Publications by authors named "Jan D Blankensteijn"

81 Publications

ACTION-1: study protocol for a randomised controlled trial on ACT-guided heparinization during open abdominal aortic aneurysm repair.

Trials 2021 Sep 19;22(1):639. Epub 2021 Sep 19.

Department of Vascular Surgery, Dijklander ziekenhuis, Maelsonstraat 3, 1624, NP, Hoorn, The Netherlands.

Background: Heparin is used worldwide for 70 years during all non-cardiac arterial procedures (NCAP) to reduce thrombo-embolic complications (TEC). But heparin also increases blood loss causing possible harm for the patient. Heparin has an unpredictable effect in the individual patient. The activated clotting time (ACT) can measure the effect of heparin. Currently, this ACT is not measured during NCAP as the standard of care, contrary to during cardiac interventions, open and endovascular. A RCT will evaluate if ACT-guided heparinization results in less TEC than the current standard: a single bolus of 5000 IU of heparin and no measurements at all. A goal ACT of 200-220 s should be reached during ACT-guided heparinization and this should decrease (mortality caused by) TEC, while not increasing major bleeding complications. This RCT will be executed during open abdominal aortic aneurysm (AAA) surgery, as this is a standardized procedure throughout Europe.

Methods: Seven hundred fifty patients, who will undergo open AAA repair of an aneurysm originating below the superior mesenteric artery, will be randomised in 2 treatment arms: 5000 IU of heparin and no ACT measurements and no additional doses of heparin, or a protocol of 100 IU/kg bolus of heparin and ACT measurements after 5 min, and then every 30 min. The goal ACT is 200-220 s. If the ACT after 5 min is < 180 s, 60 IU/kg will be administered; if the ACT is between 180 and 200 s, 30 IU/kg. If the ACT is > 220 s, no extra heparin is given, and the ACT is measured after 30 min and then the same protocol is applied. The expected incidence for the combined endpoint of TEC and mortality is 19% for the 5000 IU group and 11% for the ACT-guided group.

Discussion: The ACTION-1 trial is an international RCT during open AAA surgery, designed to show superiority of ACT-guided heparinization compared to the current standard of a single bolus of 5000 IU of heparin. A significant reduction in TEC and mortality, without more major bleeding complications, must be proven with a relevant economic benefit. TRIAL REGISTRATION {2A}: NTR NL8421 ClinicalTrials.gov NCT04061798 . Registered on 20 August 2019 EudraCT 2018-003393-27 TRIAL REGISTRATION: DATA SET {2B}: Data category Information Primary registry and trial identifying number ClinicalTrials.gov : NCT04061798 Date of registration in primary registry 20-08-2019 Secondary identifying numbers NTR: NL8421 EudraCT: 2018-003393-27 Source(s) of monetary or material support ZonMw: The Netherlands Organisation for Health Research and Development Dijklander Ziekenhuis Amsterdam UMC Primary sponsor Dijklander Ziekenhuis Secondary sponsor(s) N/A Contact for public queries A.M. Wiersema, MD, PhD [email protected] 0031-229 208 206 Contact for scientific queries A.M. Wiersema, MD, PhD [email protected] 0031-229 208 206 Public title ACT Guided Heparinization During Open Abdominal Aortic Aneurysm Repair (ACTION-1) Scientific title ACTION-1: ACT Guided Heparinization During Open Abdominal Aortic Aneurysm Repair, a Randomised Trial Countries of recruitment The Netherlands. Soon the recruitment will start in Germany Health condition(s) or problem(s) studied Abdominal aortic aneurysm, arterial disease, surgery Intervention(s) ACT-guided heparinization 5000 IU of heparin Key inclusion and exclusion criteria Ages eligible for the study: ≥18 years Sexes eligible for the study: both Accepts healthy volunteers: no Inclusion criteria: Study type Interventional Allocation: randomized Intervention model: parallel assignment Masking: single blind (patient) Primary purpose: treatment Phase IV Date of first enrolment March 2020 Target sample size 750 Recruitment status Recruiting Primary outcome(s) The primary efficacy endpoint is 30-day mortality and in-hospital mortality during the same admission. The primary safety endpoint is the incidence of bleeding complications according to E-CABG classification, grade 1 and higher. Key secondary outcomes Serious complications as depicted in the Suggested Standards for Reports on Aneurysmal disease: all complications requiring re-operation, longer hospital stay, all complications.
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http://dx.doi.org/10.1186/s13063-021-05552-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449992PMC
September 2021

Results from a nationwide prospective registry on open surgical or endovascular repair of juxtarenal abdominal aortic aneurysms.

J Vasc Surg 2021 Jun 29. Epub 2021 Jun 29.

Division of Vascular Surgery, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Juxtarenal abdominal aortic aneurysms (JRAAAs) can be treated either with open surgical repair (OSR) including suprarenal clamping or by complex endovascular aneurysm repair (cEVAR). In this study, we present the comparison between the short-term mortality and complications of the elective JRAAA treatment modalities from a national database reflecting daily practice in the Netherlands.

Methods: All patients undergoing elective JRAAA open repair or cEVAR (fenestrated EVAR or chimney EVAR) between January 2016 and December 2018 registered in the Dutch Surgical Aneurysm Audit (DSAA) were eligible for inclusion. Descriptive perioperative variables and outcomes were compared between patients treated with open surgery or endovascularly. Adjusted odds ratios for short-term outcomes were calculated by logistic regression analysis.

Results: In all, 455 primary treated patients with JRAAAs could be included (258 OSR, 197 cEVAR). Younger patients and female patients were treated more often with OSR vs cEVAR (72 ± 6.1 vs 76 ± 6.0; P < .001 and 22% vs 15%; P = .047, respectively). Patients treated with OSR had significantly more major and minor complications as well as a higher chance of early mortality (OSR vs cEVAR, 45% vs 21%; P < .001; 34% vs 23%; P = .011; and 6.6% vs 2.5%; P = .046, respectively). After logistic regression with adjustment for confounders, patients who were treated with OSR showed an odds ratio of 3.64 (95% confidence interval [CI], 2.25-5.89; P < .001) for major complications compared with patients treated with cEVAR, and for minor complications, the odds ratios were 2.17 (95% CI, 1.34-3.53; P = .002) higher. For early mortality, the odds ratios were 3.79 (95% CI, 1.26-11.34; P = .017) higher after OSR compared with cEVAR.

Conclusions: In this study, after primary elective OSR for JRAAA, the odds for major complications, minor complications, and short-term mortality were significantly higher compared with cEVAR.
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http://dx.doi.org/10.1016/j.jvs.2021.06.031DOI Listing
June 2021

More Effective Anticoagulation During Non-Cardiac Arterial Procedures Using Activated Clotting Time Guided Heparin Administration.

Ann Vasc Surg 2021 May 3. Epub 2021 May 3.

Department of Vascular Surgery, Dijklander Ziekenhuis, Hoorn, the Netherlands; Department of Vascular Surgery, Amsterdam University Medical Centers (Amsterdam UMC) location VU Medical Center, Amsterdam, the Netherlands.

Objectives: Arterial thrombo-embolic complications (ATEC) are still common during and after non-cardiac arterial procedures (NCAP) despite the administration of (a fixed bolus of) heparin. These ATEC could be due to existing individual differences in heparin sensitivity. The purpose of this study was to evaluate the feasibility and safety of an ACT guided heparin dose protocol and to evaluate if a more effective target ACT can be achieved during NCAP.

Methods: In this multi-center prospective study, 194 patients undergoing elective and non-elective NCAP were enrolled and received heparin according to a heparin dose protocol which aimed to obtain a target ACT of 250 seconds (s.), measured by the Medtronic HMS Plus. Patients received a standardized bolus of 5 000 IU followed by additional boluses depending on the actual ACT. Primary outcome was the ACT value reached. Secondary outcomes were incidence of all ATEC and haemorrhagic complications.

Results: The mean baseline ACT was 138 ± 17 s. The mean ACT five minutes after the initial heparin bolus of 5 000 IU was 197 ± 31 s. 48% of patients reached an ACT of 200 s. and six per cent of patients reached an ACT of 250 s. Additional dosages of heparin were administered in 72% of patients. With this ACT guided heparin protocol 86% of patients reached an ACT of 200 s. and 26% of patients reached an ACT of 250 s. A negative correlation was found between body weight and the ACT at T1 (P ˂ 0.001). ATEC and haemorrhagic complications occurred in 11.3% and 16.5% of patients. The lowest incidence of ATEC was found in patients with peak ACT between 200 and 250 s, namely 6.3%.

Conclusion: This ACT guided heparin protocol proved to be feasible, safe and more patients reached an ACT > of 200 s. compared to a standardized heparin bolus of 5 000 IU. Further research is needed to investigate if ACT guided heparin administration could be preferable over not monitoring the anticoagulant effect of peri-procedural heparin and results in a lower incidence of ATEC, without an increase in haemorrhagic complications.
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http://dx.doi.org/10.1016/j.avsg.2021.04.023DOI Listing
May 2021

Systematic review of embolization of type I endoleaks using liquid embolic agents.

J Vasc Surg 2021 09 1;74(3):1024-1032. Epub 2021 May 1.

Department of Vascular Surgery, Amsterdam University Medical Center, Location VUmc, Amsterdam, Zaandam, The Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Location VUmc, Amsterdam, Zaandam, The Netherlands. Electronic address:

Objective: The long-term success of endovascular aneurysm repair (EVAR) is limited by complications, most importantly endoleaks. In case of (persistent) type I endoleak (T1EL), secondary intervention is indicated to prevent secondary aneurysm rupture. Different treatment options are suggested for T1ELs, such as endo anchors, (fenestrated) cuffs, embolization, or open conversion. Currently, the treatment of T1EL with liquid embolic agents is available; however, results are not yet addressed. This review presents the safety and efficacy of embolization with liquid embolic agents for treatment of T1ELs after EVAR.

Methods: A systematic literature search was performed for all studies reporting the use of liquid embolic agents as monotherapy for treatment of T1ELs after EVAR. Patient numbers, technical success (successful delivery of liquid embolics in the T1EL) and clinical success (absence of aneurysm related death, endoleak recurrence or additional interventions during follow-up) were examined.

Results: Of 1604 articles, 10 studies met the selection criteria, including 194 patients treated with liquid embolics; 73.2% of the patients were male with a median age of 71 years. The overall technical success was 97.9%. Clinical success was 87.6%. Because the median follow-up was only 13.0 months (range, 1-89 months), data on long-term success are almost absent. Four cases (2.1%) of secondary aneurysm rupture after embolization owing to endoleak recurrence were reported. All ruptures occurred in aneurysms exceeding initial treatment diameter of 70 mm.

Conclusions: Initial technical success after liquid embolization for T1EL is high, although long-term clinical success rates are lacking. Within this review, the risk of secondary rupture is comparable with untreated T1EL at 2% with a median follow-up of 13 months, regardless of the initial success of embolization. In general, no decrease in secondary aneurysm rupture after embolization of T1EL after EVAR is demonstrated, although the results of late embolization are debated.
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http://dx.doi.org/10.1016/j.jvs.2021.03.061DOI Listing
September 2021

Patient-Specific 3-Dimensional Model of Smooth Muscle Cell and Extracellular Matrix Dysfunction for the Study of Aortic Aneurysms.

J Endovasc Ther 2021 08 26;28(4):604-613. Epub 2021 Apr 26.

Amsterdam Cardiovascular Sciences, Department of Vascular Surgery, Amsterdam University Medical Centers, Location VUmc, Amsterdam, The Netherlands.

Introduction: Abdominal aortic aneurysms (AAAs) are associated with overall high mortality in case of rupture. Since the pathophysiology is unclear, no adequate pharmacological therapy exists. Smooth muscle cells (SMCs) dysfunction and extracellular matrix (ECM) degradation have been proposed as underlying causes. We investigated SMC spatial organization and SMC-ECM interactions in our novel 3-dimensional (3D) vascular model. We validated our model for future use by comparing it to existing 2-dimensional (2D) cell culture. Our model can be used for translational studies of SMC and their role in AAA pathophysiology.

Materials And Methods: SMC isolated from the medial layer of were the aortic wall of controls and AAA patients seeded on electrospun poly-lactide--glycolide scaffolds and cultured for 5 weeks, after which endothelial cells (EC) are added. Cell morphology, orientation, mechanical properties and ECM production were quantified for validation and comparison between controls and patients.

Results: We show that cultured SMC proliferate into multiple layers after 5 weeks in culture and produce ECM proteins, mimicking their behavior in the medial aortic layer. EC attach to multilayered SMC, mimicking layer interactions. The novel SMC model exhibits viscoelastic properties comparable to biological vessels; cytoskeletal organization increases during the 5 weeks in culture; increased cytoskeletal alignment and decreased ECM production indicate different organization of AAA patients' cells compared with control.

Conclusion: We present a valuable preclinical model of AAA constructed with patient specific cells with applications in both translational research and therapeutic developments. We observed SMC spatial reorganization in a time course of 5 weeks in our robust, patient-specific model of SMC-EC organization and ECM production.
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http://dx.doi.org/10.1177/15266028211009272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276336PMC
August 2021

Inflammatory Gene Expression of Human Perivascular Adipose Tissue in Abdominal Aortic Aneurysms.

Eur J Vasc Endovasc Surg 2021 06 12;61(6):1008-1016. Epub 2021 Apr 12.

Department of Vascular Surgery, Amsterdam University Medical Centres, location VUmc, Amsterdam, the Netherlands; Department of Physiology, Amsterdam University Medical Centres, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands; Department of Vascular Surgery, Amsterdam University Medical Centres, location AMC, Amsterdam, the Netherlands. Electronic address:

Objective: Perivascular adipose tissue (PVAT) contributes to vascular homeostasis and is increasingly linked to vascular pathology. PVAT density and volume were associated with abdominal aortic aneurysm (AAA) presence and dimensions on imaging. However, mechanisms underlying the role of PVAT in AAA have not been clarified. This study aimed to explore differences in PVAT from AAA using gene expression and functional tests.

Methods: Human aortic PVAT and control subcutaneous adipose tissue were collected during open AAA surgery. Gene analyses and functional tests were performed. The control group consisted of healthy aorta from non-living renal transplant donors. Gene expression tests were performed to study genes potentially involved in various inflammatory processes and AAA related genes. Live PVAT and subcutaneous adipose tissue (SAT) from AAA were used for ex vivo co-culture with smooth muscle cells (SMCs) retrieved from non-pathological aortas.

Results: Adipose tissue was harvested from 27 AAA patients (n [gene expression] = 22, n [functional tests] = 5) and five control patients. An increased inflammatory gene expression of PTPRC (p = .008), CXCL8 (p = .033), LCK (p = .003), CCL5 (p = .004) and an increase in extracellular matrix breakdown marker MMP9 (p = .016) were found in AAA compared with controls. Also, there was a decreased anti-inflammatory gene expression of PPARG in AAA compared with controls (p = .040). SMC co-cultures from non-pathological aortas with PVAT from AAA showed increased MMP9 (p = .033) and SMTN (p = .008) expression and SAT increased SMTN expression in these SMC.

Conclusion: The data revealed that PVAT from AAA shows an increased pro-inflammatory and matrix metallopeptidase gene expression and decreased anti-inflammatory gene expression. Furthermore, increased expression of genes involved in aneurysm formation was found in healthy SMC co-culture with PVAT of AAA patients. Therefore, PVAT from AAA might contribute to inflammation of the adjacent aortic wall and thereby plays a possible role in AAA pathophysiology. These proposed pathways of inflammatory induction could reveal new therapeutic targets in AAA treatment.
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http://dx.doi.org/10.1016/j.ejvs.2021.02.034DOI Listing
June 2021

Image Fusion During Standard and Complex Endovascular Aortic Repair, to Fuse or Not to Fuse? A Meta-analysis and Additional Data From a Single-Center Retrospective Cohort.

J Endovasc Ther 2021 Feb 23;28(1):78-92. Epub 2020 Sep 23.

Department of Surgery, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands.

Purpose: To determine if image fusion will reduce contrast volume, radiation dose, and fluoroscopy and procedure times in standard and complex (fenestrated/branched) endovascular aneurysm repair (EVAR).

Materials And Methods: A search of the PubMed, Embase, and Cochrane databases was performed in December 2019 to identify articles describing results of standard and complex EVAR procedures using image fusion compared with a control group. Study selection, data extraction, and assessment of the methodological quality of the included publications were performed by 2 reviewers working independently. Primary outcomes of the pooled analysis were contrast volume, fluoroscopy time, radiation dose, and procedure time. Eleven articles were identified comprising 1547 patients. Data on 140 patients satisfying the study inclusion criteria were added from the authors' center. Mean differences (MDs) are presented with the 95% confidence interval (CI).

Results: For standard EVAR, contrast volume and procedure time showed a significant reduction with an MD of -29 mL (95% CI -40.5 to -18.5, p<0.001) and -11 minutes (95% CI -21.0 to -1.8, p<0.01), respectively. For complex EVAR, significant reductions in favor of image fusion were found for contrast volume (MD -79 mL, 95% CI -105.7 to -52.4, p<0.001), fluoroscopy time (MD -14 minutes, 95% CI -24.2 to -3.5, p<0.001), and procedure time (MD -52 minutes, 95% CI -75.7 to -27.9, p<0.001).

Conclusion: The results of this meta-analysis confirm that image fusion significantly reduces contrast volume, fluoroscopy time, and procedure time in complex EVAR but only contrast volume and procedure time for standard EVAR. Though a reduction was suggested, the radiation dose was not significantly affected by the use of fusion imaging in either standard or complex EVAR.
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http://dx.doi.org/10.1177/1526602820960444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816548PMC
February 2021

A Standardized Bolus of 5 000 IU of Heparin Does not Lead to Adequate Heparinization during Non-cardiac Arterial Procedures.

Ann Vasc Surg 2021 Feb 6;71:280-287. Epub 2020 Aug 6.

Department of Vascular Surgery, Dijklander Ziekenhuis, Hoorn, the Netherlands; Department of Vascular Surgery, Amsterdam University Medical Centers location VU Medical Center, Amsterdam, the Netherlands.

Background: In non-cardiac arterial procedures (NCAP), heparin is administered to prevent arterial thromboembolic complications (ATEC). Heparin has a nonpredictable effect in the individual patient, also known as variation in heparin sensitivity. Various dosing protocols are in use, but the optimal dose is currently still unknown. A standardized bolus of 5 000 IU heparin is most frequently used by vascular surgeons and interventional radiologists. The activated clotting time (ACT) is an established method to measure the level of anticoagulation, but has, until now, not gained widespread use in NCAP. The purpose of this study was to evaluate the anticoagulant effect during NCAP of a standardized bolus of 5 000 IU heparin by measuring the ACT.

Methods: In this prospective study, 190 patients undergoing NCAP were enrolled between December 2016 and September 2018. The ACT was measured during open and endovascular/hybrid procedures. All patients received a standardized bolus of 5 000 IU heparin. The ACT was measured by the Hemostasis Management System Plus (HMS Plus, Medtronic®), before, 5 minutes after administration of heparin, and every 30 minutes thereafter. The primary outcome was periprocedural ACT values measured. Secondary outcomes were ATEC and hemorrhagic complications.

Results: A large individual patient variability in the response to heparin was found. The mean baseline ACT in all patients was 129 ± 18 s., and the mean ACT 5 minutes after the initial bolus of heparin was 191 ± 36 s. After the initial dose of 5 000 IU heparin 60 (33%) and 10 (6%) patients reached an ACT of 200 and 250 s., respectively. Despite the use of heparin, ATEC occurred in 17 patients (9%). The lowest number of ATEC occurred in the group of patients with an ACT between 200 and 250 s.

Conclusions: A standardized bolus of 5 000 IU heparin does not lead to adequate and safe heparinization in non-cardiac arterial procedures. Patient response to heparin shows a large individual variability. Therefore, routine ACT measurements are necessary to ascertain adequate anticoagulation. Further research is needed to investigate if heparin dosing based on the ACT could result in less arterial thromboembolic complications, without increasing hemorrhagic complications.
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http://dx.doi.org/10.1016/j.avsg.2020.07.035DOI Listing
February 2021

Gutter Characteristics and Stent Compression of Self-Expanding vs Balloon-Expandable Chimney Grafts in Juxtarenal Aneurysm Models.

J Endovasc Ther 2020 Jun 21;27(3):452-461. Epub 2020 Apr 21.

Department of Vascular Surgery, Amsterdam University Medical Centers, VU Medical Center, Amsterdam, the Netherlands.

To assess in silicone juxtarenal aneurysm models the gutter characteristics and compression of different types of chimney graft (CG) configurations. Fifty-seven combinations of Excluder C3 or Conformable Excluder stent-grafts (23, 26, and 28.5 mm) were deployed in 2 silicone juxtarenal aneurysm models with 3 types of CGs: Viabahn self-expanding (VSE; 6 and 13 mm) or Viabahn balloon-expandable (VBX; 6, 10, and 12 mm) stent-grafts and Advanta V12 balloon-expandable stent-grafts (ABX; 6 and 12 mm). Setups were divided into 4 groups on the basis of increasing CG and main graft (MG) diameters. Two independent observers assessed gutter size and type as well as CG compression on computed tomography scans using postprocessing software. In the smaller diameter combinations (6-mm CG and 23-, 26-, and 28.5-mm MGs), both VSE (p=0.006 to 0.050) and ABX (p=0.045 to 0.050) showed lower gutter areas and volumes compared with VBX. In turn, the VBX showed a nonsignificant tendency to decreased compression, especially compared to ABX. Use of the Excluder C3 showed a 6-fold increase in type A1 gutters (related to type Ia endoleak) as compared to the Conformable Excluder (p=0.018). Balloon-expandable stent-grafts (both ABX and VBX) showed a 3-fold increase in type A1 gutters in comparison with self-expanding stent-grafts (p=0.008). The current study suggests that use of the Conformable Excluder in combination with VSE chimney grafts is superior to the other tested CG/MG combinations in terms of gutter size, gutter type, and CG compression.
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http://dx.doi.org/10.1177/1526602820915262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288858PMC
June 2020

No Concluding Evidence on Optimal Activated Clotting Time for Non-cardiac Arterial Procedures.

Eur J Vasc Endovasc Surg 2020 01 4;59(1):137-147. Epub 2019 Nov 4.

Department of Vascular Surgery, Dijklander Ziekenhuis, Hoorn, the Netherlands; Department of Vascular Surgery, Amsterdam University Medical Centres (Amsterdam UMC) Location VU Medical Centre (VUMC), Amsterdam, the Netherlands.

Objectives: Heparin has a non-predictable effect in the individual patient. The activated clotting time (ACT) is used to measure the level of anticoagulation after administration of heparin. To date, appropriate heparin dose protocols and corresponding therapeutic ACT values have not been established in non-cardiac arterial procedures (NCAP). The aim of this review was to study the use of ACT monitoring during NCAP, and whether an optimal ACT could be determined based on the fewest arterial thrombo-embolic complications (ATEC) and bleeding complications.

Methods: This systematic review was performed in accordance with the PRISMA Guidelines. A systematic search was conducted in MEDLINE, EMBASE, and the Cochrane database. Any associations were evaluated between peri-procedural ACT levels and ATEC and bleeding complications detected during the same admission as the primary procedure or during 30 day follow up. Also, heparin dose protocols, peri-procedural target ACTs, different ACT devices, protamine use and pre-, peri-, and post-procedural anticoagulation therapy were evaluated.

Results: In total, 21 studies with 3982 patients were included, on both open and endovascular NCAP. Four studies were primarily designed to correlate peak peri-procedural ACT with clinical outcomes; however, the definitions of the results and the clinical outcomes were too heterogeneous for analysis. There was major variability in all studied aspects of ACT measurement, heparin and protamine use, and in the type of procedures in the included studies. Overall methodological quality of the included studies was poor. No randomised controlled trials were found. Studies were at a high risk of bias.

Conclusions: This systematic review demonstrates a lack of data and no consensus in the literature concerning the optimal ACT, and the possible association with haemorrhagic complications and ATEC during NCAP.
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http://dx.doi.org/10.1016/j.ejvs.2019.08.007DOI Listing
January 2020

Design and protocol of a comprehensive multicentre biobank for abdominal aortic aneurysms.

BMJ Open 2019 08 1;9(8):e028858. Epub 2019 Aug 1.

Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Introduction: The pathophysiology and natural course of abdominal aortic aneurysms (AAAs) are insufficiently understood. In order to improve our understanding, it is imperative to carry out longitudinal research that combines biomarkers with clinical and imaging data measured over multiple time points. Therefore, a multicentre biobank, databank and imagebank has been established in the Netherlands: the '' (AAA bank).

Methods And Analysis: The AAA bank is a prospective multicentre observational biobank, databank and imagebank of patients with an AAA. It is embedded within the framework of the Parelsnoer Institute, which facilitates uniform biobanking in all university medical centres (UMCs) in the Netherlands. The AAA bank has been initiated by the two UMCs of Amsterdam UMC and by Leiden University Medical Center. Participants will be followed during AAA follow-up. Clinical data are collected every patient contact. Three types of biomaterials are collected at baseline and during follow-up: blood (including DNA and RNA), urine and AAA tissue if open surgical repair is performed. Imaging data that are obtained as part of clinical care are stored in the imagebank. All data and biomaterials are processed and stored in a standardised manner. AAA growth will be based on multiple measurements and will be analysed with a repeated measures analysis. Potential associations between AAA growth and risk factors that are also measured on multiple time points can be assessed with multivariable mixed-effects models, while potential associations between AAA rupture and risk factors can be tested with a conditional dynamic prediction model with landmarking or with joint models in which linear mixed-effects models are combined with Cox regression.

Ethics And Dissemination: The AAA bank is approved by the Medical Ethics Board of the Amsterdam UMC (University of Amsterdam).

Trial Registration Number: NCT03320408.
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http://dx.doi.org/10.1136/bmjopen-2018-028858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688677PMC
August 2019

A multilayer micromechanical elastic modulus measuring method in ex vivo human aneurysmal abdominal aortas.

Acta Biomater 2019 09 12;96:345-353. Epub 2019 Jul 12.

Department of Vascular Surgery, Amsterdam University Medical Centers, Location VU Medical Center, Amsterdam, The Netherlands; Department of Physiology, Amsterdam University Medical Centers, Location VU Medical Center, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands. Electronic address:

Abdominal aortic aneurysms (AAA) are common and potentially life-threatening aortic dilatations, due to the effect of hemodynamic changes on the aortic wall. Previous research has shown a potential pathophysiological role for increased macroscopic aneurysmal wall stiffness; however, not investigating micromechanical stiffness. We aimed to compile a new protocol to examine micromechanical live aortic stiffness (elastic moduli), correlated to histological findings with quantitative immunofluorescence (QIF). Live AAA biopsies (n = 7) and non-dilated aortas (controls; n = 3) were sectioned. Local elastic moduli of aortic intima, media and adventitia were analysed in the direction towards the lumen and vice versa with nanoindentation. Smooth muscle cells (SMC), collagen and fibroblasts were examined using QIF. Nanoindentation of AAA vs. controls demonstrated a 4-fold decrease in elastic moduli (p = 0.022) for layers combined and a 26-fold decrease (p = 0.017) for media-to-intima direction. QIF of AAA vs. controls revealed a 4-, 3- and 6-fold decrease of SMC, collagen and fibroblasts, respectively (p = 0.036). Correlations were found between bidirectional intima and media measurements (ρ = 0.661, p = 0.038) and all QIF analyses (ρ = 0.857-0.905, p = 0.002-0.007). We present a novel protocol to analyse microscopic elastic moduli in live aortic tissues using nanoindentation. Hence, our preliminary findings of decreased elastic moduli and altered wall composition warrant further microscopic stiffness investigation to potentially clarify AAA pathophysiology and to explore potential treatment by wall strengthening. STATEMENT OF SIGNIFICANCE: Although extensive research on the pathophysiology of dilated abdominal aortas (aneurysms) has been performed, the exact underlying pathways are still largely unclear. Previously, the macroscopic stiffness of the pathologic and healthy aortic wall has been studied. This study however, for the first time, studied the microscopic stiffness changes in live tissue of dilated and non-dilated abdominal aortas. This new protocol provides a device to analyse the alterations on cellular level within their microenvironment, whereas previous studies studied the aorta as a whole. Outcomes of these measurements might help to better understand the underlying origin of the incidence and progression of aneurysms and other aortic diseases.
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http://dx.doi.org/10.1016/j.actbio.2019.07.019DOI Listing
September 2019

Impaired smooth muscle cell contractility as a novel concept of abdominal aortic aneurysm pathophysiology.

Sci Rep 2019 05 2;9(1):6837. Epub 2019 May 2.

Departments of Vascular Surgery, Amsterdam University Medical Centers, location VU University Medical center, Amsterdam, The Netherlands.

Ruptured abdominal aortic aneurysms (AAA) are associated with overall mortality rates up to 90%. Despite extensive research, mechanisms leading to AAA formation and advancement are still poorly understood. Smooth muscle cells (SMC) are predominant in the aortic medial layer and maintain the wall structure. Apoptosis of SMC is a well-known phenomenon in the pathophysiology of AAA. However, remaining SMC function is less extensively studied. The aim of this study is to assess the in vitro contractility of human AAA and non-pathologic aortic SMC. Biopsies were perioperatively harvested from AAA patients (n = 21) and controls (n = 6) and clinical data were collected. Contractility was measured using Electric Cell-substrate Impedance Sensing (ECIS) upon ionomycin stimulation. Additionally, SMC of 23% (5 out of 21) of AAA patients showed impaired maximum contraction compared to controls. Also, SMC from patients who underwent open repair after earlier endovascular repair and SMC from current smokers showed decreased maximum contraction vs. controls (p = 0.050 and p = 0.030, respectively). Our application of ECIS can be used to study contractility in other vascular diseases. Finally, our study provides with first proof that impaired SMC contractility might play a role in AAA pathophysiology.
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http://dx.doi.org/10.1038/s41598-019-43322-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497672PMC
May 2019

Secondary Fill Minimizes Gutter Size in Chimney EVAS Configurations In Vitro.

J Endovasc Ther 2019 02 21;26(1):62-71. Epub 2018 Dec 21.

1 Department of Vascular Surgery, VU University Medical Center, Amsterdam, the Netherlands.

Purpose: To investigate in an in vitro model if secondary endobag filling can reduce gutter size during chimney endovascular aneurysm sealing (chEVAS).

Materials And Methods: Nellix EVAS systems were deployed in 2 silicone juxtarenal aneurysm models with suprarenal aortic diameters of 19 and 24 mm. Four configurations were tested: EVAS with 6-mm balloon-expandable (BE) or self-expanding (SE) chimney grafts (CGs) in the renal branches of both models. Balloons were inflated simultaneously in the CGs and main endografts during primary and secondary endobag filling and polymer curing. Computed tomography (CT) was performed immediately after the primary and secondary fills. Cross-sectional lumen areas were measured on the CT images to calculate gutter volumes and percent change. CG compression was calculated as the reduction in lumen surface area measured perpendicular to the central lumen line. The largest gutter volume and highest compression were presented per CG configuration per model.

Results: Secondary endobag filling reduced the largest gutter volumes from 99.4 to 73.1 mm (13.2% change) and 84.2 to 72.0 mm (27.6% change) in the BECG configurations and from 67.2 to 44.0 mm (34.5% change) and 92.7 to 82.3 mm (11.2% change) in the SECG configurations in the 19- and 24-mm models, respectively. Secondary endobag filling increased CG compression in 6 of 8 configurations. BECG compression changed by -0.2% and 5.4% and by -1.0% and 0.4% in the 19- and 24-mm models, respectively. SECG compression changed by 10.2% and 16.0% and by 7.2% and 7.3% in the 19- and 24-mm models, respectively.

Conclusion: Secondary endobag filling reduced paragraft gutters; however, this technique did not obliterate them. Increased CG compression and prolonged renal ischemia time should be considered if secondary endobag filling is used.
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http://dx.doi.org/10.1177/1526602818819494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330694PMC
February 2019

Aortic neck dilation is not associated with adverse outcomes after fenestrated endovascular aneurysm repair.

J Vasc Surg 2019 Apr 6;69(4):1059-1065. Epub 2018 Oct 6.

Division of Vascular Surgery, Harborview Medical Center-University of Washington, Seattle, Wash.

Objective: Long-term outcomes after endovascular aneurysm repair (EVAR) are threatened by aortic neck dilation (AND), graft migration, and subsequent endoleak development. The aim of this study was to determine the rate of AND and the occurrence of endoleaks after fenestrated EVAR of juxtarenal aneurysms with physician-modified endovascular grafts (PMEGs).

Methods: The study included 77 patients presenting with asymptomatic and ruptured juxtarenal abdominal aortic aneurysms treated with PMEGs who received radiologic follow-up. Analysis of computed tomography images took place on a three-dimensional workstation (TeraRecon, San Mateo, Calif). Aortic neck diameter was measured before and after EVAR at the lowest patent renal artery outer wall to outer wall. Significant AND was defined as >3-mm increase between baseline and follow-up, and sac regression >5 mm was considered significant. The patient's 1-month initial postoperative computed tomography measurement was considered baseline. The rate of AND was measured by comparing the baseline measurement with measurements at 6 months, 12 months, and annually thereafter up to 4 years.

Results: In this cohort of patients, 75% were men with a mean age of 74 ± 7.9 years. Median preoperative aneurysm size was 62 (57-73) mm, and median follow-up was 12 (3.5-30) months. Mean endograft oversizing was 17% ± 12.5%, and mean seal zone length was 41 ± 11 mm. At 1-year follow-up, the median aortic neck increase was 1.7 (0-3) mm. Maximum aneurysm size decreased dramatically during the first postoperative year, with significant sac regression in 65% of the patients. Aortic neck diameter at 1 year did correlate positively with the percentage of device oversizing. No other correlations were found. During the 4-year follow-up, there were no cases of type IA endoleaks.

Conclusions: AND does not influence outcome after endovascular repair of juxtarenal aneurysms using PMEGs. These midterm results support the applicability of PMEGs in juxtarenal aneurysm repair.
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http://dx.doi.org/10.1016/j.jvs.2018.07.037DOI Listing
April 2019

High Density of Periaortic Adipose Tissue in Abdominal Aortic Aneurysm.

Eur J Vasc Endovasc Surg 2018 Nov 14;56(5):663-671. Epub 2018 Aug 14.

Department of Vascular Surgery, VU University Medical Centre, Amsterdam, The Netherlands; Department of Physiology (Amsterdam Cardiovascular Sciences) VU University Medical Centre, Amsterdam, The Netherlands. Electronic address:

Objectives: Perivascular adipose tissue (PVAT) is currently seen as a paracrine organ that produces vasoactive substances, including inflammatory agents, which may have an impact on the vasculature. In this study PVAT density was quantified in patients with an aortic aneurysm and compared with those with a non-dilated aorta. Since chronic inflammation, as the pathway to medial thinning, is a hallmark of abdominal aortic aneurysms (AAAs), it was hypothesised that PVAT density is higher in AAA patients.

Methods: In this multicentre retrospective case control study, three groups of patients were included: non-treated asymptomatic AAA (n = 140), aortoiliac occlusive disease (AIOD) (n = 104), and individuals without aortic pathology (n = 97). A Hounsfield units based analysis was performed by computed tomography (CT). As a proxy for PVAT, the density of adipose tissue 10 mm circumferential to the infrarenal aorta was analysed in each consecutive CT slice. Intra-individual PVAT differences were reported as the difference in PVAT density between the region of the maximum AAA diameter (or the mid-aortic region in patients with AIOD or controls) and the two uppermost slices of infrarenal non-dilated aorta just below the renal arteries. Furthermore, subcutaneous (SAT) and visceral (VAT) adipose tissue measurements were performed. Linear models were fitted to assess the association between the study groups, different adipose tissue compartments, and between adipose tissue compartments and aortic dimensions.

Results: AAA patients presented higher intra-individual PVAT differences, with higher PVAT density around the aneurysm sac than the healthy neck. This association persisted after adjustment for cardiovascular risk factors and diseases and other fat compartments (β = 13.175, SE 4.732, p = .006). Furthermore, intra-individual PVAT differences presented the highest correlation with aortic volume that persisted after adjustment for other fat compartments, body mass index, sex, and age (β = 0.566, 0.200, p = .005).

Conclusion: The results suggest a relation between the deposition of PVAT and AAA pathophysiology. Further research should explore the exact underlying processes.
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http://dx.doi.org/10.1016/j.ejvs.2018.07.008DOI Listing
November 2018

An in vitro method to keep human aortic tissue sections functionally and structurally intact.

Sci Rep 2018 05 25;8(1):8094. Epub 2018 May 25.

VU University Medical Center, Department of Vascular Surgery, Amsterdam, The Netherlands.

The pathophysiology of aortic aneurysms (AA) is far from being understood. One reason for this lack of understanding is basic research being constrained to fixated cells or isolated cell cultures, by which cell-to-cell and cell-to-matrix communications are missed. We present a new, in vitro method for extended preservation of aortic wall sections to study pathophysiological processes. Intraoperatively harvested, live aortic specimens were cut into 150 μm sections and cultured. Viability was quantified up to 92 days using immunofluorescence. Cell types were characterized using immunostaining. After 14 days, individual cells of enzymatically digested tissues were examined for cell type and viability. Analysis of AA sections (N = 8) showed a viability of 40% at 7 days and smooth muscle cells, leukocytes, and macrophages were observed. Protocol optimization (N = 4) showed higher stable viability at day 62 and proliferation of new cells at day 92. Digested tissues showed different cell types and a viability up to 75% at day 14. Aortic tissue viability can be preserved until at least 62 days after harvesting. Cultured tissues can be digested into viable single cells for additional techniques. Present protocol provides an appropriate ex vivo setting to discover and study pathways and mechanisms in cultured human aneurysmal aortic tissue.
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http://dx.doi.org/10.1038/s41598-018-26549-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970251PMC
May 2018

Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis.

JAMA Cardiol 2018 01;3(1):26-33

Department of Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, England.

Importance: Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease.

Objective: To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk.

Design, Setting, And Participants: Genetic risk scores, composed of lipid trait-associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016.

Exposures: Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG).

Main Outcomes And Measures: The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk.

Results: Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95% CI, 1.41-1.96; P = 1.1 × 10-9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95% CI, 0.55-0.82; P = 8.3 × 10-5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95% CI, 1.38-2.07; P = 5.2 × 10-7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C-reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95% CI, 0.89-0.98; P = .009). The HDL-C-raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95% CI, 0.85-0.94; P = 3.7 × 10-7). Finally, the LDL-C-lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95% CI, 0.88-1.00; P = .04), but a second independent LDL-C-lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95% CI, 0.92-1.02; P = .28).

Conclusions And Relevance: The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA.
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http://dx.doi.org/10.1001/jamacardio.2017.4293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833524PMC
January 2018

Long-term survival and secondary procedures after open or endovascular repair of abdominal aortic aneurysms.

J Vasc Surg 2017 11;66(5):1379-1389

Division of Vascular Surgery, Department of Surgery, VU Medical Center, Amsterdam, The Netherlands. Electronic address:

Objective: Randomized trials have shown an initial survival benefit of endovascular over conventional open abdominal aortic aneurysm repair but no long-term difference up to 6 years after repair. Longer follow-up may be required to demonstrate the cumulative negative impact on survival of higher reintervention rates associated with endovascular repair.

Methods: We updated the results of the Dutch Randomized Endovascular Aneurysm Management (DREAM) trial, a multicenter, randomized controlled trial comparing open with endovascular aneurysm repair, up to 15 years of follow-up. Survival and reinterventions were analyzed on an intention-to-treat basis. Causes of death and secondary interventions were compared by use of an events per person-year analysis.

Results: There were 178 patients randomized to open and 173 to endovascular repair. Twelve years after randomization, the cumulative overall survival rates were 42.2% for open and 38.5% for endovascular repair, for a difference of 3.7 percentage points (95% confidence interval, -6.7 to 14.1; P = .48). The cumulative rates of freedom from reintervention were 78.9% for open repair and 62.2% for endovascular repair, for a difference of 16.7 percentage points (95% confidence interval, 5.8-27.6; P = .01). No differences were observed in causes of death. Cardiovascular and malignant disease account for the majority of deaths after prolonged follow-up.

Conclusions: During 12 years of follow-up, there was no survival difference between patients who underwent open or endovascular abdominal aortic aneurysm repair, despite a continuously increasing number of reinterventions in the endovascular repair group. Endograft durability and the need for continued endograft surveillance remain key issues.
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http://dx.doi.org/10.1016/j.jvs.2017.05.122DOI Listing
November 2017

Genetic variants associated with type 2 diabetes and adiposity and risk of intracranial and abdominal aortic aneurysms.

Eur J Hum Genet 2017 06 5;25(6):758-762. Epub 2017 Apr 5.

Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht, The Netherlands.

Epidemiological studies show that type 2 diabetes (T2D) is inversely associated with intracranial aneurysms (IA) and abdominal aortic aneurysms (AAA). Although adiposity has not been considered a risk factor for IA, there have been inconsistent reports relating adiposity to AAA risk. We assessed whether these observations have a genetic, causal basis. To this end, we extracted genotypes of validated single-nucleotide polymorphisms associated with T2D (n=65), body mass index (BMI) (n=97) and waist-hip ratio adjusted for BMI (WHRadjBMI) (n=47) from genotype data collected in 717 IA cases and 1988 controls, and in 818 AAA cases and 3004 controls, all of Dutch descent. For each of these three traits, we computed genetic risk scores (GRS) for each individual in these case-control data sets by summing the number of risk alleles weighted by their published effect size, and tested whether these GRS were associated with risk of aneurysm. We divided the cohorts into GRS quartiles, and compared IA and AAA risk in the highest with the lowest GRS quartile using logistic regression. We found no evidence for association in IA or AAA risk between top and bottom quartiles for the genetic risk scores for T2D, BMI and WHRadjBMI. However, additional Mendelian randomization analyses suggested a trend to potentially causal associations between BMI and WHRadjBMI and risk of AAA. Overall, our results do not support epidemiological observations relating T2D to aneurysm risk, but may indicate a potential role of adiposity in AAA that requires further investigation.
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http://dx.doi.org/10.1038/ejhg.2017.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477373PMC
June 2017

Transdifferentiation of Human Dermal Fibroblasts to Smooth Muscle-Like Cells to Study the Effect of MYH11 and ACTA2 Mutations in Aortic Aneurysms.

Hum Mutat 2017 04 27;38(4):439-450. Epub 2017 Jan 27.

Department of Oral Cell Biology, ACTA University of Amsterdam and VU University Amsterdam, MOVE Research Institute, Amsterdam, The Netherlands.

Mutations in genes encoding proteins of the smooth muscle cell (SMC) contractile apparatus contribute to familial aortic aneurysms. To investigate the pathogenicity of these mutations, SMC are required. We demonstrate a novel method to generate SMC-like cells from human dermal fibroblasts by transdifferentiation to study the effect of variants in genes encoding proteins of the SMC contractile apparatus (ACTA2 and MYH11) in patients with aortic aneurysms. Dermal fibroblasts from seven healthy donors and cells from seven patients with MYH11 or ACTA2 variants were transdifferentiated into SMC-like cells within a 2-week duration using 5 ng/ml TGFβ1 on a scaffold containing collagen and elastin. The induced SMC were comparable to primary human aortic SMC in mRNA expression of SMC markers which was confirmed on the protein level by immunofluorescence quantification analysis and Western blotting. In patients with MYH11 or ACTA2 variants, the effect of intronic variants on splicing was demonstrated on the mRNA level in the induced SMC, allowing classification into pathogenic or nonpathogenic variants. In conclusion, direct conversion of human dermal fibroblasts into SMC-like cells is a highly efficient method to investigate the pathogenicity of variants in proteins of the SMC contractile apparatus.
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http://dx.doi.org/10.1002/humu.23174DOI Listing
April 2017

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci.

Circ Res 2017 Jan 29;120(2):341-353. Epub 2016 Nov 29.

For the author affiliations, please see the Appendix.

Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA.

Objective: To identify additional AAA risk loci using data from all available genome-wide association studies.

Methods And Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9.

Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.308765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253231PMC
January 2017

Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms.

J Am Heart Assoc 2016 07 14;5(7). Epub 2016 Jul 14.

Surgery Department, University of Otago, Dunedin, New Zealand.

Background: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs.

Methods And Results: We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single-nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10(-5)) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10(-3)).

Conclusions: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.
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http://dx.doi.org/10.1161/JAHA.115.002603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015357PMC
July 2016

Predicting reinterventions after open and endovascular aneurysm repair using the St George's Vascular Institute score.

J Vasc Surg 2016 Jun 19;63(6):1428-1433.e1. Epub 2016 Mar 19.

Division of Vascular Surgery, Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands.

Background: Identifying patients at risk for aneurysm rupture and sac expansion after open and endovascular abdominal aortic aneurysm (AAA) repair (EVAR) may help to attenuate this risk by intensifying follow-up and early detection of problems. The goal of this study was to validate the St George's Vascular Institute (SGVI) score to identify patients at risk for a secondary intervention after elective aneurysm repair.

Methods: A post hoc on-treatment analysis of a randomized trial comparing open AAA repair and EVAR was performed. In this multicenter trial, 351 patients were randomly assigned to undergo open AAA repair or EVAR. Information on survival and reinterventions was available for all patients at 5 years postoperatively, for 79% at 6 years, and for 53% at 7 years. Open repair was completed in 173 patients and EVAR in 171, based on an on-treatment analysis. Because 17 patients had incomplete anatomic data, 327 patients (157 open repair and 170 EVAR) were available for analysis. During 6 years of follow-up, 78 patients underwent at least one reintervention. The SGVI score, which is calculated from preoperative AAA morphology using aneurysm and iliac diameter, predictively dichotomized patients into groups at high-risk or low-risk for a secondary intervention. The observed freedom from reintervention was compared between groups at predicted high-risk and predicted low-risk.

Results: The 20 patients in the high-risk group were indeed at higher risk for a secondary intervention compared with the 307 patients predicted to be at low risk (hazard ratio [HR], 3.82; 95% confidence interval [CI], 2.05-7.11; P < .001). Discrimination between high-risk and low-risk groups was valid for EVAR (HR, 4.06; 95% CI, 1.93-8.51; P < .001) and for open repair (HR, 3.41; 95% CI, 1.02-11.4; P = .033).

Conclusions: The SGVI score appears to be a useful tool to predict reintervention risk in patients after open repair and EVAR.
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http://dx.doi.org/10.1016/j.jvs.2015.12.028DOI Listing
June 2016

Invited commentary.

J Vasc Surg 2015 Sep;62(3):584

Amsterdam, The Netherlands.

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http://dx.doi.org/10.1016/j.jvs.2015.04.394DOI Listing
September 2015

In vitro feasibility of a sac-sealing endoprosthesis in a double chimney graft configuration for juxtarenal aneurysm.

J Endovasc Ther 2014 Aug;21(4):529-37

1 Department of Vascular Surgery, VU University Medical Center, Amsterdam, The Netherlands.

Purpose: To investigate in an in vitro juxtarenal aneurysm flow model the feasibility and efficacy of using a sac-sealing endoprosthesis in a chimney graft configuration.

Methods: In two experiments, a Nellix sac-sealing endoprosthesis was used as the main graft in a double-branched chimney graft configuration, using a self-expanding Viabahn stent-graft and a balloon-expandable Advanta V12 stent-graft in a pressurized silicone juxtarenal aneurysm flow model. In two consecutive experiments, the chimney graft balloons were inflated (1) at the beginning of and (2) to simulate varying renal ischemic times half-way through the injection of the sac-sealing polymer into the Nellix endobags. The balloons and were kept inflated until the endobags were filled and the polymer was cured. The aneurysm model was connected to a roller pump, pumping gelatin-water at a rate of 100 beats per minute. Before and after 24 hours of continuous flow, computed tomography (CT) scans were made using contrast injection. The CT scans were reconstructed and analyzed for gutter cross-sectional area, total gutter volume, chimney graft compression, and volume of space between the aneurysm wall and the endoprosthesis.

Results: Differences in gutter size between both types of chimney grafts were minimal. Chimney graft compression exceeded 50% if the balloons were inflated in the chimney grafts halfway through polymer injection into the endobag. Twenty-four hours of flow did not influence chimney graft patency or gutter size.

Conclusion: In a juxtarenal aneurysm flow model, we demonstrated the technical feasibility of a sac-sealing endoprosthesis in a chimney graft configuration. This early evidence suggests that balloon dilation of chimney grafts should occur over the entire period of polymer injection and curing to prevent considerable chimney graft compression.
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http://dx.doi.org/10.1583/14-4693.1DOI Listing
August 2014

[Treatment of abdominal aortic aneurysm: is there still a place for open repair?].

Ned Tijdschr Geneeskd 2014 ;158:A6994

VUmc, afd. Heelkunde, Amsterdam.

Due to lower peri-operative mortality, lower risk of complications and shorter duration of hospital stay, endovascular aneurysm repair has become preferential treatment for an infrarenal aortic aneurysm. Three randomised studies that compared endovascular repair with open repair now report follow-up data of an average of six years. The data shows a loss of peri-operative mortality advantage after two to three years. More re-interventions are performed following endovascular treatment. The predominant cause of death is due to cardiovascular events, for which optimal medical therapy is crucial. The initial mortality advantage of endovascular aneurysm repair compared to open repair is lost sooner in elderly and high-risk patients than in those patients who are relatively young and low-risk.
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December 2014

Statin therapy is associated with improved survival after endovascular and open aneurysm repair.

J Vasc Surg 2014 Jan 18;59(1):39-44.e1. Epub 2013 Oct 18.

Division of Vascular Surgery, Department of Surgery, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.

Background: The relationship between numerous risk factors and perioperative mortality after cardiovascular surgery has been studied extensively. While improved perioperative survival and fewer cardiovascular events have been related to statin therapy, its effect on long-term survival after aneurysm repair remains to be elucidated. The aim of this study is to determine the effect of statin therapy on long-term survival after open and endovascular aneurysm repair and to identify other cardiovascular and patient-related risk factors in this respect.

Methods: A post-hoc analysis of a randomized trial comparing open and endovascular abdominal aortic aneurysm repair was performed. In this multicenter trial, 351 patients were randomly assigned to undergo either open abdominal aortic aneurysm repair or endovascular repair. Patients who were on lipid-lowering medication at their inclusion in the trial (n = 135) were compared with those who were not (n = 216).

Results: During 6 years of follow-up, 118 (33.6%) patients died after randomization. Statin therapy, baseline characteristics, Society for Vascular Surgery/International Society for Cardiovascular Surgery risk factors, aneurysm size, reinterventions, antiplatelet or anticoagulant agents, and β-blockers were used to identify prognostic factors influencing survival. After identification of significant factors in a Kaplan-Meier analysis, a multivariable Cox regression analysis was applied. Statin therapy at inclusion in the trial was independently associated with better overall survival after open or endovascular aneurysm repair (hazard ratio [HR], 0.5; 95% confidence interval [CI], 0.3-0.8; P = .004). Statins were especially associated with fewer cardiovascular deaths (HR, 0.4; 95% CI, 0.2-0.9; P = .025). Several risk factors were associated with poor survival after open and endovascular aneurysm repair: age >70 (HR, 3.4; 95% CI, 2.2-5.0; P < .001), a history of cardiac disease at baseline (HR, 1.9; 95% CI, 1.3-2.8; P = .001), and moderate/severe tobacco use (HR, 1.7; 95% CI, 1.2-2.5; P = .004). Gender, aneurysm size, the need for reintervention, pulmonary disease, renal disease, carotid disease, hypertension, diabetes mellitus, antiplatelet or anticoagulant agents, and β-blockers were not significantly associated with impaired long-term survival (P > .05).

Conclusions: Despite the limitations of a post-hoc analysis of a prospectively maintained trial, we conclude that statin therapy at the beginning of the trial is independently associated with improved long-term survival after open or endovascular aneurysm repair, while age above 70 years, a history of cardiovascular disease, and tobacco use are associated with decreased long-term survival.
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http://dx.doi.org/10.1016/j.jvs.2013.07.026DOI Listing
January 2014

Recurrent dyspnea following a swollen leg in a 46-year-old man.

Chest 2013 Oct;144(4):1402-1405

Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1378/chest.13-0390DOI Listing
October 2013

A variant in LDLR is associated with abdominal aortic aneurysm.

Circ Cardiovasc Genet 2013 Oct 17;6(5):498-504. Epub 2013 Sep 17.

Background: Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalyzed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance.

Methods And Results: A genome-wide association study was conducted using 1830 cases from the United Kingdom, New Zealand, and Australia with infrarenal aorta diameter≥30 mm or ruptured AAA and 5435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with P<1×10(-4) were carried through to in silico replication in 1292 AAA cases and 30,503 controls. One single-nucleotide polymorphism associated with P<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1063 controls from the United Kingdom, 507 AAA cases and 199 controls from Denmark, and 885 AAA cases and 1000 controls from New Zealand). Low-density lipoprotein receptor (LDLR) rs6511720 A was significantly associated overall and in 3 of 5 individual replication studies. The full study showed an association that reached genome-wide significance (odds ratio, 0.76; 95% confidence interval, 0.70-0.83; P=2.08×10(-10)).

Conclusions: LDLR rs6511720 is associated with AAA. This finding is consistent with established effects of this variant on coronary artery disease. Shared causal pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA.
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http://dx.doi.org/10.1161/CIRCGENETICS.113.000165DOI Listing
October 2013
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