Download 2015 - Erasmus MC

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COEUR
A N N UA L
COEUR
ANNUAL REPORT 2015
R EPORT
2015
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COEUR
ANNUAL REPORT
2015
COEUR
Content
Preface
5
Mission
7
Organization
9
Grants and Awards
11
Education
21
PhD training
21
Research Seminars
22
Other educational activities
24
MD elective program
26
COEUR day
28
Research
39
Doctoral degrees
121
Citation Classics
136
PubMed Publications 2014
137
Colofon
188
4
Preface
We are proud to present the annual report of our Cardiovascular Research School for the
year 2015. In the reporting year, our senior scientific staff and PhD candidates have worked
on 31 research projects. Quantitatively and qualitatively their results are worth mentioning,
since altogether more than 750 PubMed/Medline articles were produced. In the latest
citation analysis, the mean normalized citation score of COEUR over the period 2010-2013
was 2.00, the highest of all Erasmus MC Research Schools, and meaning that the impact of
our publications is twice that of average within the cardiovascular field. A total of 37 PhD
candidates successfully defended their thesis and obtained the doctoral degree.
The grant funds that have been raised by COEUR investigators totals more than
2.5 million euro’s. Without doing injustice to others, we like to mention Prof. Dirk Jan
Duncker and his team, Dr. Mostafa Mokhles, PhD fellow Vivan Baggen and Prof. Wiro
Niessen, who obtained prestigious grants from CVON, STW, NOW and EUR, and the
Netherlands Heart Foundation, respectively. The reporting year was also memorable for our
colleagues Deckers, Van Geuns and Gommers, who delivered their inaugural lectures. We
congratulate them with their achievements.
Main challenges are lying ahead. Research budgets are under pressure. Scientists
are encouraged to demonstrate the value of their work for society, and to involve the lay
public in shaping their research agenda. The formation of Academic Centers of Excellence
within the Erasmus MC provides opportunities to rethink and restructure existing research
programs, and to strengthen collaborations inside and outside our Research School.
We are confident that the COEUR Principal Investigators will direct these developments
to the benefit of science, society and patients. We trust you will enjoy the presentation of
our activities in this annual report.
Eric Boersma, scientific director
Adrie Verhoeven, secretary
Felix Zijlstra, chairman
5
COEUR
6
6
Mission
The mission of COEUR is two-fold:
■ To promote basic, translational and clinical
cardiovascular research, aimed at improving
the understanding of the pathophysiology
as well as the prognosis and quality of life of
patients with cardiovascular disease
■ To train future national and international
leaders in the cardiovascular field through a
systematic scientific education and training
program
To achieve this mission, COEUR conducts
innovative research and provides high quality
training in the cardiovascular research field.
The research programs include a wide spectrum
of disciplines, such as cardiovascular biology
and pharmacology, biomedical engineering and
informatics, clinical science, clinical epidemiology
and health care research. Training involves an
individual training program and includes monthly
research seminars and an all-encompassing
cardiovascular science core curriculum.
COEUR recognizes the need for an integrative,
multidisciplinary, translational approach
and encourages national and international
collaboration.
7
COEUR
Cardiovascular Research School Erasmus University Rotterdam (COEUR)
8
Participating institutes
Board representatives
Anesthesiology and Vascular Surgery
Professor Robert Jan Stolker
Cardiology
Professor Felix Zijlstra, chairman
Cardiothoracic Surgery
Professor Ad JJC Bogers
Hematology
Professor Frank WG Leebeek
Intensive Care Medicine
Professor AB Johan Groeneveld
Internal Medicine, Pharmacology,
Vascular and Metabolic Diseases
and Division of Nephrology
Professor AH Jan Danser
Dr Anton H van den Meiracker
Professor Bob Zietse
Neurology (Vascular Neurology)
Professor Diederik WJ Dippel
Pediatric Cardiology
Professor Wim A Helbing
Radiology
(including Biomedical Imaging)
Professor Aad van der Lugt
Professor Wiro J Niessen
Surgery (Vascular Surgery)
Professor Hence JM Verhagen
Professor Eric Boersma, scientific director
Dr Adrie JM Verhoeven, secretary
Accredited (2003) by the Royal Netherlands Academy of Arts and
Sciences. Re-accreditated in 2009
Organization
10 COEUR participants
Anesthesiology
Cardiology
Graduate School
Erasmus MC
Cardiothoracic Surgery
Hematology
Intensive Care Medicine
COEUR
Scientific Advisory Board
COEUR
Board
Internal Medicine
Pharmacology, Vascular and
Metabolic Diseases
and Division of Nephrology
9
Neurology
Pediatric Cardiology
Executive
Committee
Scientific Director
Radiology
Biomedical Imaging Group
Vascular Surgery
Scientific Secretariat
Theme I
Vascular Medicine
Theme II
Acute CV Syndromes
Theme III
Chronic Cardiac Disease
COEUR
10
Grants and Awards
A selection of grants and awards obtained by
COEUR investigators in 2015 is given below.
Cardiology
Dr. Jaap Deckers has been appointed as extraordinary professor of Cardiovascular Training and
Education, on behalf of ICIN Netherlands Heart Institute. On February 6th he delivered his inaugural
lecture titled “The heart attacks that disappeared”.
Dr. Robert Jan van Geuns, who has been appointed as endowed professor of “Interventional Cardiology” on behalf of the Vereniging Trustfonds EUR,
delivered his inaugural lecture titled “Beyond the
boundaries of the stent” on April 17.
Professor Dirk-Jan Duncker (Principal Investigator), Dr. Caroline Cheng and Dr. Daphne Merkus
(Co-Investigators) obtained a prestigious CVON
grant (CVON-2014-11; RECONNECT), totalling
M€ 5 of which Erasmus MC receives k€800. CVON,
the Netherlands CardioVascular Research Initiative, is an initiative with support of the Dutch
Heart Foundation, Dutch Federation of University
Medical Centers, The Netherlands Organisation for
Health Research and Development, and the Royal
Netherlands Academy of Arts and Sciences. In
April Professor Dirk-Jan Duncker was promoted
from Associate Editor to Deputy Editor of Cardiovascular Research, the Basic Science Journal of the
European Society of Cardiology, while Dr. Daphne
Merkus was appointed as Associate Editor of Cardiovascular Research in October. Professor DirkJan Duncker, who is presently the Secretary of the
Working Group for Coronary Pathophysiology and
Microcirculation, organized a two-day Nucleus
Meeting of the Working Group in Rotterdam in
April.
PhD candidate Anouchska Autar presented her
work on NETosis at the spring meeting of The
Netherlands Society of Cardiology where she received a prize for best oral presentation.
With the Thorax Foundation dinner, Professor
Jolien Roos raised k€200 for research into the
long-term effects of congenital heart diseases.
PhD candidate Vivan Baggen received a grant
from the Dutch Heart Foundation’s Dekker Program.
Dr. Natasja de Groot was elected as board member of the European Heart Rhythm Society where
she holds the position of chair website and communication. She is member of a consortium that
received an ErasmusMC MRace grant and a grant
from the Royal Dutch Society of Pharmacy.
PhD candidate Ameeta Yaksh was rewarded for
the best poster presentation on ElectroPhysiology
Research during the spring meeting of the Dutch
Society of Cardiology; the subject of her presentation was Rhythm disturbances after LVAD implantation. PhD candidate Eva Lanters was rewarded
11
COEUR
for the best oral presentation during the autumn
meeting of the Dutch Society of Cardiology.
PhD candidate Pranav Bhagirath was rewarded
with a travel grant for the European Arrhythmia
meeting in Milan (Europace-Cardiostim).
Dr. Caroline Cheng is workproject leader in the
above mentioned CVON RECONNECT program. On
March 6, PhD candidate Maarten Brandt won the
best oral presentation award during the CardioVascular Conference basal session at the Dutch
Atherosclerosis Society meeting.
12
Dr. Hans Bosch was awarded with a STW grant for
his project on 3D-Intra-Cardiac Echography (STW
project 14279).
PhD candidate Tianshi Wang caught a lot of media attention of among others the NOS Journaal
and The Voice of America for Heartbeat Optical
Cohorence Tomography (OCT), the subject of his
thesis. It is on micromotor based intravascular
OCT that can collect around 5000 images per second. With his catheter a whole coronary can be
imaged within a heartbeat. The patents arising
from his work have been licensed to Terumo and
they are now collaborating with Terumo and Kinetron to productize this spectacular development.
On October 30th 2015, Dr. Jasper Brugts finished
his two-year fellowship Heart Failure at the University Hospital of Zurich, Switzerland. The programme was organized by the European Society
of Cardiology (ESC) and European Heart Academy
according to the “Heart Failure Association Heart
Failure Specialists Core Curriculum” for training
in heart failure, consisting of 300 hours self-study
and 300 hours of practical training and courses
at the University Hospital of Zurich with final
examinations per module. Successful completion
resulted in a diploma by ESC for accreditation in
heart failure and a certificate of Advanced Studies
of the University of Zurich. The programme was
organized by Prof Thomas Luscher and Prof Frank
Ruschitzka. The diploma was handed to Jasper by
Prof Eugene Braunwald (see photo).
Annual Report 2015
Cardio-thoracic Surgery
PhD candidate
Sahar Mokhles
was nominated
to take part in
the Global Young
Scientists Summit
(GYSS). Young
researchers
around the world
are invited to
participate in this
program, which is basically one-week of debates,
discussions and presentations. Each year there is
a new theme, and the theme for 2015 was Global
Health. Sahar was there to share insights on joint
decision-making in lung cancer patients.
Dr. Mostafa Mokhles won a Veni grant for his
project “Effective Prediction of Outcome after
Congenital Heart Surgery; Combining statistics
and clinic for improved patient care”, worth
k€250, on behalf of the general board of the Dutch
Organization for Scientific Research NWO and
the Board of ZonMW. In addition, Dr. Mostafa
Mokhles also received an EUR Fellowship worth
k€ 135 titled “Reliable predictive models for
patients with congenital heart defects”. Today,
patients with a congenital heart defect can grow
to adulthood. Unfortunately, this does require
several heart operations throughout their lives. In
these projects, he will develop models to predict
the optimum time to perform each operation, in
order to be able to minimize the total number
of heart operations. Reducing the number of
operations will not only lead to improved survival
rates and lower disease burden, but also better
quality of life.
At the 2015 Radiology Society of North Amercia
(RSNA) meeting, Marcel Dijkshoorn was awarded
with the Certificate of Merit, for his poster
“Comprehensive Evaluation of Mechanical Heart
Valves with Third Generation Dual Source CT” .
13
COEUR
Hemostasis and Thrombosis
14
Professor Frank Leebeek has been appointed as
co-chair of the Scientific Subcommittee on Von
Willebrand Factor of the International Society for
Thrombosis and Haemostasis (ISTH).
Dr. Marieke J.H.A. Kruip received an MRace
efficiency grant of k€50 for a study on DDAVP in
patients with haemophilia who undergo dental
intervention (Dental DAVID study). Dr. Moniek de
Maat received a research grant of k€30 from the
Stichting Jacoba for implementing a Calibrated
Thrombin Generation system in research projects
on Thrombosis and Haemostasis. Professor Frank
Leebeek received a grant of k€100 from the
Dutch Haemophilia Foundation for part 3 of the
Willebrand in the Netherlands Study, of which he
is the PI.
PhD candidate Shiraaz Abdul was awarded a
travel grant from the International Society on
Fibrinolysis and Proteolysis (ISFP). He used it to
set up a collaboration with Professor P Declerck
and visited the Laboratory for Therapeutic
and Diagnostic Antibodies of the Faculty of
Pharmaceutical Sciences at the University of
Leuven for one month.
PhD candidate Michelle Sonneveld received the
Prof. Heimburger award worth k€50 for research
on Complement factor H, the relation with von
Willebrand Factor and ADAMTS13, and the risk of
stroke and myocardial infarction, of which
Dr. Moniek de Maat is the PI.
At the ISTH Congress in Toronto, Canada,
PhD candidates Michelle Sonneveld and
Johan Boender received a Young Investigator
Award. Michelle was awarded for her research
on ADAMTS13 and the association with
cardiovascular disease. Johan received the award
for his presentation on bleeding phenotype
in children with von Willebrand disease. PhD
candidate Carolien Hazendonk received the
Jeanne Stibbe Bokaal of the annual scientific
meeting of the Dutch Society for Thrombosis
and Haemostasis for the best oral presentation
delivered by PhD students.
Intensive Care
Dr. Diederik Gommers has been appointed as
professor of “Intensive Care”. On September 25,
he delivered his inaugural lecture entitled
“Wu Wei”.
PhD candidate and IC-nurse Margo van Mol
received the Anna Reynvaan Praktijkprijs on
behalf of the Foundation Family and patient
Centered Intensive Care (FCIC), for the best
nursing initiative to improve patient care. Being
admitted to a Intensive Care Unit also greatly
affects close relatives. The patient may not be able
to make deliberate choices, and family are often
overwhelmed by anxiety, grief and confusion.
The Foundation has developed several initiatives
Annual Report 2015
for counseling and support of close relatives of
ICU patients, among others diaries, information
leaflets and consultation structures.The award
came with a sculpture and sum of k€5.
Professor Johan Groeneveld was awarded
Honorary membership of the European
Society of Intensive Care Medicine (ESICM)
at the Berlin meeting in October 2015, for
his “outstanding contribution to the field of
intensive care medicine”.
Internal Medicine: Pharmacology and
Nephrology
At the European Society of Hypertension meeting
in Milan, Professor Jan Danser received the Pieter
A. van Zwieten-award for his ‘outstanding contribution to research on clinical pharmacology of
drugs acting on RAAS (Renin-Angiotensin-Aldosterone-System)’.
Dr. Ton van den Meiracker was honoured with
the Willem Birkenhäger Award by the Dutch Hypertension Society during the national hypertension congress in Zeist.
Professor Jan Danser was elected Promotor of the
year 2015 by the Erasmus MC PhD students. The
election was organized by Promeras, the representive body of all Erasmus MC PhD students.Professor Danser earned this election because ‘he is
always approachable, even during holidays’, ‘does
not think along hierarchical lines’ and ‘leaves
space to others’. He is a great motivator, ‘he succeeds to keep up with the many parallel challenges, even in hard times’, and ‘problems seem less
complex after a consultation with him’. He was
also praised particularly for his language instinct.
In april, Professor Jan Danser stepped down as
chairman of the Dutch Pharmacology Society.
Dr. Antoinette Maassen van den Brink was appointed Member of the Board. She is also member
of the Dutch Headache Society and the Medical
Advisory Council of the Dutch Society of Headache
Patients. Dr. Antoinette Maassen van den Brink is
member of the Advisory Council of the Migraine
Thrust, which was erected December 9. One of the
aims of the fund is to raise funds for migraine
research in women.
Dr. Antoinette Maassen van den Brink co-authored the ZonMW report Kennisagenda Gender
en Gezondheid, which identifies lacunas in knowledge in the field of Gender and Health care, and
which offers an agenda for future policy making.
The report was offered to Mrs. Schipper, minister
of Health on June 16, and to members of Parliament on June 24. Dr. Antoinette Maassen van
den Brink is member of the Alliance Gender and
Health, which is started by Women Inc together
with the Ministry of Health, to gain recognition
for gender differences in health care. In this context, she participated in the Dress Red Day talkshows at the VUMc on September 25.
15
COEUR
The research of the project group of Antoinette
Maassen van den Brink on migraine in women
attracted vast media attention. She was interviewed on national TV during the 8 o´clock NOS
Journaal on June 16, and interviews appeared in
national newspapers AD on June 17 and Telegraaf
on December 9.
Professor Jan Danser delivered a lecture for the
general public titled ‘From poison to pill: poison
gives life’ on December 13 during the exhibition
‘The power of poison’ in Rotterdam.
16
PhD candidate Khatera Ibrahimi received the
Prof. Dr. Saxena award from the Dutch Headache
Society for her research on migraine.
At the European Society of Hypertension 2015
meeting in Milan, PhD candidates Lodi Roksnoer
and Langeza Saleh were awarded with the Alberto
Ferrari Poster Prize. Lodi’s poster was titled “Dual
AT1 Receptor/neprilysin inhibition (ARNI) vs AT1
receptor blockade in diabetic TGR(mREN2)27 rats”.
Langeza’s poster was ‘The sFlt-1/PlGF ratio associates with adverse outcomes and prolongation of
pregnancy’. The prize included free participation
and free accommodation at the conference, and a
sum of € 500.
Langeza Saleh
Annual Report 2015
Internal Medicine: Vascular and Metabolic
Diseases
Professor Eric Sijbrands obtained a grant of k€ 22
from Insuline Medical Ltd, for a study on standardmeal-time subcutaneous injection of rapid-acting
insulin.
Dr. Monique Mulder was co-applicant of a research
proposal on “Restoring memory by activating
liver x receptors (LXR)”, which was granted k€ 100
by ISAO/AFI (Internationale Stichting Alzheimer
Onderzoek/Alzheimer Forschung Initiative). She
also received a k€3 grant from the Erasmus MC SNIP
(Support Programme National and International
Projects) fund for support in grant preparations.
Dr. Jeanine Roeters van Lennep was awarded the
Corrie Hermann 2015 prize by the Dutch Society
of Female Physicians, for her contribution to advance awareness of gender differences and multidisciplinary collaboration to improve Womens’
Health. The award was handed to her on October
10 during the symposium organized to honour
the prize winner. The title of the symposium was
“Gender sensitive medicine: from utopia to clinical
practice."
17
Dr. Jeanine Roeters van Lennep obtained a Investigator initiated grant worth k€34 from Sanofi, for
a study on “Goal attainment in primary and secondary prevention in heterozygous FH patients”.
Together with T. Vanwolleghem (Gastroenterology
and Hepatology), she also obtained a MRace-pilot
grant worth k€ 47,6 for the project “Residual cardiovascular disease risk: lessons to learn from an
optimal small animal model”.
Professor Eric Sijbrands was appointed member
of the scientific committee of the Dekker grants
of the Netherlands Heart Foundation. Dr. Jeanine
Roeters van Lennep was appointed 2015 Editor of
“Focus Vasculair”, a multidisciplinary educational
journal focussed on cardiovascular medicine.
Dr. Jeanine Roeters van Lennep
COEUR
18
Neurology
Radiology, department Biomedical Imaging
The MR CLEAN trial results were published in the
NEJM in January 2015. The trial provided convincing proof of the effectiveness and safety of
thrombectomy for acute ischemic stroke. The publication led to the early termination of 4 other trials, which all confirmed the positive effect of this
treatment. The trial was elected as one of the studies that “changed the face of medicine in 2015” by
the NEJM editorial board. The study was already
cited more than 600 times in the first year after
publication. The trial received several national
and international awards. Dr. Puck Fransen, PhD
candidates Debbie Beumer and Olvert
Berkhemer received young investigator awards
from the Neurovascular section of the Dutch
Society for Neurology.
Further research aimed at improving the
intervention and extending the indication for
treatment will be done by the newly established
consortium CONTRAST (Consortium for new
treatments of acute stroke), which is coordinated
by Erasmus MC, in collaboration with AMC and
MUMC+.
Professor Wiro Niessen (BMI) was awarded the
STW Simon Stevin Meester 2015 title, the most
prestigious prize for technological scientific research in the Netherlands. With this title and the
associated lump sum of k€500, professor Niessen
is honoured for his research into computer systems that may predict future disease in individuals, and which may lead to more personalized
treatment. His research found indications that, for
example, signs of Alzheimer’s disease are already
detectable ten to fifteen years before symptoms
appear. The computer makes predictions based
on tens of thousands MRI- and CT-scans of both
healthy and affected subjects. This approach enables the identification of pathological patterns
that remain unrecognizable otherwise. The prize
was awarded to professor Niessen on November 5
during the annual conference of STW.
The Erasmus MC Stroke Center has been established
and was officially opened on March 9. The center is a
cooperation of all departments involved in research,
education and patient care concerning stroke. It aims
to improve acute treatment, prevention and knowledge of stroke (www.strokecenter.nl).
PhD candidate Marisa Lubbers received an award
for best oral presentation at the Netherlands Society of Cardiology (NVVC) meeting. PhD candidate
Raluca Chelu received a best poster award at the
North American Society of Cardiovascular Imaging (NASCI) meeting in San Diego. PhD candidate
Adriaan Coenen was awarded for his presentation
at the annual meeting of the Society of Cardiovascular Computed Tomography (SCCT) at Las Vegas.
Marcel Dijkshoorn received special recognition
for his poster presentation at the Radiology Society of North Amercia (RSNA) meeting in Chicago.
Annual Report 2015
In 2015 two successful postgraduate cardiac CT
courses, one basic and one advanced course, were
organized in the Skills Lab of Erasmus MC.
Vascular Surgery
PhD candidate Frederico Bastos Goncalves obtained his PhD degree ‘cum laude’. His thesis defence was April 1, and the title was Endovascular
aortic repair; clarifying risk factors, complications
and follow-up strategies.
The use of a new type of stent in the treatment
of abdominal aortic aneurysmata last year was
a world’s first. The new stent is now being evaluated in a large international study led by Professor
Hence Verhagen.
PhD candidate Bibi van Thiel received an accommodation grant from the European Society of
Hypertension for this year’s conference in Milan.
At this conference she gave an oral presentation
entitled: ‘Involvement of the renin-angiotensin
system in a premature aging mouse model’. For
the same project, she won the 3rd prize during
the annual PhD competition at the FIGON Dutch
Medicine Days were she gave on oral presentation.
The award also included a price of €500.
In addition, she received a travel grant
from the North American Vascular Biology
Organization NAVBO ($500) and a travel grant
from the Trustfonds (€500) to attend the NAVBO
Vascular Biology 2015 conference in Cape Cod,
Massachusetts, USA. At this meeting she gave an
oral presentation entitled: ‘Fibulin-4 Deficiency
induces Thoracic and Abdominal Aortic Wall
Dilation and Altered Plaque Morphology in
Apolipoprotein E Deficient Mice’.
19
COEUR
Education
PhD Training
COEUR offers PhD candidates a research and
education program tailored towards their
individual requirements. This program aims to
develop their knowledge and skills such that
they can become independent researchers, and
provides them with a broad basis for their future
professional career. Monitoring of the actual
education progress of individual PhD candidates
is now standard practice, and an overview of
the education obtained during the duration of
the PhD program is presented elsewhere in this
annual report. Importantly, the current education
program has received high marks during the
external visitation of COEUR late 2014.
Contents
The curriculum of 2015 comprised the following
courses:
February 12 & 13, 2015
Cardiovascular Imaging and Diagnostics
Coordinators: Professor Aad van der Lugt
(Radiology) and Dr Hans Bosch (Cardiology)
Number of participants (PhD candidates): 26
April 16 & 17, 2015
Atherosclerosis and Aneurysmal Disease
Coordinators: Dr Fop van Kooten (Neurology),
Dr Ellen Rouwet (Surgery) and Dr Jeroen Essers
(Vascular Surgery)
Number of participants (PhD candidates): 13
June 18 & 19, 2015
Congenital Heart Disease
Coordinators: Professor Jolien Roos-Hesselink
(Cardiology), Professor Wim Helbing (Paediatrics)
and Professor Ad Bogers (Cardiothoracic Surgery)
Number of participants (PhD candidates): 22
October 8 & 9, 2015
Cardiovascular Pharmacology
Coordinators: Professor Jan Danser (Internal
Medicine) and Dr Antoinette Maassen van den
Brink (Internal Medicine)
Number of participants (PhD candidates): 9
December 10 & 11, 2015
Cardiovascular Medicine
Coordinators: Professor Frank Leebeek
(Hematology) and Dr Ton van den Meiracker
(Internal Medicine)
Number of participants (PhD candidates): 14
21
COEUR
Research Seminars
January 16, 2015
Personalized Medicine
Organizers: F Zijlstra (Cardiology), E Boersma
(Cardiology), A van der Lugt (Radiology),
AJM Verhoeven (Internal Medicine) and
AH van den Meiracker (Internal Medicine)
Speakers: A van der Lugt, A Stiggelbout (LUMC),
A IJpma, EJ Sijbrands and RHN van Schaik
Number of participants: 30
22
February 25, 2015
Costs, Quality and Value in Cardiovascular
Interventions
Organizers: RLJ Osnabrugge and AP Kappetein
Speakers: AP Kappetein, NMDA Van Mieghem,
DJ Cohen (Kansas City MO USA), JB Rich (Norfolk
USA), K Isendoorn (Gupta Strategists Amsterdam),
EW Steyerberg, AJCW Janssens (Atlanta USA) and
MGM Hunink
Number of participants: 30
March 27, 2015
Secondary prevention with anti-thrombotics:
unraveling the conundrum of bleeding vs efficacy
Organizers: FWG Leebeek (Haematology),
RJ van Geuns (Cardiology) and M Valgimigli
(Cardiology)
Speakers: J Versmissen, F Costa, T Yetgin,
M Valgimigli, FWG Leebeek and P Vranckx
Number of participants: 29
September 11, 2015
Cardiovascular interventions in the Elderly
Organizers: JJM Takkenberg (Cardiothoracic
Surgery), HJM Verhagen ( Vascular Surgery) and
FUS Mattace Raso (Internal Medicine)
Speakers: FUS Mattace Raso, TA Winkel,
J Goudzwaard, JA Bekkers
Number of participants: 20
November 13, 2015
Sex and Gender Differences
Organizers: JE Roeters van Lennep (Internal
Medicine) and JA Visser (Internal Medicine)
Speakers: A Grefhorst, S Schagen, JA Visser,
IM Jazet (LUMC), MT Mulder and
JE Roeters van Lennep
Number of participants: 16
November 27, 2015
Current insights in inherited cardiomyopathies
Organizers: M Michels (Cardiology) and
RA Oldenburg (Clinical Genetics)
Speakers: RA Oldenburg, IMBH van de Laar,
HG van Velzen, JI van Waning and
J van der Velden (VUMC)
Number of participants: 26
Annual Report 2015
December 4, 2015
The role of biomarkers in the pathophysiology of
atrial fibrillation
Organizers: NMS de Groot (Cardiology) and
BJJM Brundel (Cardiology, UMCG)
Speakers: D van Marion (UMCG), E Lanters,
NMS de Groot and BJJM Brundel
Number of participants: 13
The curriculum of 2015 comprised the following
Lectures:
February 24, 2015
Professor Dulce Casarini, Department of
Nephrology, Sao Paulo, Brazil
Title: Monitoring of biological processes:
identification of biomarkers in renal diseases and
new inhibitor of renin angiotensin system
Professor Francisco Neves, Department of
Pharmaceutical Sciences, Brazil
Title: GQ-16, a partial PPARy agonist, improves
insulin sensitivity and decreases visceral
adiposity. Pharmacological and structural studies
March 17, 2015
Dr Eric Stöhr, Cardiff Metropolitan University,
Department of Physiology and Health, United
Kingdom
Title: Cardiac function with a twist – The
importance of heart muscle deformation during
exercise and hypoxia
June 3, 2015
Professor R Dechend, Max-Delbrück-Centrum für
Molekulare Medizin Berlin, Germany
Title: Integrating hypertension and immunology:
view from a cardiologist
October 6, 2015
Professor AS Kumar, Department of Cardiothoracic
Surgery, AII Institute of Medical Science, India
Title: Ross procedure in a rheumatic population &
Ross II procedure results
November 17, 2015
Dr R Draijer, Department Nutrition & Health,
Unilever, The Netherlands
Title: Science update on tea and cardiovascular
health
November 25, 2015
Dr R Boon, Centre of Molecular Medicine, Goethe
University Frankfurt, Germany
Title: Cardiovascular aging: The role of non-coding
RNA
23
COEUR
Other educational activities
24
The 20th European symposium on Contrast
Imaging, 22-23 January 2015
Contrast echocardiography has evolved
dramatically during the last decade, from a clinical
and experimental research method to a clinical
diagnostic tool. It provides a non-invasive method
for imaging the microcirculation of the heart
and of many other organs such as the liver, often
providing information which could not be found
by alternative imaging methods. This Symposium
highlighted new directions of research, early
experiments and clinical applications by both
established faculty and young investigators. One
of its strong points was the extensive interaction
between different disciplines, including clinicians
(cardiologists, radiologists, neurologists and
others), physicists and engineers, biologists and
chemists, from both academic and industrial
backgrounds. Apart from microbubble ultrasound
imaging the interaction between microbubbles
and ultrasound has been long recognized as
having great potential for drug and gene delivery.
A detailed understanding of this is vital in
exploring the use of this exciting technology. The
programme included microbubble technology,
molecular imaging and applications for both gene
and drug delivery. Since microbubble ultrasound
imaging has been crucial into atherosclerotic vasa
vasorum imaging, emphasis was directed towards
this application including 3D ultrasound vascular
technology.
The Scientific Board: Mike Averkiou, Folkert ten
Cate, Paolo Colonna, David Cosgrove, Eleanor
Stride, Edward Leen, Nico de Jong, Arend
Schinkel
Erasmus Winter Programme
February 23 – March 13, 2015
Members of COEUR participated as lecturer in
the Erasmus Winter Programme. This annual
programme provides participants from all over
the world with an invaluable opportunity to
bring themselves right up to date in the health
sciences in an unequalled academic environment.
The Programme focusses on the basics common
to all research in clinical medicine, and courses
are taught by leading international experts
in their field. The Programme emphasizes the
understanding of principles and methods of
clinical research. It provides courses for those
particularly interested in clinical trials, in drug
safety research, and in decision making in clinical
medicine. It also includes various courses in
biostatistics.
Venue: Erasmus Expo- & Congress Centre,
Rotterdam, The Netherlands
Target group: Health professionals interested in
clinical trials, drug safety research and decision
making in clinical medicine, biostatistics.
Number of participants: 212
Annual Report 2015
Optics in Cardiology
March 11-13, 2015
The 3rd Optics in Cardiology conference took place
in Lantaren Venster Rotterdam. In the past two
editions, a meeting place for clinical and technical
researchers working with optics for diagnostics
and therapy in cardiovascular medicine was
created. The program is now complete and
features a variety of topics.
The conference for scientists, clinicians and
engineers on Optics in Cardiology provided a
forum for the latest breakthroughs in applications
of light in cardiovascular medicine, highlighting
clinical, technological and translational advances
in this fast-moving field.
Part of the Optics in Cardiology program
was a special mini-symposium on March 11,
16:00, commemorating the 25th anniversary of
intravascular imaging. The distinguished speakers
were Patrick Serruys, Klaas Bom, and Jurgen
Ligthart, reporting on the development of IVUS
in the experimental echo department from prehistory till today. Thereafter, all attendents were
invited to the Stadhuis for a reception in honour of
this occasion.
Number of participants : 191
in Rotterdam. The symposium aimed to bridge
the gap between biomechanics, vascular biology
and clinical research in order to understand
more about cardiovascular disease. A number
of internationally renowned speakers with a
clinical/biological or technical background were
invited to discuss this topic for 2 days. The keynote
speakers were Prof. Dr. Chun Yuan, University
of Washington, Seattle, USA (On Biomechanical
Conditions that Predispose Vasa Vasorum to
Rupture and Cause Intraplaque Hemorrhage: An
In Vivo Magnetic Resonance Imaging Study”) and
Prof. Francesco Migliavacca, Politecnico di Milano,
Milan, IT (Stenting and computer modeling),
who presented their latest work. Furthermore, 14
excellent researchers were invited to talk about
their latest work and more than 68 abstracts (56
posters and 12 orals) were presented. Over 150
visitors from academia and industry from all over
Europe and the USA visited the symposium. The
reactions of the speakers and the visitors were
very positive, indicating that a symposium of
this kind fills an important need. The location of
the annual conferences alternates between the
North-American Continent and Rotterdam, the
Netherlands.
Shear Stress Symposium on Biomechanics in
Vascular Biology and Cardiovascular Disease
In April 2015 we celebrated the 10th anniversary of
the “International symposium on Biomechanics in
Vascular Biology and Cardiovascular Disease’. This
year’s meeting was organized in the Hilton hotel
Information market for PhD candidates
As previously, COEUR participated in the yearly
“PhD information market” in cooperation with
Erasmus MC, the combined Erasmus MC PhD’s and
the other (local) Research Schools. This event took
place on June 4. The Research Schools provided
25
COEUR
the beginning students with information on their
schools and institutes, and last-year Erasmus
MC PhD students with information about thesis
preparation and future career possibilities.
Presentations and workshops were given on
practical PhD issues including ethics and medical
communication and writing.
MD elective program
26
The 4-week course “Introduction into
methodologies and measurements” that includes
an introduction to ECG and echocardiography as
well as cerebrovascular disorders was given to 30
medical students who elected this course as part
of their 2nd year curriculum. Under the guidance
of COEUR PhD students, couples of two students
each wrote a systematic review on a current
medical question. The reviews were presented
on January 23. The review writing process was
supervised by Dr. Ron van Domburg.
PhD-training course “Cardiac Function and
Adaptation”, “Thrombosis and Haemostasis” and
“Vascular Biology”.
October 12- October 16, 2015
The venue of the course was Papendal, near
Arnhem. The courses are organized under
auspices of and with financial support from the
Netherlands Heart Foundation.
The courses are an integral part of the PhDtraining offered by the Dutch Cardiovascular
Research Institutes including COEUR. The three
courses are taught simultaneously, meaning that
each student can participate in only one of the
three courses each year. The content of the courses
is slightly modified. An important aspect of the
courses is the interaction between PhD students
from different Research Institutes. To this end,
assignments are discussed in small groups and
social activities are planned during the evenings.
Participants also present a poster of their own
research project. 5 COEUR PhD candidates were
registered.
Annual Report 2015
27
COEUR course Cardiovascular Medicine
COEUR
COEUR day 2015
28
The annual COEUR day was held the 29th of May
in ‘het Nieuwe Instituut’ with the inspiring
theme: ‘Beyond Excellence’. Of course, we all
want to strive towards excellence, but how do
we get there? How can we, together, make sure
our research organization keeps growing and
improving and how can COEUR facilitate this?
Many important but hard questions to answer.
Last year has been an important year for
COEUR. An external assessment committee
evaluated our research school which resulted
in some recommendations. Following these
recommendations but also due to changes in the
nationwide policy, the structure and policy of our
research schools will change the coming years.
During this year’s COEUR day we discussed how
these changes will or should be implemented
to make sure that, in the future, we will truly go
‘beyond excellence’.
The day started with COEUR scientific
director Prof. Eric Boersma who explained
the recommendations made by the external
committee. Did we maintain our level of
‘excellence’ as determined by previous visitations
and what are future directions for COEUR?
Next, Prof. Diederik Dippel talked us
through the role and creation of Academic
Centers of Excellence, with the Stroke Center
as a good example. Prof. Aart Jan van der Lely
enlightened us about the future of PhD and
Master education.
The research environment in the Netherlands
is undergoing changes. Prof. Ewout Steyerberg
informed us on the research policy in the Erasmus
University Medical Center, while prof. Ton van
der Steen gave an inspiring talk about research
policy in the Netherlands as a whole. After this, all
speakers were invited to join the interactive forum
where we discussed how all these changes should
be implemented in the Erasmus MC and COEUR,
what is excellent science, are we going to win a
Nobel prize in science in the coming years with
our research lines?
The Keynote lecture ‘prize winning science’
was in the hands of Prof. Michel Ferrari
(LUMC), who received a Spinoza Price for his
groundbreaking research in migraine. He
gave a personal talk about his own drives and
achievements.
Traditionally, the afternoon was dedicated to the
PhD students. First, Dr. Maud Vissers explained
the soon to be introduced Graduate School
Management System. After this, Dr. Gijs Meeusen
gave an interactive (and sometimes hilarious)
workshop on how to gain and keep the audience’s
attention when you present your work. We ended
the day with speed-presentations by PhD students
of COEUR. This year, the audience had to vote for
the best presenter, and decided that for the second
time Yanti Octavia went ‘Beyond Excellence’
in presenting her work at the department of
Experimental Cardiology.
Annual Report 2015
We hope that everyone enjoyed this day as much
as we did!
COEUR committee 2015
Jelle Schrauwen
Ayla Hoogendoorn
Kirsten Berk
Johan Boender
Eric Boersma
Erna Egelie
Carolien Hazendonk
Adrie Verhoeven
29
COEUR
30
Professor Ton van der Steen
en Johan Boender
Annual Report 2015
31
32
Professor Michel Ferrari
33
COEUR
Professor Ewout Steyerberg
34
Professor Aart Jan van der Lely
Professor Diederik Dippel
Annual Report 2015
35
36
37
COEUR
38
58
Research
The original six research themes have been converted
in a new, matrix like structure. In the new approach,
biological, pathophysiological and clinical entities are
now dominant, and the organizational scheme has now
moved to the background. The current structure follows
the example already given in the annual report of
2006, and results from both internal as well as external
recommendations. In the current set-up, the following
three major themes have been chosen:
I. Vascular Medicine
II. Acute Cardiovascular Syndromes
III. Chronic Cardiac Disease
Within these three major themes, different Research
Programs haven been created, while the various
disciplines and disease stages are now on the vertical
axis. The matrix is outlined in more detail on the
following pages, and should provide much better
insight into the various research activities within
COEUR.
39
COEUR
Discipline I
Aetiology & Pathogenesis
Themes
Discipline II
Imaging & Diagnos
Echo
Theme I
Vascular Medicine
I-A
Atherosclerosis
MRI
Molecular Biology
IVUS
CAD im
Biomechanics
Biomechanics
Periphe
Vascular Damage & Repair
I-B
Disorders of the microcirculation
Role of RAAS
Ageing
Regulation of Tone
I-C
Cardiovascular Genetics
Genetic regulation of vasculo/angiogenesis
Metabolic Diseases
I-D
Aneurysm disease
Molecular biology
Aortic imaging
Genetic regulation
Role of RAAS
Aortic remodeling
40
Theme II
Acute CV Syndromes
II-A
Hemostasis & Thrombosis
Role of hemostasis in thrombosis
II-B
Acute Coronary Syndromes
Mechanisms of Plaque Vulnerability
II-C
Stroke & Migraine
IVUS
CAD im
Biomechanics
Periphe
Causes of Stroke
Neurovascular Imaging
Pharmacology of migraine
II-D
Critical Illness and Sepsis
Microcirculation
Theme III
Chronic Cardiac Disease
III-A
Cardiac Remodeling and Failure
III-B
Arrhythmias
Atrial fibrillation
III-C
Congenital heart disease
Mechanisms of cardiac remodeling and failure
Mechanisms of cardiac remodeling and failure
3D echo
Cardiac Imaging
CV Imaging & Diagnostics
Cardiac Imaging
Ageing
Cardiogenetics
Cardiac Imaging
Annual Report 2015
Discipline II
ging & Diagnostics
maging
MSCT
Discipline III
Therapy & Prevention
Technology
Percutaneous
Interventions
CAD imaging
Image Processing
Peripheral Vessels
Clinical Decision Making in Surgery
Peripheral imaging
US Transducers
Stents and Restenosis
Cardiac Risk Evaluation and Modification
US agents
CV Surgery &
Anesthesiology
Risk Stratification &
Pharmaco Therapy
CABG
Role of RAAS
Pharmacogenomics
Image processing
Aortic endografts
Medical Manag. of aneurysm disease
Molecular imaging
41
Manag. of hemorrhag & thrombc disorders
CAD imaging
Image Processing
Peripheral imaging
US Transducers
Image Processing
Primary PCI for AMI
Cardioprotection
Biomarkers of acute coronary event
Cerebrovasc. Disease
Prognosis & Clinical Manag. of Stroke
Pharmacology of migraine
Image Processing
Stem Cell Therapy
US Transducers
Heart Transplantation
Mapping
Catheter Ablation
Image Processing
Cath Based Int.
US Transducers
Assist-Devices
ICD Therapy Stratific.
Outcome
COEUR
Themes
Discipline I
Aetiology & Pathogenesis
Echo
42
Theme I
Vascular Medicine
I-A
Atherosclerosis
2,4,5
I-B
Disorders of the microcirculation
1,2,8
I-C
Cardiovascular Genetics
I-D
Aneurysm disease
Theme II
Acute CV Syndromes
II-A
Hemostasis & Thrombosis
II-B
Acute Coronary Syndromes
II-C
Stroke & Migraine
II-D
Critical Illness and Sepsis
Theme III
Chronic Cardiac Disease
III-A
Cardiac Remodeling and Failure
III-B
Arrhythmias
III-C
Congenital heart disease
4,5,19
6,12,24
24
24
14,15
1
19
9,13
3
1,2,8,12
21
17,18
10
Annual Report 2015
Discipline II
Imaging & Diagnostics
Discipline III
Therapy & Prevention
MRI
MSCT
Technology
Percutaneous
Interventions
CV Surgery &
Anesthesiology
Risk Stratification &
Pharmaco Therapy
4,2
4,2
16,18,23
2,19
28
7,31
3
8
20
12
24
24
25
24
14,15
20
20
16,23
22
22
16,23
19
28
9,13,22
43
3,27
20,22
11,29
20,22
16,23
2,29
8,12
17,2
23,26
23
16
4,11
28
30
COEUR
Project 1
Cardiac (mal)adaptation to stress and damage
44
Ischemic heart disease, in particular myocardial infarction, and hypertension are major causes of heart failure
in western countries. Following myocardial infarction or chronic exposure to pressure-overload, the heart
undergoes extensive alterations in muscle mass and geometry. This cardiac remodeling is associated with
an increased likelihood of progression towards overt heart failure, particularly in the setting of an aging
population. Research within Project Group 1 is aimed at improving our understanding of the mechanisms
underlying the progression from ischemic and hypertensive heart disease towards heart failure in order to
identify novel targets for therapy. For this purpose, our research focuses on the pathogenesis and therapy
of (i) acute myocardial infarction, (ii) the cardiac remodeling and dysfunction that follows in the weeks
after an acute myocardial infarction or in the presence of systemic pressure-overload, (iii) myocardial and
coronary microvascular dysfunction and in post-infarct remodelled myocardium (iiii) pulmonary hypertension
secondary to hypoxia, left ventricular dysfunction or thrombo-embolic events. Furthermore, we study (v) the
effects of aging and exercise training on cardiac remodeling and dysfunction following myocardial infarction
and chronic pressure overload.
Finally, in view of the increasing prevalence of heart failure with preserved ejection fraction and the role
therein of multiple co-morbidities we also have recently begun studying the influence of risk factors, such
as diabetes, hypercholesterolemia, and renal dysfunction on coronary microvascular-, and cardiac diastolic
function.
Annual Report 2015
Principal Investigators
DJGM Duncker, D Merkus
Co-Investigators
VJ de Beer, AJJC Bogers, C Cheng, AHJ Danser, RJM van Geuns, IM Heinonen, JH Hoeijmakers, M van Houwelingen, AH van den Meiracker, IKM Reiss, AJM Roks,
JW Roos-Hesselink, OE Sorop, D Tibboel, F Zijlstra
PhD candidates
Name
Subject
GMJ de Boer
Cardiac dysfunction in aging: The role of genomic instability
RWB van Duin
Pathophysiological mechanisms in pulmonary cardiovascular disease
GJ van Essen
Does cardiovascular performance in domestic swine obey allometric scaling laws?
M van den Heuvel
Coronary microvascular dysfunction in diabetes mellitus
DPM Meijler
Pulmonary hypertension (of the neonate)
K Stam
Pulmonary Hypertension and associated Right Heart Failure: breaking the vicious circle
YJHJ Taverne
Reactive oxygen species and the endothelium. Friend or foe of the cardiovascular system?
T Yetgin
Cardioprotection during primary percutaneous coronary angioplasty
45
COEUR
Project 2
Experimental interventional cardiology, vascular injury and repair
This interdisciplinary project focuses on percutaneous interventions in the treatment of arteries (coronary
and peripheral) and their target tissues in health and disease.
1. Specifically, we study pharmacokinetics and pharmacodynamics of (device-based) pharmacologic
interventions such as drug eluting stents and scaffolds on micro- and macro-vasculature.
2. The pathophysiology of arterial thrombosis in acute ischemic syndromes such as stroke and myocardial
infarction. This work is performed in collaboration with projects 13 and 15.
3. The role of novel invasive and non-invasive imaging methods to assess these effects over time.
4. The sequelae of- and novel treatment strategies against- ischemia and reperfusion injury in the depending
tissues e.g. using biomaterials. This work is performed in collaboration with project 1.
46
Device-based (pharmacological) interventions are performed in different species and disease models,
testing various drug-eluting stents, scaffolds and other intravascular devices for their effects on micro- and
macro-vasculature. To replace, reduce and refine animal experiments, we use ex-vivo vascular models where
possible such as healthy and diseased cadaver arteries with heart-lung machines, organ-baths and lab-on-achip approaches. In addition, we employ a wide range of different disease models in large animals, ranging
from simple interventions in healthy young animals to complex dedicated models such as diet- or diabetes
induced accelerated atherosclerosis. These are used to unravel important mechanical, pharmacological and
pathophysiological effects on the response to vascular injury and repair in both coronary and peripheral
arterial beds. We study the diagnostic value of a number of imaging modalities (e.g. OCT, NIRS, IVUS, MSCT
and MRI) in order to understand how they can help to characterize the baseline environment and to study the
response of the vasculature itself as well as the effects on the depending tissues.
In collaboration with TU Delft we are modelling drug transport phenomena in health and disease. We use
routine and spectral histology such as mass spectrometry (MS) imaging (financed by NWO through a grant to
van Beusekom) to analyze the tissues at high spatial resolution both quantitatively and qualitatively.
The pathophysiology of arterial thrombosis in acute ischemic syndromes is studied in collaboration with
the clinical cardiac catheterization laboratory, the dept. of Hematology and the depts. of Neurology and
Radiology. This has resulted in two biobank projects, one for coronary thrombus aspirates (CorTAsk project)
Annual Report 2015
and one for stroke emboli (Mr Clean biobank). One of the aims is to study how thrombus phenotype affects
vascular healing, with an emphasis on NETosis, a recently discovered new thrombosis pathway which we
hypothesize plays a role in (micro)vascular injury. As such, NETosis and their resultant circulating biomarkers
are hypothesized to play a role in no-reflow in the area subjected to ischemia and reperfusion.
Principal Investigators
HMM van Beusekom, DJGM Duncker, ES Regar
Co-Investigators
AHJ Danser, DWJ Dippel, ACGM van Es, TM Luider, MPM de Maat,
G van Soest, F Zijlstra
PhD candidates
Name
Subject
ASA Autar
Arterial Thrombosis and Netosis in Acute Myocardial Infarction
N van Ditzhuijzen
A Karanasos
JN van der Sijde
Imaging of coronary interventions and early atherosclerosis in a porcine coronary model
Optical coherence tomography for guiding coronary interventions and assessing the
vascular healing response after coronary stent implantation
Retrospective analysis of the Thoraxcenter OCT data on the impact on stent procedure and
outcome
47
COEUR
Project 3
The circulation, ventilation and ethics during multiple organ failure.
Critical illness often results in multiple organ failure. Sepsis is a common source and the syndrome affects
the circulation and ventilation among other vital organ functions. The research around this typical intensive
care syndrome is thus programmed around these topics, as can be deducted from the individual projects
enumerated below. Research on the circulation in the syndrome focuses on peripheral perfusion, among others.
New techniques, like side stream dark field (SDF), laser speckle imaging and near-infrared spectroscopy (NIRS)
have been studied for assessing microvascular perfusion in septic patients. In order to minimize inflammatory
response in mechanically ventilated septic patients, a new lung monitoring device (Electrical Impedance
Tomography) is used to optimize ventilator settings. Ultimately, the syndrome can be intractable, raising
ethical issues on end-of life decisions.
48
Principal Investigators
J Bakker, J van Bommel, DAMPJ Gommers, ABJ Groeneveld, C Ince, EJO Kompanje
PhD candidates
Name
Subject
JPC van den Akker
P Blankman
M Egal
PJ van der Geest
K de Haan
B van der Hoven
MMC van Mol
S Stads
The effect of mechanical ventilation on kidney function
Optimizing ventilator settings in order to reduce inflammatory response
Acute kidney injury and fluids
De ProBic study and other diagnostics of infection
Vitamin D in critical illness
Measurement of functional liver blood flow
Reducing emotional and moral distress among Intensive Care professionals
Predicting initiation and discontinuation of continuous renal replacement therapy
in the critically ill
Improvement of care for ICU patients with delirium by early screening and
treatment
Z Trogrlic
Annual Report 2015
Project 4
Shear-stress related plaque formation & destabilization: from bench to bedside to population studies
Shear stress plays an important role in the patho-biology of the endothelium. Among others, it primes the
endothelium for atherosclerotic plaque formation, which can be found at the low and oscillatory shear
stress regions in the vasculature. However, evidence is accumulating for a role of high shear stress in plaque
destabilization. This project focuses on a) the different (molecular) aspects of the role of low or high shear
stress in the generation and destabilization of vulnerable plaques and, b) the usage of shear stress in the
prediction of plaque destabilization and future events. For that reason studies are performed in animal models
of vulnerable plaque formation as well as in patients that are treated for pathological lumen obstruction. For
those studies a combination of computational fluid dynamics and advanced catheter based or non-invasive
imaging techniques for the assessment of plaque composition is applied. Using the information from the above
described studies, we investigate whether shear stress can contribute to prediction models of atherosclerotic
plaque growth and events in a population based study.
Principal Investigators
JJ Wentzel, K van der Heiden
Co-Investigators
OH Franco, RJ van Geuns, FJH Gijsen, A van der Lugt, ES Regar, AFW van der Steen,
MW Vernooij, TH van Walsum, GP Zahnd
PhD candidates
Name
Subject
M Cibis
Image based wall shear stress measurement
K Dilba
Non-Invasive assessment of carotid Atherosclerotic Plaques for stroke Risk Prediction
A Hoogendoorn
Functional, multi-modality imaging of atherosclerotic plaque progression
EJ Meester
Non-invasive molecular imaging of inflammation to detect atherosclerosis
AM Moerman
Shear stress and atherosclerotic plaque lipodomics
JTC Schrauwen
Fusion of imaging parameters for prediction of plaque rupture in human coronary arteries
LCJ Winkel
Endothelial NOX/ROS contribution to plaque vulnerability
R Xing
Linking biomechanics to the biology of plaque progression: a non-invasive imaging study
49
COEUR
Project 4 - continued
Shear-stress related plaque formation & destabilization: from bench to bedside to
population studies
Calculating wall shear stress in coronary arteries - Jelle Schrauwen
50
The frictional force on the arterial wall caused by flowing of blood is called wall shear stress (WSS).
It has been shown that altered WSS patterns are an important factor in the onset and progression of
atherosclerosis. It has also been suggested that deviating WSS is associated with atherosclerotic plaque
destabilization, which could initialize trombotic events and potentially myocardial infarction. To better
understand the role of WSS in this process, it is important to develop tools that can obtain relevant WSS
data. My PhD project at EMC was part of a cross-collaboration between the departments of Biomedical Engineering, Cardiology and Biomedical Image Processing, and two industry partners. I focused on
computing WSS in coronary arteries of patients suffering of atherosclerosis. I worked on coupling 3D
blood flow computations to several medical imaging techniques for example CT or interventional x-ray.
Hemodynamic data such as coronary blood pressure or blood flow velocity is required as input for the
WSS computations. I developed models to calculate that hemodynamic data and compared that with
in vivo measured values. A second part of the project involved coronary OCT which is an intravascular
technique that can be used to image the arterial wall in high detail. For this project, Guillaume Zahnd
developed software that can automatically detect diseased sections of the coronary wall. For the at-risk
regions he developed a method to precisely measure the cap thickness of a plaque, which is directly
correlated with plaque rupture. These cap-thickness data from OCT were combined with the WSS data
from imaging data. The combination of image-based parameters could give insight in the rupture-risk
of coronary plaques, and in the future this might serve as additional information during interventional
procedures. These ideas were tested in collaboration with the department of interventional cardiology.
Annual Report 2015
51
Jelle Schrauwen
COEUR
Project 5
Biomechanics of the vascular wall
Plaque rupture is in the majority of the cases the underlying cause of cardiovascular events. Plaque rupture
occurs at the locations were the stress exceeds the local plaque strength. Plaques are very heterogeneous
in composition and local tissue strength. However, not much is known on the biomechanical properties
of the different plaque components. In this project we investigate at which pressure and at what location
the plaque would rupture by studying the local stress distribution and deformation of the different plaque
components under increasing loading. Therefore, in an in vitro setup atherosclerotic plaques from patients or
animal models of atherosclerosis are subjected to different pressure loadings and the local deformations are
imaged using advanced imaging techniques. This information will be used to validate computations on stress
distributions in these plaques. Advances will be made in imaging of plaque deformation and (multiscale)
modeling of the different plaque components.
52
Principal Investigators
FJH Gijsen, JJ Wentzel
Co-Investigators
M de Bruijne,C Chiastra, F Iannacconne, A van der Lugt, WJ Niessen, L Speelman, AFW van der Steen
PhD candidates
Name
Subject
AM Kok
The role of biomechanical factors in plaque progression using image based
modeling
Annual Report 2015
Project 6
Genetic regulation of vasculogenesis and angiogenesis
In this project, we have performed a genome wide expression to identify new molecular regulators of vessel
stabilization during development and disease. We have identified a list of candidate genes involved in vessel
stabilization in response to endothelial cell and mural cell interaction. A number of these clones were analyzed
using an in vitro co-culture approach in which endothelial cells and mural cells can interact to form tubules
in a 3D matrix environment. This was followed by in vivo knockdown validation of our findings in zebrafish
larvae, using morpholino technology and mutant zebrafish lines. Subsequent studies analyzed in depth the
function of the novel proteins using gain-of-function and loss-of-function analysis to determine the molecular
signaling cascade and the function of the proteins in vessel formation in development and cardiovascular
disease.
Principal Investigator
C Cheng
Co-Investigators
DJGM Duncker, F Zijlstra
53
PhD candidates
Name
Subject
MM Brandt
I Chrifi
C Zhu
Molecular Endothelial-Pericyte interaction
Effect of mural cell-endothelial cell interaction during new vessel formation
CECR1 activity in macrophages regulates tumor angiogenesis
53
COEUR
Project 6 - continued
Genetic regulation of vasculogenesis and angiogenesis
Molecular regulation of angiogenesis - Maarten Brandt
54
Angiogenesis is the process in which endothelial cells and perivascular cells create new vessels under
the influence of a broad spectrum of stimuli. This process is tightly regulated and imbalances in signaling can be a causative or progressive factor in many vascular defect associated diseases, including tumor
angiogenesis, and diabetes or metabolic risk factors related microvascular disease, leading to organ
failure. A thorough insight into the molecular mechanisms involved in angiogenesis and endothelial homeostasis, are therefore essential for maintaining vascular health and subsequent prevention of disease.
Potential strategies include manipulation of the (disturbed) angiogenic process by defining the basic
mechanisms and changing the activation of key regulators.
In our studies we try to unravel the function of several putative target genes that play important
roles in angiogenesis. One of the factors that we study is Frizzled receptor 5, which is involved in the
Frizzled-Wnt signaling cascade. From literature it is known that this receptor is indispensible in embryonic vascular development. Frizzled 5 knock-out mice show a lethal deficiency in placenta and yolk sac
angiogenesis, but the exact molecular mechanism behind this observation still lacks clarification. Using
a combination of in vitro and in vivo techniques, we try to decipher the function of this receptor in endothelial cells, and how it is involved in regulating angiogenesis.
Besides focusing on specific factors involved in angiogenesis, we also study the interaction between endothelial cells and pericytes. Pericytes are perivascular cells that induce vascular stabilization, endothelial maturation and barrier formation. Besides their well described positive role in the vascular system,
detached pericytes are recently implied to act as progenitors of extracellular matrix depositing cells in
fibrotic organs. In our study we try to find out whether this differentiation into a scarring cell type is a
direct consequence of loss of interaction with the endothelium, and if so, which cellular interaction molecules are important in preventing this trans-differentiation into a disease associated phenotype.
With these projects we hope to generate basal knowledge about vascular and perivascular biology, which might eventually serve as a foundation for future therapeutic strategies.
Annual Report 2015
55
Maarten Brandt
COEUR
Project 7
Perioperative care
Cardiovascular disease is the major cause of postoperative morbidity and mortality. In Europe, 40.000.000
surgical procedures are performed every year, with a cardiovascular mortality rate of 0.3% (133.000 patients).
To improve postoperative outcome, preoperative identification of patients at risk is performed using clinical
risk scores, biomarkers for coronary artery disease and heart failure, and cardiac imaging. The preoperative risk
assessment is linked to the intraoperative identification of acute coronary syndromes using electrocardiography
and cardiac imaging as well as newly identified biomarkers. The follow-up of these patients is performed
regularly, for early identification of cardiac events. The identification of a genetic predisposition in relation
with biomarkers and subsequent treatment is the research line of this group.
56
Principal Investigators
RJ Stolker
Co-Investigators
SE Hoeks, F van Lier, EG Mik, HJM Verhagen
PhD candidates
Name
Subject
GM Balestra
Mitochondrial function in critical illness
SIA Bodmer
Measuring of mitochondrial and microvascular oxygenation
W Galal
Correlation of pre- and perioperative ischemia in vascular surgery
F Grüne
L Khajeh
Changes of effective downstream pressure in cerebral perfusion under influence of
anaesthetics and vasoactive drugs
Benzodiazepines in perioperative care
Subject
Study
of hemostatic
and intra arterial treatment in acute ischemic stroke
Surgical
outcome; aparameters
fresh perspective
(SMARTIS)
The making of the ‘MPA-16’
Genetic and non-genetic causes of dementia
Measuring mitochondrial function in sepsis
MR CLEAN Multicenter randomized clinical trial of endovascular treatment for acute
ischemic stroke
Hypopituitarism in patients after subarachnoid hemorrhage: screening and treatment
CP Mendez-Orellana
Mechanism of language recovery after brain damage
F Nouwens
Randomized trial of speech and language therapy in aphasia after stroke
E Osei
Treatment and prognostic value of prediabetes and newly diagnosed diabetes in patients
with a TIA or minor stroke
Body temperature and prognosis in acute ischemic stroke
HJ
Mijderwijk
Name
D
Beumer
EKM
Tjeertes
MHN van Velzen
RFAG de Bruijn
MA Wefers Bettink
PSS Fransen
IR de Ridder
Annual Report 2015
57
Dr. Sanne Hoeks
COEUR
Project 8
Hypertension, the kidney and vascular ageing: focus on the renin-angiotensinaldosterone system
This project focuses on hypertension, capitalizing on four pathways to discover novel intervention pathways,
namely:
- the role of aldosterone in difficult-to-treat hypertensive subjects,
- hypertension induced by angiogenesis inhibition in patients with cancer,
- the impact of genomic instability on hypertension, and vascular and renal function, and
- the regulation of volume and osmoregulation in kidneys by WNKs and exosomes
58
An important unifying aspect in all the above topics, apart from the common relationship with hypertension,
is the involvement of the renin-angiotensin-aldosterone system (RAAS), resulting in projects that investigate
angiotensin/aldosterone interaction in the kidney, the function of the (pro)renin receptor in intercalated cells,
the vasodilator effects of endothelial angiotensin II type 2 receptors (with an emphasis on gender-related
aspects), the angiotensin-(1-7) / Mas receptor axis, the non-genomic effects of aldosterone in the vessel wall,
and the role of RAAS- and related interventions on genomic instability-related vascular and renal dysfunction.
The studies concerning genomic instability involve transgenic mice with decreased DNA repair function, and
are performed in close collaboration with the Departments of Genetics and of Vascular Surgery. Studies on
the importance of nucleotide phosphodiesterases in ageing occur in collaboration with the Department of
Epidemiology.
Annual Report 2015
Principal Investigators
AHJ Danser, EJ Hoorn, AH van den Meiracker, AJM Roks, R Zietse
Co-Investigators
A Dehghan, DJGM Duncker, J Essers, OH Franco, JHJ Hoeijmakers, GJ van der Horst,
I van der Pluijm
PhD candidates
Name
Subject
P Bautista Niño
Cyclic nucleotide phosphodiesterases in vascular aging
S Lankhorst
Hypertension and Renal Toxicity during Angiogenesis Inhibition: Salt Dependency and
Treatment Options
AD Moes
When salt turns sour: from kidney salt transport to hypertension
LCW Roksnoer
Urinary biomarkers in humans and rats: focus on diabetes and aldosteronism
L Saleh
The predictive value of the sFit-1/PIGF ratio for the diagnosis of preeclampsia
M Salih
Exosomal research on ADPKD
D Severs
The immune system and sodium balance
59
Name
JS Biedermann
Name
JS
Biedermann
J Boender
Subject
Treatment with anticoagulants
Subject
Treatment
In search ofwith
newanticoagulants
causes of Von Willebrand disease
JHCAM
Boender
Hazendonk
HCAM
Hazendonk
I van Moort
LM Schütte
SCM Stoof
In
search of Peri-Operative
new causes of PharmacokineTIc-guided
Von Willebrand disease dosing of CLOTting factor in hemophilia
OPTI-CLOT:
OPTI-CLOT:
Peri-Operative PharmacokineTIc-guided
dosing
ofof
CLOTting
“OPTI-CLOT”:Peri-Operative
PharmacokineTIc-guided
dosing
CLOTingfactor
factorininhemophilia
Clotting
Factor Disorders
Moderate
and Severe Von Willebrand Disease in the Netherlands
Moderate and Severe Von Willebrand Disease in the Netherlands
"OPTI-CLOT":Peri-Operative PharmacokineTIc-guided dosing of CLOTing factor in Clotting
DDAVPDisorders
treatment combIneD with FVIII clotting factor concentrates in patients with nonFactor
severe haemophilia
A-DAVIDwith
studyFVIII clotting factor concentrates in patients with nonDDAVP
treatment combIneD
Optimization
of
treatment
of
inherited bleeding disorders
severe haemophilia A-DAVID study
SCM Stoof
Optimization of treatment of inherited bleeding disorders
YV Sanders
YV Sanders
I van Moort
LM Schütte
COEUR
Project 8 - continued
Hypertension, the kidney and vascular ageing: focus on the renin-angiotensinaldosterone system
60
Lodi Roksnoer
Annual Report 2015
‘Targeting the renin-angiotensin-system in hypertension and diabetes’ Lodi Roksnoer
Blockers of the renin-angiotensin-system (RAS) are the cornerstone in the treatment of hypertension,
heart failure and diabetic nephropathy. Yet, morbidity and mortality of these diseases remain high,
despite near-complete suppression of the RAS. Therefore, we need new therapeutic strategies. Neprilysin
inhibitors (NEPi) prevent the breakdown of bradykinin and natriuretic peptides, promoting vasodilation and natriuresis. However, they also increase angiotensin II and endothelin-1. We studied the effects
of NEPi combined with angiotensin receptor blockade (ARB) on blood pressure, vascular reactivity, and
cardiac hypertrophy in hypertensive rats. We observed that rats treated with ARB plus a low dose of
NEPi (ARNI) had a significantly lower blood pressure than animals treated with ARB alone. The low
dose of NEPi counterbalanced the slow rise in blood pressure during prolonged RAS blockade, rather
than enhancing its immediate hypotensive effect. This beneficial effect of ARNI was abolished when a
ten-fold higher dose of NEPi was used, and this was associated with higher endothelin-1 levels. Therefore, apparently optimal dosing rather than maximal dosing is crucial. Next, we studied the effects of
ARNI on diabetic nephropathy in hypertensive rats with diabetes. To our surprise, the slow rise in blood
pressure during ARB treatment did not occur, and, therefore, ARNI was unable to exert an additional
beneficial effect on blood pressure compared to ARB treatment alone. However, ARNI-treated animals
did have less proteinuria, glomerulosclerosis, and cardiac hypertrophy. We conclude that these favorable,
blood pressure-independent effects of ARNI versus ARB, support the application of NEPi in ARB-treated
diabetic patients in future clinical trials.
61
COEUR
Project 9
Pharmacology of migraine
Migraine is a paroxysmal neurovascular disorder, which is 2-3 times more prevalent in women than in men.
Currently available drugs for the acute treatment of migraine all constrict cranial blood vessels, which most
likely mediates their therapeutic action. However, since these drugs may also constrict peripheral blood
vessels, including the coronary artery, there is a concern about cardiac side effects and these drugs are thus
contraindicated in patients with cardiovascular disease. We are investigating the neurovascular properties
of prospective antimigraine drugs. In addition, since migraine is a major cardiovascular risk factor, we focus
on the (endothelial) vascular properties of migraine patients. Because migraine occurs more often in women
and depends on hormonal fluctuations such as occurring around the menstruation, we focus on the effects of
(changing levels of) female sex hormones on mechanisms implied in the pathophysiology of migraine.
62
Principal Investigator
A Maassen van den Brink
Co-Investigators
AJJC Bogers, AJ van den Bogaerdt, AHJ Danser, MF Dirven, MD Ferrari,
AMJM van den Maagdenberg, GM Terwindt, AG Uitterlinden
Postdocs
KY Chan, KA Haanes
PhD candidates
Name
Subject
ALR Labastida
KM Linstra
AERB Rubio Beltrán
Relation between CGRP and cardiovascular disease
Migraine as determinant of stroke risk in reproductive age
Peripheral microvascular function in murine models of migraine
Annual Report 2015
CREW-MIST: Cardiovascular risk profile in women: microvascular status Katie Linstra
The CREW-MIST study is part of the national CREW project aimed at investigating the female specific
cardiovascular risk profile. Current cardiovascular risk prediction models rarely include factors exclusive
to women, such as polycystic ovary syndrome (PCOS) and pregnancy-related events, such as pre-eclampsia.
An important example of a female-specific cardiovascular risk factor is migraine, a neurovascular
headache disorder with a high prevalence among young women (~25%). It is associated with an increased risk of cardiovascular morbidity, including a twofold increased stroke risk.
Endothelial dysfunction is likely to play a pivotal role in the pathophysiology behind the association
between migraine and cardiovascular disease. The pathophysiology of cardiovascular disease might be
related to microvascular ischemia and endothelial dysfunction in women more so than in men.
For this study, 500 women between 45 and 55 years old with a medical history associated with cardiovascular disease (PE, PCOS or stroke) will be invited. Three different parameters of microvascular health
will be assessed in equal groups of women diagnosed with migraine and without migraine.
Firstly, white matter hyperintensities (WMHs) on brain MRI will be quantified. WMHs are a sign of cerebral microvascular damage and are associated with cardiovascular morbidity and migraine. In addition,
MRI of the heart and carotid arteries will be performed. Secondly, peripheral endothelial dysfunction
will be assessed using local thermal hyperaemia (LTH), an elegant method using heating of the skin of
the arm to induce changes in the dermal blood flow. Thirdly, peripheral vascular function will be evaluated using EndoPAT by measuring changes in finger pulse amplitude after occlusion of the brachial
artery.
We expect to gain insight into the additional impact of migraine on the vascular health of women
with pre-existing cardiovascular disease and the role of endothelial dysfunction in this process.
63
COEUR
Project 9 - continued
Pharmacology of migraine
64
Katie Linstra
Annual Report 2015
Project -10
Translational and Clinical Electrophysiology
Our research projects are aimed at developing innovative diagnostic tools and therapies by implementing
basic electrophysiology into daily clinical practice. Main research topics are mechanisms of (post-operative)
atrial fibrillation, dysrhythmias in patients with congenital heart disease, channelopathies and development
of electro-anatomical mapping techniques.
Atrial fibrillation (AF) is associated with significant morbidity and mortality. The prevalence of AF will continue
to rise and AF will persist to pose a major burden on public health costs. Anti-arrhythmic drugs are often
not effective in eliminating AF episodes and ablative therapy is also not so successful as first assumed. The
expected epidemic of AF necessitates research in order to develop preventive strategies, to improve existing
treatment modalities and design novel therapies. After the discovery that paroxysms of AF can be triggered
by pulmonary vein foci, isolation of the pulmonary veins was introduced as a potential curative treatment
modality. It is in general assumed that in patients with persistent AF, AF has progressed from a triggerdriven to a substrate mediated arrhythmia. In these patients, persistence of AF no longer depends on the
presence of a trigger (‘true fibrillation’) but is maintained by an arrhythmogenic substrate. Although animal
studies have provided extensive insights into the various mechanisms that can explain perpetuation of AF,
it is unknown which specific electropathological changes are relevant for the development of a substrate of
persistent AF in humans. Also, it is unknown whether different cardiac diseases result in different electropathological alterations. Particularly in patients with congenital heart disease, there are no mapping data
available. Clinical mapping data of AF are scarce and the available studies are often limited to parts of the
atria or a small number of beats. Theoretically, multi-site high density mapping can be used to localize
sources generating AF in patients with trigger-driven AF and to identify areas perpetuating AF in patients with
substrate mediated-AF. Based on the premise that AF can be eliminated by ablation of either the trigger or the
substrate perpetuating AF it is expected that multi-site high density mapping is a suitable tool to diagnose AF
thereby allowing individualization of AF treatment. The mechanism of early post-operative dysrhythmias is
studied by correlating continuous rhythm registrations with hemodynamic alterations.
65
COEUR
Project 10 - continued
Translational and Clinical Electrophysiology
Principal Investigator
NMS de Groot
Co-Investigators
M Götte, BJJM Brundel, AJJC Bogers, F Zijlstra
PhD candidates
66
Name
Subject
P Bhagirath
Cardiac imaging and electrophysiology (Haga)
L van der Does
Morphology of atrial unipolar electrograms: does it reflect the arrhythmogenic substrate
underlying atrial fibrillation ?
M de Graaf
Cardiac imaging and electrophysiology (Haga)
CA Houck
Cardiac arrhythmias in patients with congenital heart disease and channelopathies
P Knops
The arrhythmogenic substrate of atrial fibrillation
E Lanters
The role of biological markers in the pathophysiology of atrial fibrillation.
D de Marion
The role of biomarkers in the pathophysiology of atrial fibrillation.
EMJP Mouws
Development of post-operative atrial and ventricular tachycardias
A Rhagab
Cardiac arrhythmias in patients with channelopathies
TTTK Ramdjan
Mechanisms underlying dysrhythmias in patients with congenital heart disease
C Teuwen
Cardiac arrhythmias in patients with congenital heart disease and the role of Bachman’s
Bundle in development of atrial fibrillation
Post-Operative Atrial Fibrillation in the 21st century
A Yaksh
66
Annual Report 2015
The role of biological markers in the pathophysiology of atrial fibrillation
Eva Lanters
Atrial Fibrillation (AF) often progresses from a trigger dependent to a substrate mediated arrhythmia. The exact characteristics of this arrhythmogenic substrate are not completely understood. Since AF tends to recur in
40% of the patients after electrical cardioversion or isolation of the pulmonary veins, optimal understanding
of the pathophysiology is of utmost importance. Persistence of AF induces atrial remodeling on an electrical,
structural and contractile level. The combination of electrical and structural remodeling is also referred to as
electropathology. Our novel, high-resolution intra-operative epicardial mapping procedure allows localization
and quantification of electropathology in the individual patient. Biomarkers of the Heat Shock Protein (HSP)
family potentially reflect the degree of atrial electropathology, as is present in patients with AF. The main
focus of my research is to identify the extensiveness of atrial electropathology in patients undergoing cardiothoracic surgery, pulmonary vein isolation (PVI) or electrical cardioversion (ECV) for AF, with our mapping
approach and HSPs.
Epicardial mapping procedures have been performed in 600 patients undergoing cardiac surgery
for ischemic, valvular or congenital heart disease,
with or without AF. So far, we quantified the extensiveness of atrial electropathology during sinus
rhythm in CABG patients with electrically non-remodeled (“healthy”) atria. The results of this analysis
will serve as a reference dataset for all future mapping studies.
Tissue samples, including blood samples and atrial
appendages have been obtained from almost 200
cardiothoracic surgery, PVI or ECV patients included
in the HALT & REVERSE project. The samples are currently being investigated at the VU Medical Center
by our colleagues on this project.
These studies will increase our understanding of
the pathophysiology of AF and are steps towards the
development of patient tailored treatment of AF and
novel treatment strategies.
Eva Lanters
67
COEUR
Project 10 - continued
Translational and Clinical Electrophysiology
Clinical Electrophysiology Part I
Principal Investigators
NMS de Groot, T Szili-Torok
Co-Investigator
F Zijlstra
PhD candidate
Name
Title
R Bhagwandien
Outcome of catheter ablation of atrial fibrillation
Clinical Electrophysiology Part II
68
Principal Investigator
T Szili-Torok
Co-Investigators
F Zijlstra
Clinical outcomes of catheter ablation procedures for the treatment of cardiac
arrhythmias
Many patients are suffering from cardiac arrhythmias which could lead to life-threatening conditions.
Catheter ablation is a well-established therapy and has been introduced in the 1980s for the treatment of
these arrhythmias. During the past decades, it became a first-line therapy for several types of arrhythmias.
With an increasing eligible population suffering from arrhythmias, the safety of procedures is crucial to
determine which patients should be considered for ablation. Further developments are necessary to minimize
complications as much as possible.
In the past significant improvements have been made to increase safety and efficacy of ablation procedures,
such as the introduction of irrigated-tip catheters, the use of intracardiac echocardiography, and cryo-energy
ablation. New technological developments are currently available and could potentially improve the safety
and outcome of ablation procedures. One of the innovations is the remote magnetic navigation system that
allows remote manipulation of the catheter in the heart. It has been suggested that this system improves
patient safety and offers advantages for targeting complex cardiac arrhythmias. Another development is
the introduction of catheters that could measure the force that the catheter applies to the myocardium.
This provides crucial information for appropriate lesion formation and improves the efficacy of the ablation
procedures.
Annual Report 2015
Project 10 - continued
Translational and Clinical Electrophysiology
The clinical electrophysiology department at the Erasmus MC aims to investigate novel innovations to
improve safety and efficacy of catheter ablation procedures. The Erasmus MC plays an important role in the
international publications on the remote magnetic navigation system and other technological developments
for catheter ablation procedures.
PhD candidates
Name
Title
J de Heide
Improving the pre-, peri-and postprocedural care of electrophysiology patients with the nurse
practitioner a casemanager
Z Kis
The role of rotors in atrial fibrillation treatment
LJ de Vries
Etiology of Idiopathic Ventricular Tachycardia
69
COEUR
Project 11
Percutaneous Interventions in Structural Heart Disease
70
Catheter-based treatment of structural heart disease is a recent but rapidly evolving treatment modality. At
present it is primarily reserved for patients with aortic stenosis who are considered poor candidate for surgical
valve replacement. As a result of ongoing research and innovations in catheter technology, bioprosthetic
materials (scaffolding frame and tissue), imaging (3-4D, co-registration) in addition to operator experience,
it is expected that catheter-based treatment will also be available for other forms of structural heart disease
such as mitral – and aortic regurgitation, left ventricular systolic dysfunction in addition to the application of
these techniques in patients who are candidate for surgical treatment.
Research in this domain will encompass 1] clinical cohort research examining the safety and efficacy,
the evaluation of responder and non-responder by the definition of determinants of (clinical and technical)
outcome by means of single- and multicenter collaborative efforts, 2] pathophysiologic assessment of the
effects of treatment on the morphology, function and haemodynamics of various cardiac components
(myocardium, valves, ascending aorta) in collaboration with the department of radiology and experimental
cardiology, 3] randomised clinical comparison between catheter-based and surgical treatment of structural
heart disease, 4] advanced imaging allowing 3D and eventually 4D co-registration of the anatomy during
treatment (collaboration with experimental cardiology, radiology and industry)
Principal Investigator
PPT de Jaegere
Co-Investigators
RPJ Budde, RT van Domburg, MJ Lenzen, FUS Mattace Raso, NMDA Van Mieghem,
JJM Takkenberg, YJHJ Taverne, HJM Verhagen
PhD candidates
Name
Subject
N El Faquir
Advanced imaging in planning and evaluation of TAVI
L van Gils
Stroke during TAVI; aetiology and preventive measures
JA Goudzwaard
Transcatheter Aortic Valve Replacement and the elderly
Z Rahhab
Innovation in mitral valve therapy
R Rodriguez-Olivares
Paravalvular aortic regurgitation after TAVI
MJAG de Ronde-Tillmans
Influence of TAVI on quality of life in elderly patients with Aortic Stenosis
Annual Report 2015
Project 12
Cardiovascular genetics and metabolic diseases
At the Erasmus outpatient clinic for cardiovascular genetics, family based approaches are employed to
study inherited cardiovascular diseases: cardiomyopathies, congenital heart malformations, arrhythmias,
dyslipidemias, diabetes mellitus, hypertension and severe premature coronary artery disease.
Technical innovation is a hall mark of this research: for example, novel imaging modalities are used to identify
new phenotypes and high-throughput molecular analyses are performed to identify modifier genes in
addition to major locus effects.
We have identified a large number of novel genes that are associated with cardiovascular disease and related
traits. We perform molecular and biochemical studies to get a better understanding of the mechanisms
underlying the diseases and the complications.
Our clinical research is performed in patients with very rare diseases, like ßβ-myosin heavy chain defects in
noncompaction cardiomyopathy, but also more common disorders of synthesis and processing of insulin in
families with type 2 diabetes.
71
COEUR
Project 12 - continued
Cardiovascular genetics and metabolic diseases
Principal Investigators
EJG Sijbrands, F Zijlstra
Co-Investigators
CM van Duijn, ECH Friesema, M van Hoek, FUS Mattace Raso, M Michels, MT Mulder,
JE Roeters van Lennep, FWM de Rooij, JW Roos-Hesselink, AFL Schinkel, AG Uitterlinden,
AJM Verhoeven, MW Wessels
PhD candidates
72
Name
Subject
KAC Berk
Cognitive behavioral therapy after very low calorie diet in overweight
patients with type 2 diabetes
S Bos
Improvement of risk stratification in patients with familial dyslipidaemia
TTW van Herpt
Genetic and Environmental Risk Factors of Type 2 Diabetes
SM den Hoedt
Functional defects of lipid metabolism in Alzheimer’s disease
S Jainandunsing
Pancreatic beta-cell function and type 2 diabetes
RFH Lemmers
HDL and vascular complications in Diabetes Mellitus type 2
M Licona-Rashid
Vascular function and microalbuminuria
RA Neeleman
Optimizing treatment and follow-up for acute porphyric patients
B Özcan
Glycemic control in type 2 diabetes
B Spoto
Inflammatory balance and cardiovascular risk
HG van Velzen
Hypertrophic Cardiomyopathy
R Vongpromek
Lipid composition in heart and brain diseases
PA Vriesendorp
Risk stratification in hypertrophic cardiomyopahty
R Yahya
Novel diagnostic test to improve CVD risk reduction in subjects with DMII, increasing cost
effectiveness and quality of life
Annual Report 2015
Project 12 - continued
Cardiovascular genetics and metabolic diseases
Improvement of risk stratification in patients with familial hypercholesterolemia Sven Bos
Familial Hypercholesterolemia (FH) is the most common metabolic disorder that is associated with
premature cardiovascular disease (CVD). FH can be diagnosed by clinical criteria or genetically by identification of a pathogenic mutation in the LDLR gene, APOB gene or PCSK9 gene. These mutations cause
the clinical phenotype in which LDL-Cholesterol levels are severely elevated and subsequently lead to
the higher CVD risk. To lower CVD risk in FH patients cholesterol lowering agents, mainly statins, are
used. The impact of statins on the life expectancy of FH patients can hardly be overestimated. Before the
statin era half of men with FH and 12% of women with FH suffered from a myocardial infarction before
the age of fifty. However, despite statin therapy 39% of FH patients still develop CVD. The classical risk
factors: age, male sex, body mass index (BMI), hypertension, diabetes mellitus, smoking and reduces
high-density lipoprotein (HDL) levels all clearly contribute to CVD risk in FH patients. But even in the
absence of these classical risk factors some patients still develop cardiovascular events. The research in
my project focussed on identification of FH patients who are still at increased risk despite statin treatment. For identification we investigated the non-traditional risk factor Lipoprotein (a) (Lp(a)), and used
cardiovascular imaging. We found that Lp(a) was not associated with subclinical atherosclerosis in
statin-treated FH patients measured by carotid ultrasonography. Interestingly Lp(a) was associated with
aortic valve calcification measured by CT scanning in our FH patients. We also found that the presence
and severity of aortic valve calcification are increased in FH patients compared to controls. Currently, we
are investigating the clinical applicability of carotid ultrasonography in the statin-treated FH patient,
and are trying to find novel biomarkers related to CVD in FH patients by using proteomic techniques.
AC van Dijk
QJA van den Bouwhuijsen
MJ Berghout- van Gils
Name
Imaging atherosclerotic plaque in ischemic stroke
coronary heart disease and stroke
The predictive value of vulnerable plaques in the carotid arteries for risk of
determinants and prognosis of change in volume composition and morphology
Serial CT Angiography of atherosclerotic carotid plaque:
Subject
73
COEUR
Project 13
Stroke: risk factors and etiology, prognosis and treatment
74
Stroke is a heterogeneous disease; it comprises ischemic stroke, intracerebral hemorrhage and subarachnoid
hemorrhage. Stroke is a high-ranking cause of death and the most common cause of acquired disability in
The Netherlands and Western Europe. Causes of disability include motor dysfunction and disturbances of
language, memory and cognition.
Etiologic studies within this project include genetics, hemostasis (von Willebrand factor, fibrinogen),
glucose metabolism, cardioembolic disorders, and carotid plaque morphology (PARISK). New translational
research will be aimed at microvascular obstruction after thrombectomy in acute ischemic stroke.
Intervention studies include a series of multicenter RCT’s of the effect of prevention of high body temperature
and fever (PAIS). Also, we conducted a large national multicenter study of the effect of intra-arterial treatment
for acute ischemic stroke (MR CLEAN), which is now extended into a national registry of thrombectomy
interventions, and includes a database with thrombus material and neuro-imaging. Furthermore, we evaluate
early cognitive linguistic treatment of aphasia in a series of multicenter RCT’s (RATS) and the value of functional
imaging (FIAT) in patients with aphasia caused by stroke.
Data for genetic, prognostic and etiologic studies are derived from the Erasmus Stroke Study, an ongoing
hospital based registry, and from the Rotterdam study, a large population based cohort study.
Annual Report 2015
Principal Investigators
DWJ Dippel, PJ Koudstaal
Co-Investigators
HMM van Beusekom, CM van Duijn, BJ Emmer, MH den Hertog, MA Ikram, F van Kooten, LML de Lau, FWG Leebeek, HF Lingsma, A van der Lugt, MPM de Maat, M Smits,
PhD candidates
EW Steyerberg, EJG Sijbrands, MW Vernooij, EG Visch-Brink
Name
Subject
D Beumer
Study of hemostatic parameters and intra arterial treatment in acute ischemic stroke
(SMARTIS)
PSS Fransen
MR CLEAN Multicenter randomized clinical trial of endovascular treatment for acute
ischemic stroke
L Khajeh
Hypopituitarism in patients after subarachnoid hemorrhage: screening and treatment
MJHL Mulder
MR CLEAN REGISTRY
F Nouwens
Randomized trial of speech and language therapy in aphasia after stroke
E Osei
Treatment and prognostic value of prediabetes and newly diagnosed diabetes in patients
with a TIA or minor stroke
IR de Ridder
Body temperature and prognosis in acute ischemic stroke
75
COEUR
Project 13 - continued
Stroke: risk factors and etiology, prognosis and treatment
RATS-3: Rotterdam Aphasia Therapy Study; a randomized controlled trial on early
intensive treatment for aphasia due to stroke - Femke Nouwens
76
Aphasia, one of the possible consequences of stroke, affects language-processing and can have a large
impact on everyday life. Hence, most patients with aphasia receive speech and language treatment (SLT).
In the prior Rotterdam Aphasia Therapy Studies (RATS-1 and RATS-2) we studied one particular type of
SLT: cognitive-linguistic treatment (CLT). It has been hypothesized that CLT positively interacts with poststroke spontaneous neural recovery, as CLT supposedly triggers specific neural pathways for language
processing. Since neural recovery occurs temporarily after stroke, supposedly CLT should be initiated as
soon as possible.
In RATS-3 we tested the hypothesis that early initiated intensive CLT is more effective than deferred
regular SLT for the recovery of aphasia due to stroke. Over 80 Dutch institutions participated in this
multi-center randomized controlled trial. Between January 2012 and December 2014 we have included
153 patients with aphasia caused by stroke, and randomly allocated them within two weeks after stroke
to either four weeks of intensive CLT or no language treatment, followed by usual care.
Although early intensive treatment is widely promoted in rehabilitation-medicine, it appeared very difficult to reach the intended treatment intensity of 28 hours in 4 weeks. We found no statistically significant differences on the primary outcome (everyday verbal communication) between the intervention
group and control group.
Our findings show that an early boost of CLT is not more effective than later initiated usual care for
the recovery of post-stroke aphasia. Hence, there appears no urgency to start impairment-based treatment as soon as possible after stroke. We expect that our results will raise a sturdy discussion in the field
of rehabilitation-medicine, as early treatment is currently highly stimulated. However, we now know
that a later start is not detrimental, and in the light of budgetary limitations in health-care, reorganization of aphasia rehabilitation may be considered.
Annual Report 2015
77
Femke Nouwens
COEUR
Project 14
Management of hemorrhagic and thrombotic disorders
Clinical studies on bleeding disorders, including von Willebrand disease (VWD) are currently performed within
this theme. The Von Willebrand disease in the Netherlands (WiN) study is a nation-wide study coordinated by
the ErasmusMC (PI Prof dr Frank W.G. Leebeek) on the clinical aspects of VWD. In this study more than 800
patients with moderate and severe VWD are included. We have studied the impact of the disease on quality of
life and obtained more insight in diagnosis and disease burden. In addition we focus on optimal treatment of
this bleeding disorder. In the future we will focus on the genotype-phenotype association.
The etiology, diagnosis and treatment of various clinical entities of venous thrombosis are also focus of
our research. One of our interests is the site specificity of venous thrombosis, for instance hepatic and portal
vein thrombosis. In collaboration with other partners we have initiated studies on prevention and treatment
of arterial and venous thrombosis using new oral anticoagulant drugs, including direct factor IIa and Xa
inhibitors.
78
Principal Investigators
FWG Leebeek, MJHA Kruip, MH Cnossen
Co-Investigators
MPM de Maat, DC Rijken
PhD candidates
Name
Subject
JS Biedermann
Treatment with anticoagulants
J Boender
In search of new causes of Von Willebrand disease
HCAM Hazendonk
OPTI-CLOT: Peri-Operative PharmacokineTIc-guided dosing of CLOTting factor in hemophilia
EJ Huisman
Trombocytopathy in children
I van Moort
"OPTI-CLOT": Peri-Operative PharmacokineTIc-guided dosing of CLOTing factor in Clotting
Factor Disorders
LM Schütte
DDAVP treatment combIneD with FVIII clotting factor concentrates in patients with nonsevere haemophilia A-DAVID study
SCM Stoof
Optimization of treatment of inherited bleeding disorders
CSB Veen
Unexplained bleeding tendency - new diagnostic options
Annual Report 2015
Project 15
Role of hemostasis in arterial thrombosis
The studies performed in this theme are focusing on the role of coagulation factors and platelets in the
development of arterial thrombosis. Several case-control studies have been initiated to investigate the role of
hemostatic or inflammatory factors in determining the risk of first and recurrent arterial thrombotic events,
including stroke and acute coronary syndrome. Our special interest is on von Willebrand factor and fibrinolysis.
Several genetic approaches are used, including GWAS, SNP and haplotype analysis. We have obtained more
insight in the mechanism of fibrin formation and fibrinolysis by identifying new proteins binding to fibrin
using plasma proteomics techniques. In the coming years we will also focus on the role of alpha-2-antiplasmin
in arterial thrombosis. The effect of fibrin structure on the risk of thrombosis and the relationship with
atherosclerosis and angiogenesis, is studied using recombinant and plasma-purified fibrinogen forms.
Principal Investigators
FWG Leebeek, MPM de Maat, DC Rijken
Co-Investigators
JW Deckers, DWJ Dippel, PJ Koudstaal
Post-doc
S Uitte de Willige
PhD candidates
Name
Subject
S Abdul
Regulation of fibrinolysis by alpha-2-antiplasmin
MAH Sonneveld
Von Willebrand factor, ADAMTS13 and the risk of stroke
79
COEUR
Project 15- continued
Role of hemostasis in arterial thrombosis
Regulation of fibrinolysis by alpha-2-antiplasmin- Shiraaz Abdul
80
Cardiovascular thrombotic disease, a major cause of morbidity and mortality, is characterized by partial
or complete occlusion of an artery by a thrombus or blood clot. Blood clots, mainly composed of fibrin,
can be dissolved by the fibrinolytic system via plasmin which on its turn is tightly regulated by its main
natural inhibitor alpha-2-antiplasmin (a2AP or Plasmin Inhibitor). In the circulation, a2AP exists in different molecular forms by undergoing N- and C-terminal proteolytic cleavages. This heterogeneity has
a huge impact on the functionality of a2AP. My project aims to fully elucidate the role of a2AP and its
heterogeneity in pathological thrombus formation and dissolution and will include the biochemical characterization of a2AP N- and C-terminal variation and functionality and further evaluation of the clinical
relevance of a2AP heterogeneity. Studies have already elucidated the N-terminal cleavage site and responsible protease, which affects a2AP crosslinking to fibrin. Crosslinking of a2AP to fibrin renders fibrin
less sensitive for breakdown by plasmin. In contrast, the exact C-terminal cleavage site(s) and protease(s)
responsible for this cleavage are still unknown. Recently, we have identified a candidate C-terminal
cleavage area at an interesting location in the a2AP C-terminus. This candidate region will be used to
further identify the responsible protease by using a2AP recombinant mutants proteins. We will assess
the relevance of this cleavage site by measuring antigen levels of the different a2AP molecular forms and
the protease in patient samples. These studies, focusing on N- and C-terminal variation, will improve our
knowledge of the mechanisms that regulate a2AP function and eventually will help us identify novel
therapeutic targets for treatment of thrombotic disorders like Myocardial infarction, Ischemic Stroke and
Venous Thromboembolism.
Annual Report 2015
81
Shiraaz Abdul
COEUR
Project 16
Ultrasound Contrast agents
Ultrasound contrast agents (UCA) consist of gas microbubbles (1 – 10 µm) that are coated by a protein, lipid
or polymer. In addition to their diagnostic value, microbubbles have great potential as local drug delivery
systems. In project 16 we investigate the clinical and the more fundamental/ future use of UCA and targeted
UCA.
The clinical use includes the left ventricle opacification and myocardial perfusion during normal and stress
echocardiography. Further, a clinical study (ParisK) is running to detect the presence and properties of
atherosclerotic plaques in the carotid artery after administration of UCA.
82
Future use of UCA lies in ultrasound molecular imaging by using targeted microbubbles that bind to cellular
disease processes. These targeted microbubbles are functionalized using specific ligands and injected into
the human body. Upon excitation by an appropriate ultrasonic field the microbubbles start to vibrate thereby
acting as an ultrasound source. This source shows a very specific signature which differs to a great extent from
the scattering by normal/pathological tissue. For therapy the bubble can be either loaded with the drug of
choice where the drug can be locally released upon ultrasound and/or the vibrating bubble is used to enhance
the uptake of the drug. Essential in this whole process is the knowledge of the vibrating bubble, the ultrasound
field, and the imaging capabilities of the ultrasound system.
Principal Investigator N de Jong
Co-Investigators FJ ten Cate, K Kooiman, AFL Schinkel, AFW van der Steen
Postdoc
HJ Vos
PhD candidates Name
Subject
DI Beekers
Microbubble-mediated Drug Delivery
T van Rooij
Molecular Ultrasound Imaging
IV Skachkov
Sonodrugs
J Viti
Ultrasound contrast imaging methods for perfusion measurements
Annual Report 2015
Project 17
Echocardiography: Transducers and image processing
Research focuses on novel ultrasound transducers and image processing for ultrasound, with a strong accent
on novel 3D and high-framerate cardiovascular imaging. This includes matrix transducers, electronics and new
beam forming for 2D and 3D imaging of the heart, the carotid artery etc. Cardiac shear wave elastography
is an important topic. Moreover, image processing approaches for 3D image generation, 2D and 3D image
analysis and quantification by segmentation, tracking and classification are pursued.
Current applications include improved real-time 3D TEE and 3D ICE imaging, 3D echocardiography analysis,
myocardial stiffness assessment for diastolic heart failure, 4D mapping of flow in the heart, 3D imaging
and analysis of plaque in carotid arteries, and monitoring and procedure guidance of electrophysiological
interventions with 3D ultrasound. This COEUR project currently includes the MICA, PUMA, Heartin4D, 4DFlow,
3DICE and IMAGIC projects. All of these are embedded within the Medical Delta framework and involve
cooperation with TU Delft and/or Leiden University Medical Center.
The research is strongly aimed at fast clinical translation. The projects are all strongly governed by the
demands and feedback of (tentative) clinical users within the Thoraxcenter and beyond. New technology is
mostly developed on experimental research scanners, tested on phantom, ex-vivo and preclinical material,
and tested on volunteers and patients with clinical systems as soon as this is feasible and allowed. Good
contacts with ultrasound machine and transducer manufacturers assure a fast transition into commercially
available equipment.
Principal Investigators
JG Bosch, N de Jong, AFW van der Steen, HJ Vos
Co-Investigators
ML Geleijnse, A van der Lugt, T Szili-Torok, MD Verweij
Postdocs
BM van Dalen, P Kruizinga
PhD candidates
Name
Subject
D Bera
Miniature ultrasound probe for real-time three-dimensional imaging and monitoring of
Cardiac interventions
JD Voorneveld
Heart Failure and 4D Flow
83
COEUR
Project 17- continued
Echocardiography: Transducers and image processing
84
Deep Bera
Annual Report 2015
Miniature ultrasound probe for real-time three-dimensional imaging and
monitoring of cardiac interventions - Deep Bera
Transesophageal echocardiography (TEE) produces high quality ultrasound images of the heart. Unlike
a standard transthoracic echocardiogram, the transducer is mounted on a tube that passes through the
patient’s mouth, into patient’s esophagus. Currently, 3D TEE is used for real time diagnostic imaging and
image guidance in adults. There is no real time 3D imaging device for babies and infants because of the
relatively large diameter of the probe. TEE procedures in adults fail in 5-10 % of cases due to the high
level of discomfort (or intolerance) caused by the large probe in the throat. Real time 3D imaging for
visual feedback in electrophysiology procedures and valve replacements in adults is becoming increasingly important. Rhythm disorder treatments are life-saving but lengthy interventions that last up to 4-6
hours. The patient should be awake in many cases, so the discomfort of a large 3D probe is prohibitive.
Therefore, one possible solution could be a miniature 3D TEE probe which is suitable for small children
and can be inserted via patient’s nose (which is also unpleasant) causing less discomfort to the patient.
The aim of this project is to design a miniature 3D TEE probe with dimensions similar to a pediatric 2D
TEE probe (head volume approx. 1cm³, tube 5mm). Such a probe should contain built-in electronics to
accommodate the large number of elements (approx. 900) with a very limited number of cables (approx.
200) in the tube. The heat dissipation should be very low to prevent tissue heating.
Very recently we have successfully built the first of its kind low power (approx. 250mW) prototype 3D
TEE transducer with the dimensions as mentioned earlier, in collaboration with our partner research
groups in TUDelft and partner company Oldelft. This transducer includes a custom-designed integrated
circuit to achieve the functionalities we have in mind. At this moment we are characterizing the properties of the probe and doing 3D imaging experiments with it. We are also developing the signal processing tools needed to produce 3D images using this probe.
Later we will realize the real-time monitoring and fusion with multimodality applications e.g. CT or
MRI. With the integrated position sensor and full control of the 3D beamforming, a unique device for
interventional monitoring can be realized. We are very hopeful that this will lead us to a new era of
3D TEE usage.
85
COEUR
Project 18
Intravascular ultrasound techniques
Intravascular imaging is momentarily highly focusing on characterizing the composition of the atherosclerotic
plaque. Characterizing lipid content, plaque vascularization and thickness of thin caps are of particular
interest. These characteristics discriminate a stable plaque from a rupture prone or vulnerable plaque. The
latter one can cause myocardial infarctions or stroke. Plaque vascularization is measured by intravascular
ultrasound in combination with ultrasound contrast agents. Several strategies are developed to characterize
lipid content. These are based on optical coherence tomography or combination catheters where light and
sound are combined.
86
Principal Investigator AFW van der Steen
Co-Investigators G van Soest, ES Regar
Postdocs V Daechin, T Wang
PhD candidates Name
Subject
M Gnanadesigan
Tissue characterization of the atherosclerotic plaque using optical coherence tomography
S Iskander-Rizk
Photoacoustic guidance of RF ablation for atrial fibrillation
J Janjic
Image-guided Interventions and Therapy-Chronic Total Occlusions (IGIT-CTO)
A Karanasos
Innovations in the use of clinical OCT
R Pakdaman
Intelligent catheters in advanced systems for interventions
M Pekar
Endovascular devices for intracardiac application
M Visscher
Imaging Atheromics
M Wu
Intravascular photoacoustic imaging
Annual Report 2015
Project 19
Intravascular imaging and interventional cardiology
The decision making process for patients with obstructive coronary artery disease requiring revascularization
is evolving. Historically, patients with the most complex coronary artery disease were preferentially treated
by surgical revascularization: however technological advances in percutaneous therapy have ensured that
many of these patients can now receive equally effective treatment with percutaneous coronary intervention
(PCI). Intertwined with these developments are a lower threshold to investigate patients with symptoms
suggestive of coronary artery disease, an increasingly elderly population in need of revascularization, the
changing dynamics of the doctor-patient relationship, and a greater emphasis on guideline driven patient
care. Consequently decisions regarding revascularization are now more complex than ever before.
The advent of drug eluting stents (DES), which consist of a drug (immunosuppressive or antiproliferative drug),
a polymer and a metallic platform, has revolutionized the practice of interventional cardiology by significantly
reducing the rates of restenosis and repeat revascularization as compared to bare metal stents. The latest
development includes the development of a bioresorbable platform eluting similar antiproliferative drugs
trying to reduce the long-term negative impact of a permanent implant. Within this project, this subject is
studied in detail while taking into account evolvement in stent development, as well as secular trends in acute
and chronic benefits of percutanuous coronary interventions.
Principal Investigators
RJM van Geuns, PW Serruys
Co-Investigators
H Boersma, J Daemen , RT van Domburg, HM Garcia Garcia, PPT de Jaegere, ES Regar,
AFW van der Steen, F Zijlstra
PhD candidates
Name
Subject
FC Costa
RD Diletti
Bleeding and Thrombosis during percutaneous coronary intervention
Coronary Artery Atherosclerosis and Restoration Therapy in Bioresorbable Vascular Scaffold
Era
Bioresorbable Absorb scaffolds in complex lesions
Bioresorbable vascular scaffold (BVS) in real world patients
Renal Sympathetic Denervation
Prognostic Impact of Left Main Coronary Artery Anatomy
Upper Extremity Dysfunction Post TR-PCI
J Fam
CM Felix
L Feyz
CHD Girasis
EM Zwaan
87
COEUR
Project 19 - continued
Intravascular imaging and interventional cardiology
BVS in real-world patients - Cordula Felix
88
Drug-eluting stents (DES) currently form the mainstay of coronary devices used in percutaneous coronary
interventions (PCI) in many parts of the world. Despite advantages in clinical outcomes such as reduction
in target lesion revascularization rates within the first year, shortcomings related to the use of DES still
exist such as delayed arterial healing, late stent thrombosis and hypersensitivity reactions to the polymer.
In addition, from a physiological point of view, a vessel that is indefinitely caged in a metal stent may
not be desirable with long-term implications and adverse consequences such as impaired endothelial
function, the reduced potential for vessel remodeling, interference with the normal arterial healing
process and the risk of occlusion of covered side branches by neointima hyperplasia. Follow-up after one
year post implantation has shown a consistent late re-intervention rate where even some of the initial
benefit is lost. Furthermore, interference with non-invasive imaging (cardiac computed tomography or
magnetic resonance imaging) during patient follow-up and possible impairment of future treatment
options (re-PCI or coronary artery bypass surgery) are drawbacks of metallic stents.
To overcome these limitations, bioresorbable scaffolds (BRS) were developed. The BRS most studied is
the Absorb bioresorbable vascular scaffold (BVS). The BVS provides transient vessel support and gradually
elutes the anti-proliferative drug everolimus. After degradation of the polymer no foreign material
remains. Multiple studies have proven safety and feasibility of the BVS. However, in- and exclusion criteria
were rather strict and extrapolation to a more complex population is limited. The aim of my research
is investigating the performance of the BVS in a more real-world patient population, including specific
subsets as long lesions, bifurcation lesions and thrombotic lesions in the setting of an acute coronary
artery syndrome.
Annual Report 2015
89
Cordula Felix
COEUR
Project 20
Cardiac Imaging (MRI and CT)
90
The advanced cardiac imaging group is a joint initiative by the departments of cardiology and radiology
and collaborates with several (pre-) clinical departments within the Erasmus MC. In 2015 research activities
included assessment of several technological innovations and new clinical applications, i.e. computational
fluid dynamics and stress myocardial perfusion imaging to assess the hemodynamic significance of obstructive
coronary disease. Results from an on-site CT derived FFR algorithm were published this year, and participation
in an international registry on the value of CT derived FFR will start in 2016. Together with the University of
Tübingen the Erasmus MC will lead a multicentre validation study (SPECIFIC trial) of dynamic stress perfusion
CT, which will start enrolment early 2016. Ongoing investigation into the implementation of cardiac CT in
clinical practice includes the use of cardiac CT in patients with stable angina (fast-track chest pain clinic), to
exclude coronary disease in patients with congestive heart failure, and as a tool for triage of acute chest pain
in the emergency ward. Two clinical multicenter trials (CRESCENT and BEACON), a collaboration between a
total of ten Dutch centers, were completed in 2015. The CRESCENT 2 trial (with Albert Schweitzer Hospital,
Maasstad Hospital and Maastricht UMC) completed enrolment, and enrolment in the IsoCOR trial, which
compares the effectiveness of two different contrast media for coronary imaging, started enrolment. The
results of the CAMPER trial, into the potential role of cardiac CT in high-risk populations, were accepted for
publication. Combined with positron emission tomography, the value of CT imaging is investigated in the
context of prosthetic valve endocarditis. For cardiac MRI, 4D flow imaging has been investigated in particular
for patients with congenital heart disease. The group also supports research projects focussed on reduction
of the myocardial infarct size and the treatment of systemic and pulmonary hypertension. In an international
multicentre registry the use of T1-mapping for the quantification of diffuse myocardial fibrosis is applied in
patients with hypertrophic cardiomyopathy.
Annual Report 2015
Principal Investigators
K Nieman, RPJ Budde, RJM van Geuns
Co-Investigators
M Dijkshoorn, MGM Hunink, WJ Niessen, M Ouhlous, JW Roos-Hesselink,
PA Wielopolski
PhD candidates
Name
Subject
RG Chelu
Advanced MRI techniques
A Coenen
Imaging in advanced coronary artery disease
A Dedic
Clinical application of CT coronary angiography
AS Dharampal
Cardiac CT
GJR ten Kate
Imaging of coronary arteries by MSCT
M van Kranenburg
CMR of acute myocardial infarction
MM Lubbers
Clinical implementation of cardiac CT
SL Papadopoulou
Coronary atherosclerotic plaque imaging with MSCT
T Springeling
Acute myocardial infarction and MRI
91
COEUR
Project 20 - continued
Cardiac Imaging (MRI and CT)
Clinical use of CARDIAC CT - Marisa Lubbers
Stable angina is a common and disabling disorder, characterized by discomfort to the chest, typically
provoked by exertion or stress. It is caused by atherosclerotic degeneration of the coronary artery wall,
resulting in vessel lumen narrowing limiting the ability to increase blood flow and supply of oxygen
to the myocardium at instances of increased demand. The current guidelines still recommend stress
tests as first line diagnostic test for patients with stable chest pain. While considered cost effective, the
functional stress test is also known for its modest diagnostic accuracy, which in practice often leads to
multiple testing.
92
Cardiac CT is an alternative modality for diagnosing coronary artery disease. Its high sensitivity and negative predictive value makes it an excellent diagnostic examination to rule out coronary artery disease.
In the multicenter CRESCENT trial, conducted in 4 hospitals in the Rotterdam region, 350 patients with
stable angina were prospectively randomized between cardiac CT and standard functional testing. The
tiered cardiac CT protocol included a calcium scan followed by CT-angiography if the Agatston calciumscore was between 1-400. We found that one year after a cardiac CT scan, more patients were free of angina compared to patients in the functional testing group. Furthermore, after cardiac CT additional tests
were required less frequently, the final diagnosis was established sooner, resulting in lower cumulative
diagnostic costs.
This trial is followed by the CRESCENT-2 trial, in which we added myocardial perfusion imaging to the
CT algorithm. As CT-angiography has a relatively low specificity, the addition of adenosine-stress myocardial perfusion CT imaging, assessing the functional relevance of coronary narrowing, completes the
non-invasive cardiac CT evaluation. If >50% obstructive coronary disease is found on CT angiography,
it is followed by perfusion imaging: after coronary vasodilation by adenosine infusion CT images of
the myocardium will be acquired during injection of iodine contrast medium. Reduced opacification of
myocardium indicates myocardial ischemia. The effectiveness and (cost-)efficiency of this comprehensive cardiac CT workup of suspected coronary artery disease will be evaluated in comparison to standard
functional testing.
Annual Report 2015
93
Marisa Lubbers
COEUR
Project 21
Cardiac imaging (ultrasound)
Echocardiography is one of the most important diagnostic tools in cardiology. Recent advances in ultrasound
hardware and software have made 3-dimensional echocardiography and speckle tracking echocardiography
possible. These techniques are used for estimation of left ventricular function according to the classically
defined volumes and ejection fractions but also deformation and rotation imaging. Finally, plane-wave
imaging is a new research tool to investigate stiffness of the heart.
Principal Investigator
ML Geleijnse
Co investigators
RT van Domburg, AFL Schinkel
PhD candidates
94
Name
Subject
HJ Boiten
Long-term outcome after cardiac stress imaging
F Kauer
Speckle Tracking Echocardiography in hypertrophic cardiomyopathy
M Strachinaru
Diagnosing diastolic heart failure by myocardial stiffness with ultrasound shear wave
technique
Annual Report 2015
Project 22
Neurovascular imaging (MRI and CT)
Ischemic cerebral infarcts are related to the presence of atherosclerotic disease in the carotid artery. Severity
of the stenosis is a predictor of clinical symptoms and is used as parameter in the therapeutic decision as to
which patients will benefit from carotid intervention. Next to stenosis, plaque morphology is thought to
be a major determinant of cerebrovascular events.
Within this project, imaging of the atherosclerotic plaque in the carotid bifurcation with multidetector
CT and MRI is evaluated. We focus on 1) the validation of imaging parameters by comparison of images with
histology, 2) development of new structural and haemodynamic parameters of atherosclerotic disease, 3)
development and validation of automated measurements, 4) prospective studies in patients and healthy
volunteers to prove the additional value of plaque parameters in risk prediction, 5) serial imaging studies
to evaluate the natural course of the atherosclerotic disease, 6) studies into the relationship between
atherosclerotic plaque parameters and brain infarcts and white matter lesions on CT and MRI.
95
Principal Investigator
A van der Lugt
Co-Investigators
D Bos, DWJ Dippel, OH Franco, PJ Koudstaal, WJ Niessen, HJ Verhagen, MW Vernooij
PhD candidates
Name
Subject
MJ Berghout- van Gils
Serial CT Angiography of atherosclerotic carotid plaque: determinants and prognosis of
change in volume composition and morphology
QJA van den Bouwhuijsen
The predictive value of vulnerable plaques in the carotid arteries for risk of coronary
heart disease and stroke
AC van Dijk
Imaging atherosclerotic plaque in ischemic stroke
T Zadi
Silent MR Angiography
COEUR
Project 23
Image processing (Cardiovascular)
Cardiovascular imaging has gone beyond the traditional depiction of vascular luminal morphology. Stateof-the art imaging techniques have the potential to provide detailed information on the vessel wall, such as
plaque composition, elastic wall properties, and even biochemical processes that take place in the plaque.
In addition, dynamic and perfusion imaging can provide functional information, e.g. for determining the
perfusion or motion of the heart, or to study tumor activity. Owing to the growing complexity and sheer size
of cardiovascular data, in combination with the large increase in the number of studies in clinical practice
and biomedical research, there is a strong and increasing interest in robust, automated processing tools to
aid in the analysis of these data. This research line aims to develop and evaluate novel image processing
techniques for visualization, quantification, and integrated analysis of multimodal anatomical and functional
cardiovascular imaging data.
96
Principal Investigator
WJ Niessen
Co-Investigators
M de Bruijne, RJM van Geuns, S Klein, GP Krestin,
A van der Lugt, AFW van der Steen, Th van Walsum, JJ Wentzel
PhD candidates
Name
Subject
A Arias Lorza
Image analysis of the carotid artery for assessment of biomechanical stress on atherosclerotic plaques
G Dibildox
Computer Aided Image Guidance for Percutaneous Treatment of Coronary Chronic Total
Occlusions
Hua Ma
IMAGIC - intelligent image guidance in cardiac interventions
EMM Santos
Automated Intracranial Thrombus Quantification and Characterization in Computed
Tomography
Annual Report 2015
Influences of clot permeability on treatment success and functional outcome in patient with acute ischemic stroke - Emilie Santos
Acute ischemic stroke (AIS) is a medical emergency and requires fast accurate diagnosis and optimal
treatment decisions to prevent lifelong disability or death. To identify patients with a higher likelihood
of response to a particular treatment, imaging biomarkers reflecting pivotal clots characteristics from
baseline imaging is essential. AIS diagnosis and treatment decisions are often supported by Computed
Tomography (CT) imaging. Non-contrast CT and CT angiography (CTA) are attractive due to their speed
and wide availability as their protocols are in current acute care practice in many clinical centers. Based
on a combination of CT and CTA imaging and simple manual measures, “thrombus perviousness” was
developed. This biomarker reflects the permeability of the occulting clot by measuring the contrast penetration in CTA images. It is expected that clot permeability may increase downstream tissue oxygenation, improve thrombus dissolution, and augment treatment success.
The clinical relevance of the thrombus perviousness was recently confirmed in the MRCLEAN population, where strong relationships were found between the measured perviousness and patient functional
outcome and recanalization rate. Similar analysis on the DUST dataset demonstrated strong association
with intra-venous (IV-rtPA) treatment efficiency, making this measure an excellent candidate for AIS
patient stratification in acute clinical diagnosis settings.
However, in CT angiography, the quality of the image is strongly affected by the timing of imaging such
that variations in contrast agent arrival in these CTA images may result in suboptimal perviousness
measurement. Furthermore, the use of manual assessment of the contrast agent penetration in the clot
is observer dependent and prone to bias. Current researches focus on the resolution of potential delayed
filing from CTA images and the uses of automated measures based on computer vision.
97
COEUR
Project 23 - continued
Image processing (Cardiovascular)
98
Emilie Santos
Annual Report 2015
Project 24
Molecular biology of aneurysm formation
In the basic research line ‘Molecular biology of aneurysm formation‘ of the Laboratory for Experimental Vascular
Surgery (LEVAS), the molecular processes that underlie aneurysm formation are investigated through close
collaboration between the department of Genetics & Cell Biology and the department of Vascular Surgery.
The goal of this translational research line is to decrease aneurysm related mortality and reduce the need
for surgical intervention. Consequently, we focus on two research areas: 1) early detection of degenerative
changes in the aortic wall, and 2) pharmacological intervention to treat aortic wall degeneration. To this
end we make use of the scientific expertise and state-of-the-art infrastructure of our research institute as
well as the practical implications, anonymous patient data and bio-bank of the clinical research group. This
intensive collaboration ensures innovative basic research based on clear clinical relevance. This research line is
embedded in the Erasmus MC research schools Medical Genetics Centre South-West Netherlands (MGC) and
COEUR in collaboration with among others the departments of pharmacology, cardiology, clinical genetics,
bioinformatics and biochemistry.
Principal Investigator
J Essers
Co-Investigators
K Caliskan, AH Danser, DJGM Duncker, R Kanaar, DF Majoor-Krakauer, JW Roos-Hesselink,
EV Rouwet, PJ van der Spek, HJM Verhagen, MW Wessels, WFJ van IJcken
Postdoc
I van der Pluijm
PhD candidates
Name
Subject
L te Riet
Dilating versus stenosing arterial disease; identification of the genetic factors involved in
aortic aneurysm formation
BS van Thiel
Characterization of aortic aneurysm disease and the development of therapeutic strategies
JI van Waning
NCCM (noncompaction cardiomyopathy)
99
COEUR
Project 25
Endovascular Management of Aortic Aneurysms
Aortic pathology like aneurysms, dissections and traumatic ruptures were traditionally treated by open surgery
repair. In the last decade, endovascular technology became available as a minimally invasive alternative. Like
with all other new and innovative treatment modalities, results, especially long-term, are unknown and it
remains unclear whether this minimal invasive treatment is beneficial for all patients or only for the ones
declared “unfit for surgery”. Furthermore, many uncertainties remain on the best indications for stentgraft
placement: is it only advisable for aneurysmal disease or should it be used for all aortic pathology known to
eventually lead to life-threatening dilatation of the aorta. If so, in what stage of the disease should it be used:
as treatment or as prevention? Can it be seen as definitive treatment or will it turn out to be just a “bridge to
surgery”? Within this project, many sides of this new treatment are being investigated.
100
Principal Investigator
HJM Verhagen
Co-Investigators
JA Bekkers, B Muhs, E Rouwet, F Schlosser, O Schouten
PhD candidates Name
Subject
SA Cornelissen
Advances in imaging after EVAR
JMW Donker
Modern outcomes in Vascular Surgery
FHW Jonker
Thoracic Aortic Catastrophies, towards an endovascular solution
J van Keulen
Endovascular management of Aortic Pathology
JH van Laanen
Long-term CAS
KM vd Luijtgaarden
Familial Aneurysms
NF Gomes Oliveira
Controversies in endovascular aortic repair
KHJ Ultee
Clinical Outcome of Endovascular Treatment for Elective and Ruptured Abdominal Aortic
Aneurysms
Annual Report 2015
Project 26
Improvement and risk modeling in the prevention of sudden cardiac death
Heart failure (HF) remains an important issue in cardiology because of its high mortality and morbidity.
Sudden cardiac death is responsible for up to 50% of the reported mortality. The implantable defibrillator (ICD)
has proven to be effective in reducing arrhythmic death in selected patients with ischemic or nonischemic
cardiomyopathy and reduced left ventricular function. Despite the efficacy in terminating ventricular
arrhythmias, there is an on-going debate on further risk stratification of patients who will benefit most from
ICD implantation. The benefit of the ICD is attenuated by the presence of comorbidities. Identification of those
patients at high risk for mortality who may not derive benefit from ICD implantation is important for optimal
patient selection of this therapy. Erasmus MC has a cooperation with the University Hospital Basel and Seattle
University for further development of risk estimation models in primary prevention of sudden death for better
patient identification.
Next to risk modeling and clinical aspects of patients at risk for sudden death, efforts are made to incorporate
patient-reported outcomes in clinical practice and decision-making. Erasmus MC has a cooperation with Tilburg
University and University of South-Denmark Odense for research focusing on patient-reported outcomes. In
addition, Erasmus MC has played a role in the development of new innovative technologies in the prevention of
sudden death, like implementation of remote monitoring and the development of subcutaneous defibrillator.
Principal Investigator
DAMJ Theuns
Co-Investigators
MGM Hunink, LMJL Jordaens, SS Pedersen
PhD candidates
Name
Subject
L Dabiri Abkenari
Actual Insights on Prophylactic ICD Therapy
SDA Valk
Approaches to ventricular tachycardia and sudden death
101
COEUR
Project 27
Surgical aspects and clinical decision making in cardio-thoracic (including pulmonary)
interventions
102
This project concerns outcomes research, risk modelling, decision making, innovative statistical analysis and
health technology assessment of appropriate diagnostic and therapeutic measures in the area of cardiothoracic interventions.
Technological developments in surgery (and interventional cardiology as well) and peri-operative/
peri-procedural care continue to evolve at a rapid pace. In particular, the field evidence with regard
to the treatment of coronary artery disease and cardiac valvular disease is rapidly expanding. The
treatment evidence in thoracic and pulmonary disease (including transplantion) is moving as well.
One of the challenges for contemporary medicine is to apply evidence-based medicine and to rationally
implement the available therapies in clinical practice, in the appropriate patients at the appropriate time.
Current research includes outcomes research of complex aortic valve and lung cancer surgery, longitudinal
statistical modeling on serial data such as cardiac biomarkers and echocardiographic measurements over
time for the purpose of outcome prediction, the optimization of individualized prognosis prediction through
the development of novel risk models, shared decision making studies in prosthetic heart valve selection,
pediatric LVOT and RVOT surgery and NSCLC treatment selection, and cost-effectiveness studies of novel
cardio-thoracic interventions. The results should support clinical decision making.
Annual Report 2015
Principal Investigators
AJJC Bogers, JJM Takkenberg
Co-Investigators
H Boersma, AP Kappetein
PhD candidates
Name
Subject
B Arabkhani
Aortic aneurysm and aortic valve disease: Treatment options
LE de Groot-de Laat
Three-dimensional echocardiography in mitral regurgitation
SA Huygens
Health Technology Assessment of Heart Valve Prostheses
NM Korteland
Optimizing clinical decision-making in prosthetic aortic valve selection
WJ van Leeuwen
Clinical results of mitral valve surgery
APMW Maat
Surgical aspects of mesothelioma treatment
S Mokhles
Prognostication and decision making in non-small cell lung carcinoma
R van Valen
Quality improvement in the management cardio-surgical perioperative care
103
COEUR
Project 27 - continued
Surgical aspects and clinical decision making in cardio-thoracic
(including pulmonary) interventions
Prognosis and Treatment decision making in early stage Non-Small Cell
Lung Cancer - Sahar Mokhles
104
Lung cancer remains a global health problem, accounting for 18% of all cancer deaths. The treatment
options for non-small cell lung cancer (NSCLC) are based on cancer stage and patient overall health.
Although surgery is still considered standard therapy for early stage lung cancer, stereotactic ablative
radiotherapy (SABR) is a less invasive option for the treatment of NSCLC in patients with comorbidities.
In our previous studies, we identified the clinical baseline parameters that can help to determine survival of early stage NSCLC and illustrated that both patient characteristics and survival of patients undergoing surgical treatment or SABR differ considerably. In the absence of a randomized trial we performed a
propensity score matching analysis to create two similar groups in order to compare clinical outcomes.
We developed a nomogram for overall survival by using a large-intuitional cohort of NSCLC patients, and
described quality of life during the five years after treatment with SABR.
The focus of our research is also patient participation in treatment decision making and practice
variation between individual lung cancer clinicians (e.g. cardio-thoracic surgeons, lung physicians and
radiation oncologists) concerning shared decision making (SDM). In lung cancer SDM has not been
widely incorporated into routine clinical practice due to lack of familiarity with SDM. Our studies highlights the need to improve the implementation of SDM in clinical practice as clinicians report that doctors are not properly trained to implement SDM, and there is not enough consultation time to properly
engage the patient with limited health literacy in treatment decision making. Whereas, patient involvement will result in better knowledge of disease and treatment options and allow for informed decision
making.
Our research can contribute to the goal of improving SDM in the treatment of early stage NSCLC,
and it will be another step towards personalized cancer treatment.
Annual Report 2015
105
Sahar Mokhles
COEUR
Project 28
Surgery for congenital heart disease
Surgical management of congenital heart disease has improved significantly in the last decades and has
resulted in improved survival into adulthood. Thus the number of adult patients is growing. While the number
of patients to be operated at young age is more or less constant, the number of patients needing an operation
at adult age is increasing, both the number of primary operations as well as the number of reoperations due
to residual cardiac abnormalities. In particular, an abnormal load is commonly imposed on the right ventricle
or on single ventricular hearts. Residual abnormalities may cause heart failure, rhythm disturbances and may
affect quality of life. Evidence-based treatment is often lacking. Guidelines for timing of catheter intervention
and surgical therapy also may lack sufficient evidence. This project aims at outcome research with emphasis
on assessment of cardiac function in the right ventricle and in structurally abnormal hearts with conventional
imaging techniques. An important part of this theme concerns these imaging techniques on one hand and
improvement of clinical decision-making and therapy on the other.
106
Principal Investigator
AJJC Bogers
Co-Investigators
WA Helbing, AP Kappetein, JW Roos-Hesselink, JJM Takkenberg
PhD candidates
Name
Subject
JRG Etnel
Decision-making in Paediatric LVOT and RVOT Surgery
A Mookhoek
Changing Roots: remodelling after the Ross procedure
A van Saet
Pharmacokinetics and pharmacodynamics of drugs in neonates and children during
cardiopulmonary bypass
PC van de Woestijne
Pulmonary atresia with ventricular septal defect and systemic-pulmonary collateral arteries
GA Zeilmaker
Pharmacokinetics and pharmacodynamics of drugs in neonates and children during
cardiopulmonary bypass
Annual Report 2015
107
COEUR
Project 28 - continued
Surgery for congenital heart disease
Decision-making in congenital ventricular outflow tract surgery Jonathan R.G. Etnel
108
Evidence-based medicine remains difficult to universally attain in congenital cardiac surgery due to the
rarity, complexity and variability of congenital heart disease and the associated surgical procedures.
The subsequent scarcity of data and lack of treatment guidelines causes clinical decision-making in
congenital cardiac surgery to be largely based on expert opinion of the patient’s clinical state and the
available treatments. Especially the field of congenital ventricular outflow tract surgery requires many
difficult decisions to be made as each treatment option has its own inherent advantages and limitations.
Consequently, there is substantial inter-institutional practice variation as well as an ongoing discussion
on optimal patient care. In response to this major clinical practice gap, this PhD project employs
advanced methods of meta-analysis, predictive modeling, microsimulation and longitudinal data
analysis to synthesize high quality evidence on outcome after congenital ventricular outflow tract
surgery. This information is vital in clinical decision-making and will aid clinicians in deciding on the
optimal selection and timing of treatment for each patient.
Besides the clinical consequences of the advantages and limitations of each treatment option, the
choice for a certain treatment has a major impact on many non-clinical aspects of patients’ lives such
as education, career, personal finances, pregnancy and sports. Additionally, the value of each risk and
benefit to the patient varies strongly among individual patients. This makes patient preferences a
crucial element in the decision-making process. It is therefore essential to use the available evidence
to optimally inform not only clinicians, but also patients and their caregivers and to involve them in
decision-making. In this light we have developed and tested a pilot nationwide evidence-based online
information portal for patients with aortic and pulmonary valve abnormalities and their caregivers.
This information portal contains multidisciplinary information on all aspects of aortic and pulmonary
valve abnormalities, including diagnosis, treatment and implications for daily life and life planning. The
information portal will soon be implemented in daily clinical practice, which will allow us to study its
effect on patient knowledge, involvement, anxiety and quality of life. The portal will subsequently be
expanded to all common types of congenital heart disease.
Annual Report 2015
109
Jonathan Etnel
COEUR
Project 28 - continued
Surgery for congenital heart disease
Pharmacokinetics and pharmacodynamics in children during and after
cardiac surgery - Gerdien Zeilmaker
110
We also have little evidence on pain treatment after cardiac surgery in children. Morphine is the analgesic of first choice in guidelines, but these are based on small, non-randomized trials and Parmacokinetics (PK) is lacking. We performed an international survey on type and dosing of analgesics in
children after cardiac surgery. Morphine was the drug of first choice but the dosing could differ tenfold
depending on local protocol. These high morphine doses can lead to unwanted drug reactions, such as
respiratory depression and hypotension.
Starting 2016 we will perform a multi-center prospective RCT to compare morphine intravenous
with paracetamol intravenous in children after cardiac surgery (PACS study). A previous study comparing paracetamol iv with morphine iv after major noncardiac surgery in children found that paracetamol
iv is as good as morphine iv as primary analgesic. The PACS study aims to decrease the cumulative
morphine consumption in the first 48 hours after cardiac surgery by 30% in children aged 0-36 months.
During the PACS study blood-samples for PK analysis of morphine and paracetamol will be collected. The
results of the PACS study will be used to write a national PK-based guideline on the treatment of pain in
children after cardiac surgery.
Annual Report 2015
111
Gerdien Zeilmaker
COEUR
Project 29
Determinants of outcome of pediatric (congenital) heart disease
Treatment of congenital heart disease in early childhood has resulted in excellent survival in the pediatric
age range. However, residual cardiac loading abnormalities and the effects of pre-treatment hypoxaemia
may impair long term survival and quality of life. The project aims to identify early (bio)markers of suboptimal
outcome following treatment in childhood and to develop new treatment modalities to improve outcome.
Novel imaging methods and animal experiments are used for these purposes.
Principal Investigator
WA Helbing
Co-Investigators
M Dalinghaus, DJGM Duncker, LP Koopman, IKM Reis,
JW Roos-Hesselink, JJM Takkenberg, M Witsenburg
PhD candidates
112
Name
Subject
SL den Boer
Heart failure in children with cardiomyopathy. Which markers can be used to predict
outcome?
COBRA3: Congenital Heart defects: Bridging the gap between Growth, Maturation,
Regeneration, Adaption, late Attrition and ageing
Cardiomyopathy in children, CARS 2
E van den Bosch
MH van der Meulen
Annual Report 2015
CArdiomyopathy Registry Study (CARS) - Suzanne den Boer
Our research project focused on the identification of prognostic factors measured during follow-up in children
with dilated cardiomyopathy (DCM). In this prospective study we followed children with DCM from 7 pediatric cardiology departments in the Netherlands. Over a study period of four years, we included almost 100
children, who were seen at 3-6 months intervals. Outcome analysis of the pediatric DCM population in the
Netherlands demonstrated that the heart transplantation rate early after diagnosis was relatively low compared to other cohorts, with similar 1- and 5-year survival rates and heart transplantation rates after the first
year of diagnosis. This suggests that a conservative approach of listing for heart transplantation early after
diagnosis may be justified in a considerable amount of children, except for those who were admitted to the
intensive care unit at diagnosis, and who needed mechanical circulatory support during first hospitalization,
since these were risk factors for death within the first year of diagnosis. Age > 6 years at diagnosis was a risk
factor for reaching an endpoint > 1 year after diagnosis, which was mainly transplantation. Furthermore, this
is the first study in children with DCM that demonstrated that the following markers were associated with
a higher risk of death or transplantation: lower mean global longitudinal peak strain on echocardiography,
higher New York University Pediatric Heart Failure Index, lower physical functioning score on health-related
quality of life questionnaire, higher NT-proBNP, increasing NT-proBNP over time, and a lower distance walked
in 6 minutes.
Suzanne den Boer
113
COEUR
Project 30
Adult congenital heart disease
In the Netherlands, 8 out of 1000 children are born with a congenital heart defect. Due to improved
diagnostics, the introduction of the heart lung machine and open heart surgery, more than 85% of these
patients reach adulthood and nowadays there are 30.000 adults living in the Netherlands. Many of them have
late complications, such as valvular dysfunction, arrhythmias or heart failure. In addition often surgical or
catheter reintervention is necessary. Research in project 30 focuses on long-term outcome in these patients,
both after surgical correction, interventional treatment or natural history. Special emphasis on psychological
outcome, pregnancy and sports participation is important in this specific group of young adults. Also genetic
research, imaging of the complex cardiac anatomy and biomarker studies are being conducted.
114
Principal Investigator
JW Roos-Hesselink
Co-Investigators
H Boersma, AJJC Bogers, AE van den Bosch, RT van Domburg, WA Helbing, JJM Takkenberg, EMWJ Utens, M Witsenburg
PhD candidates
Name
Subject
VJM Baggen
Predicting outcome in adult congenital heart disease
IM van Hagen
Pregnancy and Cardiac Disease
AT van den Hoven
Aortic Pathology
MJG Leening
Epidemiologic aspects of cardiovascular disease. A population-based approach
ME Menting
Echocardiography in congenital heart disease
Annual Report 2015
Project 30 - contunued
Adult congenital heart disease
(Project30) Mindfulness in heart disease: a randomized controlled trial John Younge
Increased attention is being paid to potential beneficial mind-body practices. These practices such as
meditation, mindfulness training, relaxation exercises and yoga are increasingly popular in the general
population and more commonly used in the western world.
In recent years, mindfulness training has gained more attention in healthcare. By doing mindfulness, one is taught to live with an open and non-judgmental awareness towards all experiences within
the present moment. Mindfulness puts the focus on the true needs of the body and mind and therefore
also promotes a healthy lifestyle. Mindfulness therapy has been found to positively affect psychological
outcomes in a variety of clinical conditions. However, effects on physiological outcomes are limited.
We randomized 324 patients with structural heart disease to either an online mindfulness training or to
usual care. We investigated several physiological and psychological outcome parameters. After 12 weeks,
we found a borderline significant but clinically small effect in favor of mindfulness. Heart rate also
decreased significantly more with mindfulness training. Remarkably, no significant improvements were
found on subjective outcome measures, although anxiety and depressive symptoms did decrease.
Our results may indicate that online mindfulness training may be used in patients with limitations in
physical functioning, but whether it can address clinically important physiological distress factors needs
to be determined. Mindfulness training may be considered a good alternative treatment option when
other modalities have limited effect or are less feasible as a result of personal interests or clinical motives.
115
COEUR
Project 30 - contunued
Adult congenital heart disease
116
Dr. John Younge
Annual Report 2015
Project 31
Clinical epidemiology of cardiovascular diseases
In the past decades, significant improvement has been achieved in the management and outcome of patients
with cardiovascular disease (CVD). Despite these developments, CVD still is a major cause of the loss of healthy
years in The Netherlands: the annual number of fatal events is as high as 40,000. The burden of CVD is expected
to increase in the decades ahead, and it is crucial to develop and improve CVD risk prediction instruments,
and implement appropriate preventive and therapeutic measures. Traditionally, the assessment of CVD risk is
based on global risk models. However, these models fall short, as they do not utilize contemporary knowledge
on the pathophysiology of CVD. Project 31 is designed to improve CVD risk assessment and risk reduction in
individual patients. Several concepts are currently studied: (multiple) CVD biomarkers, repeated biomarker
assessment, cardiac imaging and dynamic risk modelling.
Principal Investigator
H Boersma
Co-Investigators
KM Akkerhuis, RT van Domburg, RJ van Geuns, JL Hillege, I Kardys, MJ Lenzen,
MD Levin, V Umans
PhD candidates
Name
Subject
SS Anroedh
Biomarker measurements in coronary disease and heart failure
SJ Baart
CREW: Dutch national consortium to promote Cardiovascular Healthy Aging in Women
V van den Berg
Blood biomarkers and cholesterol metabolism in coronary artery disease and heart failure
N van Boven
Serial Biomarker measurements and new echocardiographic techniques in chronic Heart
Failure patients result in Tailored prediction of prognosis (Bio-SHiFT)
M Brankovic
Biomarkers to evaluate renal function in coronary artery disease and chronic heart failure
N Buljubasic
Dynamic aspects of associations between blood biomarkers and coronary artery disease
C Liesting
Cardiotoxicity of treatment in patients with HER2Neu positive breast cancer
RM Oemrawsingh
Prognostic value of biomarkers in patients with chronic CAD
M Sunamura
Opticare: optimal cardiac rehabilitation following acute coronary syndrome
LC van Vark
Epidemiological validation and clinical implementation of candidate biomarkers in patients
with acute heart failure
117
COEUR
Project 30 - continued
Adult congenital heart disease
118
Dr. Judith Cuypers
Annual Report 2015
The “unnatural history” of congenital heart disease: outcome up to 40 years
after surgical repair - Judith Cuypers
The milestone successes since the early years of surgical congenital heart defect repair have
led to dramatic improvements in the prognosis of patients with congenital heart disease. Most
patients now survive well into their adult years and focus has shifted from mere survival to late
complications and quality of life. We need to learn which patients are at increased risk of developing serious adverse events. Outcome in patients that were treated in the earliest era of congenital heart surgery cannot thoughtlessly be extrapolated to patients that are treated later on.
New insights and developments continuously lead to new adaptations in surgical techniques.
Nevertheless, prospectively studying the long-term outcome of patients that were operated in
earlier eras, as we do in the Rotterdam Quality of Life study, remains the only way to improve
our knowledge and will provide important information and feedback for both patients and their
treating physicians.
This thesis describes the outcome beyond 30 years of follow-up in patients operated for
ASD, VSD, pulmonary stenosis, tetralogy of Fallot and transposition of the great arteries (TGA).
Survival is nearly normal in the milder defects, but clearly impaired in the more complex defect,
especially the patients with TGA, who all received an atrial switch operation and consequently
have a right ventricle supporting the systemic circulation. Late morbidity is substantial in all
groups studied, varying from mainly atrial arrhythmias in the milder defects to re-interventions,
ventricular arrhythmias and heart failure in the more complex defects. Ventricular dysfunction
was expected and confirmed in the more complex defects, but not entirely absent in the mild defects. Trying to identify predictors of outcome, we found that arrhythmias in the early postoperative period were associated with adverse late outcome in nearly all groups. Nevertheless, most
patients are leading satisfactory and fairly normal lives, fully participating in society: they have
a job, get married, have children and do everything that healthy people do.
119
COEUR
Doctoral degrees
In the year 2015, 37 COEUR PhD candidates
successfully defended their PhD thesis and
obtained a doctoral degree. Details of their
achievements are given on the next pages. Apart
from scientific accomplishments, PhD candidates
are required to document their educational
activities (courses, meetings and teaching) in their
portfolio, which is integral part of their thesis.
Thirty ECTS (European Credit Transfer Score)
points are required. In 2015, out of the doctorates
31 had included a detailed portfolio. Missing
portfolios were exclusively associated with foreign
PhD candidates. The median number of ECTS
points scored was 33. The time to PhD degree
varied between three and six years with a median
time of 4 years and six months. COEUR currently
lists 190 PhD candidates. In 2015, 11 candidates
discontinued their PhD trajectory. The drop-out
rate in 2015 was therefore about 6%.
40
121
35
30
25
20
15
10
5
0
2003
2004
2005
2006
Doctoral degrees 2003 - 2015
2007
2008
2009
2010
2011
2012
2013
2014
2015
COEUR
January 13, 2015
Christos V Bourantas
Early Detection and Invasive Sealing of Future Culprit Lesions
Promotores: professor Patrick WJC Serruys (Cardiology) and
professor Eric Boersma (Cardiology)
Copromotor: dr Hector M Garcia-Garcia (Cardialysis)
January 14, 2015
Michiel Th Voûte
Medical & Technical Considerations in Vascular Surgery
Promotores: professor Hence JM Verhagen (Vascular Surgery) and
professor Robert Jan Stolker (Anaesthesiology)
122
January 16, 2015
Jannet A Eindhoven
Cardiac Biomarkers in Adult Congenital Heart Disease
Promotores: professor Jolien W Roos-Hesslink (Cardiology) and
professor Eric Boersma (Cardiology)
Copromotor: dr Annemien E van den Bosch (Cardiology)
January 20, 2015
Michael Magro
Percutaneous Coronary Interventions in Stable and Acute Coronary Syndromes
Promotores: professor Patrick WJC Serruys (Cardiology) and
professor Robert Jan van Geuns (Cardiology)
Annual Report 2015
123
Dr. Jannet Eindhoven
COEUR
January 21, 2015
Verya Daeichin
Micro-Ultrasound Molecular Imaging
Promotores: professor Ton AFW van der Steen (Cardiology/Biomedical
Engineering) and professor Nico de Jong (Cardiology)
Copromotor: dr Hans JG Bosch (Cardiology)
February 25, 2015
Ruben LJ Osnabrugge
Cost, Quality and Value in Cardiovascular Interventions
Promotor: professor Arie Pieter Kappetein (Cardiothoracic Surgery)
124
February 25, 2015
Bruno Sevá Pessôa
The Alternative Renin-Angiotensin System: Exploration of its Therapeutic
Potential
Promotor: professor AH Jan Danser (Internal Medicine)
Copromotor: dr Anton JM Roks (Internal Medicine)
Maart 5, 2015
Sjoerd T Nauta
Myocardial infarction: temporal trends over the past three decades
Promotor: professor Jaap W Deckers (Cardiology)
Copromotor: dr Martijn Akkerhuis (Cardiology)
Annual Report 2015
Maart 10, 2015
Pieter Kruizinga
Acoustic images of the carotid artery
Promotor: professor Ton AFW van der Steen (Cardiology/Biomedical
Engineering)
Copromotor: dr Gijs van Soest (Cardiology/Biomedical Engineering)
Maart 10, 2015
Tianshi Wang
Heartbeat optical coherence tomography
Promotor: professor Ton AFW van der Steen (Cardiology/Biomedical
Engineering)
Copromotor: dr Gijs van Soest (Cardiology/Biomedical Engineering)
125
Maart 13, 2015
Michel E. van Genderen
Peripheral perfusion in relation to systemic hemodynamics and its importance
in critically ill patients
Promotor: professor Jan Bakker (Intensive Care)
Copromotor: dr Jasper van Bommel (Intensive Care)
April 1, 2015
Frederico Bastos Goncalves - CUM LAUDE
Endovascular aortic repair, clarifying risk factors, complications and follow-up
Promotores: professor Hence JM Verhagen (Vascular Surgery) and
professor Robert Jan Stolker (Anaesthesiology)
COEUR
April 22 2015
Harm A. Nieuwstadt
MRI-based biomechanical modeling of carotid atherosclerotic plaques the
stable plaque paradigm
Promotor: professor Ton AFW van der Steen (Cardiology/Biomedical
Engineering)
Copromotor: dr Frank JH Gijsen (Cardiology)
126
Mei 12, 2015
Jin Ming Cheng
Coronary artery disease from atherosclerosis to cardiogenic shock
Promotor: professor Eric Boersma (Cardiology)
Copromotores: dr K Martijn Akkerhuis (Cardiology) and dr Isabella Kardys
(Cardiology)
Mei 12, 2015
Helena J Heuvelman
Aortic Stenosis in Adults
Promotores: professor Ad JJC Bogers (Cardiothoracic Surgery) and
professor Hanneke JJM Takkenberg (Cardiothoracic Surgery)
Mei 13, 2015
Ido G Bikker
Optimization Mechanical Ventilation by Bedside Lung Monitoring Systems in
Critically iII Patients
Promotor: professor Diederik AMP Gommers (Intensive Care)
Annual Report 2015
Mei 19, 2015
John O Younge
Lifestyle in Cardiovascular Disease
Promotores: professor Jolien W Roos-Hesselink (Cardiology) and
professor Myriam GM Hunink (Radiology/Epidemiology)
Mei 22, 2015
Takashi Muramatsu
Multi-modality Imaging and Clinical Implications of Bioresorbable Scaffolds in
Complex Coronary Artery Disease
Promotor: professor Patrick WJC Serruys (Cardiology)
Copromotor: dr Yoshi Onuma (Cardiology)
Mei 27, 2015
Renée FAG de Bruijn
Emerging Determinants of Dementia
Promotores: professor Peter J Koudstaal (Neurology) and
professor Bert Hofman (Epidemiology)
Copromotor: dr Yoshi Onuma (Cardiology)
June 3, 2015
Koen Verdonk
Preeclampsia, the Renin-Angiotensin-Aldosterone System and beyond
Promotores: professor AH Jan Danser (Internal Medicine) and
professor Eric AP Steegers (Gynecology)
Copromotores: dr Ton AH van den Meiracker and dr Willy Visser (Gynecology)
127
COEUR
June 9, 2015
Sandra H Hoeboer
Biomarkers of infection and its complications in the critically ill
Promotores: professor AB Johan Groeneveld (Intensive Care) and
professor Heleen M Oudemans-van Straaten (IC-VUmc)
128
June 30, 2015
Carolina Méndez Orellana
Functional MRI of Language Processing and Recovery
Promotores: professor Aad van der Lugt (Radiology) and
professor Peter J Koudstaal (Neurology)
Copromotores: dr Marion Smits (Radiology) and dr Evy G Visch-Brink
(Neurology)
September 2, 2015
Alexander Haak
Augmenting Electrophysiology Interventions with Advanced 3D
Transesophageal Echocardiographeal Echocardiography
Promotor: professor Ton AFW van der Steen (Cardiology/Biomedical
Engineering)
Copromotor: dr Hans JG Bosch (Cardiology)
September 16, 2015
Jelle L Epker
Death and Dying in the intensive care unit
Promotor: professor Jan Bakker (Intensive Care)
Copromotor: dr Erwin JO Kompanje (Intensive Care)
Annual Report 2015
September 16, 2015
André Uitterdijk
Experimental Approaches to Acute Myocardial Infarction
Promotores: professor Dirk J Duncker (Cardiology) and
professor Wim van der Giessen († 2011)
Copromotores: dr Daphne Merkus (Cardiology) and
dr Heleen MM van Beusekom (Cardiology)
129
COEUR
September 16, 2015
Ferdi Akca
Optimizing Safety and Efficacy of Catheter Ablation Procedures
Promotor: professor Felix Zijlstra (Cardiology)
Copromotor: dr Tamas Szili – Torok (Cardiology)
October 8, 2015
Teresa Mary Kieser
Building a better bypass with emphasis on bilateral internal mammary grafting
Promotor: professor Arie Pieter Kappetein (Cardiothoracic Surgery)
130
October 9, 2015
Eva Klijn
The additional value of microcirculatory imaging in critically ill patients
Promotores: professor Jan Bakker (Intensive Care) and
professor AB Johan Groeneveld (Intensive Care)
Copromotor: dr Jasper van Bommel (Intensive Care)
October 14, 2015
Khatera Ibrahimi
Microvasculature, the Trigeminal System and Migraine; A focus on female seks
hormones
Promotor: professor AH Jan Danser (Internal Medicine)
Copromotores: dr Antoinette Maassen van den Brink (Internal Medicine) and
dr Anton H van den Meiracker (Internal Medicine)
Annual Report 2015
131
Dr. Ferdi Akca
COEUR
132
Annual Report 2015
October 20, 2015
Sjoerd SM Bossers
Outcomes after Contemporary Fontan Operation: Step by step
Promotor: professor Wim A Helbing (Pediatrics)
October 20, 2015
Nienke Duppen
Exercise training in children and young adults with congenital heart disease
Promotores: professor Wim A Helbing (Pediatrics) and
professor Maria TE Hopman (Radboud Nijmegen)
133
COEUR
October 21, 2015
Saloua Akoudad
Cerebral microbleeds: a marker of vascular brain disease
Promotores: professor Peter J Koudstaal (Neurology) and
professor Aad van der Lugt (Radiology)
Copromotores: dr Meike W Vernooij (Radiology) and dr M Arfan Ikram
(Radiology)
November 11, 2015
Yvonne Veroni Sanders
Von Willebrand Disease in the Netherlands; from genetic variation to phenotypic variability
Promotor: professor Frank WG Leebeek (Hematology)
134
December 1, 2015
Carlos M Campos
Risk Assessment in Coronary Artery Disease
Promotor: professor Patrick WJC Serruys (Cardiology)
December 8, 2015
Diego Dias Bispo Carvalho
Nonrigid Registration Methods for Multimodal Carotid Artery Imaging
Promotor: professor Wiro J Niessen (Radiology)
Copromotor: dr ir Stephan Klein (Radiology)
Annual Report 2015
December 15, 2015
Judith AAE Cuypers
The unnatural history of congenital heart disease; outcome up to 40 years after
surgical repair
Promotores: professor Jolien W Roos-Hesslink (Cardiology) and
professor Ad JJC Bogers (Cardiothoracic Surgery)
December 16, 2015
Yanti Octavia
Endothelial Nitric Oxide Synthase in Heart Failure Dr Jekyll and Mr Hyde
Promotores: professor Dirk Jan Duncker (Cardiology) and
professor Harry J Crijns (Cardiology Maastricht)
135
COEUR
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136
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186
Annual Report 2015
187
COEUR
Colofon
Edited by: Erna Egelie
Photography: Levien Willemse
Lay out: Maud van Nierop
Production and publication: COEUR Secretariat, Erasmus MC
Printing: Mediajoenit BV, Rotterdam
Contact:
188
Thoraxcentre
Erasmus MC
P.O. Box 2040
3000 CA Rotterdam
The Netherlands
Phone: +31-10-7035312
Email:
[email protected]
Website: www.coeur.nl
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COEUR
A N N UA L
COEUR
ANNUAL REPORT 2015
R EPORT
2015
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