME OF COMPOSITE GRAFT AORTIC ROOT REPLACEMENT: NEAR “CURATIVE” IMPACT ON AORTIC ROOT DISEASE

Elefteriades John A

Background

Operative choices for aortic root disease abound. We report our experience with traditional composite graft replacement in 449 patients focusing on long-term survival and freedom from late reoperation and adverse events.

Methods

The coronary button technique was used. Mean age was 56.1±14.0 years (range 14-87) with 83% males (373/449). Valve prosthesis was mechanical in 343 (76%) and bioprosthetic in 106 (24%). A modified Cabrol procedure (Dacron coronary graft) was employed in 10% (45/449) and concomitant CABG 10.9% (49/449). There were 15.8% (71/449) urgent/emergent and 8.2% (37/449) redo procedures. Survival follow-up was 100% averaging 7.0±5.1 years (range 0.1-24.8).

Results

Operative mortality occurred in 14 patients (3.1%) and was 2.2% (9/418) in non-dissection and 1.9% (7/361) in elective first-time operations. Stroke and re-exploration for bleeding occurred in 9 (2.0%) and 20 (4.5%) patients, respectively. Major late events included bleeding in 2.5% (11/435) and thromboembolism in 1.1% (5/435). At 5, 10 and 20 years, freedom from major events and reoperations on the root were 97.8%, 95.4% and 94.39%, and 99.0%, 99.0% and 97.9%, respectively. Survival in patients aged <60 years was 92.0%, 90.1% and 79.8% at 5, 10 and 20 years versus 88.4%, 67.9% and 42.6% in patients aged ≥60 years. Compared with age- and gender-matched controls, survival was not significantly different (p = 0.20).

Conclusions

Composite graft aortic root replacement is associated with low operative risk, excellent long-term survival, and low incidence of reoperation and late events. The favorable long-term results indicate an almost “curative” impact on aortic root disease.


HOW TO CLASSIFY THE DILATATIONS OF THE ASCENDING AORTA?

Corte Alessandro Della

While classification systems are available and currently used in the terminology to define aortic dissection and thoraco-abdominal aortic aneurysms, there is no such established method to classify the dilative aortopathies that affect the ascending aorta. Several types of classifications have been proposed, in particular applied to the setting of bicuspid aortic valve-related aortopathy. They are based on different criteria for classification, including: 1) the pattern of dimensions (one segment relative to another); 2) the presence of dilatation in absolute terms (need for a cut-off); 3) the combination of both the previous criteria. These will be appraised in this presentation and their respective potential for a clinical usefulness will be commented. The hypothesis will also be issued that bicuspid aortopathy might be the testing ground for the identification of the best criterion to be then applied to all other tricuspid-aortic-valve-associated dilatations of the proximal tract of the aorta.

Figure 1.

Several evidences in the literature suggest that the classification distinguishing between a “root phenotype” and an “ascending phenotype” may have both descriptive significance and prognostic meaningfulness.

media/vol4/issue5/images/aorta-04-185-g003.jpg

UPDATE ON TOTAL ARCH ENDOVASCULAR REPAIR

Clough Rachel1, 2, Haulon Stephan1

Complete replacement of the aortic arch remains one of the most complex vascular operative procedures. Open surgical repair is the reference standard but despite advances in surgical technology and techniques the mortality and neurological complication rates remain high. The arch branch endograft has been used in selective centers since 2009 and despite an initially steep learning curve, 30-day mortality rates are now similar to traditional open repair, despite taking on a significantly more morbid patient population. There are many challenges associated with this procedure, such as the integrity of the seal zones, the correct method for alignment of the device intra-operatively and consideration of the aortic valve. These will have an effect on the ease of implantation, the morbidity and mortality associated with the procedure and the long-term durability of the repair.


CHOICE OF THE BEST TRANSCATHETER SITE FOR TAVI IMPLANTATION

Radermecker Marc, Martinez Christophe, Gach Olivier, Durieux Rodolphe, Defraigne Jean-Olivier, Legrand Victor

The least invasive access for the TAVI procedure is via the common femoral artery. However, among the patients actually referred for this procedure, this route is either impracticable or unwise in approximately 15-20 % of the patients. Indeed, vascular complications and haemorrhage have a major negative impact on the outcome following this procedure.

We present the experience of the CHU of Liège over 215 cases of TAVI procedure using the Corevalve Medtronic(r)device. Our strategy implies the decision for the therapy and the selection of the vascular access in heart team. The past history of the patient, angio-CT data and the arteriography performed during the catheter evaluation are integrated.

The left axillary artery (20/215) and the right carotid artery (15/215) have been used successfully in our practice as respectively second and third choice options. This versatility enabled us to treat in a antegrade or minimally invasive fashion virtually every patient.


CRITICAL ANALYSIS OF RECENT REGISTRIES AND RANDOMIZED TRIALS

Legrand Victor

Clinical studies and registries supporting the safety and efficacy of Transcatheter Aortic Valve Implantation (TAVI) have been accumulated for the last two years. Additionally, randomized trials comparing TAVI with Surgical Aortic Valve Replacement (SAVR) showed non inferiority and even superiority of TAVI over SAVR in moderate and high risk patients as defined by STS or Euroscore II scores. Results of four randomized trials comparing SAVR and TAVI are reviewed. Patient’s characteristics, early and late clinical outcomes of each trials are presented and discussed. TAVI was associated with a significant 13% reduction in mortality at 2 years, as compare to SAVR. Survival benefit of TAVR was significant for female patients (p=0.01) and for patients undergoing transfemoral access (p=0.004). The TAVI survival benefit was consistent across high-risk and lower-risk groups and was independent of device type. Of note that TAVI is not associated with survival benefit in male patients (p=0.95). TAVI procedures were associated with fewer kidney injury, new onset atrial fibrillation and major bleeding. Conversely, fewer major vascular complications, fewer new PCMK implantation and paravalvular regurgitation occurred among SAVR patients. Large US and European registries not only confirm the increasing use of TAVI for the treatment of aortic valve stenosis, but also aim to better define patients in whom the procedure may be futile. Patients with severe kidney or lung dysfunction, those with poor LV function (LF/LG stenosis, NYHA class IV) have worse outcomes. Presence of 3 or more major organ system compromises should be considered at prohibitive risk. Additionally, frailty index and cognitive functions should also be considered in decision making. Above all, it is now clear that the best treatment of aortic valve stenosis should be discussed by a valvular heart team which goal is to confirm the indication and decide the best procedure (TAVI or SAVR), according to clinical status of the patient and local experience.


HIGH HERITABILITY OF ABDOMINAL AORTIC ANEURYSMS – A POPULATION-BASED TWIN-STUDY

Joergensen Trine Maria Mejnert

Introduction

First-degree relatives of patients with abdominal aortic aneurysm (AAA) have an increased risk of developing AAA; however, despite intensive investigation, the specific genetic factors involved in the development of the disease are still largely unknown. In twin studies the influence of genetic and environmental factors can be assessed by comparing concordance rates between monozygotic (MZ) and dizygotic (DZ) twins. Higher phenotypic similarity between MZ than DZ twins indicates a genetic attribution to the aetiology. Overall heritability can be calculated using structural equation modelling.

Aim

To investigate the heritability of AAA among Danish twins using concordance rates and heritability estimates.

Materials/methods

The Danish Twin Registry was used to identify all Danish twin pairs where both twins were alive January 1, 1977. We then identified AAA-cases using the National Patient Registry and the Registry of Cause of Death. Probandwise concordance rates were calculated and heritability estimated using structural equation modelling.

Results

We identified 414 twins with AAA; 69.8% (289/414) men and 30.2% (125/414) women. The probandwise concordance rate in MZ twins was 30% (95% CI (confidence interval):20.3;43.3%) compared with 12% (95%CI:7.0;20.1%) in DZ twins. In the heritability analysis 77% (95%CI:67;85%) of the total variance was explained by additive genetic components and 23% (95%CI:15;33%) was explained by non-shared environmental factors.

Conclusions

We found a probandwise concordance rate 2.5 times higher in MZ twins compared with DZ twins and an overall heritability of 77% which suggests a substantial genetic component in the development of AAA.


GLOBAL AND GENE SPECIFIC DNA METHYLATION IS ASSOCIATED WITH ABDOMINAL AORTIC ANEURYSMS

Toghill Bradley, Saratzis Athanasios, Verissimo Ana, Sayers Rob, , Bown Matt

Introduction

Abdominal aortic aneurysm (AAA) is a degenerative cardiovascular disease characterised by the gradual, irreversible dilation of the abdominal aorta. There is strong evidence of genetic predisposition in the development of AAA but only a small number of low-effect risk loci have been identified. It is feasible that DNA methylation, one cause of altered gene-regulation, may contribute to AAA. We recently identified that global DNA hyper-methylation was associated with large AAA and increasing aneurysm diameter. These associations were independent of ethnicity, gender, age and smoking, highlighting the potentially pathogenic effects of chronic inflammation on methylation.

Aim

To identify gene specific CpG methylation changes in the promoters of genes already known to be associated with AAA.

Work summary

Candidate gene promoters (SORT1, LDLR, IL6R, LRP1, CDKN2B and MMP9) were isolated in DNA derived from the peripheral blood mononuclear cells of 48 people with large AAA and 48 controls using DNA bisulphite conversion and bisulphite-specific PCR, then sequenced using next-generation sequencing technology. Data was analysed using open source bioinformatics software specifically designed for methylation sequencing.

Results

Changes in levels of CpG methylation were observed in people with large AAA vs controls. The LDLR and SORT1 promoters were consistently hyper-methylated across large sections in 48 AAA vs 48 controls. 21 individual CpGs were hyper-methylated in AAA at the LDLR promoter locus, with an average increase of 5.4% (+/-1.08) (P=0.002). 4 CpG sites were significantly hyper-methylated in AAA in the SORT1 promoter locus, with an average increase of 4.8% (+/-0.55) (P=0.004).

Conclusion

We have now identified that global and gene specific DNA methylation is associated with AAA. Functional corroboration is needed, but it is possible that these methylation differences are biological determinants of altered gene expression, and that DNA methylation does play a role in the disease. These genes also represent viable meQTL candidates.

References

  1.  
    Toghill et al, (2016). Genome-wide DNA methylation is associated with abdominal aortic aneurysm. SARS 2016 Meeting Abstracts, British Journal of surgery. 103(S3):1-56.

END-STAGE HUMAN ANEURYSM DISEASE IN DIFFERENT ARTERIAL POSITIONS IS SIMILAR – ANEURYSM INDUCTION IN MOUSE MODELS HOWEVER NOT

Busch Albert1, Schmidt Caroline2, Paloschi Valentina1, Erikson Per1, Ergün Süleyman3, Hartmann Elena4, Kellersmann Richard2, Otto Christoph2, Lorenz Udo2, Maegdefessel Lars1

Introduction

Aneurysm disease can occur throughout the arterial tree, with abdominal aortic aneurysm (AAA) being the most frequent central - and popliteal artery aneurysm (PAA) the most frequent peripheral one. The pathology has been well examined, yet, very little is understood regarding AAA development. Leaving aside secondary vessel enlargement due to dissection, inflammation and genetic disorders, aneurysm disease has distinct features like angiogenesis and phenotypic switching of vascular smooth muscle cells (VSMC). However, little is known about these characteristics in other than AAA.

Material and Methods

From a surgical biobank of aneurysm tissue we compared 42 AAA, 15 PAA, three ascending aortic, five iliac, three femoral, two brachial, one visceral and one carotid artery aneurysm on morphologic, protein and mRNA-expression levels. Two multi-stage mouse models of aneurysm disease, porcine pancreatic elastase infusion (PPE) and topic application of elastase (EPA), were applied to test the response to arterial aneurysm induction in different locations within the arterial system.

Results

AAAs show a wide variety in histomorphologic appearance, which can not be detected in PAA. All investigated aneurysm entities show characteristic VSMC phenotypic switching, angiogenesis, matrix remodeling, T-cell inflammation and M1-like macrophage homing. AAA and PAA, despite being of elastic and muscular artery origin respectively, have similar involvement of key transcription factors, like i.e. Krueppel-like factor 4 or myocardin. To further investigate these conditions in inducible aneurysm 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 that are best mimicked by the murine PPE model of aneurysm induction.


PHENOTYPIC SWITCHING OF SMCS IS A POTENTIAL THERAPEUTIC TARGET IN POPLITEAL ANEURYSMS

Busch Albert1, Chernogubova Ekaterina1, Li Yuhuang, Scholz Claus-Jürgen2, Kickuth Ralph3, Lorenz Udo4, Roy Joy1, Hultgren Rebecka1, Maegdefesseel Lars1

Introduction

Popliteal artery aneurysm (PAA) is an individually highly fatal disease, causing ischemia and eventual major amputation, mainly in 50-70 year old males. It is the most frequent peripheral artery aneurysm and correct treatment is challenging for clinicians, since both open and endovascular repair have only modest success rates, depending on the clinical presentation. In comparison to other aneurysm entities, little is known about its specific pathogenesis.

Material and Methods

30 Human PAA and popliteal artery samples were analyzed by immunohistochemistry, mRNA and miRNA expression analysis and protein assays on the OLink platform in order to identify key features of the disease and crucial pathways involved. Furthermore, a novel murine model of PAA is characterized for future applications in basic research.

Results

Vascular smooth muscle cells loose their contractile phenotype along with significant inflammatory and proteolytic changes in the vessel wall architecture. Extensive tissue remodeling with high cell turnover rates is a unique feature in comparison to AAA. This correlates with highly abundant expression of the apolipoproteins E and CI suggestive to have a pro-proliferative effect in peripheral vascular tissue. Additionally, array-based screening on gene and protein level revelaed the pentraxin-related protein 3 as a potential biomarker and soluble inducer of neutrophil homing. These findings are emphasized by a specific case of a solely mechanically induced PAA in a young male. External application to the femoral artery in mice induces diameter enlargement and might thus be a potential model for further research.

Conclusion

Pathogenesis of PAA shows similar histologic features than AAA, yet differs in potential pathways involved. Increased cell turnover in the aneurysmal neck area suggests evaluation of alternative treatment strategies, targeting key processes in its pathogenesis.


RESVERATROL INHIBITS AORTIC ROOT DILATATION IN THE FBN1C1039G/+ MARFAN MOUSE MODEL

Hibender Stijntje, Franken Romy, van Roomen Cindy, van der Made Ingeborg, Groenink Maarten, Zwinderman Aeilko, Mulder Barbara, de Vries Carlie, de Waard Vivian

Objective

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene. MFS patients are at risk for aortic aneurysm formation and dissection. Usually blood pressure lowering drugs are used to reduce aortic events, however, this is not sufficient for most patients. In the aorta of smooth muscle cell-(SMC) specific sirtuin-1 (SIRT1)-deficient mice, spontaneous aneurysm formation and senescence is observed. Resveratrol is known to enhance SIRT1 activity and to reduce senescence, which prompted us to investigate the effectiveness of resveratrol in inhibition of aorta dilatation in the Fbn1C1039G/+ MFS mouse model.

Approach and Results

Aortic senescence strongly correlates with aortic root dilatation rate in MFS mice. However, while resveratrol inhibits aortic dilatation, it only shows a trend towards reduced aortic senescence. Resveratrol enhances nuclear localization of SIRT1 in the vessel wall and, in contrast to losartan, does not affect leukocyte infiltration, nor activation of SMAD2 and ERK1/2. Interestingly, specific SIRT1 activation (SRT1720) or inhibition (sirtinol) in MFS mice does not affect aortic root dilatation rate even though senescence is changed. Resveratrol reduces aortic elastin breaks, and decreases microRNA(miR)-29b expression coinciding with enhanced anti-apoptotic Bcl-2 expression and decreased number of TUNEL positive cells. In cultured SMCs, the resveratrol effect on miR-29b downregulation is endothelial cell- and NF-κB-dependent.

Conclusion

Resveratrol inhibits aortic root dilatation in MFS mice by promoting elastin integrity and SMC survival, involving downregulation of the aneurysm-related miR-29b in the aorta. Based on these data, resveratrol holds promise as a novel intervention strategy for MFS patients.


IMMUNOPATHOLOGY IN PATIENTS WITH AAA

Prucha Miroslav, Stadler Petr, Sedivy Petr, Zdrahal Pavel

Abdominal aortic aneurysm (AAA) is a serious condition with unclear pathogenetic mechanism which has a high mortality rate in case of the occurrence of the most serious complication - a ruptured aneurysm. One of the discussed pathogenic factors which might be involved in the development of AAA are immunological mechanisms. Patients and methodology: We examined a total of 58 patients with AAA requiring surgery and 20 patients treated for lipid metabolism disorder without AAA in the control group. Demographic and clinical characteristics of both groups is shown in Table 1. The following parameters were examined in both groups: IgG, IgG1-IgG4, pentraxin 3, fractalkine, IL-8, Il-10, IL-15, IL-18, IL-1b, M-CSF, MPC-1, RANTES, SAP, TNF, MMP-2, MMP-3, MMP-9, MMP-12.

Results

In the AAA group of patients, statistically significantly higher concentrations of IgG4 were detected as compared to the control group. There were no significant differences in the concentration of fractalkine, IL-10, IL-15, IL-18, IL-1b, MPC-1 a TNF in both groups. RANTES concentration, as well as the concentrations of MMP 2 (p=0,02), MMP 3 (p=0,04) and MMP 9 ( p= 0,009) were significantly higher in the group of patients with AAA (p=0,0004).

Conclusion

Significantly higher concentrations of biomarkers related to immune mechanisms and inflammatory activity were detected in the group of patients with AAA. A higher frequency of increased IgG4 concentrations in patients with AAA is a reason why some AAAs are considered to be a disease associated with IgG4. A higher inflammatory activity detected in the group of patients with AAA as compared with the control group of patients with treated arteriosclerosis provides a possibility to potentially use a targeted treatment in patients with AAA.


HOW DOES IT FEEL TO HAVE AN ABDOMINAL AORTIC ANEURYSM – A PATIENT-CENTERED VIEW

Tomee Stephanie1, Gebhardt Winnie2, Lindeman Jan1, Hamming Jaap1

Aims

An abdominal aortic aneurysm (AAA) is a potentially lethal disease, which is relatively common in elderly men. As repair has only proven benefit above 5.5cm, quite a large group of patients with smaller aneurysms do not receive specific treatment. These patients are in a watchful-waiting period and have little contact with their vascular specialist. Qualitative data from patients with small AAA’s is scarce and little is known about the psychological impact of living with an aneurysm. More insights into patients’ view on diagnosis and disease burden of an abdominal aneurysm is needed to provide patients with additional support in coping this disease.

Methods

For this purpose we perform ten in-depth semi-structured qualitative interviews with AAA patients who are in a watchful-waiting period. After the interview patients are asked to fill in a few questionnaires assessing: health related quality of life (SF-36), illness perceptions (IPQ), anxiety and depression (HADS). All interviews will be audio taped and transcribed verbatim. Interview transcripts are then coded and contents will be analyzed.

Results

Preliminary analyses of data derived from ten interviews shows that patients often have little knowledge on AAA-disease and treatment options. However, they accept the conservative watchful-waiting plan proposed by the surgeon. In addition, patients rated their own health and quality of life as highly positive, despite severe comorbidity and sometimes uncertain life expectancy. In these patients, the disease burden of an AAA was very low due to the absence of symptoms and active intervention. Aneurysm patients feel they have little control over their AAA and largely rely on the surgeon for judgment.

Conclusions

Patients with small AAA are generally content with a conservative treatment plan and consider themselves to enjoy a good health despite comorbidity. In addition, patients depend on their specialist to take control in AAA treatment.


META-ANALYSIS OF THE CURRENT PREVALENCE OF SCREEN-DETECTED ABDOMINAL AORTIC ANEURYSM IN WOMEN

Ulug Pinar1, Powell Janet1, Sweeting Michael2, Bown Matthew3, Thompson Simon2

Background

Although women represent an increasing proportion of those presenting with abdominal aortic aneurysm (AAA) rupture, the current prevalence of AAA in women is unknown. The contemporary population prevalence of screen-detected AAA in women was investigated by both age and smoking status.

Methods

A systematic review was conducted, according to the PRISMA guidelines, of studies screening for AAA, including over 1000 women, aged at least 60 years, done since the year 2000. Studies were identified by searching MEDLINE, Embase and CENTRAL databases until 13th January 2016. Study quality was assessed using the Newcastle–Ottawa scoring system for cross-sectional studies2.

Results

Eight studies3-9 were identified, including only three based on population registers3,7,8. The largest studies were based on self-purchase of screening. Altogether 1,537,633 women were screened. Overall AAA prevalence rates were very heterogeneous, ranging from 0.37 to 1.53%: pooled prevalence 0.74% (95%CI 0.53 to 1.03). The pooled prevalence increased with both age (>1% for women aged over 70 years) and smoking (>1% for ever smokers and >2% in current smokers).

Conclusion

The current population prevalence of screen-detected AAA in older women is subject to wide demographic variation. However, in ever smokers and those over 70 years, the prevalence is over 1%.

Registration

PROSPERO database of systematic reviews (http://www.crd.york.ac.uk/PROSPERO) CRD42015020444

Figure 1.

Pooled prevalence of abdominal aortic aneurysm in women aged at least 60 years: eight studies with screening performed between 2001 and 2012. Values in parentheses are 95 per cent confidence intervals.

media/vol4/issue5/images/aorta-04-185-g004.jpg

References

  1.  
    PRISMA: Transparent reporting of systematic reviews and meta-analyses. Available from: www.prisma-statement.org
  2.  
    Wells GA, Shea, B., O'Connell, D., Peterson, J., Welch, V., Losos, M., Tugwell, P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp [accessed 18th December 2015].
  3.  
    Forsdahl SH, Singh K, Solberg S, Jacobsen BK. Risk factors for abdominal aortic aneurysms: a 7-year prospective study: the Tromso Study, 1994-2001. Circulation. 2009;119(16):2202-8.
  4.  
    Ogata T, Arrington S, Davis PM, Jr., Sam AD, 2nd, Hollier LH, Tromp G, et al. Community-based, nonprofit organization-sponsored ultrasonography screening program for abdominal aortic aneurysms is effective at identifying occult aneurysms. Ann Vasc Surg. 2006;20(3):312-6.
  5.  
    Hupp JA, Martin JD, Hansen LO. Results of a single center vascular screening and education program. J Vasc Surg. 2007;46(2):182-7.
  6.  
    Savji N, Rockman CB, Skolnick AH, Guo Y, Adelman MA, Riles T, et al. Association between advanced age and vascular disease in different arterial territories: a population database of over 3.6 million subjects. J Am Coll Cardiol. 2013;61(16):1736-43.
  7.  
    Svensjo S, Bjorck M, Wanhainen A. Current prevalence of abdominal aortic aneurysm in 70-year-old women. Br J Surg. 2013;100(3):367-72.
  8.  
    Palombo D, Lucertini G, Pane B, Mazzei R, Spinella G, Brasesco PC. District-based abdominal aortic aneurysm screening in population aged 65 years and older. Journal Cardiovasc Surg. 2010;51(6):777-82.
  9.  
    Bulbulia R, Chabok, M, Aslam, M, Lewington S, Sherliker P, Manganaro A et al, (2013). The prevalence of abdominal aortic aneurysm, carotid stenosis, peripheral arterial disease and atrial fibrillation among 280,000 screened British and Irish Adults. Vasc Med 2013;18(3):155.

DIAMETER GROWTH RATE AND FUTURE INDICATION FOR SURGERY CAN BE PREDICTED WITH FINITE ELEMENT ANALYSIS AND SEMI-AUTOMATIC DIAMETER MEASUREMENTS IN SMALL ABDOMINAL AORTIC ANEURYSMS

Liljeqvist Moritz Lindquist1, Hultgren Rebecka1, Gasser T. Christian2, Roy Joy1

Objective

For small abdominal aortic aneurysms (AAA), it is difficult to predict which aneurysms will require surgery and which will remain stable. We aimed to evaluate if semi-automatic diameter measurements and finite element analysis were superior at predicting the four-year progression rate and indication for surgery of AAAs compared to standard diameter measurements.

Methods

Thirty-three small AAAs with a baseline diameter of 40-50 mm were identified. ‘Standard diameters’, measured by radiologists or vascular surgeons, were collected from patient records. The aneurysms were subsequently recreated into digital, three-dimensional (3D) models by semi-automatic segmentation from the CTAs. Maximal diameter orthogonal to the aneurysms’ centerline was automatically measured and finite element analysis, yielding peak wall rupture index (PWRI), was performed. Further, growth rate between two standard diameters was studied in an overlapping group of 39 AAAs that had been measured once more after the initial CTA (baseline diameter of 40-60 mm).

Results

Diameter growth rate displayed a good correlation with baseline semi-automatic diameter (r=0.53, p=0.0006) and PWRI (r=0.44, p=0.0055) but only a trend could be observed for baseline standard diameter (r=0.31, p=0.052). After four years, 20 AAAs had received surgery or had reached indication for surgery, ie standard diameter of 55 mm, and 13 AAAs remained intact with a standard diameter of < 55 mm. Baseline semi-automatic diameter and PWRI could specifically identify aneurysms that would require surgery within four years, n=6 (30%) and n=9 (45%), respectively, whereas the baseline standard diameter could not (n=0, 0%).

Conclusion

Finite element analysis and precise diameter measurements may improve AAA growth rate predictions and allow early aortic repair in selected patients with AAA.

Figure 1.

Finite element analysis of an abdominal aortic aneurysm. Red areas represent high and blue areas low estimated rupture risk index.

media/vol4/issue5/images/aorta-04-185-g005.jpg

TRANSDIFFERENTIATION OF HUMAN DERMAL FIBROBLASTS TO SMOOTH MUSCLE LIKE CELLS: A NOVEL METHOD TO STUDY THE EFFECT OF MYH11 AND ACTA2 VARIANTS IN THE AORTIC ANEURYSM WALL

Bogunovic Natalija1, Musters René J.P.1, Micha Dimitra1, Pals Gerard1, Wisselink Willem1, Blankensteijn Jan D.1, Zandieh-Doulabi Behrouz2, Yeung Kak K.1

Introduction

Research on the pathogenesis of aortic aneurysms has revealed mutations in genes encoding the smooth muscle cell contractile proteins1-3 as key underlying causes. Mutations associated with familial aortic aneurysms have been found in MYH11 (myosin heavy chain 11), ACTA2 (smooth muscle actin alpha 2) and MYLK (myosin light chain kinase) genes, which encode integral proteins of the contractile apparatus.

Experimental Aim/Problem Definition

Currently, SMC can only be obtained by an invasive aortic biopsy. Therefore, the aim of this study is to transdifferentiate skin fibroblasts into SMC-like cells to provide a less invasive diagnostic test to study SMC function and mutations.

Work Summary

Dermal fibroblasts from 7 healthy donors and 7 patients with MYH11 or ACTA2 variants were transdifferentiated into SMC-like cells within 2 weeks by using 5ng/mL TGFβ1 and a scaffold containing collagen and elastin (matriderm). As control, cells were cultured without TGFβ1. SMC-specific markers were analyzed via qPCR, western blot and immunofluorescence. To investigate and classify the pathogenicity of the variants, cDNA sequencing was performed.

Results

The induced SMC-like cells were comparable to primary human aortic SMC in the expression of SMC specific markers on mRNA and protein level (Fig.1): ACTA2 (αSMA), SMTN (smoothelin) and CNN1 (calponin). Importantly, in patients with MYH11 or ACTA2 variants the effect on splicing was demonstrated on the mRNA level in the induced SMC, allowing classification into pathogenic or non-pathogenic variants. Moreover, the pathogenic MYH11 variants showed overexpression of contractile proteins accompanied by defective F-actin cytoskeleton formation if compared to transdifferentiated SMC from the healthy donors.

Conclusions

Direct conversion of human dermal fibroblasts into SMC-like cells is a highly efficient method to investigate the pathogenic effect of variants in genes encoding the proteins of the SMC contractile apparatus. Our findings suggest the role of defective cytoskeleton formation and disturbed contraction of SMC in aortic aneurysm formation.

Figure 1.

Representative confocal images of transdifferentiated and non-transdifferentiated cells. Upper panels: transdifferentiated SMC-like cells. Lower panels: primary dermal fibroblasts.

media/vol4/issue5/images/aorta-04-185-g006.jpg

References

  1.  
    Pannu H, Tran-Fadulu V, Papke CL, Scherer S, Liu Y, Presley C, Guo D, Estrera AL, Safi HJ, Brasier AR, Vick GW, Marian AJ, Raman CS, Buja LM, Milewicz DM. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II Hum. Mol. Genet. 2007; 16:2453-2462.
  2.  
    Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N, Bourgeois S, Estrera AL, Safi HJ, Sparks E, Amor D, Ades L, McConnell V, Willoughby CE, Abuelo D, Willing M, Lewis RA, Kim DH, Scherer S, Tung PP, Ahn C, Buja LM, Raman CS, Shete SS, Milewicz DM. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet. 2008;40:255.
  3.  
    Milewicz DM, Guo DC, Tran-Fadulu V, Lafont AL, Papke CL, Inamoto S, Kwartler CS, Pannu H. Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractiledysfunction. Annu Rev Genomics Hum Genet. 2008;9:283-302.

LIVE HUMAN ARTERIAL TISSUE SLICES FOR BENCH TOP RESEARCH ON PATHOPHYSIOLOGY OF AORTIC ANEURYSMS; UP TO 90 DAYS EX VIVO PRESERVATION

Meekel Jorn P., Musters René J.P., Doulabi Behrouz Z., Micha Dimitra, Pals Gerard, Wisselink Willem, Blankensteijn Jan D., Yeung Kak K.

Currently, research on abdominal aortic aneurysm (AAA) pathophysiology is limited to fixated cells or isolated cell cultures [1-3]. However, due to these techniques, cell-cell interactions and communication with extracellular matrix are lost. These interactions are likely to play a role in the AAA pathogenesis [4-7]. We hereby present an innovative method to cut live vascular tissue slices and preserve cell viability and cellular organization for research into AAA in which anatomical, functional and microstructural characteristics are of interest.

Peroperatively harvested tissue was transported in ice-cold Custodiol and cut into cubes. Subsequently, cubes were submerged in agarose, glued on an anvil, and cut into slices of 150 µm. Slices were cultured at 37° Celsius in media supplemented with antibiotics. Viability analysis was performed up to 92 days after harvesting using LIVE/DEAD® Viability/Cytotoxicity Kit. Cell type characterization was achieved by staining for CD45, CD68, α-SMA/smoothelin to identify leukocytes, macrophages and fibroblasts/smooth muscle cells (SMC) respectively. Additionally, tissues were digested using collagenase to study individual cells and analyze cellular populations in live tissues.

Tissue slice analysis showed a stable viability of 40% until 7 days (graph. 1) and after improvement of the protocol up to 92 days after harvesting (with outgrowth of new cells). Live cells were mainly seen centrally in the tissue, while dead cells were observed at cutting edges. Live cells were differentiated by qualitative analysis based on cell morphology and specific marker expression. The majority of studied live cells were fibroblasts/SMC. Furthermore, leukocytes and macrophages were observed. These findings were in accordance with the findings in cells of digested tissues.

Vitality and organization of tissue sections of aneurysmal and non-aneurysmal vascular tissue can be preserved until 92 days after harvesting. This study provides a solid base for further experimental research on pathophysiological mechanisms underlying aneurysms and possibly other vascular diseases.

Figure 1.

Viability of human aortic tissue slices.

media/vol4/issue5/images/aorta-04-185-g007.jpg

References

  1.  
    Cherifi H, Gogly B, Loison-Robert LS, et al Comparative study of abdominal and thoracic aortic aneurysms: their pathogenesis and a gingival fibroblasts-based ex vivo treatment. Springerplus 2015; 4:231.
  2.  
    Wang Q, Ren J, Morgan S, Liu Z, Dou C, Liu B. Monocyte chemoattractant protein-1 (MCP-1) regulates macrophage cytotoxicity in abdominal aortic aneurysm. PLoS One 2014;9(3):e92053.
  3.  
    Airhart N, Brownstein BH, Cobb JP, et al Smooth muscle cells from abdominal aortic aneurysms are unique and can independently and synergistically degrade insoluble elastin. Journal of vascular surgery 2014; 60(4):1033-41; discussion 41-2.
  4.  
    Sasai Y. Cytosystems dynamics in self-organization of tissue architecture. Nature 2013; 493(7432):318-26.
  5.  
    Pillekamp F, Reppel M, Dinkelacker V, et al Establishment and characterization of a mouse embryonic heart slice preparation. Cell Physiol Biochem 2005; 16(1-3):127-32.
  6.  
    Ghosh A, Pechota LV, Upchurch GR, Jr., Eliason JL. Cross-talk between macrophages, smooth muscle cells, and endothelial cells in response to cigarette smoke: the effects on MMP2 and 9. Molecular and cellular biochemistry 2015.
  7.  
    Vorkapic E, Lundberg AM, Mayranpaa MI, Eriksson P, Wagsater D. TRIF adaptor signaling is important in abdominal aortic aneurysm formation. Atherosclerosis 2015; 241(2):561-8.

INHIBITION OF PATHOLOGICAL VASCULAR SMOOTH MUSCLE CELL REMODELLING AS A TREATMENT STRATEGY FOR ABDOMINAL AORTIC ANEURYSM

Bailey Marc1, Rode Baptiste1, Gossain Rajendra2, Bridge Katherie1, Griffin Kathryn1, Shires Mike3, Porter Karen1, Plein Sven1, Wheatcroft Steve1, Foster Richard2, Scott Julian1, Beech David1

Introduction

Pathological vascular smooth muscle cell (VSMC) remodelling in abdominal aortic aneurysm (AAA) drives eventual VSMC senescence, loss and luminal dilation. The VSMC have not been a major target for novel AAA treatment approaches. We hypothesise that strategies to reduce this VSMC remodelling response may be beneficial in the context of novel AAA therapeutics and provide evidence for this idea using a novel small-molecule inhibitor of VSMC remodelling in murine models of AAA.

Methods

For the study we used a small-molecule inhibitor of PDGF induced VSMC remodelling delivered to mice via subcutaneous osmotic mini pump. In the first set of experiments, AAA was induced by AngII infusion to ApoE-/- mice, peri-aortic CaCl2 or peri-aortic elastase application to C57BL6/J mice. Novel treatment was delivered at the time of aneurysm induction. In the second protocol, the novel inhibitor was given only after AAA had formed in the AngII model to investigate AAA progression. The aortic lumen was visualised with 3D in-vivo ultrasound and tissue evaluated by histology and immunohistochemistry.

Results

Histological evidence of pathological VSMC remodelling was apparent in all three murine models investigated. Treatment of animals with the novel inhibitor throughout the experiment reduced VSMC remodelling and aneurysm size. The effect was particularly apparent on aortic lumen area. When the inhibitor was applied to ApoE-/- mice with established AAA following AngII infusion, no further aortic dilation occurred suggesting effectiveness against AAA progression and translational potential.

Conclusion

Pathological VSMC remodelling is apparent in multiple murine models of AAA. Inhibition of the VSMC remodelling response with a small molecule inhibitor is possible and attenuates AAA progression. Translational efforts to further understand and modulate VSMC remodelling in human AAA should be explored.


CANONICAL TGFSS-SIGNALING IS TRIGGERED BY INFLAMMTION IN HUMAN NON-SYNDROMIC ANEURYSM DISEASE, BUT IS NOT REFLECTED BY INDUCIBLE AAA MOUSE MODELS

Busch Albert1, Paloschi Valentina1, Chernogubova Ekaterina1, Holm Amina2, Otto Christoph2, Kellersmann Richard2, Kickuth Ralph3, Lorennz Udo2, Maegdefessel Lars1

Introduction

Transforming growth factor β (TGFβ) signaling has been demonstrated to be crucially involved in aneurysm pathogenesis since mutations in its receptors have been revealed to be responsible for multilocular aneurysm formation in patients with Loeys-Dietz syndrome. Despite TGFβ’s central role in cell signaling, its specific regulation in non-syndromic aneurysm formation is yet of unclear significance.

Material and Methods

We explored a biobank of human AAA and popliteal artery aneurysms to elucidate the function of different components of the TGFβ pathway by immunohistochemistry, gene expression analysis and western blot. Additionally the TGFβ-connective tissue derived growth factor (CTGF) axis was analyzed in a new mouse model of inducible juxtarenal aortic aneurysm.

Results

Canonical TGFβ signaling with increased activation of phosphorylated SMAD 2/3 was discovered independently of the grade of inflammation or the type of artery. This process was triggered by mononuclear infiltrates in the arterial media. While collagen production in increased, other downstream effects like CTGF signaling appear not elevated. Inducible murine models of AAA mimic an earlier time point of aneurysm development and demonstrate enhanced canonical TGFβ signaling in infrarenal, juxtarenal and thoracic position, as seen in two different models.

Conclusion

Canonical TGFβ signaling is elevated in human aneurysm disease. The TGFβ-CTGF-axis seems to be of lesser importance. In vivo experiments with murine inducible models can only partly reflect these conditions due to the specific role of this pathway during aneurysm development and progression.


PHENOTYPING OF TRANSGENIC PIGS TO DETERMINE THE SUITABILITY OF XENOGRAFTS IN THE TREATMENT OF AORTIC DISEASES

Strauss Ewa1, Wróblewska Joanna1, Wawrzynska Lidia1, Tomczak Jolanta1, Pukacki Fryderyk1, Kruszyna Lukasz1, Zdun Maciej2, Frackowiak Hieronim2, Oszkinis Grzegorz1

Abdominal aortic aneurysm and aortoiliac occlusive disease are the two most common vascular diseases in which surgical treatment requires the implantation of aortic prosthesis. The synthetic materials can cause graft infection, a distal potentially fatal complication of surgical treatment. This is connected with the necessity of patient re-operation and the replacement of prosthesis with biological material, such as auto- or allografts. Due to the shortage of multiorgan donors, many patients with infection of the prosthesis cannot be treated successfully. The domestic pig may be the perfect donor of easily accessible blood vessels for transplantation. Under the MEDPIG project a series of „humanized” pigs were generated by genetic engineering and breeding, to omitt species incompatibility.

We focus on the ex vivo studies of biological material harvested from several genetic variation of humanized pigs. Tissue samples are tested to identify modification the least immunogenic to human. We established over 20 primary endothelial aortic cells lines, isolated from thoracic aorta of transgenic pigs and comparable number of cell lines from control, wild type animals. In vitro studies include several cytotoxicity assays to evaluate response to the human complement and other components of human immune system. Biomechanical properties studies focus on comparative analysis of a transgenic pig and human vessels, in order to identify anatomical resemblance and ability to function in different hemodynamic conditions. Biomechanical, histological and molecular evaluation of arteries were performed before and after cryopreservation. The level of inbreeding of pigs was also evaluated genetically. In a pilot study functionality of the aortic grafts was tested in vivo through cross transplants.

Our studies demonstrate the application of transgenic pig tissue in modeling and therapy of human aortic diseases. Funded by The NCRD (grant n. INNOMED/I/17 /NCBR/2014) from the Innovative Economy Operational Programme founds, in the framework of the ERDF.


MANAGEMENT OF VISCERAL ARTERY ANEURYSMS: A 20-YEAR SINGLE CENTRE EXPERIENCE

Filippone Gianfranco1, Talarico Francesco2, La Barbera Gaetano2, Ferro Gabriele2, Valentino Fabrizio2

Visceral artery aneurysms (VAA), including renal and splanchnic lesions, are rare (0,01% up to 2% in general population) but life-threatening disease. The natural history is unknown but rupture occurs frequently particurarly when vessel dimension exceeds 2 cm that, to date,represent the threshold to intervene in asymptomatic patient. Unfortunately, when rupture occurs, mortality rate is consistent ranging from 21% when the complication is located at the hepatic artery site up to 100% when is located at the celiac artery site. Objective of this study is to review our experience with VAA treatment. Between January 1995 and August 2015, 28 VAA were treated, (21 males, 7 females) with mean age of 56 years (range 25-87). Intraoperative data included surgical appproach, type of reconstruction and associated procedure. N=19 patients were asymptomatic, n= 6 symptomatic and n=3 presented on emergency due to rupture. The most common locations were renal artery (n=10), splenic artery (n=8), hepatic artery (n=4),celiac trunk (n=3). Four patients underwent endovascular treatment (1 on emergency), 23 patients underwent open surgery (2 on emergency) and 1 patient was operated on in Minimally Invasive approach. Overall early mortality was 7.14% (2 patients in surgical group operated on emergency due to the rupture of renal aneurysm). Perioperative morbidity was 3,5% (1 patient operated on splenectomy). Late mortality was 25% (1 patient in endovascular group). We believe that surgical VAA treatment is a safe and effective procedure irrespective if it will be done open or percutaneous, mortality and morbidity are low outweighing dismal expentancy of life in untreated patients.

References

  1.  
    Pulli R, Dorigo W, Troisi N, Pratesi G, Alessi Innocenti A, Pratesi C: Surgical treatment of visceral artery aneurysms: A 25-year experience. J Vasc Surg 2008; 48:334-42.
  2.  
    Tulsyan N, Kashyap VS, Greenberg RK et al: The endovascular management of visceral artery aneurysms and pseudoaneurysms. J Vasc Surg 2007; 45:276-83.
  3.  
    Sachdev U, Baril DT, Ellozy SH et al: Management of anurysms involving branches of the celiac and superior mesenteric arteries:A comparison of surgical and endovascular therapy. J Vasc Surg 2006;44,4:718-724.

AORTIC SIZE INDEX COULD IMPROVE SURVEILLANCE OF WOMEN AND MEN WITH ABDOMINAL AORTIC ANEURYSM

Hultgren Rebecka, Lofdahl Hedvig, Roy Joy

Background

Abdominal aortic aneurysm (AAA) predominantly affects men, however the risk of rupture is higher in women resulting in a poorer outcome. Recent studies have shown that the correlation between body surface area and aortic diameter (aortic size index) could be a better predictor than aortic diameter for rupture in women, however there is a lack of knowledge within the field. This study aims at investigating the correlation between body surface area and aneurysm diameter in women and men with non-ruptured AAA.

Methods

A retrospective population based cohort study. Patients with AAA followed at the Karolinska University Hospital in Stockholm, Sweden between January 2012 and December 2014, with at least two imaging examinations performed were eligible for inclusion, 120 women and 120 men were included in the study. Data was collected through review of medical records. Means were compared using independent t-test and Mann Whitney test for continues variables. Pearson’s chi-square and Fischer’s exact test was used for categorical variables.

Results

Women had a higher mean age, but did not differ from men regarding comorbidities. The aortic diameter was similar between women and men (41.5mm versus 43.0mm, p=0.21). Women had a smaller body size area and a larger aortic size index (2.4 versus 2.1, p<0.05). Older patients had a higher aortic size index compared to younger patients. The median growth rate for the cohort was 2.2 mm per year. No difference in growth rate was shown between women and men. Larger aneurysms (median 45.0 mm) had a higher growth rate compared to smaller aneurysms (2.7 mm versus 1.6 mm, p<0.05).

Conclusion

The results supports previous reports showing that aortic size index, combined with aortic diameter could be a useful tool for improved surveillance, especially in women and older patients with small AAA. Further prospective analysis must be performed in order to define the predictive value of ASI for rupture risk.

Figure 1.

Aortic size index and aneurysm diameter for men and women.

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HOW COMMON IS THE CLASSIC TRIAD OF SYMPTOMS IN PATIENTS WITH RUPTURED ABDOMINAL AORTIC ANEURYSM?

Hultgren Rebecka, Roy Joy

Introduction

Ruptured abdominal aortic aneurysm (rAAA) is a life threatening condition with mortality around 70-90 %. Diagnostics is still depending on identification of a classic diagnostic triad of pain, hypotension and pulsatile mass. The literature is scarce regarding the true occurrence of the classic triad of symptoms in patients with RAAA [1-3]. Primary Aim: To investigate how many of admitted patients with rAAA that had the classic triad. Secondary Aim: To investigate whether a correlation between number of triad-symtoms and time to treatment and outcome can be found.

Material and Methods

Records of 283 patients with ICD code 171.3 (RAAA) diagnosed between 2009-2013 in the Stockholm County has been identified, for this analysis only patients subjected to the Karolinska University Hospital in Stockholm were reviewed retrospectively, 52 were included.

Results

The classic triad was present in 13 (25 %) of the patients with RAAA. Back or abdominal pain was present in 49 (94 %) and hypotension in 43 (83 %). Pulsating mass was found in 14 (27 %), but only in one (4 %) of the overweight patients (p=0.004). Patients with 3 out of 3 symptoms of the classic triad did not have shorter time to treatment (p=0.72) or lower 30 day mortality (p=0.41) compared to patients with less than 3 symptoms.

Conclusions

Only one fourth of the patients with RAAA have the classic triad of symptoms, which correlates with the few reports within the field. The diagnostic value of the classic triad can be discussed in the present form, however adding ultrasound for evaluation of aortic diameter would probably increase the validity.

References

  1.  
    Fielding JW, Black J, Ashton F, Slaney G, Campbell DJ. Diagnosis and management of 528 abdominal aortic aneurysms. Br Med J (Clin Res Ed). 1981;283(6287):355-9.
  2.  
    Assar AN, Zarins CK. Ruptured abdominal aortic aneurysm: a surgical emergency with many clinical presentations. Postgrad Med J. 2009;85(1003):268-7.
  3.  
    Marston WA, Ahlquist R, Johnson G, Jr., Meyer AA. Misdiagnosis of ruptured abdominal aortic aneurysms. J Vasc Surg. 1992;16(1):17-22.

SURVIVAL DISPARITY FOLLOWING AAA REPAIR HIGHLIGHTS INEQUALITY IN SOCIOECONOMIC STATUS

Khashram Manar1, Pitama Suzanne2, Williman Jonathan3, Jones Greg4, Roake Justin5

Background

Determinants of survival following abdominal aortic aneurysm (AAA) repair are well documented and are predominantly co-morbidity driven. Other patient factors such as socioeconomic status (SES) have also been suggested as factors influencing mortality. The aim of this study was to report if deprivation influences survival after AAA repair.

Methods

Consecutive patients undergoing AAA repair between July 2000 and December 2013 were identified from the national database. SES was defined as recorded on health records. A score of 1 indicates those least deprived and 10 representing the most deprived. Multivariate logistic regression model was used along with confounders included as independent variables to calculate odds ratios (OR) and survival analysis using cox proportional model to report adjusted hazard ratios (HR).

Results

5824 patients with a mean age (standard deviation, SD) of 74 (7.7) years and 78.7% males were included. The mean (SD) deprivation score was 6.1 (2.7). Deprivation categories 7-8 and 9-10 were associated with OR 1.54 (95%CI: 1.07-2.23) and 1.61 (95%CI: 1.10-2.36) respectively. The median survival follow up period was 5 years and after adjusting for confounders, deprivation categories 9-10 was associated with a higher risk of death HR=1.25 (95%CI: 1.10-1.42).

Conclusions

Patients with a lower SES have an independent risk of reduced short and long-term survival. Identifying deprivation status may represent a mechanism through which cardiovascular risk modification is initiated and maintained during follow-up. This may help reduce outcome disparities for people with lower SES and highlights the need for more emphasis on targeting at-risk groups.

Figure 1.

Adjusted Survival of deprivation categories.

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PATIENT REPORTED QUALITY AND FUNCTIONAL LIFE AFTER AAA REPAIR

Khashram Manar1, Mullen Michaela1, Jones Gregory2, Roake Justin1

Introduction

Patient reported outcomes are becoming an important health measure. Long term results from the DREAM trial shows that patients that underwent open aneurysm repair (OAR) have an improved quality of life (QOL) compared to patients that received EVAR. The aims of this study were to assess the QOL and functional outcomes for patients that underwent AAA repair in the clinical setting.

Methods

Consecutive patients who have undergone AAA repair between January 2009 and December 2014 were identified from a prospective maintained database. A questionnaire relevant for post AAA patients was developed from a literature review and the Short Form Health Survey (SF-12) was used. Patients were invited to attend a 30-minute clinical assessment appointment or a phone interview.

Results

There were 381 patients that had an AAA repair, of which 101 (26.5%) were not alive and were excluded from further analysis. Of the 280 eligible patients, 228 (85.7%) were males, 229 (74.3%) were elective procedures and 134 (43.5%) were EVAR. The minimum and median follow-up period was 12 and 42 months. In all, 223 patients were recruited and completed follow-up (inclusion rate 80%). There was no difference in SF-12 components between patients receiving OAR and EVAR. The percentage of patients that were living independently, driving and working preoperatively was 99, 93 and 27 respectively and corresponding percentages following AAA repair were: 98, 86 and 18. There was no difference between any of the SF-12 components within an age-sex matched population.

Conclusions

There were no perceived differences in QOL of patients receiving OAR or EVAR and the majority still enjoy a good QOL and have returned to their baseline activities without considerable limitations. These results may help clinicians inform realistic expectations to patients, not only on 5-year survival but also on functional outcomes when consenting or offering AAA repair.

Figure 1.

SF-12 components compared to the normal based score.

media/vol4/issue5/images/aorta-04-185-g010.jpg

AORTIC DISSECTION IN PREGNANCY WITHOUT RISK FACTORS: REVIEW OF LITERATURE

Silvestri Valeria

Introduction

Pregnancy is related to a 25-fold increased risk of aortic dissection, representing 60% of cases in women < 40 years [1], with increasing incidence in recent years ( 0.74-1.52/100000) [2]. Marfan, Ehlers-Danlos, Loeys-Dietz and Turner syndrome, or bicuspid aortic valve, are related to increased dissection risk, but dissection has been reported in pregnancy in patients without risk factors. Haemodinamic and hormonal changes in vascular structure increase wall tension and intimal shear forces, on an aortic media more susceptible to injury, making pregnancy an indipendent risk factor for dissection [3] Advanced maternal age and diffusion of assisted reproductive tecnology to overcome age related infertility, increase risk of pregnancy related hypertention, consequently dissection [4].

Work Summary

We reviewed pubmed database to identify aortic dissection cases in wich pregnancy was the only reported risk factor, excluding fibrillinopathies, Turner syndrome or bicuspid aortic valve.

Results

41 cases of aortic dissection without known risk factors were reported from 1995 to 2015. Of these, 63% occurred during pregnancy (56.1% third trimester); 36.5% in postpartum. Hypertension was the mostly reported comorbidity (36.7%), including chronic and gestational hypertension, pre-eclampsia and eclampsia, followed by obesity and smoking. According to Standford classification, 28 were type A and 17 type B, in 9 cases lesion consisted in aneurysm on dissection. Organ ischemia complicated dissection in 7 cases. Thoracic pain (73.2%) was main symptom at diagnoses, followed by neurological impairement, back and abdominal pain, dyspnea, nausea. Differential diagnosis was challenging in 14 cases (34.2%),pulmonary embolism being most frequently misdiagnosed. In three cases diagnosis was autoptic. Treatment consisted in open surgery (53.6%), endovascular (19.5%), hybrid approach (12.2%). Of five cases managed conservativelly, 4 required surgery. Time from onset to treatment ranged from <24 h (63.4%) up to 1 week. As for fetal management,emergency cesarean section was performed in 41.5% of cases, 1 surgery during pregnancy and 1 therapeutic abortion were reported. Maternal outcome was successful in 73.2%, perioperatory death being 17.1%. Fetal outcome was favorable in 26 cases, 3 autoptic findings, 2 stillbirths, 1 growth restriction recorded on follow up.

Conclusions

Aortic dissection can occur in normal pregnancy and postpartum. High index of suspecion is necessary, and it must be included in differential diagnosis in acute setting, because of high maternal-fetal mortality of this condition.

Figure 1.

Physiopathology of aortic dissection in pregnancy.

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Table 1:

Aortic dissection in pregnancy. Clinical aspects, management and outcome of 41 cases reported in literature

N 41 % N %
Timing
Pregnancy 26 63.4% 1st semester 1 2.4 %
2nd semester 2 4.9 %
3rd semester 23 56.1 %
Postpartum 15 36.6% 1st week 10 24.4 %
2nd week 4 9.8 %
3rd week 1 2.4 %
Comorbidity
Hypertension 15 chronic 4 9.8 %
gestational 7 17.1 %
pre eclampsia 2 4.9 %
eclampsia 2 4.9 %
Obesity 3 7.3%
Smoke 2 4.9%
Diabetes 0 0%
Dislipidemia 0 0%
Dissection type
Type a 24 58.5% simple type A 23 56.1 %
A+ aneurysm 1 2.4 %
Type b 17 41.5% simple type B 9 22%
B + aneurysm 8 19.5 %
Clinical aspects
Neurologic 8 19.4 % loss consciousness 5 12.2 %
emiparesis 1 2.4 %
superior hypostenia 1 2.4 %
inferior hypostenia 1 2.4 %
Back pain 14 34.1 % upper back 11 26.8 %
lower back 2 4.9 %
back side 1 2.4 %
Thoracic pain 26 63.3 % unspecified 19 46.3 %
interscapular 5 12.1 %
left shoulder 2 4.8 %
neck 1 2.4 %
retrosternal 2 4.9 %
Dyspnea 13 31.7 %
Abdominal pain 7 17.1 % epigastric 5 12.2 %
lower abdomen 2 4.9 %
Nausea 7 17.1 %
Organ ischemia 7 17.1 % cardiac (IMA) 3 7.3 %
mesenteric 2 4.9 %
stroke 1 2.4 %
multiple 1 2.4 %
Initial wrong diagnosis 11 26.6 % pulmonary embolism 4 9.8 %
eclampsia 1 2.4 %
renl stones 1 2.4 %
gallstones 1 2.4 %
cesarean pain 1 2.4 %
embolic stroke 1 2.4 %
HELPP syndrome 1 2.4 %
IMA 1 2.4 %
Timing of management
Autoptic finding 3 7.3 %
Treatment < 24 h 26 63.4 %
> 24H /no treatment 15 36.6 % 24-48 h 4 9.8 %
> 48 < 1 week 4 9.8 %
>1 week 1 2.4 %
Management planned treatment 3 7.3 %
Pharmacological 5 12.1 % successfull 1 2.4 %
unsuccessful 4 9.7%
Open surgery 22 53.6 % primary 19 46.3 %
surgery after conservative failure 3 7.3 %
Primary 7 17.1 %
after conservative failure 1 2.4 %
Hybrid surgery 5 12.2 %
Maternal outcome
Well after treatment 30 73.2 %
Mortality 11 26.8 % sudden death 4 9.8 %
preoperatory 2 2.4 %
intraoperatory 2 4.9 %
postoperatory 4 9.8 %
Fetal management
Therapeutic abortion 1 2.4 %
Surgery in preg-nancy 1 2.4 %
Emergency cesarean preop 17 41.5 %
Fetal outcome
Alive 35 85.3 % born before event 8 19.5 %
well on follow up 26 63.4 %
growth restriction 1 2.4 %
Mortality 6 14.6 % therapuetic abortion 1 2.4 %
stillbirth 2 4.9 %
autoptic finding 3 7.3 %

References

  1.  
    Nasiell J, Lindqvist PG. Aortic dissection in pregnancy: the incidence of a life-threatening disease. Eur J Obstet Gynecol Reprod Biol. 2010 Mar;149(1):120-1.
  2.  
    Banerjee A, Begaj I, Thorne S. Aortic dissection in pregnancy in England: an incidence study using linked national databases. BMJ Open. 2015 Aug 20;5(8):e008318.
  3.  
    Coulon C. Thoracic aortic aneurysms and pregnancy. Presse Med. 2015 Nov;44(11):1126-35.
  4.  
    Toshimitsu M, Nagamatsu T, Nagasaka T, Iwasawa-Kawai Y, Komatsu A, Yamashita T, Osuga Y, Fujii T. Increased risk of pregnancy-induced hypertension and operative delivery after conception induced by in vitro fertilization/intracytoplasmic sperm injection in women aged 40 years and older. Fertil Steril. 2014 Oct;102(4):1065-1070.
  5.  
    Rajagopalan S, Nwazota N, Chandrasekhar S. Int J Obstet Anesth. Outcomes in pregnant women with acute aortic dissections: a review of the literature from 2003 to 2013. 2014 Nov;23(4):348-56. doi: 10.1016/j.ijoa.2014.05.001. Epub 2014 May 14. Review.
  6.  
    Jackson S, Hong C, Wang ET, Alexander C, Gregory KD, Pisarska MD. Pregnancy outcomes in very advanced maternal age pregnancies: the impact of assisted reproductive technology. Fertil Steril. 2015 Jan;103(1):76-80. DOI: 10.1016/j.fertnstert.2014.09.037. Epub 2014 Oct 25.

SMAD2 MUTATIONS CAUSE ARTERIAL ANEURYSMS AND DISSECTIONS; A NEW PLAYER IN AN OLD STORY

Micha Dimitra1, Guo Dong-chuan2, Bogunovic Natalija1, 3, Hilhorst-Hofstee Yvonne4, van Kooten Fop5, Atmaja Dian1, 6, Overwater Eline1, 7, Cayami Ferdy1, 6, Regalado Ellen2, van Uffelen René8, Venselaar Hanka9, Faradz Sultana6, Vriend Gerrit9, Weiss Marjan1, Sistermans Erik1, Maugeri Alessandra1, Milewicz Dianna2, Yeung Kak Khee3, vanDijk Fleur10, Pals Gerard1

Introduction

Pathogenic variants in genes encoding components of the TGF-β signaling pathway have been implicated in syndromic and non-syndromic aneurysmal disease [1]. SMAD2 is phosphorylated by the TGF-β receptor upon which it translocates to the nucleus to regulate the expression of TGF-β responsive genes. Experimental aim: We aimed to identify pathogenic mutations in new genes responsible for aortic aneurysms and dissections.

Work summary

A cohort of 365 patients, aged ≤60 years, was screened by sequencing. The patients had been confirmed negative for mutations in the aneurysm-causing genes FBN1, TGFBR1, TGFBR2, ACTA2 and MYH11. Western blotting analysis was used to investigate SMAD2 and SMAD3 phosphorylation in dermal fibroblasts of the patients.

Results

Variant c.1346T>C p.(Leu449Ser) was identified in the proband of the first family, a patient with aneurysms and dissections of the cerebral and neck arteries. A de novo variant, c.1369G>A p.(Gly457Arg), was found in the proband of the second family who suffered from thoracic aortic aneurysm. A third variant, c.1163A>G p.(Gln388Arg), was identified in two siblings of family 3 with thoracic aortic aneurysm. These variants were not identified in human sequence variants databases (only c.1369G>A was reported once in ExAC database). All detected variants were found to affect evolutionary highly conserved amino acids in the MH2 domain of the protein which is responsible for interaction with SMAD3, SMAD4 and TGFBR1 receptor. In silico analysis suggested a strong pathogenic effect. The pathogenic effect was demonstrated by increased SMAD2 and SMAD3 phosphorylation in fibroblasts with the c.1369G>A mutation.

Conclusion

We propose SMAD2 mutations as a novel cause of arterial aneurysms and dissections [2]. Increased Smad signaling is in agreement with the paradoxical increased SMAD signaling which has been observed in loss-of-function mutations in syndromic and non-syndromic aneurysms [3]. Further research is warranted to investigate the molecular mechanism by which Smad2 mutations lead to aneurysm development.

References

  1.  
    Transforming growth factor-beta signaling in thoracic aortic aneurysm development: a paradox in pathogenesis. J Vasc Res. 2009; 46(2):119-137.
  2.  
    SMAD2 Mutations Are Associated with Arterial Aneurysms and Dissections. Hum Mutat. 2015 Dec;36(12):1145-9.
  3.  
    The paradoxical TGF-β vasculopathies. Nat Genet. 2012 Jul 27;44(8):838-9.

INCIDENCE, TREATMENT AND LONG-TERM CLINICAL OUTCOME IN PATIENTS WITH AORTIC GRAFT INFECTIONS

Pettersson Jennifer1, Daryapeyma Alireza2, Gillgren Peter3, Hultgren Rebecka2

Introduction

Aortic graft infections are relatively rare, with an incidence of 0.6-3%. High mortality rates continue to be a major concern in this patient category. The primary aim of this study was to identify the incidence of postoperative aortic graft infection and assess the long-term clinical outcome of different treatment modalities in a population-based cohort.

Methods

Using the in-hospital electronic patient registry and the Swedish Vascular Registry (Swedvasc), 2026 patients treated for aortic aneurysms and aortoiliac occlusive disease in Stockholm county region (pop. 2.2 million) during the period 2005-2015 were identified. Review of the patients’ records provided information on type of infection, treatment and outcome.

Results

219 suspected cases of infection were reviewed, yielding 29 patients (26 males, 3 females) with aortic graft infections. The mean age was 68.9 ± 10.7 years. Mean follow-up time was 81.4 ± 66.3 months from primary surgery (EVAR 51.3 ± 44.7; open repair 98.6 ± 71.8). The overall incidence of graft infection was 1.4% (29/2026). Ten patients had emergency surgery at the time of primary intervention (EVAR n = 5; open repair n = 5). Nineteen patients had non-emergent surgery (EVAR n = 9; open repair n = 10). The incidence of graft infection for both non-emergent and emergent cases was 1.4%. In the non-emergent group (n = 19), 11 patients were treated conservatively, seven patients underwent surgical reconstruction and there was one missing case. In the emergent group (n = 10), seven patients were treated conservatively and three underwent surgical reconstruction. There were five deaths due to graft infection in the conservatively treated group but none in the surgically treated group. All-cause mortality for the non-emergent group was 53% and for the emergent group 80%. Mortality rates based on treatment method were 78% for conservatively treated patients and 40% for surgically treated patients. In the conservatively treated group 5.6% were free of infection compared to 30% in the surgically treated group.

Figure 1.

Patient population.

media/vol4/issue5/images/aorta-04-185-g012.jpg
Figure 2.

Outcome of treatment.

media/vol4/issue5/images/aorta-04-185-g013.jpg

Conclusion

There were no significant differences between the emergent and non-emergent groups in terms of incidence of graft infection or time to infection. Surgically treated patients had better rates of eradication of infection and survival than the conservatively treated patients.

References

  1.  
    Treska V, Certik B, Molacek J. Management of aortic graft infections - the present strategy and future perspectives. Bratisl Lek Listy. 2016;117(3):125-32.

ABDOMINAL AND ILIAC ANEURYSMS REPAIR USING VARIOUS IMPLANTATION TECHNIQUES OF STENT-GRAFTS MODULES: A FIRST EXPERIENCE IN RUSSIA

Generalov Mikhail, Maystrenko Dmitry, Panov Igor, Oleschuk Anna, Ivanov Alexander

Target

To evaluate the feasibility and midterm results of a new (for the Russian market) stent-graft for suprarenal and infrarenal and iliac endovascular aneurysm repair (EVAR). METHODS: Twenty six patients (21 men, 5 women; mean age 71 years, range 59-87) with suprarenal (n=2) and infrarenal (n=21) abdominal aortic aneurysms (AAA) and iliac (n=3) aneurysms (IAA) suitable for EVAR were treated with various modular stent-grafts of JOTEC company (Germany). The maximum AAA diameter was 56 mm (48-81), mean diameter of IAA was 44 mm (38-52). The complex vascular anatomy (hostile neck and tortuous iliac artery) were in 11 (42%) cases. Most of the patients (79%) were ASA grade 3 or higher. All procedures were primary implantation.

Results

All stent-grafts were implanted at the intended position; no conversions to open surgery were necessary and no type I endoleak was noted. Two constructs were made using the Chimney technique. Abdominal bifurcation stent-grafts have been established in 21 patients. Sandwich technique has been applied in three cases of iliac aneurysms. There was no 30-day mortality. In the mean 12-month follow-up (range 8-17), no stent fractures, migrations, or secondary endoleaks were noted. The diameter of the aneurysm was reduced in 12 (46%) and remained unchanged in the 14 (54%) cases. One patient required open surgery at 3 months for thrombotic occlusion of the sten- graft branche. Two octogenarian patients died during the observation period.

Conclusion

Modular stent-grafts of JOTEC company appears safe and effective in this initial midterm clinical experience. This devises are especially suitable for complex aneurysm anatomy, such as hostile aneurysm necks or tortuous and dilated iliac arteries.


SEX DIFFERENCES IN OUTCOMES AFTER AAA REPAIR IN THE UNITED KINGDOM

Sidloff David1, Saratzis Athanasios1, Sweeting Michael2, , Bown Matthew1

Introduction

AAA screening in men is cost-effective and reduces mortality. There is no evidence that screening women is effective. However, women are four times more likely to rupture and account for 33.6% of all ruptured AAA deaths, therefore may be disadvantaged by current policies.

Problem Definition

Peri-operative risk is critical in determining the effectiveness of screening and contemporaneous estimates of these risks are lacking. We therefore aimed to compare outcomes for men and women undergoing AAA in the UK.

Work Summary

Anonymised individual data from the UK National Vascular Registry for patients who had undergone AAA repair 2010 2014 were analysed. Relevant covariates were extracted for further analysis by sex. Analyses were stratified by 5-year age bands and the primary outcome measure was in hospital mortality by gender, indication and operation. Multi-variate regression was performed to adjust for co-morbidities.

Results

33,069 patients were included. For elective open surgical AAA repair, in hospital mortality was 4.0% in men and 6.9% in women (OR 1.77, 95%CI 1.33-2.35, P=0.0001) whilst for EVAR in hospital mortality was 0.7% in men and 1.7% in women (OR 2.51, 95%CI 1.57-4.03, P=0.0001). No differences were seen in mortality after ruptured AAA repair. Elective morbidity was higher in women who were more likely to develop cardiac complications (4.3% versus 5.7%, OR 1.34 95%CI 0.99-1.82, P=0.04) and renal failure (7.0% versus 9.3%, OR 1.37, 95%CI 1.07-1.75, P=0.007) after OSR and haemorrhage (1.0% versus 1.7%, OR 1.70, 95%CI 1.07-2.71, P=0.02) and cerebral complications (0.2% versus 0.5%, OR 2.53, 95%CI 1.01-6.36, P=0.05) after EVAR. Female gender remains a significant risk factor for death (P=0.028) after adjustment.

Conclusion

Women have worse outcomes after elective AAA repair. This highlights the need for sex specific pre, peri and post-operative strategies to reduce the differences seen and may erode any benefit of screening for AAA in women.


EXPLANTATION OF A FENESTRATED ABDOMINAL ENDOGRAFT WITH AUTOLOGEOUS VENOUS RECONSTRUCTION FOR INFECTION

Terry Catherine, Daenens Kim, Houthoofd Sabrina, Maleux Geert, Fourneau Inge

Case Report

A 72-year old man underwent a three-vessel FEVAR for an asymptomatic thoraco-abdominal aneurysm of 64 mm. The immediate postoperative course was favorable. One month postoperatively he was re-admitted for urosepsis, treated with IV antibiotics. A CT scan for ongoing fever showed infection of the stentgraft with multiple intra-abdominal abscesses. The largest abscess was drained percutaneously and antibiotic therapy stabilized the patient. Revision surgery was refused at that moment. After two months the patient was discharged with lifelong oral antibiotics. During the next eight months the patient was re-admitted four times. CT imaging was always reassuring. Ten months postoperatively CT imaging showed new periaortic abscesses. Percutaneous drainage of the abscesses and IV antibiotics were applied. Then the patient agreed with revision surgery as only chance for some durable quality of life. Meanwhile, he was completely exhausted. A staged procedure was performed: First, an axillobifemoral bypass was performed to reduce cardiac afterload during clampage of the aorta and to guarantee perfusion of the legs. Two days later the endograft was explanted and an autologeous in situ venous reconstruction was performed using both superficial femoral and great saphenous vein. An aortoduodenal fistula was closed and the axillobifemoral bypass was broken down. Two revisions for bleeding were needed. During the second revision colon and small bowel ischemia was present despite patent bypasses. A subtotal colectomy and segmental enterectomy was performed. Finally the patient developed myocardial infarction and eventually multiorgan failure. The patient died three days postoperatively.

Discussion

Infectious complications after FEVAR cause a major problem. Radical surgical management is seen as last rescue if maximal conservative measures fail. Mortality and morbidity rates are very high in these ill patients. Maybe, earlier decision for radical revision surgery could improve survival rates. We demonstrated that in situ autologous venous reconstruction is technically feasible.


AORTOPATHY IN PATIENTS WITH A BICUSPID AORTIC VALVE: A PROCESS BEYOND NORMAL CARDIOVASCULAR AGEING

Grewal Nimrat, DeRuiter Marco, Goumans Marie-Jose, Klautz Robert, Lindeman Jan, Groot Adriana Gittenberger-de

Introduction

Patients with a bicuspid aortic valve (BAV) carry an increased risk for aortic dilation as compared to patients with a tricuspid aortic valve (TAV). During cardiovascular development the second heart field (SHF) and neural crest progenitor cells (NCC) guide and contribute to numerous processes such as semilunar valve formation and differentiation of vascular smooth muscle cells (VSMCs). It is therefore plausible that an altered NCC and/or SHF contribution not only can lead to the development of a BAV but is also associated with a structurally different aortic wall leading to pathology.

Methods

Ascending aorta biopsies of BAV (n=36) and TAV (n=23) both with and without dilation were investigated with classical stainings (MOVAT pentachrome, resorcin fuchsin and hematoxylin eosin). Differentiating and mature VSMCs, lamin A/C, and progerin were studied by immunohistochemistry and with western blot. A pathology score was developed based on seven histopathological criteria: mucoid extracellular matrix accumulation, inflammation, loss of smooth muscle cell nuclei, smooth muscle cell differentiation, intimal thickness, elastic fiber degradation and atherosclerosis.

Results

We found a significant difference in the structure and maturation of the aortic wall in BAV, persisting in the dilated aortic wall, presenting with a thinner intima, lower expression of several VSMC markers (p<0.05) and lowered lamin A/C expression in BAV (p<0.05) as compared to TAV. The dilated TAVs showed significantly increased progerin expression (p<0.05) as well as increased periaortic inflammation (p<0.01).

Conclusion

Our findings indicate that the structure of the non-dilated and dilated aortic wall in BAV and TAV is intrinsically different, with the latter having more aspects of ageing. In BAV there is a VSMC differentiation defect possibly linked to an altered NCC and/or SHF contribution to the aortic wall. These findings are clinically relevant, indicating the requirement for different treatment modalities for aortic dilation in TAV and BAV patients.


THE ROLE OF HEMODYNAMICS AND SHEAR STRESS ON THE ASCENDING AORTIC WALL IN PATIENTS WITH A BICUSPID AORTIC VALVE

Grewal Nimrat1, Girdauskas Evaldas2, Goumans Marie-Jose1, DeRuiter Marco1, Klautz Robert1, Van Brakel Thomas1, Groot Adriana Gittenberger-de1

Background

A bicuspid aortic valve (BAV) is the most common congenital cardiac malformation and is associated with ascending aortic dilation in 60-80%. Structural differences have earlier been noted between patients with BAV and a tricuspid aortic valve (TAV). The purpose of this study was to analyze the correlation between hemodynamics and shear stress on aortopathy in BAV patients.

Methods

BAV (n=36) (mean age 55.8 ± 8.7 years, 72% male) and tricuspid aortic valve (TAV) (n=17) (mean age 60±9 years, 82% male) patients undergoing aortic valve replacement underwent pre-operative cardiac phase-contrast cine magnetic resonance imaging (4D flow MRI) assessment to detect the area of maximal flow-induced stress in the proximal aorta. Based on these MRI data paired aortic wall samples (i.e. area of maximal shear stress (jet sample) and the opposite aortic wall (control sample)) were collected during surgery. The jet and control sample were graded by histopathology in the tunica intima, media and adventitia for the pathology score features: mucoid extracellular deposition, inflammation, elastic fiber fragmentation, smooth muscle cell differentiation, loss of smooth muscle cell nuclei, intimal thickness and atherosclerosis.

Results

Earlier described differences in the pathology score between all BAV and TAV patients were confirmed in this study [1]. Comparing the jet and control samples in both BAV and TAV, regions of maximal shear stress did not show any difference in the pathology score in the tunica media and adventitia even if corrected for aortic stenosis/ regurgitation, aortic dilation and raphe position. At the jet side all BAV and TAV patients, however, showed changes in endothelial phenotype from squamous to cuboid, an increase of the subendothelial elastic lamellae and intimal elastin filaments and increased intimal extracellular matrix deposition.

Discussion

Increased wall shear stress leads to intimal pathology with observed activation of the endothelium in both BAV and TAV patients.

References

  1.  
    Grewal N, Gittenberger-de Groot AC, Poelmann RE, et al Ascending aorta dilation in association with bicuspid aortic valve: a maturation defect of the aortic wall. J Thorac Cardiovasc Surg. 2014; 148:1583-90.

DEEP HYPOTHERMIA WITH RETROGRADE CEREBRAL PERFUSION – AS METHOD OF BRAIN PROTECTIONS IN ASCENDING AORTA AND ARCH ANEURYSMS SURGERY

Kravchenko Vitalii, Kravchenko Ivan, Cherpak Bogdan, Litvinenko Valerii, Rybakova Olena, Tarasenko Yurii, Lazorishinets Vasyliy

Introductaion

Antegrade and retrograde perfusion for cerebral protection are controversial approaches in the surgery of ascending aorta and arch. In some cases retrograde cerebral perfusion (RCP) is preferable because of technical simplicity and it allows to reach a good result.

AIM

Selection of efficient technology for RCP on the basis of clinical experience, instrumental and laboratory researches.

Materials and Methods

253 patients with ascending aortic and arch aneurysms were operated on during 1994 - 2015 (205 (81,0%) males, 48 (19,0%) females), age ranged 27 – 79 years, mean 53,4±8,2; acute (subacute) dissection took place in 224 (88,5%), chronic – in 12 (4,8%), without dissection – 17 (6,7%) pts. The main reason of aneurysms forming was: arterial hypertension, atherosclerosis – in 151 (59,7%); Marfane syndrome – 32 (12,6%); bicuspid aortic valve disease – 26 (10,3%); cystomedionecrosis – 22 (8,7%); lues – 12 (4,7%); Takajasu arteriitis – 3 (1,2%); falling from height – 2 (0,8%); unknown – 5 (2,0%). Operations` were fulfilled with heart-lung bypass, deep hypothermia and RCP through superior vena cava (SVC). Femoral artery was utilized for arterial cannulation. The following methods were used for correction: supracoronary grafting of ascending aorta with hemiarch(arch) – 179(4) (70,8%); Bentall`s operation with hemiarch (arch) – 56(4) (22,1%); isolated arch grafting – 9 (3,5%); Wheat operation with arch grafting – 5 (2,0%); aortic arch plastic – 4 (1,6%).

Results

Group I (1994-2001) – 25 operations with deep hypothermia (16-18°C), perfusion blood flow – 500-750 mlminm2, pressure in SVC – 15-25 mmHg. Mortality – 7 (28%) pts., in 2 cases the cerebral complications were the cause of death. Group II – 63 operations fulfilled in 2002-2007 yy., with deep hypothermia (12,5-14°C), blood flow rate – 250-500 mlminm2, pressure in SVC – 10-12 mmHg. Mortality – 11 (17,4%) pts. Pulmonary complications were in 5 cases, 3 (4,8%) of them died. Lethal brain injury were 1 pts (1,6%). Group III – 125 operations fulfilled in 2008-2015 yy., with deep hypothermia (18-20°C), blood flow rate – 250-500 mlminm2, pressure in SVC – 10-12 mmHg. Perfusion through femoral artery during the RCP stage was maintained permanently in group II and III. 30-day mortality – 9 (7,2%) pts. Pulmonary complications was lethal in 1 (0,8%) patient and brain lesion - 1 (0,8%) pts. Overall 30-day mortality composed 10,7%. Better clinical results in Group III were confirmed by analysis of arterial and venous blood, thermography, EEG and MRI of the brain.

Conclusion

RCP with deep hypothermia (18-20°C), pressure in SVC – 10-12 mmHg, blood flow rate – 250-500 mlminm2 with continually perfusion through femoral artery is safe method of brain protection during ascending aortic and arch correction.


ANEURYSM AT THE SITE OF REPAIR OF COARCTATION OF AORTA: FREQUENCY, METHODS OF TREATMENT, RESULTS

Kravchenko Ivan, Kravchenko Vitalii, Tarasenko Yurii, Dykuha Sergiy, Cherpak Bogdan, Tretyak Oleksandr, Lazorishinets Vasyliy

Objective

Remote period after coarctation of aorta (CoA) repair is accompanied with risk of descending thoracic aorta (DTA) aneurysm development. AIM. To inform about frequency, methods and results of treatment of aneurysms, which developed after CoA repair?

Materials and Methods

4234 patients with CoA were operated in the Institute during 1960-2015. Aneurysms after CoA repair took place in 165(3.9%) patients in period till 1 months to 38 years. Mean term from CoA repair till operation on the reason of developed aneurysm composed 16 years. Aneurysms developed in 16 (0.6%) patients after CoA repair by end-to-end anastomosis, in 17(5.7%) patients after aorta grafting with vascular graft and in 114(9.5%) cases after patch aortoplasty. Aneurysm diagnosis was established by TTETOE and verified by CT. 131(79.3%) patients were operated on, 34(20.7%) patients abstained from surgical treatment of developed aneurysms. Visceral organs protection from hypoxia was accomplished in 124(94.6%) patients by use of passive shunt from ascending to descending aorta, in 5(3.8%) patients artificial blood circulation was used. After aneurysms resection, aorta grafting was performed-in 128 (97.7%) cases, aortorrhaphy-in 3(2.3%).

Results

Hospital mortality composed 14 (10.6%). There were no renal and spinal cord complications. Out of 34 patients, who abstained from operation on different reason, 26 patients died during 7 years after diagnosis of aneurysm was established.

Conclusions

1. Coarctation of the aorta repair by patch aortoplasty is inexpedient. 2. Lifelong dispensary supervision of operated on patients is necessary for timely detection and treatment of aneurysms after coarctation of the aorta repair.


HOW QUICKLY DO ASYMPTOMATIC INFRA-RENAL ABDOMINAL AORTIC ANEURYSMS GROW? ANALYSIS OF A LARGE SINGLE-CENTRE DATABASE SURVEILLANCE DATABASE

Mistry Rakesh1, Ahmad Mehtab1, Hodson James2, Claridge Martin1, Bradbury Andrew1

Aims

To examine factors affecting AAA growth in patients entered into the surveillance programme in our unit

Methods

Retrospective interrogation of a single-centre prospectively gathered AAA surveillance database for the period between February 1993 and August 2013. Overall, 5363 AAA measurements were analysed. The average duration of follow-up was 5 years 7 months with a mean (median; range) of 10 (9; 2 to 29) measurements per person. Patient demographics including co-morbidity, smoking status, use of ‘best medical therapy’ (BMT), death and cause of death were collected. MAPD growth rate was derived by dividing the change in MAPD between the first and last scans by the time elapsed between them. The effect of patient factors on growth rates was analysed using independent sample t-tests and one-way ANOVA. A survival analysis was performed using the compound outcome of all-cause mortality or OR/EVAR. Univariate analysis was performed using Kaplan-Meier survival curves, followed by a multivariable Cox regression model with a backwards stepwise entry method.

Results

The main findings from this study are that only 20% of patients in surveillance proceeded to elective surgical repair. Patient factors did not predict rupture, which occurred in <4% of patients, of whom 41% had a last recorded MAPD <55mm. Those with MAPD growth >4.6mm/year were more likely to rupture, although only 37% of ruptures proceeded to surgery. Most patients who die in surveillance do so from non-AAA related causes, most commonly malignancy.

Conclusions

Significant numbers of patients are kept under AAA surveillance inappropriately and there is room for significant service improvement. Specifically, it is important not commence surveillance in patients who are very unlikely to ever grow to a point where AAA surgery would be contemplated on grounds or age and/or co-morbidity. Similarly, patients need to be discharged from surveillance when this likelihood becomes apparent.


OVERVIEW ABOUT THE VALUE OF FUNCTIONAL IMAGING IN THE MANAGEMENT OF AORTITIS

Samuel Bruls, Audrey Courtois, Betty Nusgens, Jean-Olivier Defraigne, Philippe Delvenne, Roland Hustinx, Michel Moutschen, Natzi Sakalihasan

Background

Aortitis is defined as an abnormal inflammatory condition of infectious or non infectious origin involving the aortic wall. Aortitis may be related to multiple causes with variable prognoses. Because of the nonspecific clinical presentation, aortitis is often overlooked and patients frequently undergo multiple tests and imaging to reach the final diagnosis. However, it is important to establish an early diagnosis as soon as possible. Indeed, this inflammatory process may deteriorate the aortic wall, resulting in potentially life-threatening vascular complications. Compared to conventional imaging tools that provide anatomical and morphological information, Positron Emission Tomography/Computed tomography (PET/CT) provides important additional information.

Methods and Results

During a 4-year period, 428 consecutive patients referred to our cardiovascular surgery department for aortic diseases underwent FDG PET/CT examinations. Among these, 19 (4.4%) patients with suspected to have aortitis. All of them had an initial positive FDG PET/CT uptake occurring in the aorta and major branches as evaluated by visual analysis of images and assessed with the final diagnosis of aortitis. During follow up, after surgery and/or starting immunosuppressive treatment, each patient undergoes PET/CT which was compared with the initial evaluation. In all cases, normalisation of FDG uptake was correlated with clinical improvement.

Conclusions

Our experience, insight this observational study, aim to illustrate the interest and the various aspects of functional monitoring with PET/CT in the management of aortitis. PET/CT constitutes a valuable imaging modality to assess the diagnosis, monitoring and planning aortitis treatment. We confirmed the importance of an early detection of inflammatory large-vessel pathology, which can constitute an important threat.


AORTIC ANEURYSM RUPTURE INTO A RETROAORTIC LEFT RENAL VEIN

Calì Filippo, Diliberti Salvina, Doffria Ernesto, Savaia Michele, Trovato Grazia, Dell’Aira Salvatore, Reina Nicola

Background

Spontaneous aorta-left renal vein fistula (ALRVF) caused by abdominal aortic aneurysm (AAA) is a rare form of intravascular aneurysm rupture. The literature series of ALRVF, updated here to about 30 reported cases, demonstrates that patients with ALRVF present with a unique clinical syndrome characterized by abdominal or left flank pain (84%), a pulsatile abdominal mass (63%), abdominal bruit or murmur (63%), hematuria (100%), and nonfunction of the left kidney on functional imaging studies (100% of patients studied).

Matherial and Method

We report the case of a patient who was transferred to our facility after a CT scan obtained at a local hospital revealed a leaking abdominal aortic aneurysm. Review of the scan showed an aorto-left renal vein fistula. Knowing this fistula was present, made the operative repair of the aneurysm and control of the fistula much more straightforward than might otherwise have been the case. Because of the critical condition and evident clinical signs of ruptured AAA, the patient was operated on immediately without any other diagnostic procedure. Transperitoneal approach was used. Intraoperative findings were consistent with the rupture of the frontal aneurysmal wall into retroperitoneal space. The operation consisted of the closure of the defect in the retroaortic left renal vein and the repair of the aneurysm. The aneurysm was replaced with impregnated tubular Dacron graft 16 mm.

Results

The postoperative recovery was successful. The patient survived the necessary surgical correction and was followed-up for 18 months, and there were no signs of cardiac or renal failure and arterio-venous insufficiency of legs.

Conclusions

Although relatively rare, major anomalies of the renal veins and perirenal vena cava should be borne in mind when operating on the abdominal aorta. Retroaortic left renal vein is a malformation in which the left renal vein courses dorsal to the abdominal aorta. In patients with abdominal aortic aneurysm, an aorto-left renal vein fistula can form if the left renal vein is sandwiched between the aneurysm wall and lumbar vertebrae. A caution is required to control bleeding from this type of fistula when an incision is made in the aortic aneurysm. In conclusion, the possibility must be entertained that the aorto-left renal vein fistula in abdominal aortic aneurysms often correlate to the retro-aortic left renal vein. This clinical condition can cause severe renal dysfunction, in spite of which an enhanced contrasted CT scan would be extremely informative preoperatively.


ADVENTITIAL ADIPOGENIC DEGENERATION: AN UNIDENTIFIED CONTRIBUTOR TO AORTIC WALL WEAKENING IN THE ABDOMINAL AORTIC ANEURYSM

Doderer S.A., Kokje V.B.C., Hamming J.F., van Bockel J.H., Lindeman J.H.N.

Objectives

To determine additional pathophysiological mechanisms driving AAA growth.

Background Data

The processes underlying abdominal aortic aneurysm (AAA) growth and ultimate rupture are complex and poorly understood. AAA is accepted as an inflammatory response with an accompanying proteolytic imbalance, however clinical intervention studies consistently fail to show a benefit from interference with these processes. There are striking associations between AAA and popliteal artery aneurysms (PAA); yet while AAAs will eventually rupture, PAA’s have a low propensity for rupture. We reasoned differences between AAA, PAA and normal aorta’s provide critical clues towards other processes involved in critical debilitation of AAA’s.

Methods

Tissue was harvested during elective open aneurysm repair or kidney transplantation for control aortas. Tissue was handled correctly and used for qPCR, microarray, IHC and in vitro studies.

Results

Histological evaluation of AAA, PAA and control aorta showed extensive fibrous changes in AAA and PAA and identified presence of large adventitial adipocyte aggregates as a unique and consistent feature of AAA (P<0.01). The combination of fibrosis and adipogenic degeneration characterize AAA as dystrophic disorder. Adipogenic differentiation is controlled by transcription factors from C/EBP family, KLF5 and PPARγ. Immunohistochemistry revealed abundant expression of these factors in AAA disease indicating the transcriptional machinery required for adipogenic differentiation is present. qPCR data confirms upregulation of KLF-5 (P<0.05) and PPARγ (P<0.05), two factors crucial in the final stages of adipogenic differentiation. Furthermore, microarray analysis between ruptured and stable AAA’s reveals upregulation of both adipogenesis (P<0.001) and PPAR (P=0.002) pathways. Adipogenic potential of AAA and control adventitial cells were underwent adipogenic differentiation in vitro showing the capability of normal cells adapt an adipogenic phenotype. AAA cells have a higher propensity to do so (P<0.05).

Conclusions

Systemic evaluation of AAA and PAA tissues shows adventitial fatty degeneration in the context of dystrophy as an additional pathophysiologic mechanism. These results should be considered in the light of failing pharmaceutical therapies and provide new avenues for pharmaceutical AAA stabilization.


PET-TC UTILITY TO ASSESS THE ABDOMINAL AORTIC ANEURYSM GROWTH AND ITS RELATIONSHIP WITH CHANGES IN ENERGETIC METABOLISM

Galindo Angel1, Moñux Guillermo1, Modrego Javier2, Delgado Roberto1, Hernandez Manuela Maria1, Lopez-Farre Antonio Jose2, Serrano Francisco Javier1

Introduction

PET-CT utility to assess AAA growth remains controversial. Factors involved in the increased metabolic activity that leads to its inflammatory activity remain unknown.

Experimental aim: to check the 18-FDG uptake by PET-CT in AAA, evaluate its correlation with diameter and growth and determine differences in those processes involved in the energetic metabolism

Work Summary

The 18-FDG PET-CT was performed in 20 patients with AAA before elective open surgery. A SUVmax >2.5 was considered as increased 18F-FDG uptake. The aneurysmal aortic wall samples collected during surgery (in case of increased uptake, two sample were collected, one of them from the highest uptake site). The expression of following proteins involved in the cellular metabolism were analyzed: aerobic (lactate-dehydrogenase, pyruvate-dehydrogenase), anaerobic (malate-dehydrogenase), beta-oxidation of fatty acids (acetyl-coenzyme-A-dehydrogenase [acilCoADH], carnitine-palmitoyltransferases [CPTs]), oxidative phosphorylation (uncoupling-proteín 1 [UCP-1]), ATP-synthase.

Results

5 patients showed an increased uptake. Therefore 25 samples were collected. There was a statistical significant difference regarding demonstrated growth of the AAA (80% in uptake group vs 20%, p=0.018) with a RR 7,4[CI 95%(1,02-54.31)]. The uptake group showed a lower aortic diameter without statistical significance (53.80±9.09 mm vs 60.87 ± 8.48 mm). We observed no differences regarding to the expression of proteins related to aerobic or anaerobic metabolism. Levels of expression acilCoADH (32.80±8.05UA vs 55.58 ± 4.28, p=0.049) and CPT-II (12.68±4.73UA vs 38.30±3.78, p=0.001) were significantly lower in the uptake group. Significantly higher levels of expression of UCP-1 were observed in the uptake group (138.64±26,57UA vs 55.05±11.12, p=0.005), with lower levels of ATP synthase (10.17±2.67 UA vs 20.11 ± 4.01)

Conclusions

metabolic changes in AAA with increased 18-FDG uptake is related to an uncoupling of the oxidative phosphorylation chain and a diminished ATP synthesis. PET-CT could be considered a potencial biomarker to detect those AAA with recent growth, but further studies are required to confirm its validity


EVIDENCE OF INTIMAL TEAR IN AORTIC INTRAMURAL HEMATOMA

Filippone Gianfranco, Franchino Rosalba, Ricasoli Alessandro, Argano Vincenzo

Aortic Intramural Hematoma (IMH) represent Class II of Acute Aortic Syndrome (AAS); this group of virulent lesions share the presence of an intimal tear but original description of IMH is reported as a “dissection without intimal tear” due to vasa vasorum rhexis. Moreover, as per Acute Dissection (AD) timing of surgery is well codified, for IMH this issue is controversial ranging from watchful waiting, eventual surgery up to emergency. Related to this the natural history described IMH as a dynamic entity with associated tendencies (regression, progression to AD, expansion or rupture) that vary geographically. To date only sporadic reports emphasize the prevalence in IMH of a tear, lesion that may contribute to justify a change in the policy protocol considering the causative role of vasa vasorum as questionable because the pressure generated by the rupture is to low to overcome the counterpression exerted from the inner lumen. We review retrospectively our data on a group of patients with diagnosis of AAS during a period between July 2013 to March 2016 focusing on natural history, radiographic follow-up and intraoperative findings of subset of patients (12,12%) affected by IMH. All IMH patients, both type A-type B, were operated on as eventual surgery, except one IMH type A that was operated on as emergency. Pre-operative and/or intraoperative findings showed in one-third of all cases the evidence of an intimal lesion. There was no intraoperative death, one patient was complicated with retrograde TAAD during Tevar procedure and was the one that suffered for permanent neurologic disorder and account for late death. Our data review, due to IMH high rate of worsening during follow-up, the coexitence of a intimo-medial tear and the favourable surgical results, led us to consider for IMH a more aggresive timing for intervention.

References

  1.  
    Lansman SL, Saunders PC, Malekan R, Spielvogel D: Acute Aortic Syndrome. J Thorac Cardiovasc Surg 2010;140:S92-7.
  2.  
    Gutschow SE, Walker CM, Martin-Jimenez S et al: Emerging Concepts in Intramural Hematoma Imaging. Radiographics 2016, May-Jun;36(3):660-74.
  3.  
    Chou AS, Zigashin BA, Charilaou P, Tranquilli M, Rizzo JA, Elefteriades JA: Long-term behaviour of Aortic Intramural Hematomas and Penetrating Ulcers. J Thorac Cardiovasc Surg 2016 Feb;151(2),361-73.

THE APPLICATION OF METABOLIC PROFILING TO ANEURYSM RESEARCH

Greco Michele1, 2, Mahim Qureshi I1, 3, Vorkas Panagiotis A3, Holmes Elaine3, Davies Alun H.1

Background/Objective

Metabonomics is a top-down systems biology approach [1] involving high resolution spectroscopic profiling of small (<1kDa) molecules (representing endpoints of metabolism) combined with computational data modeling that may be used to determine biomarkers of disease presence, unravel pathophysiological pathways, confer prognostic information, or map response to treatment. There is considerable uncertainty regarding the aetiological development and optimal management of aneurysmal disease. This study aimed to explore the diversity and outcomes of existing metabonomic research as applied to the clinical challenges for patients with abdominal aortic aneurysm (AAA).

Method

A systematic review has been performed adhering to PRISMA guidelines. All original research articles applying metabolic profiling to samples collected from patients with aneurysms were included. Non-human studies and reviews were excluded.

Results

Seven articles relevant for inclusion were identified [2-8] examining plasma/serum or tissue. All studies utilised mass spectrometry (MS) and one additionally incorporated Proton Nuclear Magnetic Resonance Spectroscopy (1H-NMR) [5]. Aminomalonic acid (GC-MS) [5], guanidinosuccinic acid (HPLC-MS) [2] and glycerol (1H-NMR) [5] emerge as biomarkers of large aneurysm presence. Results from targeted metabolic lipid profiling suggest that preferential incorporation of adipocytes into aneurysm adventitia may occur, decreasing tensile strength, thereby increasing the risk of rupture. Temporal relationships between chemical mediators of inflammation and resolution in patients undergoing open AAA repair imply differential responses in early and late healers, generating hypotheses for targeted perioperative adjunctive therapy. Limitations encountered include small study sizes, single time-point sampling, and lack of statistical correction for the likelihood of false positive discovery.

Conclusion

Current studies demonstrate the utility of metabonomic science in identifying potential biomarkers of aneurysm presence and elucidating mechanisms underlying dilating arterial disease. Further translational longitudinal studies incorporating larger, matched cohorts are required for validation of the metabolites identified, to determine metabolic variations associated with aneurysm growth and generating targets for drug design and development.

References

  1.  
    Nicholson JK, Lindon JC, Holmes E. 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica. 1999;29(11):1181-9.
  2.  
    Ciborowski M, Teul J, Martin-Ventura JL, Egido J, Barbas C. Metabolomics ith LC-QTOF-MS permits the prediction of disease stage in aortic abdominal aneurysm based on plasma metabolic fingerprint. PLoS One. 2012;7(2):e31982.
  3.  
    Vorkas PA, Isaac G, Anwar MA, Davies AH, Want EJ, Nicholson JK, et al Untargeted UPLC-MS profiling pipeline to expand tissue metabolome coverage: application to cardiovascular disease. -951749369 Anal Chem. 2015;87(8):4184-93.
  4.  
    Tanaka H, Zaima N, Sasaki T, Yamamoto N, Inuzuka K, Sano M, et al Imaging Mass Spectrometry Reveals a Unique Distribution of Triglycerides in the Abdominal Aortic Aneurysmal Wall. -951749369 J Vasc Res. 2015;52(2):127-35.
  5.  
    Ruperez FJ, Ramos-Mozo P, Teul J, Martinez-Pinna R, Garcia A, Malet-Martino M, et al -951749369 Metabolomic study of plasma of patients with abdominal aortic aneurysm. Anal Bioanal Chem. 2012;403(6):1651-60.
  6.  
    Pillai PS, Leeson S, Porter TF, Owens CD, Kim JM, Conte MS, et al Chemical mediators of inflammation and resolution in post-operative abdominal aortic aneurysm patients. Inflammation. 2012;35(1):98-113.
  7.  
    Moxon JV, Liu D, Wong G, Weir JM, Behl-Gilhotra R, Bradshaw B, et al Comparison of the serum lipidome in patients with abdominal aortic aneurysm and peripheral artery disease. Circ Cardiovasc Genet. 2014;7(1):71-9.
  8.  
    Ciborowski M, Martin-Ventura JL, Meilhac O, Michel JB, Ruperez FJ, Tunon J, et al -951749369 Metabolites secreted by human atherothrombotic aneurysms revealed through a metabolomic approach. J Proteome Res. 2011;10(3):1374-82

PREOPERATIVE FIBRINOGEN LEVELS AND EARLY OUTCOME FOLLOWING ENDOVASCULAR REPAIR OF RUPTURED ABDOMINAL AORTIC ANEURYSMS

Karkos Christos, Ifantis Aristotelis, Papadimitriou Christina, Pliatsios Ioannis, Pelekas Dimitrios, Mitka Maria-Afroditi, Papazoglou Konstantinos

Aim

To investigate the potential association between preoperative levels of fibrinogen and early outcome following endovascular aortic repair (EVAR) of ruptured abdominal aortic aneurysms (RAAAs).

Methods

Consecutive patients undergoing EVAR for RAAA between March 2010 and May 2016 were recruited from a single vascular centre. Patient details including fibrinogen levels on admission were extracted from case files and 30-day mortality was recorded. Fibrinogen levels were compared between survivors and fatal cases using the independent samples t-test.

Results

Twenty-one patients (20 males, median 71 years) with a RAAA receiving EVAR and available preoperative fibrinogen levels were included in this study. There were 16 patients with a de novo RAAA and 5 with free rupture after a previous EVAR. Of these, 3 patients died within 30 days (14.3%), one intra-operatively and two within 24 hours due to multiple organ failure. Fibrinogen levels on admission were significantly higher in the group of survivors when compared to those who died (mean ± standard deviation 456.36±183.72 versus 192.57±52.26; p=0.026).

Conclusion

This study suggests a possible relationship between fibrinogen levels on admission and early mortality in patients undergoing EVAR for a RAAA. Higher fibrinogen levels, which may indicate a preoperative hypercoagulable profile, seemed to be associated with better chances of early survival in our small series. Further and larger studies are needed to clarify this issue and possible future therapeutic implications.


INFLAMMATION AS A PREDICTOR OF ABDOMINAL AORTIC ANEURYSM GROWTH AND RUPTURE: A SYSTEMATIC REVIEW OF IMAGING BIOMARKERS

Jalalzadeh Hamid, Indrakusuma Reza, Planken R.N., Legemate D.A., Koelemay M.J.W., Balm Ron

Background

Methods are required to identify abdominal aortic aneurysms (AAAs) at increased risk of rupture. Inflammatory characteristics of AAA can be visualised using advanced imaging techniques and have been proposed as potential predictors of aneurysm progression. The objective of this review was to determine which inflammatory imaging biomarkers are associated with AAA growth and rupture.

Methods

A systematic review was carried out in accordance with the PRISMA guidelines. The electronic databases of Medline (PubMed), Embase, and the Cochrane Library were searched up to January 1, 2016 for studies to determine the potential association between inflammatory imaging biomarkers and AAA growth or rupture.

Results

Seven studies were included, comprising 202 AAA patients. 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG PET-CT) was evaluated in six studies. Magnetic resonance imaging with ultrasmall superparamagnetic particles of iron oxide (USPIO-MRI) was evaluated in one study. Two of six 18F-FDG PET-CT studies reported a significant negative correlation (r = .383, p = .015) or a significant negative association (p = .04). Four of six 18F-FDG PET-CT studies reported no significant association between 18F-FDG uptake and AAA growth. The single study investigating USPIO-MRI demonstrated that AAA growth was three times higher in patients with focal USPIO uptake in the AAA wall compared to patients with diffuse or no USPIO uptake in the wall (0.66 vs. 0.24 vs. 0.22 cm/y, p = .020). In the single study relating 18F-FDG uptake results to AAA rupture, the association was not significant.

Conclusions

Current evidence shows contradictory associations between 18F-FDG uptake and AAA growth. Data on the association with rupture are insufficient. Based on the currently available evidence, neither 18F-FDG PET-CT nor USPIO-MRI can be implemented as growth or rupture prediction tools in daily practice. The heterogeneous results reflect the complex and partially unclear relationship between inflammatory processes and AAA progression.

References

  1.  
    Reeps C, Essler M, Pelisek J, Seidl S, Eckstein HH, Krause BJ. Increased 18F-fluorodeoxyglucose uptake in abdominal aortic aneurysms in positron emission/computed tomography is associated with inflammation, aortic wall instability, and acute symptoms. J Vasc Surg. 2008;48(2):417-23; discussion 24.
  2.  
    Richards JM, Semple SI, MacGillivray TJ, Gray C, Langrish JP, Williams M, et al Abdominal aortic aneurysm growth predicted by uptake of ultrasmall superparamagnetic particles of iron oxide: a pilot study. Circulation Cardiovascular imaging. 2011;4(3):274-81.
  3.  
    Kotze CW, Rudd JHF, Ganeshan B, Menezes LJ, Brookes J, Agu O, et al CT signal heterogeneity of abdominal aortic aneurysm as a possible predictive biomarker for expansion. Atherosclerosis. 2014;233(2):510-7.
  4.  
    Morel O, Mandry D, Micard E, Kauffmann C, Lamiral Z, Verger A, et al Evidence of Cyclic Changes in the Metabolism of Abdominal Aortic Aneurysms During Growth Phases: 18F-FDG PET Sequential Observational Study. J Nucl Med. 2015;56(7):1030-5.
  5.  
    Nchimi A, Cheramy-Bien JP, Gasser TC, Namur G, Gomez P, Seidel L, et al Multifactorial relationship between 18F-fluoro-deoxy-glucose positron emission tomography signaling and biomechanical properties in unruptured aortic aneurysms. Circulation: Cardiovascular Imaging. 2014;7(1):82-91.
  6.  
    Kotze CW, Menezes LJ, Endozo R, Groves AM, Ell PJ, Yusuf SW. Increased metabolic activity in abdominal aortic aneurysm detected by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). European journal of vascular and endovascular surgery: the official journal of the European Society for Vascular Surgery. 2009;38(1):93-9.
  7.  
    Sakalihasan N, Van Damme H, Gomez P, Rigo P, Lapiere CM, Nusgens B, et al Positron emission tomography (PET) evaluation of abdominal aortic aneurysm (AAA). European Journal of Vascular and Endovascular Surgery. 2002;23(5):431-6.

BIOMECHANICAL IMAGING MARKERS AS PREDICTORS OF ABDOMINAL AORTIC ANEURYSM GROWTH OR RUPTURE: A SYSTEMATIC REVIEW

Indrakusuma Reza, Jalalzadeh Hamid, Planken R.N., Marquering H.A., Legemate D.A., Koelemay M.J.W., Balm Ron

Objectives

Biomechanical characteristics, such as wall stress, are important factors in the pathogenesis of abdominal aortic aneurysms (AAA) and can be visualised and quantified using imaging techniques. This systematic review aims to present an overview of all biomechanical imaging markers that have been studied in relation to AAA growth and rupture.

Methods

A systematic review was carried out in accordance with the PRISMA guidelines. A search in Medline, Embase and the Cochrane Library identified 1503 potentially relevant articles. Studies were included if they assessed biomechanical imaging markers and their potential association with growth or rupture.

Results

Twenty-seven articles comprising 1730 patients were included. Eighteen studies performed wall stress analysis using Finite Element Analysis (FEA), thirteen of which used Peak Wall Stress (PWS) to quantify wall stress. Ten of thirteen case-control FEA studies reported a significantly higher PWS for symptomatic or ruptured AAAs than for intact AAAs. However, in some studies there was confounding bias due to baseline differences in aneurysm diameter between groups. Clinical heterogeneity in methodology obstructed a meaningful meta-analysis of PWS. Three out of five FEA studies reported a significant positive association between several wall stress markers – such as PWS and 99th percentile stress – and growth, one study reported a significant negative association and one other study reported no significant association. Studies assessing wall compliance, the augmentation index and wall stress analysis using Laplace’s law, computational fluid dynamics (CFD) and fluid-structure interaction (FSI) were also included in this systematic review.

Conclusions

PWS is significantly higher in symptomatic or ruptured AAAs in most FEA studies. However, confounding bias, clinical heterogeneity and lack of standardisation limit the interpretation and generalisability of the results. Also, there is conflicting evidence on whether increased wall stress is associated with growth.

References

  1.  
    Fillinger MF, Marra SP, Raghavan ML, Kennedy FE. Prediction of rupture risk in abdominal aortic aneurysm during observation: wall stress versus diameter. J Vasc Surg. 2003;37(4):724-32.
  2.  
    Fillinger MF, Raghavan ML, Marra SP, Cronenwett JL, Kennedy FE. In vivo analysis of mechanical wall stress and abdominal aortic aneurysm rupture risk. J Vasc Surg. 2002;36(3):589-97.
  3.  
    Venkatasubramaniam AK, Fagan MJ, Mehta T, Mylankal KJ, Ray B, Kuhan G, et al A comparative study of aortic wall stress using finite element analysis for ruptured and non-ruptured abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2004;28(2):168-76.
  4.  
    Vande Geest JP, Schmidt DE, Sacks MS, Vorp DA. The effects of anisotropy on the stress analyses of patient-specific abdominal aortic aneurysms. Ann Biomed Eng. 2008;36(6):921-32.
  5.  
    Truijers M, Pol JA, Schultzekool LJ, van Sterkenburg SM, Fillinger MF, Blankensteijn JD. Wall stress analysis in small asymptomatic, symptomatic and ruptured abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2007;33(4):401-7.
  6.  
    Gasser TC, Auer M, Labruto F, Swedenborg J, Roy J. Biomechanical rupture risk assessment of abdominal aortic aneurysms: model complexity versus predictability of finite element simulations. Eur J Vasc Endovasc Surg. 2010;40(2):176-85.
  7.  
    Erhart P, Roy J, de Vries JP, Liljeqvist ML, Grond-Ginsbach C, Hyhlik-Durr A, et al Prediction of Rupture Sites in Abdominal Aortic Aneurysms After Finite Element Analysis. J Endovasc Ther. 2016;23(1):115-20.
  8.  
    Vande Geest JP, Di Martino ES, Bohra A, Makaroun MS, Vorp DA. A biomechanics-based rupture potential index for abdominal aortic aneurysm risk assessment: demonstrative application. Ann N Y Acad Sci. 2006;1085:11-21.
  9.  
    Speelman L, Hellenthal FA, Pulinx B, Bosboom EM, Breeuwer M, van Sambeek MR, et al The influence of wall stress on AAA growth and biomarkers. Eur J Vasc Endovasc Surg. 2010;39(4):410-6.
  10.  
    Speelman L, Schurink GW, Bosboom EM, Buth J, Breeuwer M, van de Vosse FN, et al The mechanical role of thrombus on the growth rate of an abdominal aortic aneurysm. J Vasc Surg. 2010;51(1):19-26.
  11.  
    Boyd AJ, Kuhn DC, Lozowy RJ, Kulbisky GP. Low wall shear stress predominates at sites of abdominal aortic aneurysm rupture. J Vasc Surg. 2015.
  12.  
    Xenos M, Labropoulos N, Rambhia S, Alemu Y, Einav S, Tassiopoulos A, et al Progression of abdominal aortic aneurysm towards rupture: refining clinical risk assessment using a fully coupled fluid-structure interaction method. Ann Biomed Eng. 2015;43(1):139-53.
  13.  
    Wilson KA, Lee AJ, Hoskins PR, Fowkes FGR, Ruckley CV, Bradbury AW. The relationship between aortic wall distensibility and rupture of infrarenal abdominal aortic aneurysm. J Vasc Surg. 2003;37(1):112-7.

THE ASSOCIATION OF MMP9 AND MMP13 FUNCTIONAL GENETIC POLYMORPHISMS AND ABDOMINAL AORTIC ANEURYSM IN A GREEK POPULATION

Makrygiannis Georgios, Mourmoura Evanthia, Spanos Konstantinos, Roussas Nikolaos, Tsezou Aspasia, Giannoukas Athanasios

Background

An imbalance between extracellular matrix (ECM) production and degradation, towards the degradation has been importantly related with AAA. Metalloproteinases (MMPs) are principal enzymes of ECM remodeling and their proteolytic activities have been related with the pathophysiology of AAA. Genetic variations can influence the transcription of genes coding MMPs and the function of coding proteins. This case-control study was designed to investigate the possible association of genetic polymorphisms of the MMP9 and MMP13 genes in the etiology of AAA.

Material and Methods

A prospective non-randomized case control study was undertaken including AAA patients from a tertiary center and controls from a AAA screening program, assessing differences in genotype and allele frequencies of the MMP9 (-1561C/T) and MMP13 (-77A/G) single nucleotide polymorphisms (SNPs). The selected SNPs were genotyped using standard polymerase chain reaction and restriction-fragment-length polymorphism methods. Clinical characteristics of the patients and controls were collected.

Results

The SNP MMP9 (-1561C/T) was analyzed in a sample of 182 AAA patients (mean age 72.9±7.5) and 166 controls (mean age 71.5±7.1), whereas the SNP MMP13 (-77A/G) was analyzed in a sample of 171 AAA patients (mean age 72.6±7.6) and 161 controls (mean age 71.2±9.3). Statistical difference was reached in genotype (p=0.034) and allele frequencies for SNP MMP13 (-77A/G). The G allele was more frequent in patients with AAA than in control group [142 vs. 108, p=0.034, OR (95% CI) 1.41 (1.03–1.93)]. No significant differences in genotype or allele frequencies for the MMP9 polymorphism were detected.

Conclusion

Significant genotypic and allelic associations were observed between MMP13 (-77A/G) polymorphism and AAA in a Greek population, supporting its potential involvement in AAA pathogenesis, while no correlation was identified between MMP9 and AAA.


CAN AORTIC ROOT REPLACEMENT WITH A GRAFT AFFECT CARDIAC FUNCTION IN PATIENTS WITH MARFAN SYNDROME?

Mosquera Laura Muino, François Katrien, Bové Thierry, De Wolf Daniel, De Backer Julie

Background

Marfan syndrome (MFS) is a hereditable connective tissue disorder characterized by skeletal, ocular and cardiovascular manifestations. The most know and life-threatening cardiovascular condition is aortic root dilation and dissection. Different surgical techniques to replace the aneurysmatic or dissected aorta with a graft are possible. Recently, decreased left ventricular function, leading to cardiomyopathy in some cases, and arrhythmias have also been identified as an important cause of mortality in these patients. Furthermore, abnormal myocard has been shown in different mice models of MFS. Nevertheless, risk factors favouring the development of ventricular dysfunction and arrhythmias are not well known. We, therefore, wanted to investigate the effect of aortic surgery by inserting a rigid graft on cardiac function in patients with MFS.

Methods

We selected all patients from our cohort who underwent aortic root replacement (AoRR). We retrospectively collected demographic and clinical data and we reviewed systolic and diastolic parameters on echocardiography at 3 different time points: before surgery, 6 months after surgery and during the last follow up.

Results

Thirty-three MFS patients underwent AoRR. Twenty-eight patients (84,9%) had and aortic valve sparing surgery (6 of which with associated aortoplasty). The rest underwent a Bentall procedure. Median aortic root before surgery was 52,5mm (IQR 49-56) and 13 patients (39,4%) had at least moderate aortic regurgitation. Median time of follow up was 5 years (IQR 2-10,5). Left ventricular end diastolic and systolic diameters (LVEDD, LVESD) decreased significantly during the first 6 months after surgery (56,75 vs 52,75mm; p<0,001 and 37,16 vs 32,16mm; p=0,018 respectively). At the last follow-up, LVEDD was similar to 6 months after surgery, but LVESD significantly increased (36,1mm, p= 0,02). Increase of LVESD lead to decreased left ventricular ejection fraction (LVEF) (59,57 at 6months vs 52,86% at follow-up, p=0,016). No changes in diastolic parameters were observed.

Right ventricular function was also affected by AoRR: TAPSE decreased after surgery to a suboptimal value and remained like this during follow-up (22,3mm before surgery, 17mm at 6m and 16,52mm during last FU, p< 0,001).

Conclusion

These results support the hypothesis that the placement of a rigid graft might influence cardiac function on long term. Our study is limited in the fact that it was retrospective and that no comparison group has been used.

References

  1.  
    Pyeritz RE. Marfan syndrome: 30 years of research equals 30 years of additional life expectancy. Heart. 2008 Nov 25;95(3):173-5.
  2.  
    De Backer JF, Devos D, Segers P, Matthys D, François K, Gillebert TC, et al Primary impairment of left ventricular function in Marfan syndrome. Int J Cardiol. 2006 Oct;112(3):353-8.
  3.  
    Alpendurada F, Wong J, Kiotsekoglou A, Banya W, Child A, Prasad SK, et al Evidence for Marfan cardiomyopathy. Eur J Heart Fail. 2010 Oct;12(10):1085-91.
  4.  
    Yetman AT, Bornemeier RA, McCrindle BW. Long-term outcome in patients with Marfan syndrome: is aortic dissection the only cause of sudden death? J Am Coll Cardiol. 2003;41(2):329-32.
  5.  
    Aydin A, Adsay BA, Sheikhzadeh S, Keyser B, Rybczynski M, Sondermann C, et al. Observational Cohort Study of Ventricular Arrhythmia in Adults with Marfan Syndrome Caused byFBN1 Mutations. Er F, editor. PLoS ONE. 2013 Dec 13;8(12):e81281.
  6.  
    Cook JR, Carta L, Bénard L, Chemaly ER, Chiu E, Rao SK, et al Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome. J Clin Invest [Internet]. 2014 Feb 17.
  7.  
    Campens L, Renard M, Trachet B, Segers P, Muino Mosquera L, De Sutter J, et al Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans. Pediatr Res. 2015 Sep;78(3):256-63.

CHOLESTEROL PRECURSORS IN PATIENTS WITH AAA

Prucha Miroslav, Sedivy Petr, Stadler Petr

Introduction

Abdominal aortic aneurysm (AAA) is a serious condition with unclear pathogenetic mechanism. One of the discussed factors involved in its pathogenesis is arteriosclerosis. We focused in our study on the detection of biomarker concentrations which are far more precise in monitoring the balance between cholesterol synthesis and absorption, namely campesterol, sitosterol and lanosterol as markers of cholesterol absorption, and desmosterol and lathosterol as markers of cholesterol synthesis.

Patients and Methods

We examined a total of 58 patients with AAA requiring surgery and 20 patients treated for lipid metabolism disorder without AAA in the control group. Demographic and clinical characteristics of both groups is shown in Table 1. The following parameters were examined by means of mass spectrometry: campesterol, sitosterol, lanosterol, desmosterol, and lathosterol. In addition, lipoprotein-associated phospholipase A2 (Lp-PLA2) and hsCRP serum concentrations were examined.

Results

The difference of Lp-PLA2 concentrations in both groups was not statistically significant. hsCRP concentration was significantly higher in the group of patients with AAA (p=0.007). No differences between both groups were found for cholesterol absorption markers - campesterol a sitosterol (p=0.96 and 0.65 respectively). By contrast, cholesterol synthesis markers - lanosterol, desmosterol and lathosterol - were significantly higher in the AAA group of patients as compared to the control group (p=0.004; p=0.0005 and p=0.0002 respectively, Table 1).

Conclusion

In the AAA group of patients, statistically significantly higher concentrations of hsCRP were detected as compared to the control group. Cholesterol synthesis markers were statistically significantly higher in the AAA group while cholesterol absorption markers were not statistically significantly different in both groups. It suggests an imbalance in cholesterol synthesis in patients with AAA and a potential possibility of targeted adjustment of hypercholesterolemia therapy in patients with AAA who are treated with statins.


GENE EXPRESSION SIGNATURE IN PATIENTS WITH ABDOMINAL AORTIC ANEURYSM

Prucha Miroslav, Sedivy Petr, Stadler Petr, Zdrahal Pavel

Introduction

Abdominal aortic aneurysm (AAA) is a serious condition with unclear pathogenetic mechanism and progression. Etiology is clearly multifactorial in nature and is being further investigated. In our study, we compared gene expression in abdominal aortic aneurysm tissue and unaffected tissue of the same patient.

Patients and Methods

A total of 48 patients with AAA in whom surgery was necessary were included into the study. Two samples (5x5 mm) of the entire arterial thickness were collected from each patient during AAA surgery. One sample was collected from the aneurysm at the site with the largest dilation seen macroscopically while the second sample was collected from the aneurysm neck where the tissue had no aneurysm changes. Subsequently, the gene expression profiles using microarryas (Illumina) were compared in RNA extracted from samples. Demographic and clinical characteristics of the patients is seen in Table1.

Results

Altogether, 2185 genes were found to be upregulated and 2100 downregulated. Analyzing the gene list based on the biological pathways they belong to and using Panther and Nature pathway revealed that regulation of „Inflammation mediated by chemokine and cytosine signaling pathway, „integrin signaling pathway“, „T and B cell activation“ were the the most important pathways.

Conclusion

We demonstrated different gene expression in the tissue with aneurysm changes and the sample of healthy vessel. The changes related to inflammation regulation by means of immunity mechanisms comprising T and B lymphocyte subpopulations. Understanding these mechanisms may potentially aid in better understanding etiopathogenetic mechanisms of aneurysm and its treatment.


THE NATURAL HISTORY OF A LARGE AORTA IS GREATER CARDIOVASCULAR RISK

Sidloff David, Saratzis Athanasios, Bown Matthew

Introduction

Ultrasound screening for AAA is cost effective and reduces AAA related mortality. Excess cardiovascular morbidity and mortality is well recognised in patients with AAA, however, AAA screening has no formal role in cardiovascular risk reduction which may be an opportunity missed.

Problem Definition

The aim of this study is to characterise the association of cardiovascular mortality with aortic diameter utilising a single screening cohort.

Work Summary

Consent was gained to analyse the NHS AAA screening cohort (2013-2014) and the UK Health Episode Statistics/Office for national statistics deaths dataset. Patients who did not attend screening were excluded. Data relating to maximum AP aortic diameter, study date, date of death and cause of death (ICD-10) were extracted. Cardiovascular death included those ICD codes pre-specified by the Global Burden of Disease studies. Relative risks were calculated to compare groups and log-rank survival analysis performed.

Results

240,954 patients were included and mean aortic diameter was 18mm (SD 3mm). 3,235 patients (1.34%) had a sub-aneurysmal aorta (25-29mm) and 2,981 (1.24%) had an AAA (>30mm). At three years 34 patients in the sub-aneurysmal group (1.1%, RR 2.25, 95% CI 1.61 – 3.14, P=0.0001) and 61 in the small AAA group (5.3%, RR 4.2 95%CI 3.34-5.47, P=0.0001) had a cardiovascular related death compared to those with a normal aorta (<24mm). Overall cardiovascular survival decreased with progressive aortic dilation (Figure 1, Log Rank P=0.0001).

Figure 1.

Cardiovascular survival from time of screening.

media/vol4/issue5/images/aorta-04-185-g014.jpg

Conclusion

The natural history of an enlarging aorta is progressive cardiovascular risk. Aortic screening is currently an opportunity missed to address this risk in those with and without AAA.

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Cite this article as: Sakalihasan N. 5th International Meeting on Aortic Diseases: New Insights into an Old Problem. AORTA (Stamford). 2016;4(5):185-218. DOI: 10.12945/j.aorta.2016.16.500

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