The Center for Aortic Aneurysms in the Erasmus MC is a clinical and research institute, with a strong educational focus, offering state of the art innovative early diagnosis, treatment, and –follow-up of patients and family screening for aortic aneurysms with the overall goal to reduce mortality due to aneurysm rupture within the framework of sustainable health. The Principal Coordinator of this ACE is Prof Dr. H.J.M. Verhagen, the Coordinating Leading Investigator is Dr. I van der Pluijm
Our joint strategy:
Maintain and expand our large clinical program for the treatment of thoracic, thoraco-abdominal, and abdominal aneurysms
Provide dedicated “one-day-fast-track” outpatient clinics for aortic aneurysm patients which includes diagnostics (ultrasound and CT), anesthesiologic and clinical genetics consultation
Identification of genetic factors that play a key role in both aortic aneurysm formation as well as complication risk prediction
Fundamental research and genome wide analysis techniques are used to unravel underlying molecular pathways in order to develop aneurysm-risk profiling models based on molecular pathway diagnostics to offer better individualized treatment and screening for patients and their families.
In this setting we want to achieve the best possible care and treatment for individual patients and their relatives with a clear focus on risk stratification and improvement of treatment modalities. Aortic aneurysm care and research are embedded in an ongoing multidisciplinary setting attending thoracic, thoraco-abdominal, and abdominal aneurysms, based on a strong and focused cooperation between the Departments of Vascular Surgery, Cardiology, Thoracic Surgery, Anesthesiology, Radiology, Pathology, Molecular Genetics and Clinical Genetics. We offer dedicated “one-day-fast-track” outpatient clinics for aortic aneurysm patients, which includes diagnostics (ultrasound and CT/MRI), anaesthesiologic and clinical genetics consultation, coordinated by nurse-practitioners. Genetics play a key role in aortic aneurysm formation and our departments are currently combining sophisticated bioinformatics analysis of large scale family-based whole exome and whole genome studies with the development of functional readouts to identify and confirm novel genetic causes.
The multidisciplinairy approach allows combined analysis of clinical and genetic data to find risk factors for clinical outcome and complications, and study the role of these factors together with gender and aging in the pathogenesis of aortic aneuryms. We collect and use information from family histories, clinical features and the genetic whole exome analysis to make a balanced genetic risk stratification and classify cases accordingly. In this way we provide novel risk-related treatment for patients and also appropriate recommendations for targeted screening of relatives. Thereby, we improve aneurysm care and treatment compared to the current situation in the Netherlands, where aneurysm diagnosis is usually made as an incidental finding, or after emergency hospitalization for aneurysm rupture or dissection. Furthermore, identification of genetic factors allows for better evidence-based personalized advice on thresholds for treatment strategies where current practice is mainly based on maximum diameters of the aneurysm.
Clearly, this also leads to improved care for aneurysm patients and contributes to sustainable health.
Genome wide analysis techniques are used to unravel underlying molecular pathways in order to develop aneurysm-risk profiling models based on molecular pathway diagnostics to offer better individualized treatment and screening for patients and their families.
Simultaneously, based on these data, functional assays are performed to delineate molecular pathways and targets, resulting in novel insights into aneurysmal disease, eventually leading to novel treatment targets. Perioperative cardiovascular risk stratification is essential in the decision making process around all invasive interventions, especially in the aneurysm patients with co-morbidity where procedural risks are high and alternative treatment strategies are usually not present. With the addition of innovative practice based risk profile programs and biomarkers, evaluation of different treatment options, all with their pros and cons, will be done with “evidence based arguments”.
We have bimonthly meetings in which we discuss active issues concerning aortic aneurysm patient care, research and education. Next to that, we organize 'internal ACE days' in which we actively discuss ongoing research collaborations and (inter)national grant opportunities. Furthermore, we are establishing a joint ACE Aortic Aneurysm website.
Multidimensionality: This ACE uniquely combines expertise in clinical care, genetic and fundamental research of aortic aneurysms. These expertises consist of clinical management, radiology, pathology, and genome diagnostics, combined with bioinformatics and fundamental research. As such, we organize bimonthly ACE meetings where we discuss our multidisciplinary research approach
We make use of clinical data, tissue expression data and family based genome information and combine this with development of methods for fast and reliable functional assays to study novel genetic variants. Tissues are stored in an aneurysm biobank and the clinical and genetic data is stored in our secure database.
Multidisciplinary: Our ACE is a collaboration between clinical departments with unique aortic aneurysm expertise and several basic research groups combining diagnostic and research oriented genetic studies with fundamental aneurysm research thus achieving 'from bench to bedside' results.
Specifically, we have an intensive collaboration between the TAA and AAA molecular/genetic research groups including the exchange of material and protocols and direct lab-collaborations.
Next to that we have written and obtained several joint grants:
- Genetische Research naar Abdominale Aorta Aneurysma Genen (GRAAG) 2012-2016 Stichting Lijf en Leven
- Genexpressie analyse ter detectie van de moleculaire mechanismen van aneurysmavorming (GAMMA) 2014-2018 Stichting Lijf en Leven
- 2016-2020. Stichting Lijf en Leven. Biomarkers bij aneurysma patiënten.
- 2015-2018. Stichting Lijf en Leven. RAVE: dual antiplatelet therapy for vascular surgery patients.
- ErasmusMC grant. SMAD3-Related Aneurysms-Osteoarthritis Syndrome, An integrative functional analysis of SMAD3 patient mutations to provide insight into genotype-phenotype relation, and recommendations for a clinical work-up
- Jacoba Breen stichting 2016 'Preclinical ultrasound imaging system' (Visualsonics 2100)
- Nederlandse Hartstichting 2014-2018: 'studying the etiology and searching for risk factors in patients with familial thoracic aortic aneurysms'
- ErasmusMC grant 2016-2020. 'Childhood-onset Thoracic Aortic Aneurysm (CHITAA) study: an integrated approach'
- Dekker Beurs Nederlandse hartstichting: Studying the etiology and searching for risk factors in patients with familial thoracic aortic aneurysms
- Human disease model award: In vitro models for the aging microvasculature in heart failure and renal disease
Education levels This ACE is embedded in education at several levels. We teach Medical bachelors and masters, educate and train doctors and specialists in training at the department of Surgery and Cardiology as well as PhD students at involved departments. We provide regional nurse training for vascular departments.
In addition, we co-organize the monthly MolMed Bridge meetings, educating researchers on state-of-the-art topics. We are active members of the COEUR (Cardiovascular Research School Erasmus MC), and frequently organize COEUR research seminars on 'Aortic Aneurysms'. The Molecular Genetics department is involved in the MGC research school, providing training in topics relevant to this ACE. PI's involved in this ACE actively contribute in teaching of all the different aspects mentioned and are active in their respective (international) professional societies and the associated educational programs. For example, one of our members covered the topic 'gardiogenetics in society' for the minor Genetics in Society. Next to this, an international symposium on aortic pathology is jointly organized by the our ACE members, every other year.
Innovation/development As here we combine fundamental, genetic and clinical expertise, this is a unique opportunity to innovate education at a multidisciplinary level. Thereby PhD students that start within our ACE are trained both in (fundamental) research as well as in clinical aspects. The focus of this training (research/clinic) depends on the research project requirements.
Feedback Education feedback is provided through questionnaires and outcomes are implemented when applicable.
International students We provide teaching to students from an international origin like the close and fruitful collaboration with Hospital de Santa Marta in Lisbon in Portugal.
Societal Relevance to Research, Education and Patient Care
Societal impact will be significant as the results from our studies will allow identification of family members at high risk and only those with increased genetic risk will be placed on an ultrasound follow up screening protocol, allowing targeted screening. Early identification of individuals at risk allows timely elective repair, decreases morbidity and reduces the number of expensive aortic aneurysm rupture surgeries.
The relatives who do not have an increased familial risk do not need the repeated ultrasound screening and this will save costs. Currently a national consensus statement is being developed by a national multidisciplinary working group providing uniform and evidence-based recommendations for the cardiogenetic care of patients with (thoracic) aortic aneurysms and their family members.
Within VASCERN we have chosen to pursue 3 main goals:
Goal 1: Realise the potential of European cooperation regarding highly specialised healthcare for patients and for healthcare systems by exploiting innovations in medical science and health technologies
Goal 2: Reinforce research, epidemiological surveillance like registries and provide training for healthcare professionals
Goal 3: Encourage the development of quality and safety benchmarks and help develop and spread best practice within and outside the European Reference Network
By following these objectives, VASCERN aims to:
– Reduce the delay in diagnosing the disease;
– Improving awareness for the disease among caregivers (General Practitioners (GPs), school doctors, general public);
– Reduce care gaps/lost-to-follow up during the transition phase from pediatric to adult care;
– Improve the quality of family counseling;
– Reduce redundant tests/increasing the use of relevant tests for the disease;
– Improve medical knowledge by shared experience, and clinical trials.
The focus and heavy involvement of this ACE in the various educational levels and courses contributing to a better understanding of aneurysm aspects ranging from clinical procedures to basic molecular insights will have a trickledown effect and help in the training of future aneurysm specialists and researchers.
Viability of Research, Education and Patient Care
A large clinical program already exists for the treatment of thoracic, thoraco-abdominal, and abdominal aneurysms, based on strong and focused cooperation, with a clear multidisciplinary decision strategy (Vascular surgery, Cardiology, Thoracic surgery, Anesthesiology, Clinical Genetics).
There are dedicated "one-day-fast-track" outpatient clinics for aortic aneurysm patients which includes diagnostics, anesthesiologic and clinical genetics consultation, coordinated by nurse-practitioners. Future identification of genetic factors allow for better evidence-based personalized advice on thresholds for treatment strategies where current practice is mainly based on maximum diameters, and allows further investigation of the molecular mechanisms involved in aneurysmal disease. Altogether this secures improved and top-level care for aneurysm patients. In addition, we our ACE is embedded in the European Reference Network for aortic aneurysms (VASCERN). All senior PIs are actively involved in international societies and global education in the field. Clinical partners give input for international medical guidelines and researchers share and communicate new fundamental insights worldwide. Given the importance of novel surgical procedures we also maintain a network of industrial relations securing in-depth insight in novel technologies.
All members are involved in research schools and master/bachelor programs. Our combination of top-class clinical care, clinical genetic and fundamental functional (molecular)research is unique in the Netherlands.
Thanks to joining forces within the ACE aortic aneuryms, as well as with VASCERN, we now have a unique and leading position compared to other institutes in the Netherlands by combining aneurysm research, care and education.
Key and relevant publications of the last five years
- Systematic Review and Meta-Analysis of the Outcome of Treatment for Type II Endoleak Following Endovascular Aneurysm Repair. Ultee KHJ, Büttner S, Huurman R, Bastos Gonçalves F, Hoeks SE, Bramer WM, Schermerhorn ML, Verhagen HJM. Eur J Vasc Endovasc Surg. 2018 Aug 10
- Intermodality variation of aortic dimensions: How, where and when to measure the ascending aorta.
- Decreased mitochondrial respiration in aneurysmal aortas of Fibulin-4 mutant mice is linked to PGC1A regulation. van der Pluijm I, Burger J, van Heijningen PM, IJpma A, van Vliet N, Milanese C, Schoonderwoerd K, Sluiter W, Ringuette LJ, Dekkers DHW, Que I, Kaijzel EL, Te Riet L, MacFarlane E, Das D, van der Linden R, Vermeij M, Demmers JA, Mastroberardino PG, Davis EC, Yanagisawa H, Dietz H, Kanaar R, Essers J. Cardiovasc Res. 2018 Jun 21
- Long-term outcomes of standard endovascular aneurysm repair in patients with severe neck angulation. Oliveira NFG, Gonçalves FB, Hoeks SE, Josee van Rijn M, Ultee K, Pinto JP, Raa ST, van Herwaarden JA, de Vries JPM, Verhagen HJM. J Vasc Surg. 2018 Jun 15
- Expert consensus recommendations on the cardiogenetic care for patients with thoracic aortic disease and their first-degree relatives. Verhagen JMA, Kempers M, Cozijnsen L, Bouma BJ, Duijnhouwer AL, Post JG, Hilhorst-Hofstee Y, Bekkers SCAM, Kerstjens-Frederikse WS, van Brakel TJ, Lambermon E, Wessels MW, Loeys BL, Roos-Hesselink JW, van de Laar IMBH; National Working Group on BAV & TAA. Int J Cardiol. 2018 May 1;258:243-248
- A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. Schepers D, Tortora G, Morisaki H, MacCarrick G, Lindsay M, Liang D, Mehta SG, Hague J, Verhagen J, van de Laar I, Wessels M, Detisch Y, van Haelst M, Baas A, Lichtenbelt K, Braun K, van der Linde D, Roos-Hesselink J, McGillivray G, Meester J, Maystadt I, Coucke P, El-Khoury E, Parkash S, Diness B, Risom L, Scurr I, Hilhorst-Hofstee Y, Morisaki T, Richer J, Désir J, Kempers M, Rideout AL, Horne G, Bennett C, Rahikkala E, Vandeweyer G, Alaerts M, Verstraeten A, Dietz H, Van Laer L, Loeys B. Hum Mutat. 2018 May;39(5):621-634.
- Higher 30 Day Mortality in Patients with Familial Abdominal Aortic Aneurysm after EVAR. van de Luijtgaarden KM, Bastos Gonçalves F, Hoeks SE, Blankensteijn JD, Böckler D, Stolker RJ, Verhagen HJM. Eur J Vasc Endovasc Surg. 2017 Aug;54(2):142-149.
- The impact of endovascular repair on management and outcome of ruptured thoracic aortic aneurysms. Ultee KHJ, Zettervall SL, Soden PA, Buck DB, Deery SE, Shean KE, Verhagen HJM, Schermerhorn ML. J Vasc Surg. 2017 Aug;66(2):343-352.e1
- Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor. Gillis E, Kumar AA, Luyckx I, Preuss C, Cannaerts E, van de Beek G, Wieschendorf B, Alaerts M, Bolar N, Vandeweyer G, Meester J, Wünnemann F, Gould RA, Zhurayev R, Zerbino D, Mohamed SA, Mital S, Mertens L, Björck HM, Franco-Cereceda A, McCallion AS, Van Laer L, Verhagen JMA, van de Laar IMBH, Wessels MW, Messas E, Goudot G, Nemcikova M, Krebsova A, Kempers M, Salemink S, Duijnhouwer T, Jeunemaitre X, Albuisson J, Eriksson P, Andelfinger G, Dietz HC, Verstraeten A, Loeys BL; Mibava Leducq Consortium. Front Physiol. 2017 Jun 13;8:400
- Endovascular Treatment of Common Iliac Artery Aneurysms With an Iliac Branch Device: Multicenter Experience of 140 Patients. Jongsma H, Bekken JA, Bekkers WJ, Zeebregts CJ, van Herwaarden J, Hoksbergen A, Cuypers P, de Vries JP, Verhagen HJ, Fioole B. J Endovasc Ther. 2017 Apr;24(2):239-245
- Risk of abdominal aortic aneurysm (AAA) among male and female relatives of AAA patients. van de Luijtgaarden KM, Rouwet EV, Hoeks SE, Stolker RJ, Verhagen HJ, Majoor-Krakauer D. Vasc Med. 2017 Apr;22(2):112-118
- Editor's Choice - Management of Descending Thoracic Aorta Diseases: Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS). Riambau V, Böckler D, Brunkwall J, Cao P, Chiesa R, Coppi G, Czerny M, Fraedrich G, Haulon S, Jacobs MJ, Lachat ML, Moll FL, Setacci C, Taylor PR, Thompson M, Trimarchi S, Verhagen HJ, Verhoeven EL, Esvs Guidelines Committee, Kolh P, de Borst GJ, Chakfé N, Debus ES, Hinchliffe RJ, Kakkos S, Koncar I, Lindholt JS, Vega de Ceniga M, Vermassen F, Verzini F, Document Reviewers, Kolh P, Black JH 3rd, Busund R, Björck M, Dake M, Dick F, Eggebrecht H, Evangelista A, Grabenwöger M, Milner R, Naylor AR, Ricco JB, Rousseau H, Schmidli J.
- One-Year Follow-Up After Hybrid Thoracoabdominal Aortic Repair. van de Graaf RA, Grüne F, Hoeks SE, Ten Raa S, Stolker RJ, Verhagen HJ, van Lier F. Vasc Endovascular Surg. 2017 Jan;51(1):23-27.
- Defective Connective Tissue Remodeling in Smad3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-β Signaling. van der Pluijm I, van Vliet N, von der Thusen JH, Robertus JL, Ridwan Y, van Heijningen PM, van Thiel BS, Vermeij M, Hoeks SE, Buijs-Offerman RMGB, Verhagen HJM, Kanaar R, Bertoli-Avella AM, Essers J. EBioMedicine. 2016 Oct;12:280-294
- Perioperative Complications are Associated With Adverse Long-Term Prognosis and Affect the Cause of Death After General Surgery. Tjeertes EK, Ultee KH, Stolker RJ, Verhagen HJ, Bastos Gonçalves FM, Hoofwijk AG, Hoeks SE.World J Surg. 2016 Jun 14
- Life expectancy and causes of death after repair of intact and ruptured abdominal aortic aneurysms. Bastos Gonçalves F, Ultee KH, Hoeks SE, Stolker RJ, Verhagen HJ. J Vasc Surg. 2016 Mar;63(3):610-6
- Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections. Bertoli-Avella AM, Gillis E, Morisaki H, Verhagen JM, de Graaf BM, van de Beek G, Gallo E, Kruithof BP, Venselaar H, Myers LA, Laga S, Doyle AJ, Oswald G, van Cappellen GW, Yamanaka I, van der Helm RM, Beverloo B, de Klein A, Pardo L, Lammens M, Evers C, Devriendt K, Dumoulein M, Timmermans J, Bruggenwirth HT, Verheijen F, Rodrigus I, Baynam G, Kempers M, Saenen J, Van Craenenbroeck EM, Minatoya K, Matsukawa R, Tsukube T, Kubo N, Hofstra R, Goumans MJ, Bekkers JA, Roos-Hesselink JW, van de Laar IM, Dietz HC, Van Laer L, Morisaki T, Wessels MW, Loeys BL. J Am Coll Cardiol. 2015 Apr 7;65(13):1324-36.
- First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm. van de Luijtgaarden KM, Heijsman D, Maugeri A, Weiss MM, Verhagen HJ, IJpma A, Brüggenwirth HT, Majoor-Krakauer D. Hum Genet. 2015 Aug;134(8):881-93
- L. te Riet, E. D. van Deel, B. S. van Thiel, E. Moltzer, J.N. van Vliet, R. Ridwan, R. van Veghel, P. M. van Heijningen, J. L. Robertus, I. M. Garrelds, M. Vermeij, I. van der Pluijm, A.H.J. Danser, J. Essers AT1 Receptor Blockade, but not Renin Inhibition, Reduces Aneurysm Growth and Cardiac Failure in Fibulin-4 Mice. J. Hypertension 2015, 34(4):654-65
- N.W.M. Ramnath, L.J.A.C. Hawinkels, P.M. van Heijningen, L. te Riet, M. Paauwe, M. Vermeij, A. H.J. Danser, R. Kanaar, P. ten Dijke, J. Essers. Fibulin-4 deficiency increases TGF-beta signalling in aortic smooth muscle cells due to elevated TGF-beta2 levels. Sci Rep 2015; 5, 16872
- Thoracic aortic surgery: an overview of 40 years clinical practice. Bekkers JA, te Riele RJ, Takkenberg JJ, Bol Raap G, Hofland J, Roos-Hesselink JW, Bogers AJ. J Thorac Cardiovasc Surg. 2014 Jan;147(1):332-43.
- Arterial elongation and tortuosity leads to detection of a de novo TGFBR2 mutation in a young patient with complex aortic pathology. van de Luijtgaarden KM, Bastos Gonçalves F, Majoor-Krakauer D, Verhagen HJ. Eur Heart J. 2013 Apr;34(15):1133
- Aggressive cardiovascular phenotype of aneurysms-osteoarthritis syndrome caused by pathogenic SMAD3 variants. van der Linde D, van de Laar IM, Bertoli-Avella AM, Oldenburg RA, Bekkers JA, Mattace-Raso FU, van den Meiracker AH, Moelker A, van Kooten F, Frohn-Mulder IM, Timmermans J, Moltzer E, Cobben JM, van Laer L, Loeys B, De Backer J, Coucke PJ, De Paepe A, Hilhorst-Hofstee Y, Wessels MW, Roos-Hesselink JW.J Am Coll Cardiol. 2012 Jul 31;60(5):397-403
- Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM, Hoedemaekers YM, Willemsen R, Severijnen LA, Venselaar H, Vriend G, Pattynama PM, Collée M, Majoor-Krakauer D, Poldermans D, Frohn-Mulder IM, Micha D, Timmermans J, Hilhorst-Hofstee Y, Bierma-Zeinstra SM, Willems PJ, Kros JM, Oei EH, Oostra BA, Wessels MW, Bertoli-Avella AM. Nat Genet. 2011 Feb;43(2):121-6
PhD theses of the last five years
- K.H.J. Ultee, Prognostics in aortic and peripheral artery disease, October 2016
- Bibi van Thiel, Multimodality ImAging of Cardiovascular Dysfunction, July 2016
- Koen van de Luijtgaarden, Genetics of Abdominal Aortic Aneurysm, 8 Jan 2016
- Luuk te Riet, April 5, 2015, Renin-Angiotensin System and Genetic Factors in Aneurysms: A Translational Approach
- F. M. Bastos Goncalves., Endovascular aortic repair; clarifying risk factors, complications and follow-up, 1 april 2015 CUM LAUDE.
- M.Th. Voute. Medical and technical considerations in vascular surgery14 januari 2015
- E.J. Bakker. Cardiac complications after non-cardiac surgery; perioperative risk prediction and reduction strategies, 2 oktober 2013
- D van der Linde; Congenital aortic stenosis and aneurysms, 19 april 2013
- J.A. Bekkers; Decades of surgery on the thoracic aorta; 14 november 2012
- IMBH van de Laar 27 juni 2012
- Els Moltzer, March 23, 2011, Aortic pathology and the role of the rennin –angiotensin
Non-scientific publications related to the ACE
- Structure and cell biology of the vessel wall. B.S. van Thiel, I. van der Pluijm, R. Kanaar, A.H.J. Danser, J. Essers. (Chapter 1 in ESC Textbook of Vascular Biology, 2017).
- Aneurysma zit vaak in de familie- Hence Verhagen; https://www.nd.nl/nieuws/nederland/aneurysma-zit-vaak-in-de-familie.1610444.lynkx, 25 april 2016
- Interview in ErasmusMC Monitor ‘de waarde van ziek weefsel; nieuw onderzoekmodel medicatie hartpatiënten’ (value of diseased tissue; new research model for medication of heart patients), I van der Pluijm, J. Essers, dec 2016
- Bookchapter in Clinical Cardiogenetics (2016); Chapter 17: Heritable Thoracic Aortic Disorders, I.M.B.H. van de Laar
- Jan 2015 Press release Dutch Heart Association Dekker beurzen: https://www.hartstichting.nl/onderzoek/erfelijkheid-aneurysma
- Endovascular Today; an interview with Hence J.M. Verhagen; http://evtoday.com/2011/10/an-interview-with-hence-jm-verhagen-md-phd/
- Jan 2011 Press release Erasmus MC: Oorzaak voor plotseling scheuren slagader gevonden
- Jan 2011 Volkskrant: Aneurysma voor zijn met dna-onderzoek
- Richtlijn: Diagnostiek, preventie en behandeling van veneuze trombo-embolie en secundaire preventie van arteriële trombose (2008, ISBN: 978-90-8523-193-6)
- 2007 Newspaper article: ‘vondst gen hulp bij aanpak aneurysma’ Telegraaf 9 feb 2007, Nu.nl, BN de stem
- Representation of the pre-clinical imaging facilty, Amie facility expert; http://www.erasmusmc.nl/amie/
- International patent cooperation treaty (PCT) nr. PCT/NL2005/000532 ‘Non-human animal model for cardio-vascular disease’. J. Essers, A. Garinis, R. Kanaar