Circulating Matters Progress Report 2010>2012

Transcription

Progress Report
2010 > 2012
Circulating
matters
Institute for Cardiovascular Research
VU University Medical Center
I C A R -V U m c
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ailure Hypertrophic Car
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Progress Report
P r o gr e s s R ep o r t 2010 / 2011
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2010 > 2012
ulmonay Arterial Hyper
ascular Imaging Focus
Circulating matters
ronary Syndrome and
Reproduction and Va
n Diabetis Mellitus and
Research Chronic KidI C A R -V U m c
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Content
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ICaR-VU the Institute
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General information
13Research
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Education
Information
Colophon
Institute for Cardiovascular Research
Vrije Universiteit (ICaR-VU)
VU University Medical Center (VUmc)
Coordination
van der Boechorststraat 7
1081 BT Amsterdam
Telephone +31-20-4448111
Fax +31-20-4448255
[email protected]
www.vumc.com/icar-vu
© 2013 ICaR-VU
Victor van Hinsbergh
Isabelle Vergroesen
Jolanda van der Velden
Text
Scientists of ICaR-VU
Editor
Lisa Kohn
Photography
Harry Meijer (pages 4, 8,12,
28, 42, 44, 50, 56, 62, 72, 74,
80, 86, 92, 98, 104, 110)
Dirk de Jong (last pages)
Design and layout
Corina van Riel, Amsterdam
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62
Theme H
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Theme V
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80
86
92
98
104
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Research
Research
Research
Research
Research
Research
Research
Research
Research
Research
Research
Group
Group
Group
Group
Group
Group
Group
Group
Group
Group
Group
Diastolic Heart Failure
Hypertrophic Cardiomyopathy
Pulmonary Arterial Hypertension
Cardiovascular Imaging
Coronary Syndrome and Repair
Aneurysm Reproduction and Vascular Function
Diabetes Mellitus and Obesity
Nutrition Research
Chronic Kidney Disease
Acute and Perioperative Care
Print
Roto Smeets GrafiServices
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I C aR -V U / T h e In s tit ut e
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Preface
This is the 2010-2012 Progress Report for
the Institute for Cardiovascular Research at
VU University Medical Center (ICaR-VU).
Over the last 20 years, the ICaR-VU has
acquired a solid identity in the field of
cardiovascular research in The Netherlands
and Europe. Since its foundation in 1992,
the Institute has been dedicated to providing
better joint research education for basal and
clinical PhD students, and promoting the
interaction between clinical and basic
research. Currently, the majority of research
projects falls under two themes ‘Improvement
of Cardiac Function in Heart Failure’ and
‘Improvement of Vascular Function in
Metabolic Diseases’.
A thorough evaluation of the overall research
program took place in 2010-2011. This led to
the fine-tuning of the relationships between
patient care and research, and added support
from the participating clinical and preclinical
departments. In 2012 three specific programs
were defined within the two themes: ‘Heart
Failure and Pulmonary Arterial Hypertension’,
‘Circulation and Metabolism’ and ‘Ischemia
and Repair’.
In the period 2010-2012, the ICaR-VU became
coordinator of, and a participant in, various
European programs and clinical trials;
expanded its external funding and further
increased its scientific output.
In addition to the PhD program, which has its
roots in the Cardiovascular Research School
CARMA, a Research Master Program was
created in 2010 for excellent students who aim
to pursue cardiovascular research.
In 2012 the ICaR-VU started participating in
the Rembrandt Institute, in collaboration with
the Amsterdam Medical Center, Leiden University Medical Center and Sanquin, which
has further strengthened our cardiovascular
research.
I would like to thank all the participants in the
ICaR-VU for their enthusiasm and personal
contributions to the success of the Institute.
Victor W.M. van Hinsbergh
Director of the ICaR-VU
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The Institute
One of the main tasks of the ICaR-VU is
to stimulate and promote interdisciplinary
research to be able to cover the range
from patient to gene
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Profile
Organisation
Education
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Profile
The Institute for Cardiovascular Research of the VU
University (ICaR-VU) was founded in 1992 on the
basis of the Dutch University Education Act (WWO).
The initial purpose of the research school was the
education of graduate students (PhD students) in all
aspects of cardiovascular function and cardiovascular diseases. Today the Institute has grown into an
internationally recognized platform for high quality
interdisciplinary translational research and research
education on heart, vessels and related metabolism
at the VU University and VU University Medical
Center.
The ICaR-VU is one of the five research institutes
of the VU University Medical Center (VUmc) and
participates in Human Health and Life Sciences,
one of the four focus areas of the VU University
Amsterdam. The ICaR-VU facilitates research groups
of clinical and/or pre-clinical investigators from
18 departments in four divisions of VUmc, thus
facilitating a multidisciplinary approach to
research, patient care and medical education.
More than 265 professionals work in the ICaR-VU,
and execute research programs in interdisciplinary
research teams, bringing together clinical investigators, basal investigators and graduate students.
The ICaR-VU stimulates cooperation, aims to create
new facilities for clinical and basal research in order
to strengthen translational research and to identify
opportunities for future improvement of its research
and patient care. The network within the Institute
enables excellent students to come into contact with
top scientists in the PhD education program, and
Cardiovascular Research Master program, a teaching
program that began in 2009.
One of the main tasks of the ICaR-VU is to stimulate
and promote interdisciplinary research to enable
‘from patient to gene’ coverage. Therefore, the
research is focused on a limited number of
cardiovascular diseases with a strong emphasis on
translational research and aims to improve patient
care. This choice has led to a much better and more
coherent program, does away with the traditional
barriers between clinical and preclinical departments, and stimulates multidisciplinary research.
Thus, it was decided that the Institute would
concentrate on heart and blood vessels themes.
By integrating patient care and research projects
and focusing on selected cardiovascular research
niches the ICaR-VU has established an excellent
international position at the forefront of international cardiovascular research.
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Mission Statement of the ICaR-VU
‘Search for
Scientific Solutions
for Cardiovascular
Suffering’
Strategies
The ICaR-VU mission has the following strategies:
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The management and all members of the ICaR-VU will
ensure that the research effort remains focused on the two
themes; through high quality basic, applied and clinical
research.
2
The management and all members of the ICaR-VU will
ensure continuity through a meticulous system of quality
assurance and through pursuit of a high degree of
financial independence.
3
The management and all members of the ICaR-VU
will ensure that graduates of the Institute, in addition
to graduating with high quality theses, are sufficiently
prepared to successfully join the labor market.
An important step towards this goal is to provide
excellent education to graduate students.
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Research
The Institute for Cardiovascular Research at VU
University Medical Center in Amsterdam offers a
first class location for conducting translational
cardiovascular research, providing a bridge
between the laboratory bench and clinical
problems at the bedside. The Institute is dedicated
to making advancements in biomedical research
and clinical treatment strategies through close
collaboration between basic scientists and clinicians. One of the main tasks of The ICaR-VU
is to stimulate and promote interdisciplinary
research covering the range ‘from patient to gene’.
Therefore, the research is focused on a limited
number of cardiovascular diseases with a strong
emphasis on translational research and the aim
of improving patient care. This choice leads to a
much better and more coherent program, does
away with the traditional barriers between clinical
and preclinical departments, and stimulates multidisciplinary research.
It was decided that research within the ICaR-VU
would concentrate on two themes:
Theme H: Improvement of Cardiac Function in
Heart Failure (including the activities of the
Pulmonary Artery Hypertension Center VUmc).
Theme V: Improvement of Vascular Function in
Metabolic Diseases
Since 2012 has been concentrating on:
– Program on Ischemia and Repair
– Program on Circulation and Metabolism (including
research activities of the Diabetes Center VUmc)
The development of improved techniques is an
integral aspect of our themes and programs. For
example imaging techniques, which play a prominent role in research on heart and vessels. The
recent opening of a PET-MRI facility at the VUmc
will further boost the existing imaging expertise in
the cardiovascular field.
The success of the thematic approach with the
alignment of patient care and research projects is
reflected by an increase in external funding and an
improvement in the quality of the output.
The current Theme Leaders are:
Prof. dr. Jolanda van der Velden (Physiology),
Prof. dr. Anton Horrevoets (Molecular Cell Biology
and Immunology),
Prof. dr. Yvo Smulders (Internal Medicine),
Prof. dr. Carlo Gaillard (Nephrology),
Prof. dr. Niels van Royen (Cardiology).
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Structure ICaR-VU
Dean / Board of Directors
Think Tank
ICaR-VU Directorate
Science Committee
Theme Heart
Heart Failure and
Pulmonary Arterial Hypertension
Project Project Project Project Project
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2
3
4
5
......... ......... ......... ......... .........
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External Advisory Board
Education Committee
Theme Vessels
Ischemia
and Repair
Circulation
and Matabolism
Project Project Project Project Project
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7
8
9
10
......... ......... ......... ......... .........
The Directorate is responsible for the management
of the Institute and is supported by the directorate
advisor Dr. I. Vergroesen. The directorate is advised
and supported by the Theme Leaders and the
Science Committee with regard to the research
projects and research in general and by the
Education Committee with regard to all aspects of
PhD, MsC and BSc education covered by the
Institute. Furthermore, the External advisory Board
and Think Tank, an internal board of upcoming
scientists, also advise the Directorate.
The research projects in the Institute are under the
direct supervision of the project leaders. The Theme
Leaders are responsible for coordination and
quality of the research themes within the Institute.
They coordinate the evaluation of new research
project proposals and discuss these with the Project
Leaders. The Theme Leaders participate in the
Science Committee and advise the Directorate and
the other members of the Science Committee on
the quality of the projects and their suitability
within the Institute and Theme programs.
The Education Committee is responsible for the
coordination of all education matters of junior
scientists, in particular the PhD program. They also
advise on the Cardiovascular Research Master
program and on the scientific aspects of the
cardiovascular research education of medical
bachelor students.
The External Advisory Board advises the Directorate on general internal and external policy of the
Institute as well as its scientific and education
programs. In principle, the Advisory Board meets
with the Directorate and the Theme Leaders of the
ICaR-VU twice a year.
The Think Tank was formed in 2005, as an internal
board of upcoming scientists by the Directorate.
There is a monthly meeting of the Think Tank during
which current scientific matters and strategic
issues are freely discussed. The Think Tank looks
critically at specific research and advises on talent
strategy. The Think Tank proposes cutting edge
research topics that need attention in colloquia.
The Science Committee is made up of Theme
Leaders and selected key scientists covering the
major expertise and disciplines of the Institute.
Monthly, they meet with the Directorate to advise
on all scientific matters including general and
strategic matters and to approve decisions on newly
proposed research projects.
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Management
Committees
DIRECTORATE
RESEARCH
The Directorate is responsible
for the management of the
Institute.
Theme Leaders
The Theme Leaders are responsible for coordination and quality
of the research themes.
Director
prof. dr. V.W.M. van Hinsbergh
Department of Physiology
Vice-Directors
prof. dr. H.W.M. Niessen
Department of Pathology
prof. dr. A.C. van Rossum,
Department of Cardiology
Directorate-Advisor
dr. I. Vergroesen.
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The Theme Leaders coordinate the
research in the themes and judge
new projects and discuss projects
with the Project Leaders.
The Theme Leaders advise the
Science Committee of the
Institute on the quality of
individual projects before the
start.
The Theme Leaders as of
September 2011:
Theme H
prof .dr. J. van der Velden
prof. dr. N. van Royen
Theme V
prof. dr. A.J.G. Horrevoets
prof. dr. C.A.J.M. Gaillard
prof. dr. Y.M. Smulders
Project Leaders
Within the themes, programs
and projects are carried out.
The basic research unit is the
project. The research projects
are under the direct supervision
of the Project Leaders.
For names of the Project Leaders
see the second and third section
of this Progress Report, where
the themes are explained in more
detail. To qualify as a Project
Leader, one has to have
experience in science (at least
PhD), be able to obtain grants,
and supervise cardiovascular
research projects within the
ICaR-VU. The Directorate
decides on the appointment
of new Project Leaders.
ADVISORY COMMITTEE
SCIENCE COMMITTEE
This Committee advises the
Directorate on general policy
and other matters. In principle,
this Committee meets with the
Directorate and Theme Leaders
of the ICaR-VU, twice a year.
This Committee advises the
Directorate on almost all
scientific matters, as well as on
general and strategic issues.
The final approval of projects is
their responsibility.
This Committee consists of
senior scientists from different
departments, which participate
in the ICaR-VU, and the Theme
Leaders, DEC representative and
the chair of the Education
Committee.
prof. dr. A.J.M. Donker
Professor emeritus of Internal
Medicine VUmc, chair
prof. dr. W.G. van Aken
Medicine, Vice Chair
prof. dr. P. Brakman
Medicine, Leiden University
prof. dr. D.J. Duncker
Professor Cardiology, EMC
prof. dr. W.J. Paulus
Physiology, chair
prof. dr. H.J. Blom
Clinical Chemistry
prof. dr. M. Diamant
Internal Medicine
drs. G.A. van Leijenhorst
Medical Director, Merck, Sharp
& Dohm, Haarlem
prof. dr. R.J.B.J. Gemke
Pediatrics
prof. dr. C.J.L.M. Meijer
Professor emeritus of the
Department of Pathology, VUmc
prof. dr. C.J.M. de Groot
Obstetrics and Gynecology
(from March 2012)
prof. dr. T.J. Rabelink
Professor of Nephrology, LUMC
prof. dr. C.B.M. Oudejans
Clinical Chemistry
dr. W.S. Simonides
Physiology
prof. dr. A. Vonk Noordegraaf
Pulmonology
Nefrology, Theme Leader Vessels
(as of September 2011)
dr. J.G.F. Bronzwaer
Cardiology,
chair Education Committee
dr. A.A. van Lambalgen
Physiology
DEC-representative
prof. dr. A.B.J. Groeneveld
Intensive Care Medicine,
Theme Leader Vessels
(until July 2011)
prof. dr. A.J.G. Horrevoets
Molecular Cell Biology
and Immunology,
prof. dr. N. van Royen
Cardiology,
Theme Leader Heart
prof. dr. Y.M. Smulders
Internal Medicine,
prof. dr. J. van der Velden
Physiology
Theme Leader Heart
prof. dr. N. Westerhof
Professor emeritus of
Physiology, VUmc
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EDUCATION COMMITTEE
THINK TANK
In the second half of 2005
the Directorate created
the so called the ICaR-VU
‘Denktank’ (Think Tank).
There is a monthly meeting
of the Think Tank
during which upcoming
scientific matters and
occasionally strategic issues
are openly discussed.
For discussion on specific
topics several ad-hoc
members can be invited
depending on the topic.
dr. C. Boer
Anesthesiology, chair
dr. P. Knaapen
Cardiology
dr. R.A. Bouwman
Anesthesiology
dr. J.D. Blankensteijn
Vascular Surgery
dr. P. Krijnen
Pathology
dr. E.H. Serné
Internal Medicine
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Scientists
dr. H.J. Bogaard
Pulmonology
All teaching activities related to
Cardiovascular Research falls
under the responsibility of the
Education Committee.
dr. M. van Dijk
Clinical Chemistry
dr. J.G.F. Bronzwaer
Chairman Education Committee
dr. C.A.C. Ottenheijm
Physiology
dr. G.P. van Nieuw Amerongen
(until January 2012)
dr. M.C. de Waard
Intensive Care Medicine
dr. E.H. Serné
(as of January 2012)
Physiology, chair.
(until September 2011)
Nefrology
(until September 2011)
drs. J. Aman
Representative PhD students
(until January 2011)
drs. E. R. Paalberends
Representative PhD- students
(as of January 2011)
prof. dr. G.J.M. Stienen
Chairman CVR-master
200
Number
Committees
180
160
dr. E. Kanters
Coordinator CVR-master
140
dr. I. Vergroesen
Coordinator WFO, HP and
PhD students
100
Shellice Sairras
(2009-2011)
Mathijs Baart
(2010-2011)
Stephanie Ragghoe
(2011-2012)
Chris Happé
(2011-2012)
Iris van Moort
(2012-)
Vera Verbruggen
(2012-)
Students CVR-master
Figure 1: Number of persons involved in
the Institute related to the Themes. Persons
involved in both themes are counted twice,
and all researchers involved arriving or
leaving within a year count once, as do MD’s
who combine clinical duties and research.
So, it is only an indication of the maximum
number of people involved.
*Numbers for 2012 are best value available
in January 2013.
120
80
60
40
20
0
2010
2011
Heart
2012*
2010
2011
Vessels
2012*
Researchers (clinical and basal) involved in the Institute related to their position
60
FTE
18
50
40
30
dr. A. Beishuizen
20
dr. G.P. van Nieuw Amerongen
Physiology
10
0
2010
2011
Heart
2012*
2010
2011
Vessels
2012*
Researchers (full time equivalents) involved in the Institute related to the funding
PhD/MD
Postdoc/ fellow
UHD + UD
Full Professor
Figure 2: Number of FTE scientific personnel working in the Institute per year and
related to the Themes. The different colors
correspond to the funding categories. PhD
students count for maximal 0.75 FTE, due to
educational tasks. Clinical PhD students (MD)
count for 0.2-0.75 FTE depending on their
clinical and educational tasks. Scientific staff
may have educational, clinical and managerial
tasks in addition to their research. People arriving or leaving count only for the month they
were employed by VUmc. Data are provided by
the departments participating in the ICaR-VU.
*Numbers for 2012 are best estimates
available in January 2013.
Industry Funding
Charity/Europe
Government Research Grants
Direct Funding PhD/MD
Direct Funding Staff
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350
300
250
200
150
Refereed articles
Books or bookchapters
PhD-theses
Professional publications
100
50
0
2009
2010
2011
Heart
2012
2009
2010
2011
Vessels
Figure 4: The impact of the published
papers, as can be judged from the relative
impact of the journal in which the article
is published, is shown. All international
refereed publications are set to 100%
for each year.
NB Data for 2012 are not yet available.
80%
60%
18
16
14
12
8
3,100
22
2,900
20
2,700
18
2,500
16
2,300
2,300
14
2,100
2,100
12
1,900
1,900
10
1,700
1,700
Papers
Citations PP
1,500
0
1997-2007 1997-2009
1997-2008
1997-2009
1997-2011
1997-2009
1997-2010
1.8
100%
200
Other
50%
Top 25
180- 50%
Top 11 - 25%
160
Top 10%
20%
2008
2009
2010
Heart
Quality of publication
2011
2008
2009
1,500
1997-2010
3,1005: Citation of papers 1997-2010.
Figure
Papers: number of papers in Web of Science
2,900
published by the ICaR-VU, since 1997.
Citations
2,700 PP: average citations per paper
excluding self-citations.
2,500
Figure 6: MNCS: Mean Normalized Citation Score (crown indicator), i.e. mean of
citations related to the average number of
citations in the field of interest. For a group
which scores just average of all the groups
participating in the same research field the
MNCS would be 1.00. VUmc expects its
research institutes to score 1.3 or higher.
1.6
1.4
1.2
40%
40%
20
24
The CWTS, Center for Science & Technology Studies, compares the impact of the research of universities and its
institutes to the field of science to which it belongs. For the Institute the most recent data are the papers
published between 1997-2010. Since the CWTS started the analysis in 1997 the number of papers included in the
analysis has increased, For the ICaR-VU the number of citations per paper, excluding self-citations, since 1997
has increased from 14 to 21.
100%
60%
22
10
2012
Overview of number of publications related to type of publication
80%
0%
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Number of papers
Figure 3: The number of publications is
shown per year and for each theme. We
included 2009 to show the trend over a
longer period. The professional publications
are mostly in Dutch.
*Numbers for 2012 are best estimates
available in January 2013..
400
Number of papers
450
Citations per paper exclusive selfcitationas
Citations
Citations PP excluding self-citations
Number
Papers and Impact
21
2010
Vessels
2011
140
120
100
80
60
1.8
2004 - 2007
2005 - 2008
2006 - 2009
2007 - 2010
1
0.8
60
1.6
ICaR-VU
1.4
Heart
MNCS (Citation Crown Indicator CWTS)
1.2
50
Vessels
40
30
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A Selection of Awards in 2010 - 2012
Life Time Achievement Award
International Young Investigator Awards
Nico Westerhof, the first Director of the ICaR-VU,
received the Artery Lifetime Achievement Award from the
Artery Society in October 2011.
He accepted the Award with a lecture ‘The Tale of Two
Circulations’. After retiring as Director of the ICaR-VU he
has remained active as a scientist in the Pulmonary Arterial
Hypertension group. He is an expert on physics of the aorta
and left ventricle and over the past 10 years he has used this
expertise to better understand the physics of the right
ventricle and pulmonary artery system.
Jurjan Aman, PhD student in the Vascular Function in
Sepsis Group, received a special award from the European
Society of Intensive Care Medicine in October 2011 for
studies on imatinib and pulmonary permeability (20,000
euro).
Karima Farhat, PhD student in the Nephrology group won
a Young Investigator Award for clinical abstracts
at International Society of Peritoneal Dialysis (ISPD) in
September 2012 in Kuala Lumpur.
Nazha Hamdani, postdoc in the Diastolic Heart Failure group
won the best Young Scientist Award and the best published
manuscript of 2012 of the Deutsche Gesellschaft für
Kardiologie (Franz-Maximilian-Groedel-Forschungspreis),
the best Poster presentation Award at 77th Annual Meeting
of the German Cardiac Society (March 2012) and
2 presentation awards at the 2012 MEDIA- event for her
presentations: 1. The pathophysiology of heart failure with
preserved ejection fraction. 2. Myofilament phosphorylation
and function in heart failure with preserved ejection fraction.
Paul Krijnen, postdoc in the Acute Coronary Syndromes and
Repair won The Investigative Pathology in Cardiovascular
Diseases Award of the Association for European Cardiovascular Pathology in April 2012
Esther Kuijper, PhD student of the Reproduction and Vascular
Function group won Galton Award for Best Student paper at
14th International Congress of Twin studies April 2012.
Rick Meijer, PhD student in the Vascular Function in Metabolic diseases Group, received the Young Investigator’s Award
of the European Society of Microcirculation and the Gesellschaft für Mikrozirkulation und Vaskuläre Biologie at their
joint meeting in München 2011.
Thesis Awards
Silvia Rain, PhD student in of the pulmonary arterial hypertension group was awarded the ESC First Contact Initiative
Grant of European society of Cardiology in April 2012.
Vasco Sequeira, PhD student in the Hypertrophic Cardiomyopathy group received a Young Investigator Award at
Winter Meeting – Heart Failure Association (European Society
of Cardiology) – Les Diablerets, Switzerland; January, 2012.
Annemieke Smorenberg, Master student in the group of
Vascular Function in Sepsis received The First Prize Poster
Award: XIVth Congress of the European Shock Society
August 2011.
Hari K Thulluru, PhD student in the Reproduction and
Vascular Function group won The YW Loke New Investigator
Travel Award from The International Federation of Placenta
Associations (IFPA) in September 2012.
Linda Jufferman, presently a post doc in the Imaging group,
received the prof. dr. AA Knoop Award 2010 for Best Physiological Thesis (2008-2009) for her thesis; ‘Ultrasound and
microbubble-targeted delivery of drugs and genes, cellular
bio-effects’
Frances de Man, presently a postdoc in the Pulmonary
Arterial Hypertension group received the Jacob Hamburger
Award of the Dutch Physiological Society for the Best
Physiological Thesis in 2009-2010. The title of her thesis was:
‘Muscle function, exercise training and beta-blocker
treatment in pulmonary arterial hypertension’.
Louis Handoko, presently AIOS Cardiology, received the prof.
dr. A.A. Knoop Award 2012 for Best Physiological Thesis
(2010-2011) with his thesis, entitled ‘Right heart failure in
pulmonary hypertension, lessons from the left heart’.
Mariëlle van de Veerdonk, PhD student at the Pulmonary
Arterial Hypertension Group, received a Young Investigator
Award of the European Respiratory Society 2010.
Paul Wijnker, PhD student in the Hypertrophic Cardiomyopathy group received a Young Investigator Award for the best
oral presentation at Summer School Cardiovascular Science
(Basic Science Summer School), Sophia Antipolis (Nice),
France, June 2011, a Young Investigator Award at the 41st
European Muscle Conference: of the European Society for
Muscle Research, Rhodes, Greece, September 2012 and a Best
Poster Award + Travel Award 2012 at Frontiers in Cardio
Vascular Biology - Second meeting of the ESC Council on
Basic Cardiovascular Science, London, United Kingdom,
March 2012.
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Grants 2010 - 2012
In 2010 we obtained 35 grants with an
average of 282,000 euro
External Grants obtained by the ICaR-VU 2010 in kEuro (selection)
Walter Paulus
P7, The Metabolic Road to Diastolic Heart Failure (MEDIA) total
K
of 12,100 kEuro for 20 participating organizations.
1700
Pieter Koolwijk
FES (NIRM) Cardiovascular WP6 Angiogenesis and hypoxia.1611
Bert van Rossum
I ndustry, diverse projects Heart Failure and Ischemic heart disease.
CTMM COHFAR prospective CRT study.1200
Walter Paulus and
CVON: Approaching Heart Failure by Translational Research of RNA mechanisms).800
WO VIDI grant, Sarcomeric dysfunction as a target for treatment in
N
primary human cardiomyopathy.
Bert van Rossum
Industry: Estimate of research grants obtained for cardiology projects.867
Hans Niessen, icw H de Wit and Rob Beelen
NWO apparatuur middelgroot: Cryo-Electron Microscopy.670
Geerten van Nieuw-Amerongen
Netherlands Heart Foundation, Dekker established investigator:
Targeting of vulnerable loci in the endothelium.550
800
Hans Niessen and Paul Krijnen
Industry, Biomarker detection and therapy development in viral myocarditis.670
Anton Vonk Noordegraaf
NWO, translational grant, Betablocker therapy in pulmonary arterial hypertension.500
Judith Huirne and Hans Brölmann
NWO, HELLP-syndrome detection.430
Michaela Diamant
I ndustry (Investigator initiated grant): The effect of GLP-1 receptor activation on
central reward and satiety circuits in response to food stimuli in obesity and diabetes.425
René Musters and
Joost Sluijter (UMCU) BMM, P1.05 LUST (FES) Localized Ultra-sound Small RNA Transmittal.
Total of 1,164 kEuro. Marie van Dijk
NWO, VENI: HELLP-babies: mutations in a novel non-coding RNA.250
Coen Ottenheijm
Beatrixfonds, Myofilament-based muscle weakness in faciosca-pulohumeral dystrophy.250
Erik Serné
HS junior staff Targeting inflammation-related microvascular dysfunction to
N
improve cardiometabolic risk in rheumatoid arthritis and obesity.220
Arthur Bouwman
Arthur Bouwman
375
ZonMw Clinical Fellowship. Perioperative activation of adenosine monophosphateactivated kinase improves anesthetic cardio protection in type diabetes mellitus:
role of cardio protective kinases.160
Young Investigator Dutch society for Anesthesiology. The metabolic profile of the heart
modulates its sensitivity to ischemia: an experimental approach to study the impact of
lifestyle modification on preservation of perioperative cardiac function.
50
Piet ter Wee, Ed Eringa
‘Nierstichting:’ The FGF23 – klotho – vitamin D axis as a new instrumental target to
Rene Musters combat the cardiovascular risk of chronic kidney disease: The NIGRAM Consortium.
(Nijmegen, Groningen, Amsterdam) Total 1,500,000 euro.500
Harry Lafeber
I ndustry: Studies Towards the Effects of Postdischarge nutrition of preterm infants
(STEP I study). The first 6 months after birth. 400
Harry Lafeber
I ndustry: Studies Towards the Effects of Postdischarge nutrition of preterm infants
(STEP II study). The first seven years after birth.260
Michaela Diamant, icw
Miriam Sturkenboom
and Judith Huirne P7: SAFEGUARD: Safety of Novel Anti-Diabetic Drugs.330
NWO/ VEMI: Hysteroscopic resection of uterine cesarean scar defect (niche) in
patients with abnormal bleeding, a randomized controlled trial.249
Yvo SmuldersEffect of Adalimumab on Inflammatory Activity in
Mike Nurmohamed Atherosclerotic lesions in Patients with Reumatoid Arthritis. 220
Tjeerd Germans 170
NHS Dekker grant for AIOS. Energetics in hypertrophic cardiomyopathy:
translation between MRI, PET and cardiac myofilament function. I C A R -V U m c
25
26
P r o gr e s s R ep o r t 2010 > 2012
27
Grants 2010 - 2012
Geerten van Nieuw Amerongen and Peter Hordijk (Sanquin)
Rembrandt Research Grant 2012: RhoGTPases in the endothelium:
localized activity, cross-talk and relevance for barrier function
and inflammation (Total 500).250
Nazha Hamdani
PhD Grant, Early Career Researchers of Ruhr University Bochum:
The giant titin protein as a novel therapeutic target for diastolic heart failure. 250
Nazha Hamdani
PhD Grant, Science and Technology Foundation Germany: The impact of obesity and
diabetes mellitus on the pathophysiology of Diastolic Heart Failure.250
M. Bremmer (EMGO)
(i.c.w. M. Diamant)
EFSD/EASD; ‘Bright light for better mood and metabolic control. The efficacy of
Bright Light Treatment in Type 2 Diabetes and comorbid Major Depression’ Richard G. IJzerman (i.c.w. NCA)
ZonMw (VENI); ‘The role of central reward and satiety centers in the etiology of obesity:
genetic and environmental influences’.250
Paul Knaapen
Abbot Vascular ‘Impact of Vascular Reparative Therapy on Vasomotor Function
and Myocardial Perfusion’.225
Coen OttenheijmNWO VIDI Grant ‘Muscle weakness in Nemaline Myopathy:
what is the cause and can it be treated?’800
Bert van Rossum Industry: Estimate of research grants obtained for cardiology projects.750
Hans van Goudoever Danish Government ‘Neo Immune’ coordinator. Total group: 5000.500
Hans van Goudoever FP7: European network Early Nutrition. Total group: 11000.450
Hans van Goudoever Nutricia Foundation: Long term impact of nutritional management.440
Christa Boer, and Evert Verhagen (EMGO+)
NWO prevention Fund ‘Increasing habitual physical activity to reduce the surgical
risk of hyperglycemia and complications in patients with metabolic syndrome
(POSITIVE study)’.435
Hans van Goudoever FP7: Prevent ROP total of group: 4000.400
Yvo Smulders Identifying the right patient to treat, by estimating absolute treatment effect for
individual patients based on randomized clinical trial data.
ZonMw Programma Goed Gebruik Geneesmiddelen 2012-2016 (co-applicant).374
Christianne De Groot (i.c.w. dr. C. Wagner, EMGO)
ZonMw Improving obstetrical care by multidisciplinary team training for patient
referral situations. The LOCOMOTIVE Study: Local Obstetrical Collaboration
Multidisciplinary On-site Team training effectIVEness Study.372
Harry Lafeber Industry: Step study’s funding for 2012.320
Henk Blom
FP7: European network and registry for homocystinurias and methylation defects
VUmc coordinator (total 700).
Michaela Diamant
Eli Lily: ‘The effects of real-time continuous glucose monitoring in patient with
type 1 diabetes mellitus and impaired hypoglycemia awareness (IN CONTROL STUDY)’.260
Harm-Jan Bogaard and Geerten van Nieuw Amerongen
Lung Foundation: ’The pulmonary endothelium fails to adapt to increasing shear stress:
Role of blood flow velocity in the development of pulmonary arterial hypertension‘.250
Christianne de Groot
(principal investigator)
ZonMw: Regional perinatal network within the education and training region
(OOR) of VUmc.250
300
250
The ICaR-VU was successful in obtaining research grants in 2010-2012. In 2010 all types of funding increased compared to
prior years. Researchers of the ICaR-VU were active in European consortia, national research platforms, charity research funds
and industry competitions.
Figure 7: External grants obtained by researchers of the ICaR-VU in 2004-2012. Government grants include: Dutch organizations for
research supported by the government like
NWO/ZonMw/STW/FES. Charity organizations include: Netherlands Heart Foundation,
Dutch Kidney Foundation, Dutch Diabetic
Society, Asthma-Fund. Data were provided by
the project leaders participating in the ICaRVU. More details are published in the year
reports. 2012 is the best available estimate
at the end of January 2013.
12,00
Euro’s *10
6
10,00
8,00
6,00
4,00
2,00
0,00
2003
2004
2005
External Funding Research
2006
2007
2008
2009
2010
2011
2012
Year
Funding by NWO/ZonMw/STW/FES
Funding by Industry
Funding by Charity Organizations/FP7
Total external funding
I C A R -V U m c
27
28 P r o gr e s s R ep o r t 2010 > 2012
29
Education
The ICaR-VU, started with an educational focus on
its PhD students; now the ICaR-VU provides challenging
educational programs for Bachelor, Master and PhD
students in medical and life science research.
Bachelor-education
Master-education
The ICaR-VU participates in research education in
the medical bachelor program. Each year, 40 medical
bachelor students choose Cardiovascular Research
for their scientific training. They write a bachelor
thesis in small groups under the supervision of PhD
students. A workshop program on the research
within the Institute is organized to help them to
choose their practical research training. Theoretical
education is tested by an oral examination.
The Cardiovascular Research Master provides an
international education program for excellent
students who are looking for a career in cardiovascular research. It was accredited by the NVAO in
2008 and provides a structured 2-year program
within cardiovascular sciences for a limited number
(up to 25) of students. The first curriculum of the
Cardiovascular Research Master was in September
2009. This Research Master Program preselects for
bright and motivated students with a life-science
or related bachelor degree.
Each year, as a part of a special honors program,
3-6 medical bachelor students start specialized
cardiovascular research projects (during their
medical bachelor education), in order to gain
research experience and to write their first scientific
paper. They continue the data acquisition and
analysis at the start of their master program and
finish writing the paper in the second year of their
master-education. Most of these students combine
research and medical training and start a PhD
education after their MD graduation.
PhD training program
The ICaR-VU offers PhD students a research and
education program that is tailored to individual needs.
Research training at the front-line of cardiovascular
research in the laboratory and the clinic is the primary
goal for a PhD student, who will spend most of their
time on a research training project collaborating with
the ICaR-VU scientists. At the start of their research
training, an agreement is made to follow highly specialized topical and/or complementary courses taught by
senior scientists at the ICaR-VU, including visiting
senior scientists, or other highly qualified teachers.
I C A R -V U m c
29
30
P r o gr e s s R ep o r t 2010 > 2012
PhD Training Program
The PhD-curriculum consists of five categories
of activities:
1Courses contributing to the PhD students general
scientific education (i.e. statistics, scientific
English, animal research, clinical research regulations, writing grant proposals).
2 Participation in weekly progress meetings of the
research team; supported by PhD-supervisor.
3Participation in cardiovascular knowledge transfer
(colloquia, symposia, lectures, presentation of own
papers and posters).
4Special courses training students to become
independent researchers and widening the scope
of their knowledge (organized for PhD students in
Cardiovascular Research by the ICaR-VU or by
the Netherlands Heart Foundation).
5Visits to other labs to enhance cooperation
between groups and learn new technical skills.
PhD Students and Projects
In addition to the monthly scientific colloquia
organized by the Institute, symposia are organized
by the participating research groups on special
occasions, as well as lectures by visiting scientists.
45
40
35
30
PhD students
25
The PhD students in the Institute have a basic life
science or medical background. The majority follow
the regular full-time PhD project and program. They
include comparable numbers of students with an MD
background, who will specialize after their research
training, and basic science PhD students (from
Medical Biology, Epidemiology, Physics or Technology
backgrounds). Many international students are
among this latter group. In addition a number of
clinicians combine clinical duties and research;
these projects are embedded in the Institute.
20
15
10
5
0
2009
2010
2011
2012
Twice a year a special themed afternoon is organized by the education committee
for all PhD students in ICaR-VU:
Figure 9: The number of PhD students active
within the ICaR-VU is gradually increasing
as is reflected by the number of PhD
projects in progress. The average duration of
the regular PhD research project is 4 years.
The duration of combined specialization and
research is more variable. In Theme Vessels
more clinical research is combined with a
specialist training program.
90
80
70
‘Ethical dilemma’s in clinical and preclinical research’
by prof. dr. Tjard de Cock Buning, dr. Christa Boer
(member METC VUmc), December 2011.
‘Posterworkshop’ How do you get the attention
of your public, by Catriona Ester VU University
Language Center, April 2012.
‘Good science vs Fraud’ How can you be sure that all
your papers are based on solid data by prof. dr. Nico
Westerhof and prof. dr. Henk de Regt, December 2012.
Figure 8: Education background of the PhD
students who are ICaR-VU graduates. The
Basic science group has a MSc background
and follow a regular 4 year PhD program.
The MD regular group represents Medical
Doctors that follow the regular 3-4 year
PhD program, the MD special group members combine clinical training and research.
The MD external group combines clinical
work outside VUmc with research under the
supervision of an ICaR-VU scientist. In the
external group the work and graduation
took place outside VUmc under co-supervision of ICaR-VU scientists.
Basic Science
MD regular
MD special
MD external (B)
External (D)
PhD graduations ICaR-VU
100
‘Meet the criticasters’ How is your paper judged, before
it is accepted for publication? by prof. dr. Anton J.G.
Horrevoets and prof. dr. Walter J. Paulus, March 2010.
‘PhD graduation in perspective’ What will you do after
graduating for your PhD? by dr. ir. Roel G.M. Breuls,
and dr. Erik H. Serné, November 2010.
‘Successful writing’ How do you prepare your paper and
how did others before you? by prof. dr. Nico Westerhof
and prof. dr. Jolanda van der Velden, April 2011.
31
60
50
40
30
20
10
Theme H
Theme V
0
2009
2010
2011
2012
Number of PhD projects in progress
I C A R -V U m c
31
32 P r o gr e s s R ep o r t 2010 > 2012
33
PhD Degrees Awarded in 2010
DATE
CANDIDATE
PROMOTOR(ES)
CO-PROMOTOR(ES)
TITLE THESIS
V
28-10
Cathelijne Snijders
W.P.F. Fetter
T.W. Schaaf
H.A. Molendijk
R.A. Lingen
Sources and consequences of reactive
oxygen species in right ventricular hypertrophy and right ventricular failure.
Voluntary reporting and systematic analysis
of incidents in neonatal intensive care:
the Neosafe study.
V
17-11
Iris J.G. Ketel
C.B. van Lambalk
C.D.A. Stehouwer
E.H. Serné
R. van Homburg
Vascular function and insulin sensitivity
in lean and obese PCOS.
DATE
CANDIDATE
PROMOTOR(ES)
CO-PROMOTOR(ES)
TITLE THESIS
V
22-01
Cora M.L. Beckers
V.W.M. van Hinsbergh
G.P. van Nieuw
Amerongen
Spatial-temporal signalling controlling
endothelial permeability.
H
25-01
Everaldo M. Redout
W.J. Paulus
W.S. Simonides
R.J.P. Musters
theme
theme
H
04-03
Barbara M.A. Schout
L.H.B. Bemelmans
A.J.J.A. Scherpbier
A. Hendrikx
F. Scheele
Training in Urology: from virtual to reality.
V
23-11
Annemarie M.C.
Simonis-Bik
M.H.H. Kramer
J.C.N. Geus
E.W.M. Eelhoff
Genetic influences on β-cell function.
H
19-03
Martijn A. Bekedam
A.C. van Rossum
W.J. van der Laarse
Skeletspieren bij hartfalen.
V
24-11
Margo N. Schilte
J. v.d. Born
V
26-03
Kirsti S.S. Steen
B.A.C. Dijkmans
W.F. Lems
M. Boers
M.T. Nurmohamed
Decline of NSAID gastropathy in rheumatoid
arthritis.
R.H.J. Beelen
P.M. ter Wee
Anti-inflammatory therapy and biomarker
analysis during peritoneal dialysis.
V
10-12
Vincent Jongkind
W. Wisselink
V
29-03
Melanie van der
Heijden
A.B.J. Groeneveld
G.P. van Nieuw
Amerongen
Determinants of vascular leakage in sepsis
and acute lung injury.
New techniques in minimal invasive and
open surgery of the aorta.
V
03-12
Floor Remmers
A.C. van Rossum
R.M. Heethaar
M.J.W. Götte
Myocardial strain, torsion and untwisting in
the normal and failing heart measured with
magnetic resonance tagging.
Developmental programming of energy
balance.
Iris K. Russel
H.A. Delemarrevan der Waal
R.A.H. Adan
V
14-12
Leonard P.
van der Zwan
C.A.J.M. Jacobs
P.G. Scheffer
T. Teerlink
The interplay of oxidative stress and
inflammation in atherosclerosis:
an epidemiologic approach.
P.A.F.M. Doevendans
M.C. Verhaar
C.A.J.M. Gaillard
B. Braam
Circulating cells in heart and renal failure.
J.H. Beijen
M. Diamant
D.P.M. Brandjes
Chubby children: weighing the risk.
J.L.H.R. Bosch
R.M. Verdaasdonk
F.P. van Swol
R.J.A. van Moorselaar
Towards improved bladder cancer diagnosis
using fluorescence imaging and Raman
spectroscopy.
H
14-04
V
15-04
Rose-Marieke B.G.E.
Breukers
A.B.J. Groeneveld
A.R.J. Girbes
J.R.C. Jansen
Preload and cardiac output in the critically ill.
V
20-05
Wineke Bakker
C.D.A. Stehouwer
E.C. Eringa
P. Sipkema
Vascular insulin resistance through fat.
V
10-06
Marieke G. Peetsold
R.J.B.J. Gemke
H.A. Heij
H
14-06
M. Louis Handoko
W.J. Paulus
A. Vonk Noordegraaf
Right Heart failure in pulmonary
Hypertension, lessons from the left Heart.
H
14-06
Frances S. de Man
P.E. Postmus
W.J. van der Laarse
A. Vonk Noordegraaf
Muscle function, exercise training and
beta-blocker treatment in pulmonary arterial
hypertension.
V
23-06
Koen L. Deurloo
J.M.G. van Vugt
M.A. Blankenstein
A.C. Bolte
Early prediction of pre-eclampsia and
intrauterine growth restriction in pregnancy.
V
08-09
Annemone van Zwol
W.P.F. Fetter
V
06-10
Fleur M.F. Rosiervan Dunne
J.I.P. de Vries
H.J. Odendaal
G. van Wezel-Meijler
H.P. van Geijn
Fetal brain imaging in pregnancies at risk for
preterm birth.
V
07-10
Wiebe de Vries
J.J.L.M. Bierens
K. Monsieurs
R.W. Kosterd
Remember fast - Act skillfully. Training
methods for Basic Life Support: an analysis
from educational perspective.
Long term results after repair of congenital
diaphragmatic hernia and esophageal atresia.
Glutamine-enriched enteral nutrition in very
low birth weight infants, six years of
follow-up.
EXTERNAL DEFENCES
H
UU
08-04
Kim E. Jie
V
UU
15-09
Mariska vanVliet
H
UU
28-10
Matthijs C.M.
Grimbergen
All theses listed here had a Promotor or co-Promotor from the ICaR-VU, although some were defended at other universities,
as mentioned in the section external defences.
I C A R -V U m c
33
34 P r o gr e s s R ep o r t 2010 > 2012
35
DATE
CANDIDATE
PROMOTOR(ES)
V
06-01
Ingeborg H. Linskens
J.M.G. van Vugt
M.A. Blankenstein
V
27-01
Laura Vroling
H.M.W. Verheul
H.J. Broxterman
theme
CO-PROMOTOR(ES)
TITLE THESIS
theme
DATE
CANDIDATE
PROMOTOR(ES)
CO-PROMOTOR(ES)
TITLE THESIS
Pathophysiology of impaired glucose
metabolism: the role of the renin angiotensin
system.
Prenatal screening in twin pregnancies.
V
06-07
Nynke van der Zijl
M. Diamant
E.E. Blaak
Circulating endothelial and progenitor cells
during anti-angiogenic treatment in cancer
patients.
V
08-07
Thomas J. Cramer
H.W.M. Niessen
V
09-09
Mark S. Fineman
M. Diamant
R.J. Heine
Development of immediate and sustainedrelease formulations of the glucagon-like
peptide-1 receptor agonist exenatide for the
treatment of patients with type 2 diabetes.
V
09-09
Mathijs C.M. Bunck
M. Diamant
R.J. Heine
Clinical effects of the GLP-1 receptor agonist
exenatide in patients with type 2 diabetes.
H
15-02
Viola Kooij
G.J.M. Stienen
J. van der Velden
Contractile Function of the Human Myocardium. Impact of Troponin Phosphorylation.
V
16-02
Yolanda M. de Mooij
J.M.G. van Vugt
AC Gittenbergerde Groot
M.N. Bekker
Increased nuchal translucency. Lymphatic
development and blood flow alterations in
fetuses with nuchal edema.
A.J. Gale
Inactivation of coagulation factors Va and
VIIIa by activated protein C.
H
09-03
Serge A. van
Wolferen
A. Vonk Noordegraaf
A. Boonstra
J.T. Marcus
Monitoring the right ventricle in pulmonary
arterial hypertension. A non-invasive
approach.
V
28-09
Ester M. Weijers
P. Koolwijk
V
01-04
Lukas B.
Uittenbogaard
J.M.G. van Vugt
M.C. Haak
The Fetal Heart. Critical appraisal of
three-dimensional echocardiography.
Fibrin matrices for tissue engineering.
Naturally occurring fibrinogen variants
alter cellular characteristics.
V
26-10
Ilse E.A.M. Westerbeek
R.M. van Elburg
V
21-04
Izhar C. van Eijk
B.A.C. Dijkmans
Y.M. Smulders
M.T. Nurmohamed
D. v. Schaardenburg
Modulation of cardiovascular risk factors and
inflammation in rheumatic diseases.
H.N. Lafeber
W.P.F. Fetter
Enteral supplementation of neutral and
acidic oligosaccharides in preterm infants.
H
18-11
Katja van den Hurk
26-04
Sabine J. van Dijk
G.J.M. Stienen
J. van der Velden
Sarcomeric function and protein changes in
human cardiomyopathy: mutation or
phenotype.
O. Kamp
M.J. Alssema
Diabetes and the Heart.
H
J.M. Dekker
M.G.A.A.M. Nijpels
V
30-11
Adrie Seldenrijk
B.W.J.H. Penninx
M. Diamant
H.P.J. v. Hout
H.W.J. v. Marwijk
Depression, Anxiety and Subclinical
Cardiovascular Disease.
V
18-05
G. Margret Bartelds
B.A.C. Dijkmans
L.A. Aarden
M.T. Nurmohamed
G.J. Wolbink
Clinical implications of immunogenicity.
V
02-12
Mark van Heerde
J.J. Roord
D.G. Markhorst
Preservation of spontaneous breathing
during high-frequency oscillatory ventilation.
V
24-05
Susan Collins
W.W.A. Zuurmond
S.A. Loer
R.S.G.M. Perez
Complex Regional Pain Syndrome type 1
Assessment and treatment targeting central
sensitization.
V
16-12
Koen J. Hartemink
A.B.J. Groeneveld
A. Beishuizen
Cardiovascular markers and mediators in
human septic shock.
H
19-12
Gert Jan Mauritz
A. Vonk Noordegraaf
J.T. Marcus
V
25-05
G. Frederiek
Estourgie-van Burk
D.I. Boomsma
H.A. Delemarrevan der Waal
W.P.F. Fetter
M. Bartels
Variation in growth and the influence of early
growth in later life: a twin-sibling study.
Insights into the progression of right
ventricular failure in pulmonary arterial
hypertension.
V
22-12
Michel E. Weijerman
R.J.B.J. Gemke
A.M. van Furth
V
27-05
Berbel J.R. Sluijter
R.J. Scheper
P.A.M van Leeuwen
D. de Gruijl
M.P van der Tol
Cutaneous Melanoma: Predictors of Patient
Survival and the Potential of Priming of the
Sentinel Lymph Node.
V
30-05
Robert E. Verloop
A.J. van Zonneveld
P. Koolwijk
Progenitor Cells and Hypoxia in Angiogenesis.
V
31-05
Ilse A.C. Vermeltfoort
G.J.J. Teule
P.G.H.M. Raymakers
Diagnosis and prognosis of cardiac syndrome X.
H
04-07
Luuk-Jon Rijzewijk
M. Diamant
A.A. Lammertsma
Metabolic Imaging in Gluco-Lipotoxic Heart
and Liver Disease in Type 2 Diabetes.
Consequences of Down syndrome
for patient and family.
EXTERNAL DEFENCES
In 2011, C.J.M de Groot, H.J Blom, P.A.M. van Leeuwen and V.W.M. van Hinsbergh were Promotors for a total of 6 individual
thesis defenses at other universities. The details of these can be found in the annual report of the ICaR-VU 2011 at
www.vumc.com/branch/icar-vu/infoicarvu/AR/
I C A R -V U m c
35
36 P r o gr e s s R ep o r t 2010 > 2012
37
DATE
CANDIDATE
PROMOTOR(ES)
CO-PROMOTOR(ES)
TITLE THESIS
H
03-07
Marijn P. Rolf
R.M. Verdaasdonk
A.C. van Rossum
M.B.M. Hofman
Velocity Measurements in Cardiac Magnetic
Resonance Imaging.
Myocardial O2 supply and O2 utilization of
the right ventricle in pulmonary arterial
hypertension.
H
04-07
Sebastiaan A. Kleijn
A.C. van Rossum
O. Kamp
Novel aspects of left ventricular quantification with three-dimensional echocardiography. Validation and clinical applications.
R. Nieuwland
Postprandial dysmetabolism and cell-derived
microparticles as cardiovascular risk factors
in metabolic syndrome and type 2 diabetes
mellitus.
V
05-09
Neelke C. v.d. Weerd
P.M. ter Wee
M.L. Bots
M.P.C. Grooteman
P.J. Blankestijn
Hemodiafiltration and Hepcidin. Effects on
renal anemia and cardiovascular disease in
hemodialysis patients.
V
19-09
Daan v. Abel
C.B.M. Oudejans
M. van Dijk
A. Vonk Noordegraaf
Th.C.J. Faes
Towards a better description of cardiovascular function in pulmonary hypertension.
Modeling and clinical practice.
The role of transcription factor STOX1A in
transcriptional networks associated with
neurodegeneration.
H
21-09
Nabil Saouti
A. Vonk Noordegraaf
A. Boonstra
The Load of Pulmonary Hypertension.
Annemieke v. Dijk
H.W.M. Niessen
A.C. van Rossum
F.J. van Milligen
New therapies for myocardial infarction:
inflammation inhibitors and adipose stem cells.
H
27-09
Christine J. Pol
W.J. Paulus
W.S. Simonides
Milan C. Richir
P.A.M. v. Leeuwen
Th.P.G.M. de Vries
T. Teerlink
The importance of the arginine/ADMA ratio
on the bioavailability of nitric oxide and
organ function in critically ill patients.
Impaired cardiac thyroid hormone signaling
during heart failure.The role of type III
deiodinase.
V
28-09
Jessica Sipkens
H.W.M. Niessen
C.D.A. Stehouwer
J.A. Rauwerda
Homocysteine as a risk factor for the
development of cardiovascular disease the
role of NOX proteins.
V
10-10
Fleur Schouten
J.W.R. Twisk
Y.M. Smulders
M.R. de Boer
I. Ferreira
Fat Distribution and Arterial Stiffness.
The Amsterdam Growth and Health
Longitudinal study.
V
01-11
Milou P.H. Busard
C. van Kuijk
J.H.T.M. van
Waesberghe
V. Mijatovic
Advances of MR imaging in endometriosis.
V
23-11
Daniël H. v. Raalte
M. Diamant
V
26-11
Ronald J. Trof
A.B.J. Groeneveld
A.R.J. Girbes
A. Beishuizen
Optimizing fluid management in critically ill
patients.
V
07-12
Daniëlle M.E.
v. Assema
A.A. Lammertsma Ph.
Scheltens
B.N.M. van Berckel
M. Lubberink
Blood-brain barrier P-glycoprotein function
in aging and Alzheimer’s disease.
DATE
CANDIDATE
PROMOTOR(ES)
CO-PROMOTOR(ES)
TITLE THESIS
V
24-02
Eelco v. Duinkerken
M. Diamant
F.J. Snoek
M. Klein
F. Barkhof
Type 1 Diabetes and the Brain: A Bittersweet
Relationship?
H
21-03
Yeun Ying Wong
A. Vonk Noordegraaf
P.G.H.M. Raijmakers
W.J van der Laarse
V
26-03
Maarten
E. Tushuizen
M. Diamant
A. Sturk
H
27-03
Taco Kind
H
17-04
V
20-04
theme
On the pathological remodeling of large
arteries.
23-04
Frank Helderman
A. Vonk Noordegraaf
R. Krams
25-04
Stefan A.J. Timmer
A.C. v. Rossum
A.A. Lammertsma
V
09-05
Shaikh A.
Nurmohamed
A.B.J. Groeneveld
P.M. ter Wee
V
09-05
Matteus A.M. Linsen
W. Wisselink
A.W.F. Vos
Endovascular aortic aneurysm repair:
alternative strategies.
V
14-05
Jan Willem Kuiper
A.B.J. Groeneveld
R.J.B.J. Gemke
F.B. Plötz
Mechanical Ventilation and Acute Kidney
Injury.
V
16-05
Mark G. Vervloet
P.M. ter Wee
01-06
Georgios F.
Giannakopoulos
H.J. Bonjer
F.C. Bakker
Triage and assessment of injuries in early
trauma care.
14-06
Johannes A.
v.d. Heide
A. C van Rossum
O. Kamp
Three-dimensional echocardiography for left
ventricular quantification in heart failure.
19-06
Olga Bondarenko
A.C. van Rossum
A.M. Beek
Myocardial Viability in Patients With Chronic
Ischemic Myocardial Dysfunction: Evaluation
by Cardiovascular Magnetic Resonance.
21-06
Lonneke Smeding
A.B.J. Groeneveld
M.C.J. Kneyber
F.B. Plötz
Sepsis, mechanical ventilation and the heart.
V
H
V
H
H
V
P. Knaapen
M. Lubberink
Myocardial Perfusion and Metabolic Imaging
in Hypertrophic Cardiomyopathy. Unraveling
the Pathophysiology.
theme
Optimizing continuous renal replacement
therapy in the ICU.
Managing disorders of bone and mineral
metabolism in chronic kidney disease.
Diabetogenic effects of glucocorticoid
drugs:the knowns and the unknowns.
EXTERNAL DEFENCES
In 2012 J.B. van Goudoever, R.J.B.J. Gemke, M. Diamant, C.A.J.M. Gaillard, H.J. Blom, R.M. Verdaasdonk, M.P.C. Grooteman
and C. Boer were (co-)Promotors for a Promovendus at another university. A total of 11 external theses were defended in
2012. Details will be available April 2013 at www.vumc.com/branch/icar-vu/infoicarvu/AR/
I C A R -V U m c
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38 P r o gr e s s R ep o r t 2010 > 2012
I C aR -V U / T h em e H
Theme H
Improvement of Cardiac Function
in Heart Failure
The studies in Theme H
aim to unravel pathomechanisms
underlying myocardialand pulmonary remodeling and
impaired cardiac function
39
2
Introduction
Toptalents
Research Groups
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Theme H / Heart Failure
Ischemia
and Repair
Circulation and
Metabolism
Imaging
Heart Failure and
Pulmonary
Arterial
Hypertension
Heart failure is the most frequent cause of hospitalization in Western societies. Despite advances in
treatment, the prognosis of heart failure patients
remains poor. Progressive deterioration of myocardial
function is a key feature of chronic heart failure and
is the result of many different pathological processes
affecting the myocardium. Heart failure studies
within the ICaR-VU Theme H aim to unravel
cellular pathomechanisms underlying myocardialand pulmonary remodeling and impaired cardiac
function.
The main research areas of Theme H are Heart
Failure and Pulmonary Arterial Hypertension. Our
research activities include clinical and preclinical
collaborations at both a national and an international level. There are three research groups focusing
on: diastolic heart failure, hypertrophic cardiomyopathy and right ventricular failure in pulmonary
arterial hypertension (PAH). Cardiovascular Imaging
studies play a prominent role in all three. Within
these research groups the patients form the basis of
clinical and basic studies, which sets the stage for
a translational research approach.
There are many interrelationships amongst Theme H
research groups as well as with Theme V of the
ICaR-VU. Recent studies have indicated that diastolic
heart failure is a common feature in different patient
groups and suggest that diastolic dysfunction is a
significant determinant of disease outcome. The
research groups aim to unravel the pathomecha-
nisms underlying diastolic dysfunction. In addition
to this, studies on cardiac metabolism is a common
research subject for all three groups including:
deranged metabolism as risk factor in diastolic heart
failure; impaired efficiency of cardiac contraction
caused by mutant sarcomeric proteins in inherited
forms of cardiomyopathies and perturbations in
oxygen supply and utilization in the hypertrophied
heart as observed in PAH-induced right heart failure.
Studies in the heart are paralleled by studies in
Theme V, which focus on vascular remodeling and
dysfunction caused by increased metabolic risk
(diabetes) and pulmonary hypertension. A classic
example of the collaboration between themes H and
V is represented in the study of pulmonary hypertension patients. While pulmonary arterial hypertension
causes vascular remodeling and as such represents a
primary pulmonary disease, mortality in pulmonary
arterial hypertension patients is strongly associated
with right ventricular dysfunction. The research
group right heart failure in PAH aims to develop
specific treatments targeted at the right ventricle
and/or pulmonary circulation to intervene in the
vicious circle triggered by high arterial pressures.
Likewise, cardiac and vascular studies on diastolic
heart failure and hypertrophic cardiomyopathy are
combined to improve diagnostics and to develop
preventive and curative measures for the treatment
of heart failure.
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Focus on Toptalent
Nebulin, a multi-functional giant
Coen Ottenheijm (VIDI Grant 2012)
Muscles function through a delicate interplay between
innumerable proteins. Defects in these proteins cause
this interplay to crash, resulting in life-threatening
muscle diseases. Coen Ottenheijm’s research aims to
provide insights into how one defective protein - the
giant protein nebulin – leads to impeded contractility
of the muscle causing nemaline myopathy, a debilitating
muscle disease. It is expected that these insights will
open new therapeutic windows for patients with
nemaline myopathy, a disease for which no effective
therapy currently exists.
Perioperative cardio-vascular function in
cardiometabolic disease
Arthur Bouwman (ZonMw Clinical Fellowship
2010 & Young Investigator Dutch society for
Anesthesiology 2010)
Patients with cardiometabolic disease are prone to
perioperative cardiovascular complications. Anesthetic
agents protect against ischemic injury by the activation
of protective signaling pathways. Diabetes mellitus and
obesity reduce the efficacy of anesthetic-induced
cardioprotection. Here we are focusing on interventions
(insulin-sensitizing medication and lifestyle modification) that have the potential to restore cardioprotective
signaling. These insights will provide new perioperative
strategies for patients with cardiometabolic disease who
undergo anesthesia and surgery.
The giant titin protein as novel therapeutic
target for diastolic heart failure
Nazha Hamdani (Early Career Researchers Grant,
Mercator foundation Germany, 2012)
Heart failure with preserved ejection fraction (HFpEF) is
a major clinical problem for which there is currently no
established therapy. The elastic protein titin represents
a novel target for intervention, given that there are
significant titin-mediated changes in elasticity associated with HFpEF. We are investigating the effect of
potential pharmacological interventions on cGMP-PKG
signaling, titin isoform expression, phosphorylation and
passive stiffness. Our studies will improve understanding
of HFpEF pathophysiology and may (even) lead to new
effective therapies.
ENGINE of the muscle in hypertrophic
cardiomyopathy
Tjeerd Germans (Netherlands Heart Foundation,
Dekker Grant 2011)
The mechanism underlying the development of maladaptive hypertrophy in inherited hypertrophic cardiomyopathy (HCM) is poorly understood. Mutant sarcomeric
proteins may impair myocardial energetics and trigger
disease development. We are combining in-vitro determination of myocardial energetics in cardiac tissue with
non-invasive data on myocardial metabolism and
function with hybrid MRI/PET of the same patients. Our
studies will enhance our knowledge of HCM pathogenesis
and form the basis of new therapeutic strategies for the
prevention and reversal of disease progression.
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Research Group
‘Our extensive collaborative research endeavor will achieve
a better understanding of diastolic heart failure, improved
diagnostic algorithms, and novel therapeutic inroads’
Focus
The focus of our studies is on
diastolic heart failure (DHF). Over
the last two decades it has
become evident that more than
50% of all heart failure patients
suffer from impaired diastolic
function with preserved left
ventricular ejection fraction
(HFpEF). Despite modern heart
failure therapy, prognosis of
HFpEF has not improved in
recent years. This epidemiological finding has confirmed the
neutral result of numerous large
clinical trials testing modern
pharmacotherapy in patients
with DHF. HFpEF is of heterogeneous etiology but usually
occurs in patients suffering from
obesity, arterial hypertension and
type 2 diabetes. The vast majority (~80%) of HFpEF patients are
exposed to metabolic risk factors
and the rising incidence of
DHF, therefore, mirrors current
epidemics of obesity and type
2 diabetes.
Collaboration
We collaborate in order to explore
the involvement of metabolic
risk in the pathogenesis of DHF
using a multidisciplinary approach. Studies on cellular
pathomechanisms are combined
with clinical trials based on
existing national and international collaborations. In vivo
assessment of left ventricular
structure, perfusion, metabolism
and contractile function using
echocardiography, cardiovascular
magnetic resonance imaging,
positron emission tomography
and multi-detector computed
tomography form an essential
part of our diastolic heart failure
research. In vivo clinical characteristics are combined with
cellular studies in human cardiac
preparations. In addition to this,
several large- and small-animal
models are being used to unravel
the pathomechanisms underlying
impaired diastolic function.
Unique
Our research group is unique as
our in vitro and in vivo observations in humans are a crucial
basis for the subsequent targeted
approaches in mice and a largeanimal model. An excellent
example of the success and
impact of these approaches was
the observation of increased
cardiomyocyte passive stiffness
in diastolic heart failure patients,
which until then, had never been
observed in any animal model.
This observation has set the stage
for many follow-up studies in
animal models and forms the
basis for clinical treatment
strategies.
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Present and Future Research
Prominent clinical features of myocardial dysfunction in
HFpEF are slow relaxation and high diastolic stiffness.
In recent years, we have shown that intrinsic cardiomyocyte stiffness is a major cause underlying diastolic
stiffness. The high cardiomyocyte stiffness is largely
determined by the giant cytoskeletal protein titin,
whose phosphorylation pattern is altered during cardiac
disease. Our most recent studies suggest that hypophosphorylation of titin is the underlying cause of high
passive stiffness. With our cellular studies we aim to
define the contribution of passive stiffness, myofilament calcium-sensitivity and perturbations in intracellular calcium-handling to cardiomyocyte stiffness. In
addition to this, extensive studies of the extracellular
matrix are being performed in the Department of
Pathology to assess its role in disease pathogenesis.
Our current research projects are part of the large
collaborative MEDIA project sponsored by the European
Commission. In 2009 the committee on diastolic heart
failure (founded by the Heart Failure Association of the
European Society of Cardiology) chaired by Walter
Paulus created MEDIA (the MEtabolic road to DIAstolic
heart failure). The focus is on the interaction between
metabolic risk and diastolic heart failure, and in January
2011 the project began with funding of €12.1 million
divided among seven work packages, 20 universities and
small-medium enterprises. Investigators in work
package one, are creating novel animal models of
diastolic heart failure by exposing rodents or pigs to a
high metabolic risk. Three of the work packages cover
cardiomyocyte, extracellular matrix, and systems
biology, respectively. The remaining three work packages are clinically oriented and deal with biomarkers,
imaging, and small proof-of-concept trials whereby
modulation of metabolic risk is tested as a cure for
diastolic heart failure.
Recent advances in the field of microRNAs have
provided a novel research field, which may be explored
to identify targets for future clinical application. The
surprising stability of circulating microRNAs has created
the possibility for developing next-generation biomarkers. Inhibition of selected microRNAs is powerful and
holds great promise of becoming the next generation
therapeutics. With recent funding from CVON (Cardiovascular Research in the Netherlands) we will evaluate
whether specific RNA based candidate mechanisms
(microRNAs, lncRNA, RNA binding proteins) are of
particular relevance in diastolic heart failure. Within
the ARENA (Approaching Heart Failure by Translational
Research of RNA Mechanisms) consortium several
research groups in the Netherlands (see National
collaborations) have joined forces to explore the
relevance of novel crucial RNA molecules in systolic and
diastolic heart failure in the context of diastolic
dysfunction, ageing, diabetes and gender. We aim to
establish the role of RNA-based regulation in the
contractile dysfunction of the failing heart. Identified
microRNAs and their target genes will be linked to
modifications of extracellular matrix and of myofilament proteins and to contractile properties of isolated
cardiomyocytes.
Participants
Project leaders
Physiology
Nazha Hamdani
Alice Muller
Walter Paulus
Warner Simonides
Ger Stienen
Internal Medicine
Michaela Diamant
Pathology
Paul Krijnen
Hans Niessen
Cardiology
Jean Bronzwaer
PhD students
Physiology
Constantijn Franssen
Loek van Heerebeek
Rob Janssen
Christine Pol
Everaldo Redout
Internal Medicine
Weena Chen
Renate van Genugten
Diane de Goede
Larissa van Golen
Susanne Kleijer
Luuk-Jon Rijzewijk
Mark Smits
Collaborations
National
EMC, Rotterdam
Vincent de Beer
Dennis Dooijes
Dirk Jan Duncker
Ellen Kaptein
Daphne Merkus
Theo Visser
MUMC, Maastricht
Stephane Heymans
Casper Schalkwijk
Leon de Windt
Marc van Bilzen
AMC, Amsterdam
Jan Baan Jr
Bas de Mol
Jan Piek
Yigal Pinto
Jan Tijssen
UMCU, Utrecht
Cees van Echteld
Cees van de Kolk
Annette van den Toorn
UMCG, Groningen
Maarten van den Berg
Jan Jongbloed
Adriaan Voors
OLVG, Amsterdam
Aernout Somsen
Freek Verheugt
International
Antwerpen, Belgium
Marc Demolder
Leni van der Kerkhoven
Nancy, France
Romain Eschalier
Berlin, Germany
Carsten Tschöpe
Bochum, Germany
Wolfgang Linke
Heidelberg, Germany
Johannes Backs
Pavia, Italy
Stefano Perlini
Francesco Salinaro
Perugia, Italy
Giuseppe Ambrosio
Emilia Biscottini
Pisa, Italy
Maja Marchini
Alessandro Saba
Riccardo Zucchi
Porto, Portugal
Ines Falcão-Pires
Cristina Gavina
Adelino Leite-Moreira
Daniela Miranda-Silva
Daniel Moreira-Goncalves
Debrecen, Hungary
Zoltán Papp
Attila Borbely
Oslo, Norway
Svend Aakhus
William Louch
Gabor Kunszt
Ole Sejersted
Dublin, Ireland
Mark Ledwige
Kenneth McDonald
Atlanta, USA
Tsukasa Kawahara
Rochester, USA
Barry Borlaug
Support staf
Physiology
Edwin Kanters
Wies Lommen
Ruud Zaremba
Marian Zuidwijk
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Research Highlight
Data from PhD/post-doc projects: Loek van Heerebeek (Physiology),
Nazha Hamdani (Physiology Amsterdam & Bochum)
Heart failure with preserved ejection fraction (HFpEF) is a major cause
of morbidity and mortality, and is found in up to 50% of all patients
with the clinical features of chronic heart failure. Diastolic left
ventricular (LV) dysfunction due to high LV stiffness and slow LV
relaxation are important contributing factors in HFpEF. Most HFpEF
patients are exposed to metabolic risk factors, and the increasing
incidence of HFpEF, therefore, reflects the current epidemics of obesity
and type 2 diabetes. Despite the clinical importance of HFpEF, its
pathophysiology remains poorly understood and treatment options
remain limited.
Our recent studies in a large-animal model of HFpEF (Hamdani et al.
2011) and HFpEF patients (van Heerebeek et al. 2012) have highlighted
the important phenomenon of elevated intrinsic cardiomyocyte
stiffness (Figure A). We demonstrated that elevated intrinsic cardiomyocyte stiffness is caused by phosphorylation deficits of the giant
sarcomeric protein titin (Borbely et al. 2005/2009; Hamdani et al.
2011; van Heerebeek et al. 2012) and that these alterations contribute
to high diastolic LV stiffness. In addition to this, endomyocardial
biopsies of HFpEF patients showed increased nitrosative/oxidative
stress and impaired nitric oxide bioavailability, which down-regulates
myocardial cyclic GMP/protein kinase G (PKG) signaling. This causes
hypophosphorylation of titin, which enhances cardiomyocyte and LV
diastolic stiffness. Both the in vitro (Figure B) administration of PKG
and in vivo administration of sildenafil raised PKG activity and reduced
cardio-myocyte and LV stiffness. Our studies clearly show the importance of cGMP-PKG signaling for myocardial remodeling in HFpEF and
strongly suggest that readily available, low-toxicity pharmaceutical
agents that influence the cGMP/PKG pathway may represent a novel
therapeutic opportunity in HFpEF patients.
Δ F passive after PKG (kN/m2)
A
p<0.05
4.5
p<0.01
3.0
1.5
0.0
HFPEF
HFREF
p<0.001
B
AS
p<0.001
p<0.001
F passive (kN/m2)
Treatment Challenges and Novel Therapeutic Targets
Selected Publications 2010-2012
8
p<0.01
6
p<0.01
4
2
0
HF
RE
HF
F
R
+
EF
PK
G
HF
PE
HF
F
P
+
EF
PK
G
AS
AS
+P
KG
Figure A: Larger fall in cardiomyocyte
Fpassive after PKG administration in HFPEF
than in HFREF or AS. HFPEF indicates heart
failure with preserved ejection fraction;
HFREF, heart failure with reduced ejection
fraction; AS, aortic stenosis; and PKG,
protein kinase G.
Figure B: Higher cardiomyocyte Fpassive
in HFPEF than in HFREF or AS with a
significant fall in Fpassive after PKG
administration in all 3 conditions.
eerebeek L, Hamdani N, Falcão-Pires I,
H
Leite-Moreira AF, Begieneman MPV,
Bronzwaer JGF, van der Velden J, Stienen
GJM, Laarman GJ, Somsen A, Verheugt
FW, Niessen, HWM Paulus WJ.
Low myocardial protein kinase
G activity in heart failure with
preserved ejection fraction.
Circulation 2012; 126:830-39.
F alcão-Pires I, Palladini G, Gonçalves N,
van der Velden J, Moreira-Gonçalves D,
Miranda-Silva D, Salinaro F, Paulus WJ,
Niessen HW, Perlini S, Leite-Moreira AF.
Distinct mechanisms for diastolic
dysfunction in diabetes mellitus and
chronic pressure-overload.
Basic Research in Cardiology 2011;
106:801-04.
amdani N*, Bishu GK*, Ogut O, Kruger
H
M, Mohammed SF, Ohtani T, Ahmed A,
Brozovich FV, Burnett JR, Linke WA,
Redfield MM.
Sildenafil and B-type natriuretic
peptide acutely phosphorylate titin
and improve diastolic distensibility
in vivo.
*Both authors contributed equally.
Circulation 2011; 124:2882-91.
arluccio E, Biagioli P, Alunni G, Murrone
C
A, Leonelli V, Pantano P, Biscottini E,
Paulus WJ, Ambrosio G.
Advantages of deformation
indices over systolic velocities in
assessment of longitudinal systolic
function in patients with heart failure
and normal ejection fraction.
European Journal of Heart Failure 2011;
13:292-302.
F alcão-Pires I, Hamdani N, Borbély A,
Gavina C, Schalkwijk CG, van der Velden
J, van Heerebeek L, Stienen GJM, Niessen
HWM, Leite-Moreira AF, Paulus WJ.
Diabetes mellitus worsens diastolic
left ventricular dysfunction in aortic
stenosis through altered myocardial
structure and cardiomyocyte stiffness
Circulation 2011; 124:1151-59.
P ol CJ, Muller A, Zuidwijk MJ, van Deel
ED, Kaptein E, Saba A, Marchini M,
Zucchi R, Visser TJ, Paulus WJ,
Duncker DJ, Simonides WS.
Left-ventricular remodeling after
myocardial infarction is associated
with a cardiomyocyte-specific
hypothyroid condition.
Endocrinology 2011; 152:669-69.
Krijnen
PAJ, Sipkens JA, Molling JW,
Rauwerda JA, Stehouwer CDA, Muller A,
Paulus WJ, van Nieuw Amerongen GP,
Hack CE, Verhoeven AJ, van Hinsbergh
VWM, Niessen HWM.
Inhibition of Rho-ROCK signaling
induces apoptotic and non-apoptotic
PS exposure in cardiomyocytes via
inhibition of flippase.
Journal of Molecular and Cell
Cardiology 2010; 49:781-90.
Kroon
MH, van den Hurk K, Alssema M,
Kamp O, Stehouwer CD, Henry RM,
Diamant M, Boomsma F, Nijpels G,
Paulus WJ, Dekker JM.
Prospective Associations of B-Type
Natriuretic Peptide With Markers of
Left Ventricular Function in
Individuals With and Without Type 2
Diabetes: An 8-year follow-up of
the Hoorn Study.
Diabetes Care 2012; 35 12:2510-4.
v an den Hurk K, Alssema M, Kamp O,
Henry RM, Stehouwer CD, Smulders YM,
Nijpels G, Paulus WJ, Dekker JM.
Independent associations of glucose
status and arterial stiffness with left
ventricular diastolic dysfunction: an
8-year follow-up of the Hoorn Study.
Diabetes Care 2012; 35:1258-64.
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Research Group
‘It is of the utmost clinical and societal importance
to identify the cause of transition from mutation
to cardiac remodeling and failure’
Focus
Collaboration
Unique
The focus of our studies is on
inherited hypertrophic cardiomyopathy (HCM), as it represents
a major cause of morbidity and
mortality with a prevalence of
~1:500 people worldwide; in the
Netherland HCM affects ~50,000
people. Individuals with HCM die
of sudden cardiac arrest or develop cardiac disease at a young
age. Mutations are most frequently found in genes encoding
sarcomeric proteins. Due to
improved genetic screening,
many mutation carriers at risk of
developing HCM are identified,
but at present the pathomechanisms underlying onset and
progression of cardiac dysfunction, remodeling, and the occurrence of arrhythmias are still
unidentified. It is of the utmost
clinical and societal importance
to identify the cause of cardiac
remodeling and failure.
We collaborate because an
integrated in vitro (preclinical)
– in vivo (clinical) research
approach is essential for unraveling the early HCM disease
process and identifying novel
points of clinical intervention in
order to interrupt the progression
of this complex and currently
untreatable disorder. Longitudinal studies of early stage and
manifest patient cohorts on the
clinical side are coupled with
advanced basic methodologies
to establish the mechanistic links
between mutations on the one
hand, and the pathogenic molecular and cellular mechanisms
that cause cardiomyopathy on
the other.
we are the first to directly link
cellular energetic and contractile
properties with in vivo energetic
and contractile cardiac performance in human.
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By definition, the mechanism of HCM begins with the
defective mutant protein. Our research aims to unravel
the complex road from the initial insult (genotype) to
the end-stage remodeled phenotype. Follow-up studies
of in vivo left ventricular structure, perfusion, metabolism and contractile function using echocardiography,
CMR and PET are performed in mutation carriers
without cardiac disease and patients with manifest
HCM to delineate changes in cardiac performance and
structure during disease progression. As a first step in
understanding the pathophysiology of HCM, functional
assays and proteomics are performed in human myocardium to reveal sarcomeric changes specific for inherited
cardiomyopathies. Newly developed protein exchange
experiments are used to prove causality between the
mutant protein and cellular dysfunction. In vitro data
on cardiac performance are linked to in vivo measurements of cardiac performance. Within our translational
research we will identify cellular changes that are
causative for the transition from mutation to cardiac
remodeling and failure. This knowledge will be used to
enable treatment of HCM at an earlier stage of the
disease.
It has been suggested that sarcomeric mutations lead
to inefficient ATP utilization of sarcomeres, which leads
to a higher energy demand. Increased sarcomeric ATP
utilization causes oxidative metabolism to be increased
relative to cardiac work, rendering the heart less
efficient. Indeed, in a recent study we observed reduced
myocardial efficiency in mutation carriers compared to
controls. At present, a translational approach including
PET/CMR studies is being used to establish whether
impaired energy utilization is a primary defect of
mutant sarcomeres and leads to deficits in energy
utilization in human cardiomyopathy (ENGINE study).
In the future, PET studies will be expanded to include
mutation carriers and involve analysis of glucose and
lipid metabolism. Importantly, metabolic agents, which
are already used in clinical practice as antianginal
agents, may be used as an adjunctive therapy to
improve cardiac energetics. We aim to investigate
whether add-on metabolic therapy prevents cardiac
dysfunction in mutation carriers and improves
myocardial energetics and contractility in manifest
HCM patients.
Our clinical studies are run in parallel with basic studies
using cardiac samples from late stage manifest HCM
patients. More advanced basic methodologies are
crucial for investigating the initial pathomechanisms
triggered by the mutation during the early stage of
cardiomyopathy. We aim to optimize a heart muscle
system based on human pluripotent stem cells that
resemble both the early and more advanced stages of
HCM in order to study the initial and progressive
cellular changes in cardiomyopathy development.
Recent studies have suggested that the level of toxic
mutant sarcomeric protein is an important determinant
of disease onset and progress, and that regulation of
mutant protein expression most likely resides, at least
partially, at the RNA level. As part of the CVON-funded
ARENA project, RNA mechanisms involved in hypertrophy and cardiac dysfunction will be investigated in
the HCM patient group in close collaboration with Yigal
Pinto (AMC) and Leon de Windt (MUMC).
53
Participants
Project leaders
Cardiology
Aernout Beek
Tjeerd Germans
Paul Knaapen
Bert van Rossum
Physiology
Coen Ottenheijm
Ger Stienen
Pathology
Hans Niessen
Medical Physics
Tim Marcus
Mark Hofman
Cardiac Surgery
Alexander Vonk
Radiology & Nuclear Medicine
Adriaan Lammertsma
Clinical chemistry
Cees Oudejans
PhD students
Cardiology
Stefan Timmer
Wessel Brouwer
Ahmet Güçlü
Sebastiaan Kleyn
Thelma Konings
Physiology
Viola Kooij
Sabine van Dijk
Rosalie Paalberends
Josine de Winter
Aref Najafi
Paul Wijnker
Vasco Sequeira
Louise Nijenkamp
Saskia Lassche
Barbara Joureau
Support staf
Physiology
Nicky Boontje
Max Goebel
Michiel Helmes
Ruud Zaremba
Clinical Chemistry
Joyce Mulders
Postdoctoral fellows
Physiology
Diederik Kuster
Rob Wüst
Visiting scientist
Tucson, USA
Jessica Regan
Florence, Italy
Benedetta Tosi
Sydney, Australia
Michaela Kreissl
Collaborations
National
Erasmus, MC Rotterdam
Folkert ten Cate
Dirk Duncker
Daphne Merkus
Michelle Michels
Arend van Schinkel
Marjon van Slegtenhorst
Antonius Hospital, Nieuwegein
Jurrien ten Berg
Aladin Yilmaz
MUMC, Maastricht
Stephane Heymans
RU, Nijmegen
Baziel van Engelen
Richard Dekhuijzen
Leo Heunks
Johannes van der Hoeven
AMC, Amsterdam
Jacques de Bakker
Imke Christiaans
Maarten Groenink
Yigal Pinto
Hanno Tan
Arthur Wilde
UMCG, Groningen
Bart de Smet
Dirk van Veldhuisen
UMCU, Utrecht
Cees van Echteld
Pieter Doevedans
VU, Amsterdam
Martijn Heijmans
Jaap Seidel
International
Florence, Italy
Corrado Poggesi
Hamburg, Germany
Lucie Carrier
Manheim, Germany
Siegfried Labeit
Oxford, UK
Charles Redwood
Hugh Watkins
London, UK
Steve Marston
Boston, USA
Alan Beggs
Elizabeth DeChene
Michael Lawlor
Chicago, USA
Thomas Irving
Sakthivel Sadayappan
Baltimore, USA
Anne Murphy
Jennifer van Eyk
Tucson, USA
Henk Granzier
Sydney, Australia
Cris dos Remedios
Egypt
Hossam Kandil
Khalid Sorour
Yasser Abd El-Hady
Japan
Atsu Aiba
Hiroyuki Sorimachi
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Research Highlight
Time
Impaired cardiac relaxation at early stage of HCM
Diastolic
circumferential
strain rate
Peak
shortening
160 D
carriers
controls
†
peak DCSR (%.s-1)
To investigate the effect of a genetic disorder a study in familial hypertrophic cardiomyopathy patients with founder mutations in the gene
(MYBPC3) encoding cardiac myosin binding protein C (cMyBP-C) was
initiated in 2007 in collaboration with Folkert ten Cate and Michelle
Michels of the Thorax Center at the Erasmus MC in Rotterdam.
Our study in the HCM patients carrying a MYBPC3 founder mutation
revealed depressed cardiomyocyte function and reduced expression
of cMyBP-C (i.e. haploinsufficiency) (van Dijk et al. 2009; Circulation
– heart failure 2012). Moreover, cardiac magnetic resonance studies
have revealed that MYBPC3 mutation carriers with normal wall
thickness were already exhibiting regional systolic and diastolic
dysfunction, indicating that abnormal intrinsic myocardial properties
underlie reduced cardiac function and precede cardiac hypertrophy
(Germans et al. 2010). Most evident were the perturbations in diastolic
function of the heart muscle as indicated by a high calciumsensitivity
of myofilaments in cardiac tissue from patients with manifest HCM
and the decreased diastolic circumferential strain rate in mutation
carriers (see figure). Moreover, the healthy mutation carriers were
already showing enlargement of the left atrium, which is an important
indicator of diastolic dysfunction. Overall, our studies suggest that
diastolic dysfunction of the mutant sarcomeric protein may trigger
development of cardiac hypertrophy and failure.
Strain (Ecc)
Data from PhD projects: Sabine van Dijk (Physiology), Tjeerd Germans
(Cardiology), Wessel Brouwer (Cardiology), Stefan Timmer (Cardiology)
120
†
✽
†
†
80
0
IS
AS
AN
AL
IL
IN
Segmental comparison of basal left
ventricular segments between carriers and
controls. Data are presented as mean
± standard error of the mean as indicated
by the red bars (carriers) and blue bars
(controls). Peak diastolic circumferential
strain rate is reduced in almost every
segment in carriers compared to controls.
IS = inferoseptal, AS = anteroseptal,
AN = anterior, AL = anterolateral,
IL = inferolateral, IN = inferior, peak
DCSR = peak diastolic circumferential
strain rate, *= p<0.05, †= p<0.01.
rouwer WP, van Dijk SJ, Stienen GJM,
B
van Rossum AC, van der Velden J,
Germans T.
The development of familial hypertrophic cardiomyopathy; from
mutation to bedside.
European Journal of Clinical Investigation 2011; 41:568-78.
opeland O, Sadayappan S, Messer AE,
C
Stienen GJM, van der Velden J,
Marston SB. Analysis of cardiac
myosin binding protein-C phosphorylation in human heart muscle.
Journal of Molecular and Cellular
Cardiology 2010; 49:1003-11.
v an Dijk SJ, Paalberends ER, Najafi A,
Michels M, Sadayappan S, Carrier L,
Boontje NM, Kuster D, van Slegtenhorst
M, Dooijes D, dos Remedios C, ten Cate
FJ, Stienen GJM, van der Velden J.
Contractile dysfunction irrespective
of the mutant protein in human
hypertrophic cardiomyopathy with
normal systolic function.
Circulation – Heart Failure 2012;
5:36-46.
ermans T, Götte MJW, Rüssel IK,
G
Spreeuwenberg MD, Doevendans PA, van
der Geest RJ, Pinto YM, van der Velden J,
Wilde AAM, van Rossum AC.
How do hypertrophic cardiomyopathy
mutations affect myocardial function
in carriers with normal wall thickness?
Assessment with cardiovascular
magnetic resonance.
Journal of Cardiovascular Magnetic
Resonance 2010; 12:13.
K ooij V, Saes M, Jaquet K, Zaremba R,
Foster DB, Murphy AM, dos Remedios C,
van der Velden J, Stienen GJM.
Effect of troponin I Ser23/24
phosphorylation on calcium-sensitivity in human myocardium depends
on the phosphorylation background.
Journal of Molecular and Cellular
Cardiology 2010; 48:954-63.
K ooij V, Boontje NM, Zaremba R,
Jaquet K, dos Remedios C, Stienen GJM,
van der Velden J.
Protein kinase C α and ε phosphorylation of troponin and myosin binding
protein C reduce calcium-sensitivity
in human myocardium.
105:289-300.
Ottenheijm CAC, Hooijman P,
DeChene ET, Stienen GJM, Beggs AH,
Granzier H.
Altered myofilament function
depresses force generation in patients
with nebulin-based nemaline myopathy (NEM2).
Journal of Structural Biology 2010; 170:
334-43.
üssel IK, Brouwer WP, Germans T,
R
Knaapen P, Marcus JT, van der Velden J,
Götte MJW, van Rossum AC.
Increased left ventricular torsion
in hypertrophic cardiomyopathy
mutation carriers with normal wall
thickness.
Resonance 2011; 13:3.
T immer SAJ, Germans T, Brouwer WP,
Lubberink M, van der Velden J, Wilde
AAM, Lammertsma AA, Knaapen P,
van Rossum AC.
Carriers of the hypertrophic cardiomyopathy MYBPC3 mutation are
characterized by reduced myocardial
efficiency in the absence of hypertrophy and microvascular dysfunction.
European Journal of Heart Failure 2011;
13:1283-89.
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Research Group
Right Ventricular Failure in PAH
‘Our studies focus on the mechanisms and treatment of right
ventricular failure and pulmonary arterial hypertension, and
as such bridge the two main the ICaR-VU themes H & V’
Focus
Collaboration
The primary focus of our research
is to increase life expectancy and
improve quality of life of patients with right ventricular (RV)
failure due to pulmonary arterial
hypertension (PAH). PAH is a
rare and fatal disease with a
3-year life expectancy of 58%.
Although PAH is primarily a
lung disease, the majority of
PAH-patients die as a result of
RV failure. Progressive pulmonary vascular remodeling in PAH
results in an increase in pressure
in the pulmonary circulation.
To cope with an almost 4-fold
increase in pressure, the right
ventricle enlarges (RV hypertrophy). Ultimately, the RV fails
to keep up with its increased
after-load and RV failure
develops.
The VUmc pulmonary hypertension clinic is tertiary referral
center for the diagnosis of PAH
and chronic thromboembolic
pulmonary hypertension in the
Netherlands. To date more than
2000 patients have been seen. In
2005 the VUmc Pulmonary
Hypertension Knowledge Center
was founded, with the aim to
improving survival and quality
of life in PAH. Our collaborative
studies focus on the mechanisms
and treatment of RV failure and
PAH, and as such bridge the two
main the ICaR-VU themes H & V.
Studies in PAH patients combine
cardiovascular imaging of the
RV and pulmonary circulation,
pulmonary haemodynamics and
clinical trials. Data obtained at
the bedside are translated into
basic research questions and
form the basis of our studies at
the bench. Animal models have
been developed that enable us
to investigate changes at the
different stages of RV failure and
test (therapeutic) interventions.
The translational collaborations
are aimed at dissecting the
pathomechanisms underlying
cardiac and vascular failure in
PAH and represent a true bedside-bench-to-bedside approach.
Unique
Based on our central position
as tertiary referral center and
well-structured clinical and basic
experimental research, we are
able to immediately implement
experimental observations in the
clinical setting. A good example
of our bench-to-bedside approach
is the ZonMw-funded translational research, in which we
are investigating the efficacy
of β-blocker therapy in a
randomized clinical trial.
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Understanding the mechanisms underlying RV failure
in PAH begins with clinical observations. All our
PAH-patients have been followed using MRI since
1997, which has led to an extensive database of more
than 1000 patients and more than 100 peer reviewed
publications. These studies have provided fundamental
insight into the mechanisms of RV failure (van de
Veerdonk et al. 2011). By means of hemodynamic
modeling we are able to give an accurate description
of the load and RV work of pulmonary hypertension
(Saouti et al. 2010). We are now focusing on the
correct assessment of RV-arterial coupling and its
clinical application. By comparing PAH-patients with
similar RV loading conditions, but a difference in
survival (long versus short term), we expect to reveal
the mechanisms of the disease progression. In future
studies we will investigate whether a genetic predisposition determines the outcome of PAH-induced
RV failure through genetic screening of stable and
progressive PAH-patients. In addition to the genetic
characteristics, we will determine morphological
characteristics and load-independent measures of
RV contractility and relaxation in this patient cohort.
Research to develop treatment strategies for the
prevention of RV failure is highly translational and
based on clinical and animal studies. In rat studies we
have shown that β-blocker therapy effectively reversed
RV remodeling and failure in PAH (Research highlight).
At present the efficacy of β-blockers is being studied in a
randomized clinical trial. Moreover, we have shown that
exercise improved exercise capacity and muscle function
in stable PAH-patients, due to improved oxygen handling
of the quadriceps muscle (de Man et al. 2009). Rat
studies have revealed that exercise can improve RV
function in stable PAH, while it exerts a detrimental
effect in progressive PAH (Handoko et al. 2009).
During development of PAH-induced RV disease, there
is a transition from right myocardial hypertrophy to RV
failure. One of the underlying causes of this transition
may be development of hypoxia in hypertrophied
cardiomyocytes. Studies in papillary RV muscles have
revealed increased rate of oxygen consumption,
together with increased diffusion distances for oxygen
and reduced myoglobin concentration and capillary
density in PAH compared to control rats. This may lead
to a condition where oxygen supply to the cardiomyocytes is limiting cardiac output (Wong et al. 2010;
Ruiter et al. 2011). Similar findings have been obtained
in PAH-patients (Wong et al. 2011; Ruiter et al. 2012).
Current studies are investigating the role of disturbed
cardiolipin metabolism, which may cause oxidation of
cytosolic NADH by cytochrome c and is the underlying
cause of reduced mitochondrial efficiency.
Our studies on pulmonary vascular remodeling and
RV failure are highly interrelated and form the basis
for our future studies. Regardless of the primary cause,
an elevated pressure in the pulmonary circulation
almost invariably leads to RV failure and death. We
hypothesize that an imbalance in TGFβ and BMP
signaling and a vicious circle of alterations in pulmonary blood flow velocity and pressure, are at the basis
of progressive pulmonary vascular remodeling and RV
heart failure. Our aim is to break the vicious circle
and identify key factors that increase the probability
of developing pulmonary hypertension, pulmonary
vascular remodeling and RV dysfunction.
Participants
Project leaders
Internal Medicine
Erik Serné
Medical Physics
Theo Faes
Tim Marcus
Physiology
Willem van der Laarse
Geerten van Nieuw-Amerongen
Coen Ottenheijm
Nico Westerhof
Pulmonology
Harm Jan Bogaard
Anco Boonstra
Frances de Man
Piet Postmus
Anton Vonk Noordegraaf
Radiology & Nuclear Medicine
Adriaan Lammertsma
PhD students
Pulmonology
Karin de Boer
Bart Boerrigter
Jasmijn van Campen
Herman Groepenhoff
Frank Helderman
Wouter Jacobs
Taco Kind
Gert-Jan Mauritz
Esther Nossent
Nabil Saouti
Onno Spruijt
Pia Trip
Marielle van der Veerdonk
Pim Welvaart
Serge van Wolferen
Pulmonology & Physiology
Chris Happé
Emmy Manders
Michiel de Raaf
Silvia Rain
Gerrina Ruiter
Robert Szulcek
Yeun Ying Wong
Cardiology
Louis Handoko
Support staf
Physiology
Silvia Bogaards
Pulmonology
Ingrid Schalij
Visiting scientist
Åarhus, Denmark
Stine Andersen
Jacob Gammelgaard Schultz
Collaborations
National
EMC, Rotterdam
Dirk Duncker
Daphne Merkus
LUMC, Leiden
Peter ten Dijke
Marie-José Goumans
Berend Hierck
Hubert Vliegen
Ernst van der Wall
UMCG, Groningen
Rolf Berger
Beatrijs Bartelds
International
Åarhus, Denmark
Stine Andersen
Jacob Gammelgaard Schultz
Brussels, Belgium
Robert Naeije
Cambridge, UK
Nick Morrell
London, UK
Martin Wilkens
Paris, France
Marc Humbert
Christophe Guignabert
Stanford, USA
Marlene Rabinovitch
Sydney, Australia
Cris dos Remedios
Tucson, USA
Henk Granzier
Virginia, USA
Norbert Voelkel
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Research Highlight
Right Ventricular Failure in PAH
A
% right heart failure
Based on PhD/postdoc studies by Frances de Man, Louis Handoko and
Harm-Jan Bogaard
*
100
PH
50
0
20
B
PH+biso
25
30
Time (days)
RV Afterload
mmHg/ml
1500
n.s.
1000
500
0
Control
C
PH
PH+biso
RV Contractility
***
1500
mmHg/ml
Whether neurohormonal dysregulation represents a compensation to
maintain cardiac output and systemic blood pressure or a mediator
contributing to development of right heart failure, was previously
unclear. To demonstrate that neurohormonal up-regulation may not
be harmless, we investigated the contribution of increased sympathetic
nerve activation in our PAH rat model. Previous studies had already
demonstrated that sympathetic overstimulation by means of exercise
training could precipitate right heart failure (Handoko et al. 2009).
Therefore, we hypothesized that inhibiting sympathetic activation with
a cardiac-specific β-blocker (bisoprolol) could have beneficial effects
on disease progression (de Man et al. 2012). At the same time,
Bogaard et al. (2011) investigated effects of the a-selective β-blocker
carvedilol. Both rat studies revealed that interference in the sympathetic nerve activation reduced disease progression and improved
RV function and morphology in PAH (figure).
The renin-angiotensin-aldosteron-system (RAAS) is another important
neurohormonal system. Compared to the recognized detrimental
effects of sympathetic activity, little was known about the role of
RAAS in PAH. In collaboration with Marc Humbert and Christophe
Guignabert (Paris), we were able to reveal severe systemic and local
RAAS up-regulation. More importantly, RAAS-inhibition by means of
angiotensin receptor blocker (losartan) could delay disease progression,
restore arterial-ventricular coupling and reduce pulmonary vascular
remodeling in our rat PAH model (de Man et al. 2012). Our studies
suggest that neurohormonal up-regulation in PAH is not harmless. In
order to translate these findings to the clinic, we initiated a safety
and efficacy study for the use of β-blockers in patients financed by a
ZonMw translational research grant. A similar study will be initiated
to investigate usefulness of angiotensin receptor blockers.
Manifest right heart failure
500
0
Control
D
PH
PH+biso
RV relaxation
60
mmHg/ml
Neurohormonal dysregulation in patients with
pulmonary arterial hypertension
Bogaard HJ, Mizuno S, Guignabert C, Al
Hussaini AA, Farkas D, Ruiter G,
Kraskauskas D, Fadel E, Allegood JC,
Humbert M, Vonk-Noordegraaf A,
Spiegel S, Farkas L, Voelkel NF.
Copper Dependence of Angioproliferation in Pulmonary Arterial
Hypertension in Rats and Humans.
American Journal of Cellular Molecular
Biology 2012; 46: 582-91.
Bogaard HJ, Natarajan R, Mizuno S,
Abbate A, Chang PJ, Chau VQ, Hoke NN,
Kraskauskas D, Kasper M, Salloum FN,
Voelkel NF.
Adrenergic receptor blockade reverses
right heart remodeling and dysfunction in pulmonary hypertensive rats.
American Journal of Respiratory and
Critical Care Medicine
2010; 182:652-60
de Man FS, Handoko ML, van Ballegoij JJ,
Schalij I, Bogaards SJ, Postmus PE, van
der Velden J, Westerhof N, Paulus WJ,
Vonk-Noordegraaf A.
Bisoprolol delays progression towards
right heart failure in experimental
pulmonary hypertension.
Circulation Heart Failure
2012; 5:97-105.
de Man FS, van Hees HW, Handoko ML,
Niessen HWM, Schalij I, Humbert M,
Dorfmüller P, Mercier O, Bogaard HJ,
Postmus PE, Westerhof N, Stienen GJM,
van der Laarse WJ, Vonk-Noordegraaf A,
Ottenheijm CAC.
Diaphragm muscle fiber weakness
in pulmonary hypertension
American Journal of Respiratory
and Critical Care Medicine
2011; 15;183:1411-18.
Ruiter G, Lankhorst S, Boonstra A,
Postmus PE, Zweegman S, Westerhof N,
van der Laarse WJ, Vonk-Noordegraaf A.
Iron deficiency is common in
idiopathic pulmonary arterial
hypertension.
European Respiratory Journal
2011; 37:1386-91.
Saouti N, Westerhof N, Helderman F,
Marcus JT, Boonstra A, Postmus PE,
Vonk-Noordegraaf A.
Right ventricular oscillatory power
is a constant fraction of total power
irrespective of pulmonary artery
pressure.
American Journal of Respiratory
and Critical Care Medicine
2010; 182:1215-1320.
van der Veerdonk MC, Kind T, Marcus JT,
Mauritz GJ, Heymans MW, Bogaard HJ,
Boonstra A, Marques KM, Westerhof N,
Vonk-Noordegraaf A.
Progressive right ventricular dysfunction in patients with pulmonary
arterial hypertension responding to
therapy.
Journal of the American College of
Cardiology 2011; 58:2511-19.
Wong YY, Ruiter G, Lubberink M,
Raijmakers PG, Knaapen P, Marcus JT,
Boonstra A, Lammertsma AA,
Westerhof N, van der Laarse WJ,
Vonk-Noordegraaf A.
Right ventricular failure in idiopathic
pulmonary arterial hypertension is
associated with inefficient myocardial
oxygen utilization.
Circulation Heart Failure 2011;
4:700-06.
Wong YY, Handoko ML, Mouchaers KT,
de Man FS, Vonk-Noordegraaf A,
van der Laarse WJ.
Reduced mechanical efficiency of rat
papillary muscle related to degree of
hypertrophy of cardiomyocytes.
American Journal of Physiology
Heart and Circulatory Physiology
2010; 298:H1190-97.
**
40
20
0
Control
PH
PH+biso
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63
Research Group
‘Advanced imaging is essential for non-invasive
diagnosis of cardiovascular diseases and for monitoring
response to therapy’
Focus
Collaboration
Unique
The focus of our studies is on the
development, implementation
and clinical validation of novel
imaging methods in various
groups of cardiovascular
patients. In order to combine
anatomical, functional and
molecular information; there is
strong emphasis on hybrid
imaging equipment, in particular
PET/CT and, more recently, PET/
MRI. With respect to functional
and molecular processes,
measurements of myocardial
perfusion and flow reserve,
oxygen and glucose consumption, fibrosis, and cardiac innervation are now available for
clinical research and/or patient
care, whilst methods for measuring unstable plaques and, more
generally, inflammatory processes are under development.
We collaborate with various
groups (e.g. from Cardiology,
Physiology, Pulmonology,
Endocrinology, Vascular Surgery,
etc) within the ICaR-VU, for a
variety of reasons: to test new
(or existing) imaging methods in
specific patient populations, to
gain new pathophysiological
information based on validated
non-invasive imaging procedures, and to assess the value of
an imaging method for diagnostic purposes. In addition to this,
there is an international collaboration on the diagnostic use of
oxygen-15 labelled water for
measuring myocardial blood
flow.
Our research group is unique
because of its truly translational
character. New tracers and
methods are being developed,
evaluated in preclinical studies,
used in clinical pathophysiological research studies, and
finally assessed as potential
diagnostic tools. The group is
multidisciplinary and is made
up of clinicians, chemists,
physicists, biologists, pharmacologists and others.
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Cardiovascular imaging provides a unique and noninvasive means for obtaining information in both
healthy controls and various groups of cardiovascular
patients. Based on a range of imaging modalities
(ultrasound, CT, MRI, SPECT, PET) many anatomical,
physiological and molecular parameters can be
measured and related to clinical characteristics.
Imaging research can be divided into three interconnecting lines. First, there is extensive research in the
development of new imaging methods. This is especially
true for PET, where new radiotracers together with
appropriate tracer kinetic models for quantification of
the resulting PET data are being developed. To a lesser
extent this is also true for other imaging modalities,
e.g. the development of new sequences for MRI and
the application of kinetic models to MRI or CT data.
The second line of research is the use of validated
imaging methods in selected groups of patients. These
studies are always in collaboration with and based on
relevant research questions from clinical ‘user’ groups.
Input from the imaging group remains important,
as the validity of an imaging procedure under pathophysiological conditions must always be considered.
This is even more important if studies are performed
before and after an intervention (e.g. a drug study).
Once a method has been developed and it has been
shown to provide valuable information about disease,
the final line of research is to assess whether the
method could lead to improved diagnostic accuracy.
This often entails large patient groups and linking
(blind) reading of the images with final outcome of
the patients.
In recent years, hybrid equipment has become available,
providing the opportunity to measure multiple parameters in a single scanning session. In particular, there
has been extensive research on the PET/CT combining
CT angiography with PET measurements of myocardial
perfusion and flow reserve. It is expected that the
recent installation of a PET/MRI scanner will provide
a similar stimulus for multimodality imaging.
Participants
Projectleaders
Cardiology
Cor Allaart
Carel de Cock
Otto Kamp
Paul Knaapen
Bert van Rossum
Gerrit Veen
Nuclear Medicine
and PET Research
Ronald Boellaard
Otto Hoekstra
Adriaan Lammertsma
Physiology
Rene Musters
Linda Juffermans
Physics and
Medical Technology
Tim Marcus
Mark Hofman
Ruud Verdaasdonk
PhD students
Pathology
Benno Naaijkens
Cardiology
Farid Afsharzada
Frank Bernink
Ibrahim Danad
Ahmed Güçlü
Johannes van der Heide
Sebastiaan Kleijn
Tessa Konings
Lourens Robbers
Iris Russel
Stefan Timmer
Lina Wu
Karin de Boer
Sebastiaan Roos
Sven Brinkman
Physics and
Medical Technology
Marijn Rolf
Nuclear Medicine
and PET Research
Danielle van Assema
Hans Harms
Collaborations
National
AMC, Amsterdam
Bart Biemond
Berthe van Eck
Jan Piek
Arthur Wilde
EMC, Rotterdam
Folkert-Jan ten Cate
Wim van der Giessen
Felix Zijlstra
UMCG, Groningen
Bart de Smet
René Tio
Dirk van Veldhuisen
International
Turku, Finland
Juhani Knuuti
Essen, Germany
Thomas Buck
Milan, Italy
Eustachio Agricola
Paolo Camici
Osaka, Japan
Hidehiro Lida
Uppsala, Sweden
Mark Lubberink
London, UK
Mark Monaghan
Petros Nihoyannopoulos
Dudley Pennell
Boston, USA,
Stanton Shernan
Durham, USA
Robert Judd,
Raymond Kim
Michele Parker
New haven, USA
Lissa Sugeng
Omaha, USA
Thomas Porter
Nuclear Medicine
and PET Research
Marc Huisman
Cees van Kuijk
Pieter Raijmakers
Bert Windhorst
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Research Highlight
Cardiac PET/CT: Advanced hybrid imaging for the
diagnosis of coronary artery disease
Danad I, Raijmakers PG, Appelman YE,
Harms HJ, de Haan S, Marques KM,
van Kuijk C, Allaart CP, Hoekstra OS,
Lammertsma AA, Lubberink M,
van Rossum AC, Knaapen P.
Quantitative relationship between
coronary artery calcium score and
hyperemic myocardial blood flow as
assessed by hybrid O-15-water PET/CT
imaging in patients evaluated for
coronary artery disease.
Journal of Nuclear Cardiology 2012; 19:
256-64.
Clinical research from the departments of Cardiology and Nuclear Medicine
and Radiology
Coronary artery disease (CAD) is the leading cause of death in Western
countries. Invasive coronary angiography (ICA), in combination with
invasive coronary pressure measurements, is considered the gold standard
for CAD diagnosis. The invasive nature of this procedure with potential
hazardous complications, limits its application for initial diagnostic
purposes. Noninvasive imaging techniques to evaluate the severity of CAD
are needed. Computed tomography coronary angiography (CTCA) has
emerged as alternative for ICA. CTCA has proven its value in clinical
cardiology for accurately ruling out CAD due to an excellent sensitivity
and negative predictive value. Unfortunately, observed epicardial coronary
lesions require further functional testing given the low specificity and
positive predictive value of CTCA (Groothuis et al. 2012). Positron emission
tomography (PET) allows for noninvasive quantification of myocardial
perfusion. Although [15O]-water is considered the ideal perfusion tracer
and we have a long track record of evaluating myocardial perfusion for
research purposes (Knaapen et al. 2004, 2009), until recently this tracer
was considered unsuitable for clinical purposes given its low count
statistics, elaborate post-processing, and poor image quality for diagnostic
evaluation. However, clinical software has been developed by our group to
generate high quality parametric myocardial perfusion and viability images
in a quantitative manner (Harms et al. 2011). These technical in-house
developments have propelled a clinical cardiac hybrid PET/CT imaging
program that allows for comprehensive evaluation of both anatomy and
function in patients suspected of CAD within a single session of 30
minutes at low radiation burden (figure). This hybrid approach yields
excellent diagnostic accuracy that is superior to single modality imaging
(Danad et al. 2013). At present, prospective investigations are ongoing to
compare the hybrid imaging approach with more conventional methods to
assess myocardial perfusion, such as single photon computed tomography.
Example of a hybrid cardiac PET/CT image
of a patient evaluated for coronary artery
disease. The combined perfusion images,
obtained with [15O]-water PET during
vasodilator stress, are fused with CT based
coronary angiography. This patient displayed
a coronary lesion in the proximal LAD.
Hemodynamic significance was subsequently
confirmed by regional perfusion impairment
in the vascular territory of the LAD and the
patient was referred for invasive coronary
angiography and percutaneous coronary
intervention.
Groothuis JGJ, Beek AM, Meijerink MR,
Brinckman SL, Heymans MW,
van Kuijk C, van Rossum AC.
Positive predictive value of computed
tomography coronary angiography in
clinical practice.
International Journal of Cardiology
2012; 156: 315-19.
Harms HJ, Knaapen P, de Haan S,
Halbmeijer R, Lammertsma AA,
Lubberink M.
Automatic generation of absolute
myocardial blood flow images using
[O-15]H2O and a clinical PET/CT
scanner.
European Journal of Nuclear Medicine
and Molecular Imaging 2011; 38:
930-39.
Kleijn SA, Brouwer WP, Aly MFA,
Russel IK, de Roest GJ, Beek AM,
van Rossum AC, Kamp O.
Comparison between three-dimensional speckle-tracking echocardiography and cardiac magnetic resonance
imaging for quantification of left
ventricular volumes and function.
European Heart Journal: Cardiovascular
Imaging 2012; 13: 834-39.
Timmer SAJ, Germans T, Gotte MJW,
Russel IK, Lubberink M, Ten Berg JM,
Ten Cate FJ, Lammertsma AA, Knaapen P,
van Rossum AC.
Relation of Coronary Microvascular
Dysfunction in Hypertrophic Cardiomyopathy to Contractile Dysfunction
Independent from Myocardial Injury.
American Journal of Cardiology 2011;
107: 1522-28.
Kleijn SA, Aly MFA, Terwee CB,
van Rossum AC, Kamp O.
Comparison Between Direct Volumetric and Speckle Tracking Methodologies for Left Ventricular and Left
Atrial Chamber Quantification by
Three-Dimensional Echocardiography.
American Journal of Cardiology 2011;
108: 1038-44.
Vermeltfoort IA, Raijmakers PG,
Lubberink M, Germans T, van Rossum AC,
Lammertsma AA, Knaapen P.
Feasibility of subendocardial and
subepicardial myocardial perfusion
measurements in healthy normals
with O-15-labeled water and positron
emission tomography.
Journal of Nuclear Cardiology 2011; 18:
650-56.
Lubberink M, Harms HJ, Halbmeijer R, de
Haan S, Knaapen P, Lammertsma AA.
Low-Dose Quantitative Myocardial
Blood Flow Imaging Using O-15Water and PET Without Attenuation
Correction.
Journal of Nuclear Medicine 2010; 51:
575-80.
Rolf MP, Hofman MBM, Gatehouse PD,
Markenroth-Bloch K, Heymans MW,
Ebbers T, Graves MJ, Totman JJ, Werner
B, van Rossum AC, Kilner PJ, Heethaar RM.
Sequence optimization to reduce velocity offsets in cardiovascular magnetic
resonance volume flow quantification
- A multi-vendor study.
Resonance 2011; 13: a18.
Wong YY, Ruiter G, Lubberink M,
Raijmakers P, Knaapen P, Marcus TJ,
Boonstra A, Lammertsma AA,
Westerhof N, van der Laarse WJ,
Vonk-Noordegraaf A.
Right ventricular failure in idiopathic
pulmonary arterial hypertension is
associated with inefficient myocardial
oxygen utilization.
Circulation Heart Failure 2011; 4: 700-6.
I C A R -V U m c
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68 P r o gr e s s R ep o r t 2010 > 2012
I C aR -V U / T h em e V
Theme V
Improvement of Vascular Function
in Metabolic Diseases
Studies in Theme V aim to unravel
pathomechanisms underlying acute
and chronic vascular disorders
3
Introduction
Toptalents
Research Groups
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70 P r o gr e s s R ep o r t 2010 > 2012
Theme V / Vascular Failure
Circulation and
Metabolism
Ischemia
and Repair
Imaging
Heart Failure and
Pulmonary
Arterial
Hypertension
Vascular failure lies at the heart of many of the pathologies encountered in a multitude of large patient
groups who visit our Medical Center. Because of this
diversity our research groups are focused on selected
aspects of vascular disorders of specific pathologies
seen in several large patient groups. This research is
done from both a clinical and basic science angle,
in a translational approach to advance insights into
underlying mechanisms, to improve diagnosis and to
find innovative treatments. The main research programs
that form the basis of Theme V are centered on two
subthemes: Ischemia and Repair and Circulation and
Metabolism.
The first program, Ischemia and Repair, focuses on
beneficial and pathological remodeling of the vasculature. It is comprised of research groups that study
effects of: ischemia-induced angiogenesis and acute
coronary syndromes, the life-threatening aneurysms
of the aorta, and vascular aspects surrounding human
reproduction and complications of pregnancy. Within
this research program we define relevant pathways in
a clinical bedside-to-bench genomics approach, which
we aim to translate into innovative approaches to
patient care via a sound basal laboratory research line.
The second program, Circulation and Metabolism,
focuses on the aspect of the general circulation in
multiple organs and how it is affected by metabolic
and acute challenges. Here the research groups study
effects of metabolic derangements like diabetes,
effects of nutrition on vascular health, the vascular
complications of kidney disease and life-threatening
cardiovascular complications in the perioperative
setting.
The studies in these research areas range from: clinical
trials, vascular and cellular physiology in humans and
animal models, cell and molecular biology laboratory
studies to large genomic and genetic studies. They all
have strong clinical-preclinical collaborations. The
majority of the groups are based in the clinical departments of Cardiology, Internal Medicine, Nephrology,
Gynecology, Pediatrics and Surgery and the preclinical
departments of Physiology, Pathology, Clinical Chemistry
and Molecular Cell Biology and Immunology. There are
many interrelationships between the research topics of
Theme V as well as between these and the topics
covered by Theme H the second ICaR-VU theme, as heart
and vascular systems are closely related.
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72 P r o gr e s s R ep o r t 2010 > 2012
Focus on Toptalent
Stopping leaky blood vessels
Geerten van Nieuw-Amerongen (Established
Investigator 2011 – Netherlands Heart Foundation)
The FGF23 – klotho – vitamin D axis as a
new instrumental target to combat the
cardiovascular risk of chronic kidney disease
Marc Vervloet (Dutch Kidney Foundation, 2011)
Just like a bursting dike, one weak spot in the vascular
wall is enough to cause problems for a large area.
Leaking blood vessels cause complications such as
edema (tissue swelling) and worsening of atherosclerosis, and may become life threatening when they
affect the heart or the lungs. The research of Geerten
van Nieuw Amerongen aims to unravel how weak spots
in the blood vessels originate and expects to find
new leads for sealing the dangerous little holes in
the vessel wall.
HELLP-babies: mutations in a novel
non-coding RNA
Marie van Dijk ( VENI, ZonMw, 2010)
The HELLP-syndrome occurs in approximately 1 in 200
pregnancies and, although the symptoms start in the
third trimester in the mother, the origin of the disease
is found in the first trimester fetal placenta. Indeed,
the chromosomal region genetically linked to this
disease contains mutations in children born from
HELLP-pregnancies. This region consists of a novel long
non-coding RNA with an unknown function. Marie van
Dijk aims to characterize the function of this noncoding RNA and its dysfunction in the HELLP-syndrome.
This knowledge will be used to develop a test for early
disease detection.
In the last few years the circulating proteins fibroblast
growth factor 23 and klotho have emerged as modulators of mineral metabolism and, independent from
that, to be involved in cardiovascular structure and
function. In the translational research plan, in collaboration with the department of Physiology of UMCN and
Nephrology UCMG, the regulation of expression, shedding into the circulation, biological effects at the tissue
level and clinical aspects of these proteins are being
studied. There are two PHD students at each university.
How does red wine help treat type 2
diabetes and hypertension?
Erik Serné (Netherlands Heart Foundation, Dekker Junior
Staff Grant, 2010)
Epidemiological data suggest that moderate red wine
consumption reduces the incidence of diabetes by an
impressive 40-60% and has beneficial effects on blood
pressure. The underlying mechanisms are far from clear,
but are thought to involve improvement of insulin
resistance and endothelium-dependent vasodilatation
by red wine polyphenols. Erik Serné is investigating
whether shared insulin-signaling pathways in metabolic
and vascular tissues may provide a target for red wine
polyphenols and explain the beneficial effects on insulin
resistance and blood pressure.
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74 P r o gr e s s R ep o r t 2010 > 2012
Research Group
Acute Coronary Syndrome and Repair
‘A unique feature is the use of porcine models combined
with MRI imaging, which allows us to closely mimic the
procedures encountered in the hospital’
Focus
Our studies focus on understanding the molecular and cellular
mechanisms that drive perfusion
of poorly vascularized tissues that
are at risk of necrosis from a
deficit of oxygen and nutrients.
This can be encountered e.g. in
the heart after an Acute Myocardial Infarction (AMI) due to a
blocking of the coronary circulation, in peripheral tissues as a
result of metabolic disorders like
diabetes, and during the implantation of tissue engineered
scaffolds. Two intertwined
research lines are being pursued
on the patient groups we study.
The first focuses on acute coronary syndrome (ACS), in which
we would like to preserve the
microvasculature of the heart
after successful treatment of AMI
with percutaneous coronary
intervention (PCI) and stimulate
arteriogenesis. The second
focuses on establishing perfusion
in artificial tissues and grafts as
part of a program on regenerative
medicine.
Collaboration
In a multi-disciplinary approach,
we combine clinical trials and
resulting physical and imaging
measurements from Intervention
Cardiology, with pathological
insights, cellular analysis and
genomics in order to establish the
molecular profiles that distinguish individual patients. By
linking cellular and molecular
data to patient characteristics, we
can establish underlying mechanisms and key molecular switches
that we validate in a variety of
animal models ranging from
small rodents (mice and rats) to
pigs. These models are used to
test effects of revascularization
after artificially induced AMI in
the heart, arteriogenesis after
obstruction of blood supply in
the hindlimb and angiogenesis in
artificial tissues (fibrin and
matrigel plugs). In addition to the
well studied endothelial cells, we
have set up a unique collaboration centered around a number of
bone marrow-derived and peripheral blood cell types that have
recently been established to play
important roles in angiogenesis.
Unique
Our research group is unique in
its combination of complementary expertise, which allows us to
establish a strong translational
research program from gene to
protein to cell to tissues to
animal models and patients.
Another unique feature is the use
of porcine models combined with
MRI imaging, which allows us to
closely mimic the procedures
encountered in the catheterization room of the hospital.
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76 P r o gr e s s R ep o r t 2010 > 2012
Participants
Acute coronary syndrome
We have collected a large number of genomic profiles
of circulating cells, most notably monocytes, as well as
blood samples from patients undergoing PCI. By linking
these profiles to physical data such as pressure-flow
profiles (CFI) and imaging data (CMR) we have identified immunological pathways that correlate to patient
outcome. A well-established collateral vasculature in
patients was modulated by molecules like interferonbeta and galectin-2 from circulating monocytes, which
were validated in small animal models (Highlight). Our
current focus is on understanding the underlying signal
transduction pathways of these proteins, which should
yield innovative targets for intervention that can be
translated to the clinic. We participated in a number of
clinical trials like the ICIN-initiated HEBE stem cell trial,
the EXAMI trial and the ongoing PREDICT-MVO trial.
Here, we found genomic and cellular profiles that
correlate with acute microvascular obstruction (MVO)
and late left ventricular remodeling at 3-4 months after
successful PCI, which may lead to the development of
heart failure.
Using culture models and state-of-the-art immunological approaches, we are establishing the exact phenotype of monocyte subtypes and their role in both
scarring and angiogenesis/arteriogenesis. This is done in
collaboration with the department of Vascular Medicine
at LUMC. The role of coagulation in intramyocardial
hemorrhage as a driving force for MVO is studied in
close collaboration with the department of Vascular
Medicine of the AMC. The role of reactive oxygen
species in ischemia and reperfusion injury from a
variety of cell types is studied through analysis of the
role of NOX-enzymes from endothelial cells, monocytes
Projectleaders
Cardiology
Niels van Royen
Yolande Appelman
MCBI
Anton Horrevoets
Tineke van der Pouw-Kraan
Pathology
Paul Krijnen
Hans Niessen
Physiology
Pieter Koolwijk
and cardiomyocytes. Our recent studies have yielded
innovative insights into the role of actin fibers and
newly identified small molecules in vascular remodeling
induced by shear stress.
Tissue engineering
In recent years we have participated in the Dutch
Program of Tissue Engineering and the Netherlands
Institute of Regenerative medicine. Here, our focus lies
in the establishment of novel angiogenesis-stimulating
approaches in order to achieve proper vascularization of
tissue-engineered scaffolds/constructs, to obtain
adequate function and maintenance of long-term
viability. It is important to understand how the molecular interaction between angiogenic factors, vascular
cells, matrix proteins (e.g. different variants of fibrinogen) and hypoxia-inducible factors is organized in time
and space to guide the formation of new blood vessels.
As an example, the vascularization of skin grafts is
optimized in collaboration with the department of
Dermatology. Human endothelial cells are established
from healthy donors and patients using either circulating endothelial progenitor cells or adipose-derived
mesenchymal stem cells. The role of the latter cell type
is also studied in myocardial regeneration after differentiation into cardiomyocytes. Current approaches aim
to evaluate the role of hypoxic preconditioning of the
endothelial cells and mesenchymal stem cells in order to
make them more resistant to long term hypoxic conditions that occur in the body after implantation of the
constructs. Using genomic approaches, protein chemistry,
a unique hypoxia culture chamber and animal models of
vascularization we are establishing a number of molecular targets for improving vascularization.
PhD students
Cardiology
Paul Teunissen
Maurits Hollander
Elise Eerenberg
MCBI
Thomas Leyen
Sylvia Nieuwenhuis
Cansu Yildirim
Anja van der Laan
Pathology
Benno Naaijkens
Umit Baylan
Nynke Hahn
Ellis ter Horst
Physiology
Dimitri Tasev
Tessa Nauta
Robert Verloop
MCBI
Julie Favre
Physiology
Ester Weijers
Supportstaf
MCBI
Josefien Baggen
Marloes van den Broek
Ruud Fontijn
Pathology
Mark Begieneman
Physiology
Jan van Bezu
Michiel van Wijhe
Collaborations
National
AMC, Amsterdam
Ed van Bavel
Chantal van der Horst
Jan Mekkes
Jan Piek
Allard van der Wal
Menno de Winther
CWI, Amsterdam
Roeland Merks
EMC, Rotterdam
Moniek de Maat
Jean-Luc Murk
LUMC, Leiden
Paul Quax
Tom Rabelink
MUMC, Maastricht
Stephane Heymans
Sanquin, Amsterdam
Peter Hordijk
Sander Tas
Jan Voorberg
UMCU, Utrecht
Imo Hoefer
International
Frankfurt, Germany
Reinier Boon
Stefanie Dimmeler
Patras, Greece
Lily Papadimitriou
Jeruzalem, Israel
Eli Keshet
Sendai, Japan
Yasufumi Sato
Bern, Switzerland
Christian Seiler
Lund, Sweden
Anna Blom
Bristol, UK
Andrew Newby
Stephen White
Leeds, UK
Robert Ariens
London, UK
Rob Krams
Manuel Mayr
Boston, USA
Mathias Nahrendorf
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78 P r o gr e s s R ep o r t 2010 > 2012
Research Highlight
Angiogenesis
Galectin-2 expression is dependent on the rs7291467
polymorphism and acts as an inhibitor of arteriogenesis
Placebo
A
Galectin-2
Pre-OK
By Anja van der Laan, Niels van Royen and Anton Horrevoets
Post-OK
Day-2
Day-7
120
B
Perfusion restoration (%)
In patients with obstructive coronary artery disease (CAD), the growth
of collateral arteries (arteriogenesis) can preserve myocardial tissue
perfusion and function. Monocytes modulate this process, by locally
supplying the necessary growth factors and degrading enzymes.
Knowledge on the factors involved in human arteriogenesis is scarce.
The aim of the present study is to identify targets in monocytes that
are critical for arteriogenesis in patients with CAD. A total of 50
patients with a chronic total coronary occlusion were dichotomized
according to their collateral flow index. From each patient, RNA was
isolated from unstimulated peripheral blood monocytes, monocytes
stimulated by lipopolysaccharide (LPS) or interleukin-4, and from
macrophages. Transcriptomes were analyzed by full genome microarray
analysis, comparing good to bad collateral patients, dichotomized on
median Collateral Flow Index, as measured during PCI. Increased
mRNA expression of galectin-2 was found in three (unstimulated and
LPS-stimulated monocytes, and macrophages) out of four monocytic
cell types of patients with a low capacity of the collateral circulation.
Additionally, galectin-2 mRNA expression was significantly associated
with the rs7291467 polymorphism in LGALS2 encoding galectin-2
in all four monocytic cell types. Patients with the rs7291467 CC
genotype displayed the highest galectin-2 expression, and tended to
have a lower arteriogenic response. In order to evaluate the effect of
galectin-2 on arteriogenesis in vivo, we used a murine hindlimb model.
Treatment with galectin-2 markedly impaired the perfusion restoration
at Day 7. Collectively, these results identify galectin-2 as a novel
inhibitor of arteriogenesis. Modulation of galectin-2 may constitute
a new therapeutic strategy for stimulation of arteriogenesis in patients
with CAD.
100
0.002
80
60
40
Boon RA, Urbich C, Fischer A, Fontijn RD,
Seeger FH, Koyanagi M, Horrevoets AJG,
Dimmeler S.
Kruppel-like factor 2 improves
neovascularization capacity of aged
proangiogenic cells.
European Heart Journal 2011;
32:371-77.
0.08
20
0
Boon RA, Leyen TA, Fontijn RD, Fledderus
JO, Baggen JM, Volger OL, van Nieuw
Amerongen GP, Horrevoets AJG.
KLF2-induced actin shear fibers
control both alignment to flow
and JNK signaling in vascular
endothelium.
Blood 2010; 25;115:2533-42.
Pre-OK
Post-OK
Day 2
Day 7
C
Galectin-2 impairs arteriogenesis in the
murine hindlimb model
The effect of galectin-2 treatment on
arteriogenesis in a murine hindlimb model
was investigated using laser-Doppler perfusion imaging (A, B). Paraffin sections from
left adductor muscle were stained for
macrophages using Mac-3 (C). Counterstaining was performed with hematoxylin,
visualizing nuclei in blue.
van Dijk A, Naaijkens BA, Jurgens WJ,
Nalliah K, Sairras S, van der Pijl RJ, Vo K,
Vonk ABA, van Rossum AC, Paulus WJ,
van Milligen FJ, Niessen HWM.
Reduction of infarct size by intravenous injection of uncultured
adipose derived stromal cells in a
rat model is dependent on the time
point of application.
Stem Cell Research 2011; 7:219-29.
Hahn NE, Meischl C, Kawahara T,
Musters RJ, Verhoef VM, van der Velden
J, Vonk ABA, Paulus WJ, van Rossum AC,
Niessen HWM, Krijnen PAJ.
NOX5 expression is increased in
intramyocardial blood vessels and
cardiomyocytes after acute myocardial
infarction in humans.
American Journal of Pathology 2012;
180:2222-29.
Krijnen PAJ, Hahn NE, Kholová I, Baylan
U, Sipkens JA, van Alphen FP, Vonk ABA,
Simsek S, Meischl C, Schalkwijk CG,
van Buul JD, van Hinsbergh VWM,
Niessen HWM.
Loss of DPP4 activity is related to a
prothrombogenic status of endothelial
cells: implications for the coronary
microvasculature of myocardial
infarction patients.
107:233.
van der Laan AM, Schirmer SH, de Vries
MR, Koning JJ, Volger OL, Fledderus JO,
Bastiaansen AJ, Hollander MR, Baggen
JM, Koch KT, Baan J Jr, Henriques JP,
van der Schaaf RJ, Vis MM, Mebius RE,
van der Pouw-Kraan TCTM, Quax PHA,
Piek JJ, Horrevoets AJG, van Royen N.
Galectin-2 expression is dependent on
the rs7291467 polymorphism and
acts as an inhibitor of arteriogenesis.
European Heart Journal 2012;
33:1076-84.
Schirmer SH, Bot PT, Fledderus JO, van
der Laan AM, Volger OL, Laufs U, Böhm
M, de Vries CJ, Horrevoets AJG, Piek JJ,
Hoefer IE, van Royen N.
Blocking interferon {beta} stimulates
vascular smooth muscle cell proliferation and arteriogenesis.
Journal of Biological Chemistry. 2010;
5;285:34677-85.
Weijers EM, van Wijhe MH, Joosten L,
Horrevoets AJG, de Maat MP,
van Hinsbergh VWM, Koolwijk P.
Molecular weight fibrinogen variants
alter gene expression and functional
characteristics of human endothelial
cells.
Journal Thrombosis and Haemostasis
2010; 8:2800-09.
Weijers EM, van den Broek LJ,
Waaijman T, van Hinsbergh VWM,
Gibbs S, Koolwijk P.
The influence of hypoxia and
fibrinogen variants on the expansion
and differentiation of adipose tissuederived mesenchymal stem cells.
Tissue Engineering Part A 2011;
17:2675-85.
79
80 P r o gr e s s R ep o r t 2010 > 2012
Research Group
Aneurysm
‘Our translational studies have resulted in the
implementation of a new surgical technique for our
standard patient care’
Focus
Our studies focus on the identification of the underlying causes
of initiation, progression and
rupture of aortic aneurysms,
because of its high prevalence
(8% of males older than 65) and
devastating hemodynamic and
physiological consequences.
Mortality rates after an abdominal aortic aneurysm (AAA)
rupture are exceptionally high
(80%), and in the event of
survival, neurological complications and multi-organ failure are
common. If an AAA ruptures,
only 50% will reach the hospital
alive and even if they reach the
hospital alive the mortality rate
increases to 80%. Moreover, 30%
to 50% will not survive the acute
repair. The most important
predictive value of an aneurysm
rupture is the growth of the
aneurysm in diameter. According
to the Dutch consensus, surgical
intervention is indicated when:
the diameter exceeds 5.5 cm in
men and 5.0 cm in women; the
diameter expands more than 1 cm
per year or when a patient
experiences symptoms. Regardless of these criteria aneurysms
still rupture and the pathophysiology of AAAs remains unclear.
Even though there have been
surgical advances, the prognosis
of ruptured AAAs remains poor
and the overall mortality high.
Therefore, it is of the utmost
importance to improve current
therapeutic possibilities and to
develop new surgical techniques.
To do so, we need to investigate
the pathophysiology of the
development of aortic aneurysms
and other large arterial diseases.
We are also focusing on updating
current treatments like endovascular/ laparoscopic repair of aortic
aneurysms.
Collaboration
Vascular diseases are associated
with both cardiac and renal
disease. Identification of the
pathophysiology of aortic aneurysms requires intensive collaborations between the departments
of Physiology, Cardiology,
Nephrology, Pathology, General
Surgery, Cardio Thoracic Surgery
and Clinical Genetics.
Unique
We are unique as we provide
translational research, which can
lead to the elucidation of pathomechanisms underlying vascular
pathologies and the best treatment options for the patients. Our
translational studies have already
resulted in the implementation of
a new surgical technique for our
standard patient care.
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82 P r o gr e s s R ep o r t 2010 > 2012
The pathological etiology of aneurysms may be associated with a focal atherosclerotic presentation of
systemic vascular disease in which massive vascular
wall degradation leads to aortic dilation. Alternatively,
genetic mutations can lead to errors in cell signaling
and result in mutated vascular collagen and extracellular matrix production. A third possible cause is
infection of the aorta that leads to a weakening of the
vascular wall and the development of an aneurysm.
Our research projects are divided into three areas. First
there are the experimental studies in which the
department of Vascular Surgery collaborates with the
departments of Nephrology and Physiology, which is of
great importance for sharing knowledge and use of
central facilities. New surgical techniques for decreasing kidney damage triggered by inflammation factors
and oxidative stress, as a result of suprarenal aortic
clamping in aneurysm repair surgery, have been
investigated in a rat model. This study has resulted
(Research highlight) in the implementation of a new
surgical technique for our standard patient care.
Together with the departments of Pathology and
Clinical Genetics a tissue bank has been established
that contains frozen vascular tissue samples of over
125 patients, blood samples and live cell cultures. This
database is used to investigate genetic factors and
intracellular signaling pathways associated with the
decrease of vascular wall strength and aneurysm
development.
The second area involves clinical studies. In a prospective study we investigate possibilities for minimal
invasive surgical techniques by endovascular and
(robot-assisted) laparoscopic aortic repair surgery.
A retrospective study on infections in aortic grafts
has led to a prospective clinical study investigating the
possibilities of Positron Emission Tomography (PET) as
a new diagnostic imaging tool for aortic graft infection.
The third area involves our participation in multi-center
randomized controlled trials: The AJAX-trial is a
collaboration between AMC, OLVG and VUmc in order
to improve the outcome of ruptured aorto-iliac aneurysm repair surgery. In 2011 the trial was completed
and the results have been submitted to The Lancet.
Together with the LUMC the medical treatment of small
aneurysms is being investigated in a randomized
controlled trial. In collaboration with the St. Antonius
Hospital in Nieuwegein a randomized controlled trial is
examining the changes in renal amino acid metabolism
after renal ischemia reperfusion injury in patients
undergoing open AAA repair using amino acid stable
isotope tracers. Furthermore, we are using these amino
acid tracers to study the possible protective effect
of a perioperative supplement of alanyl-glutamine on
renal metabolism after ischemia reperfusion injury.
Minimal invasive surgery is a key point for the department of Vascular Surgery. In future studies we will
investigate the possibilities of minimal invasive
techniques in surgical repair of dilating and occlusive
arterial disease. A new region of interest for our group,
in collaboration with the departments of Cardiology
and Radiology, will be the treatment of occlusive
arterial disease using micro bubble enhanced ultrasound. We will also continue our search on biomarkers
of AAA development and investigate the pathophysiology of AAA in close collaboration with the departments
of Physiology, Cardiology, Pathology and Clinical
Genetics.
Participants
Projectleaders
Clinical Genetics
Gerard Pals
Petra Zwijnenburg
Physiology
Rene Musters
Geert Jan Tangelder
Vascular Surgery
Jan Blankensteijn
Paul van Leeuwen
Willem Wisselink
PhD students
Clinical Genetics
Dimitra Micha
Physiology
Rick Kwekkeboom
Vascular Surgery
Saskia Brinkmann
Nikki Buijs
Harm Ebben
Vincent Jongkind
Menno Groeneveld
Matteus Linsen
Hillian Nederhoed
Wouter Niepoth
Joyce Struik
Mechteld Vermeulen
Kak-khee Yeung
Vascular Surgery
Arjan Hoksbergen
Support staf
Physiology
Sylvia Bogaards
Vascular Surgery
Laura van Wieringen
Collaborations
National
AMC, Amsterdam
Ron Balm
Dink Legemate
Bas de Mol
EMC, Rotterdam
Aida Bertoli-Avella
Marc van Sambeek
UMCG, Groningen
Eric Verhoeven
Cisca Wijmenga
UMCM, Maastricht
Petra Boelens
Cornelis Dejong
Marcel van de Poll
UNCN, Nijmegen
Sebastian Bredie
UMCU, Utrecht
Monique Prinssen
Annette Baas
Diederick Grobbee
Edwin Cuppen
Catharina Hospital, Eindhoven
Jaap Buth
Philippe Cuypers
Joep Teijink
International
Reykjavik, Iceland
Stefansson, Kari
Unnur Thorsteinsdottir
Warsaw, Poland
Elzbieta KompanowskaJezierska
Leicester, UK
Nilesh Samani
Robert Sayers
London, UK
Rob Krams
Australia
Jonathan Golledge
Joseph Moxon
New ealand
Andre van Rij
Gregory Jones
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84 P r o gr e s s R ep o r t 2010 > 2012
Research Highlight
A
Data from PhD project KK Yeung
Cold perfusion through the arteries during renal ischemia has been
suggested to diminish postoperative renal damage after juxtarenal
aortic aneurysm repair. As the kidneys play a key role in dimethylarginine metabolism, which in turn is associated with renal hemodynamics, we hypothesized that the protective effect of cold perfusion
is associated with preserved renal extraction of dimethylarginines.
Renal ischemia was induced in 3 groups of anesthetized Wistar rats,
which underwent suprarenal aortic clamping (45 min) with no
perfusion (group 1), renal perfusion with 37°C saline (group 2), and
renal perfusion with 4°C saline (group 3), followed by 90 min of renal
reperfusion in all groups. The sham group had no clamping. In group 3
(renal ischemia with cold perfusion), postoperative serum creatinine
levels as well as the presence of luminal lipocalin-2 and its associated
brush-border damage were lower compared to groups 1 and 2.
Furthermore, renal extraction of asymmetrical (ADMA) and symmetrical (SDMA) dimethylarginine as well as the arginine/ADMA ratio, which
defines the bioavailability of nitric oxide, remained intact in group 3
only. The arginine/ADMA ratio correlated with cortical flow, lipocalin-2, and creatinine rises. Warm and cold renal perfusion (groups 2
and 3) during ischemia were similarly effective in lowering protein
nitrosylation levels (i.e. oxidative stress), plasma creatinine levels
(Figure A), renal leukocyte accumulation (Figure B), neutrophil
gelatinase-associated lipocalin (NGAL) expression in distal tubules,
and urine NGAL. These data support the clinical use of cold renal
perfusion during renal ischemia in situations where renal ischemia is
inevitable, as it reduces tubular damage and preserves renal extraction
of dimethylarginines. Renal perfusion with saline per se during renal
ischemia is effective in diminishing renal leukocyte accumulation
and oxidative stress.
0.6
0.6
P=0.002
P=0.002
0.4
0.4
P=0.007
P=nsP=0.007
P=ns
P=0.047
P=0.047
0.2
0.2
0.0
0.0
sham
sham
no
warm
cold
perfusion
perfusion
perfusion
no
warm
cold
perfusion perfusion perfusion
Figure A. Absolute rise in creatinine
level (mg/dL) in the 4 groups (see text).
Ns = 0.084.
B
Number
Number
of CD45
of CD45
positive
positive
cellcell
nuclei
nuclei
per per
cellcell
image
image
Clinical use of cold renal perfusion during suprarenal
aortic clamping
Absolute
Absolute
riserise
in creatinine
in creatinine
levellevel
(mg/dL)
(mg/dL)
Aneurysm
300
300
250
250
200
200
150
150
100
100
50
50
0
0
sham
no perfusion
sham
warm
perfusion
no perfusion
cold perfusion
warm
perfusion
cold perfusion
cortex
cortex
*
*
*
*
cortico- lis of Henle medulla
medullary
cortico- lis of Henle medulla
medullary
Figure B. Number of leukocytes per full
microscopic image in 4 kidney areas of
the 4 groups. Significant differences (P <
0.05) between the perfusion groups and the
group without renal perfusion during renal
ischemia are shown at the top of the boxes
marked with an asterisk (*).
de Bruin JL, Baas AF, Buth J, Prinssen M,
Verhoeven EL, Cuypers PW, van Sambeek
MR, Balm R, Grobbee DE, Blankensteijn
JD; DREAM Study Group.
Long-term outcome of open or
endovascular repair of abdominal
aortic aneurysm.
New England Journal of Medicine 2010;
20:362:1881-89.
Jongkind V, Yeung KK, Linsen MA,
Heidsieck D, Coveliers HM,
Hoksbergen AW, Wisselink W.
Direct videoscopic approach to the
thoracic aorta for aortic endograft
delivery: evaluation in a human
cadaver circulation model.
Journal of Endovascular Therapy 2010;
17:12-18.
de Bruin JL, de Jong S, Pol J, van der Jagt
M, Prinssen M and Blankensteijn JD.
Residual Infrarenal Aortic Neck
following Endovascular and Open
Aneurysm Repair.
European Journal of Vascular and
Endovascular Surgery 2012; 43: 415-18.
van de Laar IMBH, Oldenburg RA, Pals G,
Roos-Hesselink JW, de Graaf BM,
Verhagen JMA, Hoedemaekers YM,
Willemsen R, Severijnen LA, Venselaar H,
Vriend G, Pattynama PM, Collee M,
Majoor-Krakauer D, Poldermans D,
Frohn-Mulder IME, Micha D, Timmermans J, Hilhorst-Hofstee Y, BiermaZeinstra SM, Willems PJ, Kros JM,
Oei EHG, Oostra BA, Wessels MW,
Bertoli-Avella AM.
Mutations in SMAD3 cause a
syndromic form of aortic aneurysms
and dissections with early-onset
osteoarthritis.
Nature Genetics 2011; 43: 121-26.
Buijs N, van Bokhorst-de van der
Schueren MA, Langius JA,
Leemans CR, Kuik DJ, Vermeulen MA,
van Leeuwen PAM.
Perioperative arginine-supplemented
nutrition in malnourished patients
with head and neck cancer improves
long-term survival.
American Journal of Clinical Nutrition
2010; 92:1151-56.
Jongkind V, Diks J, Yeung KK, Cuesta MA,
Wisselink W.
Mid-term results of robot-assisted
laparoscopic surgery for aortoiliac
occlusive disease.
Vascular 2011;19:1-7.
Linsen MAM, Jongkind V, Nio D,
Hoksbergen AWJ and Wisselink W.
Pararenal aortic aneurysm repair using
fenestrated endografts.
Journal of Vascular Surgery 2012; 56:
238-46.
Vermeulen MAR, Ligthart-Melis GC,
Buijsman R, Siroen MPC, van de Poll
MCG, Boelens PG, Dejong CHC,
van Schaik C, Hofman MBM,
van Leeuwen PAM.
Accurate perioperative flow measurement of the portal vein and hepatic
and renal artery: A role for preoperative MRI?
European Journal of Radiology 2012; 81:
2042-48.
Yeung KK, De Gouyon Matignon C,
Renwarin L, Tjon-A-Fat MR, Teerlink T,
van Leeuwen PA, Musters RJ,
Wisselink W, Tangelder GJ.
Hypothermic renal perfusion during
aortic surgery reduces the presence of
lipocalin-2 and preserves renal
extraction of dimethylarginines in
rats.
American Journal of Physiology; Renal
Physiology 2011; 301:F1231-41.
85
86 P r o gr e s s R ep o r t 2010 > 2012
Research Group
Reproduction and Vascular Function
‘Pregnancy provides a unique window of opportunity for
exposing the hidden risks of vascular disease in women
at the earliest stage possible’
Focus
Our studies focus on cardiovascular disease in women by
using pregnancy as a unique
predictor for cardiovascular
events occurring later in life.
Cardiovascular disease is the
single leading cause of death for
women in developed countries,
and claims the lives of more
women than all forms of cancer
combined. All women face the
threat of cardiovascular disease.
However, symptoms of cardiovascular disease tend to occur
about 10 years later in women
than in men, while women often
have different symptoms of
coronary artery disease than
men. Pregnancy allows a unique
opportunity to challenge these
gender-specific differences.
The physiological demands
of pregnancy on the maternal
cardiovascular system and the
need to establish a connection
between the maternal and fetal
vascular systems can catapult
a woman into a metabolic
syndrome that predisposes to
vascular endothelial dysfunction
and atherosclerosis. By focusing
on pregnancy as a cardiovascular
stress test for later life and by
focusing on the shared pathophysiology of hypertensive
disorders before, during and after
pregnancy with cardiovascular
disease later in life, pregnancy
provides a unique window of
opportunity for exposing the
hidden risks of vascular disease
in women at the earliest stage
possible.
Collaboration
Vascular homeostasis during
pregnancy is maintained by
highly dynamic multi-level,
multi-organ, and multi-pathway
interactions. Consequently our
collaborative clinical and
preclinical research is multidisciplinary, multi-methodological
and addresses all stages (before,
during and after pregnancy).
Unique
we combine state-of-the art
molecular methods, e.g. genomewide sequencing permitting the
exploration of novel layers of
biological information with
well-defined patient cohorts to
deliver clinical milestones from
bench-to-bedside. An excellent
example of the success and
impact of these approaches was
the identification of the gene
responsible for the HELLP
syndrome, the first large noncoding gene linked to a Mendelian disorder with autosomal
recessive inheritance.
87
88 P r o gr e s s R ep o r t 2010 > 2012
Currently our ongoing multi-disciplinary studies are
researching the underlying functional mechanistic
defect of the HELLP syndrome with a focus on the novel
non-coding RNA. There are ongoing functional studies
to improve understanding of the interaction between
maternal and fetal genes, found in genetic screens and
a mouse model in order to identify the cause of reduced
spiral artery remodeling in pre-eclampsia. Multicenter
follow-up studies are being performed to investigate
the relationships between microcirculation, vascular
insulin resistance and ß-cell function in a cohort of
PCOS patients. Women with a twin pregnancy after
IVF are being studied for their neovascularization
profile. Observational cohort studies are being performed to look at the role of niche- and fibroid-related
vascularity in bleeding- and implantation disorders
using innovative diagnostic methods.
Long-lasting disease-causing changes that persist years
after a previous challenge are by definition epigenetic
in nature. The hypothesis-free identification of these
epigenetic changes will be tackled by methyl-C
sequencing. The phenotypic consequences as reflected
in the RNA of endothelial-derived microparticles will be
analyzed by RNA sequencing. We will study discordant
monozygotic twin sisters and epigenetic profiling of
children born from (un)complicated pregnancies. In
addition, we will include the well-documented cohorts
of the Hypitat and Hyras studies.
We will explore the hypothesis that both hypertension
in pregnancy and cardiovascular disease in later life
share pathophysiological features of cardiac, (micro)
vascular and metabolic perturbations. Generalized
(micro) vascular dysfunction is a predictor of cardiovascular disease. In women with severe hypertension
in prior pregnancy we will look at local and systemic
vascular dysfunction leading to an increased prevalence
of the metabolic syndrome, arterial stiffness, impaired
microcirculation and altered microparticle levels.
Additionally, these women will be tested on systemic
level for diastolic heart dysfunction, one of the earliest
signs of cardiac failure, especially in ‘asymptomatic’
women. In collaboration with the EMGO institute
we will develop lifestyle intervention studies.
We collaborate in national studies to expand this
knowledge through in-depth evaluations of large
well-phenotyped patient groups with PCOS, early
menopause and pregnancy related hypertension.
The specific role of the hyperandrogenic condition,
as present in PCOS patients, in relation to CVD will
be explored in collaboration with the University of
Gent. The etiology of impaired implantation and
pregnancy outcome in women with benign uterine
disorders is still unclear. Nevertheless, we expect
abnormal vascularity and neovascularisation to play
a key role.
Participants
Project leaders
Clinical Chemistry
Marie van Dijk
Cees Oudejans
Annemiek Bolte
Hans Brölmann
Christianne de Groot
Peter Hompes
Judith Huirne
Velja Mijatovic
Nils Lambalk
Marieke Lambers
Hanneke de Vries
John van Vugt
PhD Students
Clinical Chemistry
Daan van Abel
Hari Thulluru
Bauke Adriaanse
Heleen Betjes
Noortje van den Boogaard
Eva Bouwsma
Nicole Burger
Milou Busard
Kim Dreyer
Koen Deurloo
Leonoor van Eerden
Wietske Hermes
Lisette van der Houwen
Floortje van Kesteren
Iris Ketel
Dorrit Kieslinger
Els Groeneveld
Petra Janssen
Tamar König
Esther Leushuis
Ingeborg Linskens
Marjolein Louwerse
Marleen Nahuis
Lotte van Nieuwenhuis
Melanie van Os
Barbara Stoelinga
Maaike Tasma
Chantal Tromp
Lucas Uittenbogaard
Marjolein Bij de Vaate
Griet Vandenberghe
Christine van Velzen
Carlijn Vergouw
Lucet van der Voet
Sanne Visser
Machteld Witmer
Support staf
Clinical Chemistry
Omar Michel
Joyce Mulders
Ankie Poutsma
Allerdien Visser
Collaborations
National
AMC, Amsterdam
Ben Mol
Patrick Bossuyt
Suzanne Geerlings
EMC, Rotterdam
Hans Duvekot
LUMC, Leiden
Kitty Bloemenkamp
UMCG, Groningen
Annemieke Hoek
Mariëlle van Pampus
UMCM, Maastricht
Jan Nijhuis
Christine Willekes
UMCN, Nijmegen
Mallory Woiski
UMCU, Utrecht
Frank Broekmans
Bart Fauser
Martijn Oudijk
Anneke Kwee
International
Adelaide, Australia
Robert Norman
Brussels, Belgium
Olivier Donnez
Jacques Donnez
Montreal, Canada
Daniel Dufort
Toronto, Canada
Steve Lye
Aarhus, Denmark
Margit Dueholm
Copenhagen, Denmark
Olav Istre
Le Kremlin Bicêtre, France
Herve Fernandez
Shatin, Hong Kong
Dennis Lo
Tel Hashomer, Israel
Motti Goldenberg
Pamplona, Spain
Juan Alcazar
Malmö, Sweden
Lil Valentin
London, UK
Tom Bourne
Pittsburgh, USA
Mirka Jones
Wakeforest, USA
Robert Taylor
89
90 P r o gr e s s R ep o r t 2010 > 2012
Research Highlight
Pre-Eclampsia
HELLP-babies link a novel lincRNA to the
trophoblast cell cycle
Burger NB, Einarsson JI, Brolmann HAM,
Vree FEM, McElrath TF, Huirne JAF.
Preconceptional laparoscopic
abdominal cerclage: a multicenter
cohort study.
American Journal of Obstetrics and
Gynecology 2012; 207:273.e1.
By Marie van Dijk, Hari Thulluru and Cees Oudejans
The HELLP syndrome is a pregnancy-associated disease inducing
Hemolysis, Elevated Liver enzymes and Low Platelets (HELLP) in the
mother. Although HELLP symptoms occur in the third trimester in the
mother, the origin of the disease can be found in the first trimester fetal
placenta. An essential connection between the maternal and fetal
circulations is made during the first trimester, by the fetal genesmediated mechanism of trophoblast invasion into the maternal placental
bed. Failure of this local early process by (epi)genetic defects leads to
aberrant trophoblast differentiation with incomplete maternal vessel
wall adaptation in the placental bed. This local defect is followed by
compensatory mechanisms of the hypoxic placenta. Changes in the
release of PlGF, sEng and sFlt trigger maternal TGFß-dependent NOSmediated vasodilation. Finally, months after the initial event, maternal
endothelial cell damage with systemic symptoms (hypertension, proteinuria, convulsion, elevated liver enzymes, low platelets) results. By
multipoint non-parametric linkage, pedigree structure allele sharing
and haplotype association analysis of affected sisters and cousins,
we have demonstrated that the HELLP locus resides in an intergenic
region on 12q23.2 between PMCH and IGF1. By strand-specific RT-PCR
complemented with RACE and FISH, a novel non-coding RNA transcript
of 205,012 bases with (peri)nuclear expression in the extravillous
trophoblast was identified. By siRNA-mediated knockdown followed by
RNA-sequencing, the HELLP lincRNA was found to classify as an
activator affecting a large set of genes involved in the cell cycle.
Furthermore, by blocking potential mutation sites as identified in HELLP,
families decreased the invasion capacity of extravillous trophoblasts.
This large non-coding gene is the first underlying Mendelian disorder
with autosomal recessive inheritance. Our data demonstrate that
pregnancy exposes hidden risks of vascular disease in women involving
biological mechanisms that have not been previously described.
Expression (green) in perivascular
extravillous trophoblast cells of the long
intergenic noncoding RNA (lincRNA)
associated with the HELLP syndrome. In
normal pregnancy, these fetal cells actively
modify the vessel wall of the maternal spiral
arteries to establish a connection between
the maternal and fetal vascular systems.
In pre-eclampsia and the HELLP syndrome,
by a fetal gene defect, this process fails to
trigger a cascade of events ultimately
leading to maternal endothelial cell damage
with systemic symptoms of hypertension
and proteinuria.
van Dijk M, van Bezu J, van Abel D,
Dunk C, Blankenstein MA, Oudejans
CBM, Lye SJ.
The STOX1 genotype associated with
pre-eclampsia leads to a reduction
of trophoblast invasion by αT-catenin
upregulation.
Human Molecular Genetics 2010; 19:
2658-67.
van Dijk M, Thulluru HK, Mulders J,
Abdul-Hamid O, Poutsma A, Windhorst
S, Kleiverda G, Sie D, Lachmeijer AMA,
Oudejans CBM.
HELLP-babies link a novel lincRNA
to the trophoblast cell cycle.
Journal of Clinical Investigation 2012;
122: 4003-11.
Gaugler-Senden IPM, Tamsma JT,
van der Bent C, Kusters R, Steegers EAP,
de Groot CJM.
Angiogenic Factors in Women Ten
Years after Severe Very Early Onset
Preeclampsia.
Plos One 2012: 7; e43637.
Groeneveld E, Lambers MJ, Stakelbeek
ME, Mooij TM, van den Belt-Dusebout
AW,Heymans MW, Schats R, Hompes PG,
Hoek A, Burger CW, van Leeuwen FE,
Lambalk CB; on behalf of the OMEGAproject group. 2012.
Factors associated with dizygotic
twinning after IVF treatment with
double embryo transfer.
Human Reproduction 2012; 12:2966-70.
de Groot CJM, van der Mast BJ, Visser W,
De Kuiper P, Weimar W, Van Besouw NM.
Preeclampsia is associated with
increased cytotoxic T-cell capacity to
paternal antigens.
American Journal of Obstetrics and
Gynecology 2010; 203:496.e1-6.
Ketel IJ, Serné EH, Ijzerman RG,
Korsen TJ, Twisk JW, Hompes PG,
Smulders YM, Homburg R,
Vorstermans L, Stehouwer CD,
Lambalk CB.
Insulin-induced capillary recruitment
is impaired in both lean and obese
women with PCOS.
bij de Vaate AJ, Brölmann HA, van der
Voet LF, van der Slikke JW, Veersema S,
Huirne J.
Ultrasound evaluation of the
caesarean scar: relation between a
niche and postmenstrual spotting.
Ultrasound in Obstetrics and Gynecology 2011; 37:93-99.
Vergouw CG, Kieslinger DC, Kostelijk EH,
Botros LL, Schats R, Hompes PG,
Sakkas D and Lambalk CB.
Day 3 embryo selection by metabolomic profiling of culture medium
with near-infrared spectroscopy as an
adjunct to morphology: a randomized
controlled trial.
91
92 P r o gr e s s R ep o r t 2010 > 2012
Research Group
Diabetis Mellitus and Obesity
‘Only a multi-disciplinary approach can fully explore
the most promising pathways to prevent, treat and cure
diabetes and its cardiometabolic complications’
Focus
Our research efforts focus on the
pathophysiology of type 2 diabetes
(T2DM) and its metabolic and
cardiovascular complications. The
obesity and diabetes (‘diabesity’)
pandemic as well as the ensuing
cardiovascular disease incidence
rates, are leading threats to public
health in the 21st century. Our
group explores novel pathophysiologic mechanisms underlying insulin resistance and β-cell
dysfunction, the two key defects
in T2DM, as well as pathways
leading to the development of
cardiovascular disease. This
integrative approach may enable
us to identify novel targets for the
development of future preventive
and therapeutic strategies.
Collaboration
Research into the pathophysiology of diabetes requires solid
multi-disciplinary collaborations.
Epidemiological and pathophysiological aspects of T2DM, and
its cardiovascular and microvascular complications have been
an internationally successful
research focus of the VUmc for
more than 20 years (The Hoorn
Study, multiple clinical/pathophysiology and intervention
studies). Currently, interdisciplinary collaborations between the
Diabetes Center and the departments of Vascular Medicine,
Cardiology, Radiology and
Nuclear Medicine & PET Research
enable interactions amongst
investigators with complementary interests and expertise, as
well as the use of cutting edge
phenotyping imaging modalities.
Collaborations with surrounding
interfaculty research institutes,
including the Institute for
Research in Extramural Medicine
and the Neuroscience Campus
Amsterdam enable research in
innovative management and care
strategies to improve metabolic
control, self-management and
quality of life, as well as research
into the causes and consequences
of diabetes in relation to the brain.
These collaborations offer opportunities to create out-of-the-box
approaches that may lead to
significant advances in the field.
Unique
Our research group is unique as it
provides a facilitating framework
for conducting multi-disciplinary
basic and clinical research and
encourages the scientific development of young investigators.
Our clinical research unit, a joint
initiative of the Diabetes Center
and department of Vascular
Medicine, offers researchers
specialized technical assistance
as well as a network of colleagues
from across the medical and
scientific community.
93
94 P r o gr e s s R ep o r t 2010 > 2012
Our research has been focusing on several aspects of
the pathogenesis of key-defects of T2DM, i.e. beta-cell
dysfunction and insulin resistance, as well as diabetesrelated microvascular and cardiovascular pathologies:
postprandial hyperlipidemia, effects of ectopic fat, and
shared insulin-signaling pathways in metabolic and
vascular target tissues. In addition, several studies are
focusing on incretin biology and pleiotropic effects of
incretin-based therapies, including those on the heart,
vasculature, beta-cell function, kidney and gastrointestinal system.
Postprandial hyperglycemia and hyperlipidemia have
been associated with increased cardiovascular risk. We
demonstrated that postprandial increases in glucose
and triglycerides, especially in T2DM, are accompanied
by pro-atherosclerotic functional changes in HDL and
LDL particles and oxidative stress. Recent experimental
studies show that incretin-based therapies, i.e. glucagon-like peptide-1 receptor agonists (GLP-1RA) and
inhibitors of the incretin degrading enzyme dipeptidyl
peptidase 4, may decrease postprandial hyperlipidemia
by reducing intestinal lipoprotein formation. We were
able to confirm these findings in T2DM patients,
showing that both therapies significantly reduced
postprandial glycemic excursions, triglycerides, triglyceride-rich lipoproteins, as well as oxidative stress
variables. In ongoing studies we will further explore
possible pleiotropic effects of incretins on vascular
function, kidney and cardiovascular health.
T2DM is a progressive disease due to a relentless
decline in beta-cell function. Investigators at the
Diabetes Center showed that 3-year treatments with
GLP-1RA versus basal insulin conferred beta-cell
protection in T2DM patients. Current findings from an
extensive international collaboration suggest a link
between genetic factors and incretin biology, including
the response to incretin-based therapies.
The brain may be regarded as a target organ of diabetes-related (micro)vascular complications, whereas the
brain, in its role as key regulator organ of cardiometabolic functions, has also been implicated in the
development of cardiometabolic abnormalities in
high-risk populations. Therefore, current and future
research will focus on the interactions among diabetes,
the brain, metabolism and cognition.
Obesity is associated with adipose tissue accumulation
in ectopic locations that may disturb organ function. In
both pre-diabetic and T2DM populations we have found
increased ectopic fat accumulation. Ectopic fat,
particularly liver fat, was associated with insulin
resistance, but also with impaired myocardial perfusion
and metabolism.
Adipose tissue is also located around blood vessels, so
called perivascular adipose tissue (PVAT). We have
demonstrated that metabolic insulin resistance is
characterized by pathway-specific impairment in
PI3-kinase–dependent signaling, which in endothelium
may cause imbalance between NO production and
secretion of endothelin-1, limiting nutritive blood flow,
and thus insulin and substrate delivery to target tissues
and possibly increasing vascular resistance. PVAT-derived
cytokines may contribute to impairment of insulin’s
metabolic and vascular actions by modulating insulin
signaling (Highlight). Recent funding from the Netherlands Heart Foundation (Serné) is enabling us to further
characterize impaired vascular insulin signaling and
whether it can be targeted by red wine polyphenols.
Participants
Projectleaders
Clinical Chemistry
Rien Blankenstein
Henk Blom
Peter Scheffer
Tom Teerlink
Internal Medicine
Michiel van Agtmael
Michaela Diamant
Mark Kramer
Mike Nurmohamed
Erik Serné
Yvo Smulders
Ophthalmology
Annette Moll
Physiology
Etto Eringa
Geert-Jan Tangelder
PhD students
Clinical chemistry
Mariska Davids
Ruben Essen
Monica Rocha
Milan Richir
Leonard van der Zwan
Internal medicine
Liselotte Bloemendaal
Michiel de Boer
Marije Bomers
Mathijs Bunck
Stieneke Doornweerd
Nalini Elmont-Radhakishun
Mark Fineman
Renate van Genugten
Tibor Hajos
Herman Hofstee
Jacqueline Hornstra
Katja van den Hurk
Judith Kuenen
Jennifer ten Kulve
Rick Meijer
Linde Morsink
Marcel Muskiet
Daniël van Raalte
Fleur Schouten
Alper van Sijl
Jorn Woerdeman
Nienke Wijnstok
Nynke van der Zijl
Ophthalmology
Huang-Ton Nguyen
Physiology
Wineke Bakker
Erik van Poelgeest
Support staf
Internal Medicine
Jennifer Benit
Jeannette Boerop
Sandra Gassman
Ingrid Knufman
Physiology
Caro-Lynn Alta
Sophie Luikinga
Collaborations
National
LUMC, Leiden
Marie-Jose Goumans
Leen ‘t Hart
Hildo Lamb
Albert de Roos
MUMC, Maastricht
Ellen Blaak
Jan Glatz
Joost Luiken
Coen Stehouwer
Hans Vink
UMCG, Groningen
Bert Groen
Bruce Wolffenbuttel
AMC, Amsterdam
John Karemaker
Rienk Nieuwland
Mireille Serlie
Guus Sturk
WU, Wageningen
Sander Kersten
Willem de Vos
Slotervaart zh, Amsterdam
Ines von Rosenstiel
Jos Beijnen
Dees Brandjes
EMC, Rotterdam
Eric Sijbrands
Miriam Sturkenboom
UMCN, Nijmegen
Jan Smit
UMCU, Utrecht
Harold de Valk
International
Aarhus, Denmark
Allan Flyvbjerg
Copenhagen, Denmark
Carolyn Deacon
Jens Juul Holst
Erik Richter
Praag, Czech Republic
Martin Haluzik
Helsinki, Finland
Marja-Riitta Taskinen
Hannele Yki-Järvinen
Paris, France
Bernard Viollet
Dusseldorf, Germany
Hobart, Australia
Margriet Ouwens
Steve Rattigan
Tübingen, Germany
Andreas Fritsche
Hans-Ulrich Häring
Padua, Italy
Andrea Mari
Glasgow, Scottland
Naveed Sattar
Göteburg, Sweden
Ulf Smith
London, UK
John Yudkin
Charlottesville, USA
Eugene Barrett
Chapel Hill, USA
John Buse
95
96 P r o gr e s s R ep o r t 2010 > 2012
Research Highlight
Metabolic Vascular Disease
baseline capillary
density (n/mm2)
A
70
50
30
-30
0
60
meal
peak reactive
hyperaemia (n/mm2)
Hyperinsulinemia-induced whole-body glucose uptake during a
euglycemic-hyperinsulinemic clamp is partly mediated by increased
capillary density. We hypothesized that physiological insulinema in
response to a mixed meal may also enhance microvascular function,
which, however, may be impaired in insulin resistant individuals and
patients with type 2 diabetes (T2DM). Twelve men with uncomplicated
T2DM, 13 with metabolic syndrome (MetS) and 12 age-matched
healthy normoglycemic controls, mean age 57±6 years, underwent skin
capillary video-microscopy before and 60 and 120 min following a
standardized mixed-meal to measure capillary density at baseline and
during post-occlusive peak reactive hyperemia (PRH), also termed
capillary recruitment. Oral glucose insulin sensitivity (Matsuda-Index)
and postprandial hyperglycemia (2h-AUCglucose) were calculated.
Fasting baseline capillary density (BCD) was similar among groups,
but fasting PRH was lowest in T2DM (p<0.05). Postprandially, both
BCD and PRH increased linearly in all groups (p<0.001), however,
the meal-related increase in BCD was significantly lower in T2DM and
MetS versus controls (both p<0.05). At all time points, postprandial
PRH was lower in both T2DM and MetS versus controls (both p<0.05).
In pooled analysis, postprandial mean PRH correlated with MatsudaIndex (r=0.386, p=0.018) and inversely with 2h-AUCglucose (r=-0.336,
p=0.042). In conclusion, gradual deterioration of meal-related capillary
recruitment was paralleled by decreasing insulin sensitivity and
postprandial hyperglycemia, as assessed in healthy normoglycemic
men, men with the MetS and those with overt T2DM. These findings
suggest that in both pre-diabetic conditions and in overt T2DM
microvascular dysfunction might contribute to postprandial
dysglycemia. (Diabetologia 2012; in press).
120
Time (min)
B
Bunck MC, Corner A, Eliasson B, Heine RJ,
Shaginian RM, Wu Y, Yan P, Smith U,
Yki-Jarvinen H, Diamant M, Taskinen MR.
One-year treatment with exenatide
vs. insulin glargine: effects on postprandial glycemia, lipid profiles,
and oxidative stress.
Atherosclerosis 2010; 212:223-29.
Rocha MS, Teerlink T, Janssen MCH,
Kluijtmans LAJ, Smulders YM, Jakobs C,
de Almeida IT, Rivera I, Castro R,
Blom HJ.
Asymmetric dimethylarginine in adults
with cystathionine beta-synthase
deficiency.
Atherosclerosis 2012; 222: 509-511.
Diamant M, van Gaal L, Stranks S,
Northrup J, Cao D, Taylor K, Trautmann M.
DURATION-3: Exenatide once weekly
resulted in significant reductions in
HbA1c compared to insulin glargine
titrated to target in patients with type
2 diabetes.
Lancet 2010; 375:2234-43.
van Sijl AM, van den Oever IAM,
Peters MJL, Boers M, Dijkmans BAC,
van Halm VP, Smulders YM, Voskuyl AE,
Nurmohamed MT.
Subclinical renal dysfunction is
independently associated with
cardiovascular events in rheumatoid
arthritis: the CARRE Study.
Annals of the Rheumatic Diseases 2012;
71: 341-344.
70
50
30
-30
0
60
120
Time (min)
meal
AUC Glucose (mmol l -1 2h-1)
By Michaela Diamant and Erik Serné (supported by the Netherlands
Heart Foundation)
C
1500
1000
500
0
r - 0.336
p =0.042
0
40
60
80
100
mean PRH (n/mm2)
50
40
Matsuda Index
Diabetes Mellitus, Obesity and Cardiovascular Complications
D
r 0.386
p = 0.018
30
20
10
0
0
40
60
80
100
mean PRH (n/mm2)
Postprandial course of baseline capillary density
(fig. A and B) and peak reactive hyperemia (fig. B
and C) in men with type 2 diabetes (red line),
men with the metabolic syndrome (broken line)
and healthy normoglycemic controls (blue line).
Pooled linear regression analysis of mean postprandial peak reactive hyperemia (PRH) with (C)
2h-AUC for glucose as a measure of postprandial
glucose disposal, and (D) Matsuda Index as a
measure of insulin sensitivity.
van Duinkerken E, Schoonheim MM,
Sanz-Arigita EJ, IJzerman RG, Moll AC,
Snoek FJ, Ryan CM, Klein M, Diamant M,
Barkhof F.
Resting-State Brain Networks in Type
1 Diabetic Patients With and Without
Microangiopathy and Their Relation to
Cognitive Functions and Disease
Variables.
Diabetes 2012; 61: 1814-21.
Meijer RI, Serne EH, Smulders YM,
van Hinsbergh VWM, Yudkin JS, Eringa EC.
Perivascular Adipose Tissue and Its
Role in Type 2 Diabetes and Cardiovascular Disease.
Current Diabetes Reports 11: 211-17,
2011.
den Uyl D, van Raalte DH, Nurmohamed
MT, Lems WF, Bijlsma JWJ, Hoes JN,
Dijkmans BAC, Diamant M.
Metabolic effects of high-dose
prednisolone treatment In early
rheumatoid arthritis: diabetogenic
effects and inflammation reduction
on the balance.
Arthritis Rheumatism 2012; 64:639-46.
van der Zijl NJ, Moors ,CCM, Goossens
GH, Hermans MH, Blaak EE, Diamant M.
Valsartan improves beta-cell function and insulin sensitivity in
normotensive subjects with impaired
fasting glucose and/or impaired
glucose tolerance (PancREatic betacell dySfunction rEstoRed by Valsartan
Effects – PRESERVE Study).
Diabetes Care 2011; 34:845-51.
van der Zijl NJ, Serné EH, Goossens GH,
Moors CC, IJzerman RG, Blaak EE,
Diamant M.
Valsartan-induced improvement in
insulin sensitivity is not paralleled
by changes in microvascular function
in individuals with impaired glucose
metabolism.
Journal of Hypertension 2011;
29:1955-62.
97
98 P r o gr e s s R ep o r t 2010 > 2012
Research Group
Nutrition Research
‘Optimization of nutritional support during the first postnatal weeks may reduce occurrence of metabolic syndrome
and associated cardiovascular disease’
Focus
In recent years nutritional
research in very low birth weight
preterm infants (VLBW) has
focused on the prevention of
protein malnutrition during the
first postnatal weeks. At this
early age, the nutritional protein
fortification depends on amino
acid infusion via a central vein
due to the immature gastrointestinal tract. In 2010 the
ESPGHAN nutrition committee
proposed new guidelines on
nutrition. In particular, the
relative increase of the protein
fraction in the nutrition of these
infants is aimed at preventing
early postnatal weight loss to
reduce morbidity, and to stimulate neurodevelopment. On the
other hand, an increasing
number of follow-up studies in
VLBW infants indicate that
specifically in the infants that
show rapid growth after preterm
birth, there is already a development of clinical signs of a
metabolic syndrome during early
infancy, leading to cardiovascular disease later in life. Our
research is focused on the effects
of early modifications of nutritional support on growth,
metabolism and body composition in VLBW and small for
gestational age infants.
Collaboration
The departments of Pediatrics,
Neonatology and Vascular
Surgery join their efforts to
investigate effects of infantile
nutritional support on early
growth, and development of
vascular disease in later life.
Unique
Our research group is the only
center in The Netherlands where
nutrition related research is
performed with a focus on
clinical studies in a high risk
perinatal population. We have
world renowned experts known
for the development of very
special customized infant
formulas. Full expertise is
available for neonatal intensive
care, pediatric follow-up into
adulthood with laboratory
technology on growth and
metabolism, anthropometry,
bodycomposition and stable
isotope mass spectrometry.
99
100 P r o gr e s s R ep o r t 2010 > 2012
Fetal growth is characterized by the interaction of
the fetal genome and its environment. The fetal
environment, in turn, is influenced by the mother’s
environment, metabolism and by the placenta.
Intra-uterine growth is regulated by genetic factors,
essential substrates, and endocrine factors. In utero,
important growth-regulating hormones are insulin
and thyroxin, and insulin-like growth factors (IGFs)
that are regulated independent of growth-hormone.
After birth the regulation of IGFs becomes increasingly
growth hormone dependent. It is suggested that growth
regulation may be permanently altered, i.e. programmed,
in utero and even during infancy. By changes in the
nutritional, hormonal and/or metabolic factors afforded
by the mother during critical periods of development,
reprogramming imposes lasting or lifelong changes in
the structure and physiology of her offspring. Low birth
weight, as a proxy of intrauterine growth retardation is
associated with chronic diseases in adulthood, such as
hypertension, cardiovascular disease, insulin resistance,
and type 2 diabetes. Comparable mechanisms are
suggested from the long-term observational studies
of the Dutch famine that describe the onset of type 2
diabetes at later age in the offspring of mothers that
were malnourished during the winter of 1944 -45. In
particular the third trimester of pregnancy is considered
to be a critical phase for the programming of body
functions. Hence, a shortage of nutrients during this
phase followed by an abundance of nutrients after birth
results in the onset of the metabolic syndrome,
as demonstrated by a more than 25 percent rise in
body mass index. This condition has been associated
with obesity, insulin resistance, glucose intolerance,
and hypertension followed by vascular disease. In
long-term follow-up studies of preterm infants born
in 1983 in the Netherlands (Project On Preterm and
SGA birth [POPS cohort]) signs of the appearance of the
metabolic syndrome at 19 years of age were observed,
when growth was (too) rapid during the first postnatal
months. From these observations it may be suggested
that nutritional interventions in VLBW preterm infants
are only possible if they are performed during the
golden window of programming after preterm birth.
In ongoing studies we investigate effects of postdischarge nutrition of preterm infants during the first
6 months after birth (STEP I study) and the first seven
years after birth (STEP II study). The latter study was
initiated in March 2011. A total of 120 infants will
have been investigated at age 7 by 2013.
Studies by the Pediatrics department, hosted by the
ICaR-VU and EMGO, focus on the relationship of fetal
and infantile growth with anthropometry, insulin
sensitivity and cardiovascular function at age 5 in
a multi-ethnic birth cohort (ABCD study; funded by
ZonMw). In addition, we investigate determinants of
early programming of cardiometabolic profile; we study
the relationship between birth weight and (accelerated)
growth, and physical activity and physical fitness at
primary school age. Ethnic differences in metabolic and
cardiovascular function are studied in 5-year-old
children.
Participants
Project leaders
Clinical Chemistry
Tom Teerlink
Internal medicine
Abel Thijs
Pediatrics
Ruurd van Elburg
Reinoud Gemke
Hans van Goudoever
Harrie Lafeber
Joost Rotteveel
Mirjam van Weissenbruch
Vascular surgery
Paul van Leeuwen
PhD students
Clinical Chemistry
Mariska Davids
Internal medicine
Floor Neelemaat
Pediatrics neonatology
Eline Amesz
Jolice van den Berg
Jorrit de Kieviet
Monique van de Lagemaat
Ilse Westerbeek
Annelies van Zwol
Dutch human milk bank
Willemijn Corpeleijn
Stefanie Kouwenhoven
Pediatrics general
Marieke de Beer
Gerrit van den Berg
Arend van Deutekom
Marieke Peetsold
Michel Weijerman
University of Amsterdam
Aimee van Dijk
Marieke de Hoog
Research nurses
Pediatrics
Anneke Cranendonk
Sandra Diepenhorst
Annemiek de Lange
Coördinator
Dutch human milk bank
Ineke van Vliet
Collaboration
National
AMC, Amsterdam
Elvira van Dalen
Bas de Mol
Karien Stronks
Rien de Vos
Tanja Vrijkotte
Bascule, Amsterdam
Theo Doreleijers
EUR, Rotterdam
Guenther Boehm
Onno Helder
Anita Hokken-Koelega
Marijn Vermeulen
GGD, Amsterdam
Manon van Eijsden
UMCU, Utrecht
Frank van Bel
VU, Amsterdam
Jaap Oosterlaan
International
Auckland, New Zealand.
Jane Harding
Cambridge, UK.
David Dunger
Southampton, UK
Caroline Fall
Clive Osmond
Yogyakarta, Indonesia.
Achmad Surjono
101
102 P r o gr e s s R ep o r t 2010 > 2012
Research Highlight
Nutrition
How optimal early postnatal nutrition in very low
birth weight infants may reduce the risk of metabolic
syndrome in adult life
Special VUmc-designed high protein/normal energy ‘postdischarge’
formula for infants successfully reduces rise in body fat
Over the last three years we have published the results of our Study
Towards the Effects of Postdischarge nutrition (STEP study) using our
unique formula (Amesz et al. 2010; van de Lagemaat M et al. 2011, 2012A).
Only limited effects of calcium, phosphorus and vitamin D supplementation
in special preterm formula, fortified human milk and postdischarge formula
could be observed on bone development in small for gestational age (SGA)
born preterm infants, suggesting that prenatal conditions for bone
accretion cannot simply be replicated after birth (van de Lagemaat, 2012B).
Long-term follow-up studies investigating body composition in our cohort
of infants are now in progress.
The ICaR-VU equipment investment award for Human Milk Bank in VUmc
Recently the first scientific study of the first Dutch human milk bank
began. In this early nutrition study (ENS) the possible beneficial role
of donor milk in the prevention of necrotizing enterocolitis and enhancement of proper growth and development of extremely preterm infants
is being investigated. This study received an ICaR-VU equipment
investment award to enable the purchase of a body composition
measuring plethysmography device for infants
95 % Cl sds weight
About 30 years ago, after observing the rapid decline in growth velocity
when preterm infants were discharged from the hospital with nutrition
that was equal to that given to term infants, a specially composed
nutrition for preterm infants (preterm formula) was introduced. However,
this special nutrition not only led to rapid growth but also to a sharp rise
in body fat, resulting in an increased risk of type 2 diabetes and cardiovascular disease in later life.
0,50
0,00
-0,50
-1,00
-1,50
0
PDF
3,00
6,00
corrected age in months
TF
Length
0,50
95 % Cl sds length
By H.N. Lafeber
Bodyweight
0,00
-0,50
-1,00
-1,50
0
PDF
3,00
6,00
corrected age in months
TF
Effects of PDF (post discharge formula)
or TF (term formula) on Body Weight and
Length expressed as 95% confidence interval
of standard deviation score normalized for
Dutch preterm infants.
Amesz EM, Schaafsma A, Cranendonk A,
Lafeber HN.
Optimal growth and lower fat mass in
preterm infants fed a protein-enriched
post discharge formula.
Journal of Pediatric Gastroenterololgy &
Nutrition 2010; 50:200-07.
van den Berg G, van Eijsden M,
Vrijkotte TG, Gemke RJBJ
Educational inequalities in perinatal
outcomes: the mediating effect of
smoking and environmental tobacco
exposure.
PLoS One 2012; 7:e37002.
Corpeleijn WE, Kouwenhoven SMP,
Paap MC, van Vliet I, Scheerder I,
Muizer Y, Helder OK, van Goudoever JB ,
Vermeulen MJ.
Intake of Own Mother’s Milk during
the First Days of Life Is Associated
with Decreased Morbidity and Mortality in Very Low Birth Weight Infants
during the First 60 Days of Life.
Neonatology 2012; 102: 276-281.
Davids M, Richir MC, Visser M, Ellger B,
van den Berghe G, van Leeuwen PAM,
Teerlink T.
Role of dimethylarginine dimethylaminohydrolase activity in regulation
of tissue and plasma concentrations
of asymmetric dimethylarginine in
an animal model of prolonged
critical illness.
Metabolism-Clinical and Experimental
2012; 61: 482-490.
van Dijk AE, Van Eijsden M, Stronks K,
Gemke RJBJ, Vrijkotte TG.
Maternal depressive symptoms, serum
folate status, and pregnancy outcome:
results of the Amsterdam Born
Children and their Development study.
American Journal Obstetrics Gynecology
2010; 203:563.e1-7.
Weijerman ME, van Furth AM, van der
Mooren MD, van Weissenbruch MM,
Rammeloo L, Broers CJM and Gemke RJBJ.
Prevalence of congenital heart defects
and persistent pulmonary hypertension
of the neonate with Down syndrome.
European Journal of Pediatrics 2010;
169: 1195-99.
de Hoog ML, van Eijsden M, Stronks K,
Gemke RJBJ, Vrijkotte TG
Ethnic differences in cardiometabolic
risk profile at age 5-6 years: the ABCD
study.
PLoS One 2012;7:e43667.
Westerbeek EA, van den Berg JP,
Lafeber HN, Fetter WP, Boehm G,
Twisk JW, van Elburg RM.
Neutral and acidic oligosaccharides in
preterm infants: a randomized,
double-blind, placebo-controlled trial.
American Journal of Clinical Nutrition
2010; 91:679-86.
de Kieviet JF, Oosterlaan J, Vermeulen RJ,
Pouwels PJ, Lafeber HN, van Elburg RM.
Effects of glutamine on brain development in very preterm children at
school age.
Pediatrics 2012; 130,1121-27.
van de Lagemaat M, Rotteveel J,
Muskiet FA, Schaafsma A, Lafeber HN.
Post term dietary-induced changes in
DHA and AA status relate to gains in
weight, length, and head circumference
in preterm infants.
Prostaglandins Leukot Essent Fatty Acids
2011; 85:311-16.
van de Lagemaat M, Rotteveel J,
van Weissenbruch MM, Lafeber HN.
Small-for-gestational-age pretermborn infants already have lower
bone mass during early infancy.
Bone 2012; 51:441-46.
103
104 P r o gr e s s R ep o r t 2010 > 2012
Research Group
Chronic Kidney Disease
‘Cardiorenal interaction and related metabolic pathophysiological mechanisms are being studied in newly developed
animal and cellular experimental models and multicenter
intervention studies’
Focus
Collaboration
Unique
Chronic kidney disease (CKD) is
associated with markedly
increased cardiovascular risk
and, on the other hand, renal
function is the major determinant of the outcome of heart
failure. We focus on the underlying pathophysiological mechanisms relevant for the cardiorenal interaction and the burden
of cardiovascular disease in CKD.
More specifically we are interested in mechanisms such as
CKD-associated cardiomyopathy,
vascular calcification, and
anemia and iron metabolism in
patients with heart and/or renal
failure.
We collaborate in order to study
mechanisms that are associated
in the outcome of CKD patients,
such as vascular calcification
and the red cell-iron axis. We
use cell-cultures, animal models
and human intervention studies,
for our translational research
program. On a therapeutic level,
based on the assumption that the
high incidence of cardiovascular
disease is related to the retention
of uremic toxins, we co-initiated
the first prospective randomized
multicenter trial, comparing two
distinct renal replacement
strategies, on-line hemodiafiltration and hemodialysis. The main
study outcome has recently been
published, further analyses are
being performed and a follow-up
study is being designed.
Our concept of cardiorenal
interaction creates a unique
platform to study the pathophysiology behind the complications
in renal and cardiac disorders.
We study cardiorenal interaction
and related metabolic pathophysiological mechanisms in newly
developed animal experimental
models, cell studies and multicenter intervention studies. This
approach allows for delineation
of mechanisms pivotal in both
heart and renal failure and the
development of relevant therapeutic approaches. A novel area
of study in this respect is our
interest in the molecular circadian clock that regulates appropriate timing of metabolic
processes in almost all organs,
including the heart and kidney.
105
106 P r o gr e s s R ep o r t 2010 > 2012
Disturbances in the fibroblast growth factor 23
(FGF23)- klotho-vitamin D axis lead to vascular
dysfunction, calcification and left ventricular
hypertrophy and are associated with cardiovascular
morbidity and mortality in CKD patients. In a consortium program the role of vitamin D, klotho and
FGF23 on the handling of minerals and cardiovascular
function and structure is studied. In prospective clinical
studies the modifiability of both FGF23 and klotho is
assessed. To further study the FGF23-Klotho hypothesis
we have shifted the focus of our peritoneal dialysis
research to the actions of vitamin D. As part of a 7th
Marie Curie European framework grant we are studying
the influence of active vitamin D on inflammation and
peritoneal membrane function in peritoneal dialysis.
Similarly, anemia and iron deficiency are strongly
associated with cardiovascular outcomes in patients
with heart and/or kidney failure. In our view these
non-hemodynamic mechanisms are paramount in
the deleterious interaction between the heart and
the kidney. Although iron compounds are widely used
some basic data and clinical hard endpoint studies
are missing. The department has the Dutch lead for
an international, multicenter, randomized study to
investigate the comparative efficacy and safety of
an intravenous iron compound.
The molecular circadian clock regulates appropriate
timing of metabolic processes in almost all organs,
including the heart and kidney. Previously we have
shown that in CKD a markedly disturbed circadian
sleep-wake rhythm exists in conjunction with impaired
secretion of melatonin. Now we are studying the effect
of renal replacement therapy including renal transplantation on circadian rhythm and the molecular make-up
of the peripheral clock. We are investigating quality of
life and cardiovascular parameters related to circadian
disturbances before and after the living donor renal
transplantation procedure in both the kidney donor and
acceptor. We also aim to connect, our previously
published, circadian disturbances in CKD to molecular
changes in the peripheral cell clock gene expression in
CKD patients.
The goal of the department of Nephrology is to further
focus research on the cardiorenal interaction including
diastolic dysfunction and on the two non-hemodynamic
cardiorenal connectors that are currently being studied,
the fibroblast growth factor 23 (FGF23)-klotho-vitamin
D axis and the red cell-iron axis. With respect to
arterial calcification, the role of vitamin K binding by
phosphate binder therapy will be a subject of future
studies. Since vitamin K deficiency leads to a deficiency
of MGP, an important inhibitor of vascular calcification,
this research line will complement the fibroblast growth
factor 23 (FGF23)-klotho-vitamin D axis research that
focuses more on vascular function and cellular trans
differentiation, instead of calcification.
Participants
Project leaders
Clinical Chemistry
Peter Scheffer
Tom Teerlink
Internal Medicine
Erik Serné
Pediatrics
Michiel Schreuder
Joanna van Wijk
MCBI
Rob Beelen
Nephrology
Carlo Gaillard
Muriel Grooteman
Marc Vervloet
Piet ter Wee
Physiology
Ed Eringa
René Musters
Geert-JanTangelder
PhD students
Aaltje Adema
Annet Bouma
Fenna van Breda
Isabelle Chapdelaine
Mireille Emans
Karima Farhat
Evelina Ferrantelli
Tom Foster
Claire den Hoedt
Aegida Neradova
Albert Mazairac
Kaatje Le Poole
Marije Russcher
Andrea Stavenuiter
Oanh Thang
Melissa Verkaik
Neelke van der Weerd
Rik Westland
Support staf
Adry Bakker Diepenbroek
Eelco Keuning
Nanne Paauw
Dennis Schooneman
Marjon van Vliet
Hiske Wellink
Visiting Scientist
Cecilia Giachelli
Denis Fouque
Gerard Friedlander
Makoto Kuro-O
Leon Schurgers
Catherine Shanahan
Myles Wolf
Collaboration National
UMCM, Maastricht
Leon Schurgers
UMCN, Nijmegen
René Bindels
Joost Hoenderop
UMCG, Groningen
Gerard Navis
Jeroen Hillebrands
UMCU, Utrecht
Pieter Doevedans
Marianne Verhaar
MCA, Alkmaar
Menso Nubé
International
Montreal, Canada
Renée Lévesque
Lyon, France
Denis Fouque
Paris, France
Gerard Friedlander
Aachen, Germany
Vincent Brandenburg
Milano, Italy
Mario Cozzolino
Barcelona, Spain
Jordi Bover
Stockholm, Sweden
Tobias Larsson
London, UK
Catherine Shanahan
Dallas, USA
Makoto Kuro-O
Miami, USA
Myles Wolf
Seattle, USA
Cecilia Giachelli
107
108 P r o gr e s s R ep o r t 2010 > 2012
Research Highlight
Nefrology and Cardiovascular Diseases
100
lowflux HD
online HDF
80
survival (%)
In hemodialysis (HD) patients the high incidence of cardiovascular
disease is, at least partially, related to the retention of uremic toxins in
the middle and large-middle molecular range. During hemodiafiltration
clearance of such middle molecular weight substances is achieved by
convection, while standard hemodialysis provides only small molecule
clearance. Indeed, in observational studies treatments with hemodiafiltration was related to improved survival.
In CONTRAST (the CONvective TRAnsport Study), the first prospective,
randomized multicenter trial comparing hemodiafiltration with
hemodialysis, patients were followed for more than 3 years. Disappointingly, all-cause mortality and a composite of fatal and non-fatal
cardiovascular events were not influenced by treatment assignment
(figure A). However, a reduction of all-cause mortality was observed
in patients who received high volume hemodiafiltration (hazard ratio
upper tertile [›21.95 liters/treatment] 0.62; 95% CI 0.41-0.93), even
after correction for confounders and dialysis facility (figure B). As this
finding results from an ‘on-treatment’ analysis, it might be explained
by dose-targeting-bias (the ‘best’ patients achieving highest convection volumes). However, the effect remained after correction for
a large number of confounders. Furthermore, the fact that a huge
(up to 2-fold) difference in mean convection volumes existed between
the different participating centers suggests that convection volumes
were not the result of patient factors. A follow-up study is being
designed to compare high volume hemodiafiltration to standard
therapy in patients in which high volume hemodiafiltration is feasible.
Also, intermediate endpoints are currently being analyzed, such as ESA
resistance, cardiac dysfunction, and markers of atherosclerotic disease
burden and vascular stiffness. Lastly, this well characterized and
prospectively followed cohort of 715 chronic HD patient will be used
to study the impact and course of specific biomarkers (e.g. hepcidin,
markers of protein energy wasting and inflammation).
A
60
40
20
0
B
0
1
2
3
4
time (years)
5
6
1,2
1,0
Hazard Ratio
Cardiovascular outcome and renal replacement therapy
Does dialysis treatment modality affect hard endpoints?
0,8
p=0.016
0,6
de Borst MH, Vervloet MG, ter Wee PM,
Navis GJ.
Cross Talk Between the ReninAngiotensin-Aldosterone System
and Vitamin D-FGF-23-klotho in
Chronic Kidney Disease.
Journal of the American Society of
Nephrology 2011; 22:1603-09.
Braam B, Cupples WA, Joles JA,
Gaillard CAJM.
Systemic arterial and venous
deter-minants of renal hemodynamics
in congestive heart failure.
Heart Failure Reviews 2011; 17:161-75.
0,4
0,2
0
LFHD
low
medium
high
online HDF
Figure A: survival curve for time to death
from any cause, based on life table analyses
using 3 month time periods.
HD= hemodialysis. HDF= hemodiafiltration
Figure B: Risk of all-cause mortality by
tertiles of achieved convection volume
(liters per treatment) as compared to
lowflux HD (LFHD); adjusted for determinants of mortality and center differences.
Online HDF: low = <15.5 L,
medium = 15.5-20.3 L, high= >20.3 L.
Brandenburg VM, Vervloet MG, Marx N.
The role of vitamin D in cardiovascular
disease - from present evidence to
future perspectives.
Atherosclerosis 2012; 225:253-63.
Grooteman MP, van den Dorpel MA,
Bots ML, Penne EL, van der Weerd NC,
Mazairac AH, den Hoedt CH,
van der Tweel I, Lévesque R, Nubé MJ,
ter Wee PM, Blankestijn PJ; CONTRAST
Investigators.
Effect of online hemodiafiltration on
all-cause mortality and cardiovascular
outcomes.
Journal of the American Society of
Nephrology 2012; 23:1087-96.
Ronden RA, Houben AJ, Teerlink T,
Bakker JA, Bierau J, Stehouwer CDA,
de Leeuw PW, Kroon AA.
Reduced renal plasma clearance
does not explain increased plasma
asymmetric dimethylarginine in
hypertensive subjects with mild to
moderate renal insufficiency.
American Journal of Physiology Renal
Physiology 2012; 303:F149-56.
Russcher M, Koch B, Nagtegaal E,
van der Putten K, Ter Wee P,
Gaillard CAJM.
The role of melatonin treatment in
chronic kidney disease.
Frontiers in Bioscience 2012;
17:2644-56.
Thang OH, Serné EH, Grooteman MP,
Smulders YM, Ter Wee PM, Tangelder GJ,
Nubé MJ.
Capillary rarefaction in advanced
chronic kidney disease is associated
with high phosphorus and bicarbonate
levels.
Nephrology Dialysis and Transplantation
2011; 26:3529-36
Vervloet MG, van Ittersum FJ, Buttler R,
Heijboer A, Blankenstein MA, ter Wee PM.
Effects of dietary phopshate intake on
fibroblast growth factor 23.
Clinical Journal of American Society of
Nephrology 2011; 6:383-89.
van der Weerd NC, Grooteman MPC,
Bots ML, van den Dorpel MA,
den Hoedt CH, Mazairac AHA, Nube MJ,
Penne EL, Gaillard CAJM, Wetzels JFM,
Wiegerinck ET, Swinkels DW,
Blankestijn PJ, ter Wee PM.
Hepcidin-25 in Chronic Hemodialysis
Patients Is Related to Residual Kidney
Function and Not to Treatment with
Erythropoiesis Stimulating Agents.
Plos One 2012; 7:e39783.
Westland R, Wijk JAE van, Schreuder MF.
The reason why mother nature
provided us with two kidneys: the risks
of a congenital solitary functioning
kidney.
Nephrology Dialysis and Transplantation
2012; 27:2603-04.
109
110 P r o gr e s s R ep o r t 2010 > 2012
Research Group
Acute and Perioperative Care
‘The acute and perioperative setting requires intensive
collaboration between involved specialties, as most patients
are treated by a multidisciplinary team’
Focus
The acute care for patients with
life-threatening conditions and
perioperative and postoperative
management of surgical patients
requires an integrative knowledge of cardiovascular physiology and the function of vital
organs. In particular, the anesthetic regime, surgery, fluid
resuscitation, shock, bleeding
and metabolic alterations induce
a generalized stress response that
may contribute to deterioration
of patient outcome.
In the research line Acute &
Perioperative Care we focus on
novel strategies for the diagnosis,
prevention and treatment of
complications due to tissue
hypoperfusion in the acute and
perioperative setting. We particularly emphasize the interaction
between tissue hypoperfusion
and ischemia/reperfusion injury,
hemostatic abnormalities and
vascular dysfunction by exploring underlying mechanisms
using a translational approach.
Collaboration
Research in the acute and
perioperative setting requires
close collaboration between
involved specialties, as most
patients are treated by a multidisciplinary team. Therefore, our
research lines adhere to existing
chains of care in order to achieve
a high level of agreement
between our scientific interests
and routine clinical practice.
The Acute & Perioperative Care
research group involves activities
of the departments of Anesthesiology, Cardio-Thoracic Surgery,
Emergency Medicine, General
Surgery, Intensive Care Medicine
and Physiology.
Unique
We are unique in our multidisciplinary research approach
that translates physiological
research into clinical practice,
and the fact that our research
lines are closely related to the
clinical chain of care.
111
112 P r o gr e s s R ep o r t 2010 > 2012
The department of Anesthesiology mainly focuses on
acute and perioperative disturbances in organ perfusion, with specific attention to ischemia-reperfusion
injury, hypoperfusion-related shock, microcirculatory
dysfunction, hemostatic alterations and endothelial
activation. The concept of tissue hypoperfusioninduced abnormalities in the coagulation cascade
and micro-circulation can be transferred to different
patient categories, including surgical and trauma
patients, and patients with cardiopulmonary arrest.
However, as treatment strategies are not easily generalized among distinct patient categories, more insight
is required into the exact mechanisms that lead to
tissue hypoperfusion and damage in different clinical
settings. Our research areas involve close collaboration
with other ICaR-VU specialties. Most of our research is
translational in nature and consists of clinical and
parallel preclinical studies.
In the department of Cardio-Thoracic Surgery, most
studies are focused on perioperative blood management
and the effect of cardiopulmonary bypass on (impaired)
hemostasis. In close collaboration with the department
of Pathology we additionally investigate the relationship between valve disease and inflammation.
Scientific research in the Emergency Department
has blossomed over the last few years and mainly
focuses on three topics: hemodynamic monitoring
in the emergency setting, delirium prevention in the
emergency setting and improvement of patient flow.
Our investigations contribute to improvement of
healthcare strategies in the acute setting.
The research in the department of Intensive Care
Medicine (ICU) is comprised of clinical trials and
investigator-initiated research. The main areas of
interest are hypothermia, infection diseases, sepsis,
nutrition & metabolism and pharmacokinetics.
We are aiming to build a preclinical research line to
allow from-bed-to-bench and from–bench-to-bed
investigations. In close collaboration with the departments of Anesthesiology and Cardiology a translational
research program has been initiated that includes
studies in critically ill patients, in animal models of
critical illness, as well as molecular and biochemical
studies of patient samples.
One of the research lines in the department of Physiology is aiming to identify the mechanisms that underlie
the remarkable sensitivity of the diaphragm muscle
to mechanical unloading during mechanical ventilation,
which has recently been shown by our group.
This diaphragm weakness is now considered a major
contributor to weaning failure in the ICU and has been
suggested to be contributing to postoperative pulmonary complications. We use unique diaphragm biopsies
from mechanically ventilated patients in combination
with novel KO mouse models to identify the pathways
that trigger these rapid changes in the diaphragm
following unloading. In our research we specifically
focus on the role of titin, a giant mechanosensing
protein. These recent studies on diaphragm dysfunction
illustrate the interaction between vascular and muscle
studies within the ICaR-VU.
Participants
Project leaders
Anesthesiology
Christa Boer
Arthur Bouwman
Stephan Loer
Patrick Schober
Lothar Schwarte
Cardio-thoracic Surgery
Alexander Vonk
Hans Niessen
Emergency Medicine
Jaap Bonjer
Leo Geeraedts
Prabath Nanayakkara
Albertus Beishuizen
Armand Girbes
Johan Groeneveld
Angelique Spoelstra
Monique de Waard
Pediatric Intensive Care
Dick Markhorst
Pediatric Surgery
Hugo Heij
Physiology
Geerten van Nieuw Amerongen
Coen Ottenheijm
Ger Stienen
PhD students
Anesthesiology
Chantal Boly
Bas Bossers
Charissa van den Brom
Carolien Bulte
Simone Dekker
Gaby Franschman
Sander Keet
Nick Koning
Michael Meesters
Victor Viersen
Cardio-thoracic surgery
Dennis Veerhoek
Daan van Velzen
Emergency Medicine
Nadia Alam
Mahi Dzelili
Durk Linzel
Edmee Schrijver
Irene Vegting
General Surgery
Koen Hartemink
Evelien de Jong
Jan Krul
Physiology
Jurjan Aman
Melanie van der Heiden
Pleuni Hooijman
Lonneke Smeding
Support staff
Anesthesiology
Rob van den Akker
Silwana Arensma
Erna Alberts,
Ingrid van den Hull
Physiology
Jan van Bezu
Collaboration
National
AMC, Amsterdam
Marcus Hollmann
Janneke Horn
Can Ince
Benedict Preckel
Rienk Nieuwland
Marcus Schultz
UMCN, Nijmegen
Nico Hoogerwerf
Lizzy van Pampus
Pieter Vos
EMC, Rotterdam
Frank Leebeek
Dick Rijken
WFG, Hoorn
Jens Peter Hering
RKZ, Beverwijk
David Mackie
UMCG, Groningen
Martin Kneyber
Thomas Scheeren
MUMC, Maastricht
Hans Vink
International
Sydney, Australia
Nigel Clarke
Angers, France
Christophe Baufreton
Daniel Henrion
Berlin, Germany
Michael Gotthardt
Dusseldorf, Germany
Artur Fournell
Olaf Picker
Ingo Schwartges
Frankfurt, Germany
Kaij Zacharowski
Rome, Italy
Salvatore Disomma
Tokyo, Japan
Hiroyuki Sorimachi
London, UK
Louella Vaughan
Boston, USA
Alan Beggs
Joseph Brain
James Butler
Jeffrey Fredberg
Chicago, USA
Stephan Huveneers
Thomas Irving
Richard Minshall
Heidelberg, Germany
Siegfried Labeit
Detroit, USA
Richard Novak
Rochester, USA
Gary Sieck
113
114 P r o gr e s s R ep o r t 2010 > 2012
Research Highlight
Peri Operative Patients
Endothelial barrier function and microcirculatory
perfusion during extracorporeal circulation
Aman J, van Bezu J, Damanafshan A,
Huveneers S, Eringa EC, Vogel SM,
Groeneveld ABJ, Vonk Noordegraaf A,
van Hinsbergh VWM, van Nieuw
Amerongen GP.
Effective treatment of edema and
endothelial barrier dysfunction with
imatinib.
Circulation 2012; 126:2728-38.
A
Data from Nick Koning (Anesthesiology), Christa Boer (Anesthesiology),
Geerten van Nieuw-Amerongen (Physiology), Martijn Overmars (Anesthesiology/
Physiology), Alexander Vonk (Cardio-Thoracic Surgery).
B
Perfused vessel density
8
C
Atasever B, van der Kuil M, Boer C,
Vonk A, Schwarte L, Girbes AR, Ince C,
Beishuizen A, Groeneveld ABJ.
Red blood cell transfusion compared
with gelatin solution and no infusion
after cardiac surgery: effect on
microvascular perfusion, vascular
density, hemoglobin, and oxygen
saturation.
Transfusion 2012; 52:2452-58.
6
4
2
CPB + 60’
CPB + 10’
60’ CPB
10’ CPB
30’ CPB
0
Pre-CPB
Perfused vessel density
(vessels / recording)
10
1800
Resistance (ohm)
In a rat model for cardiopulmonary bypass (CPB) we have shown that
extracorporeal circulation is associated with reduced microcirculatory
perfusion through a decrease in perfused vascular density. This observation is paralleled by disturbed tissue oxygenation. Subsequently, we
investigated the effects of pulsatile flow on these microcirculatory
alterations and have shown that restoration of pulsatility during
extracorporeal circulation preserves microcirculatory perfusion during
surgery, as well as improves postoperative microvascular recovery,
irrespective of system hemodynamics. Patient and animal studies have
further shown that hemodilution and low hematocrit, which are
considered to be important mediators of microcirculatory perfusion
abnormalities, could only partially explain the observed reduction in
microvascular perfusion during extracorporeal circulation. Furthermore,
exposure to extracorporeal circulation was associated with increased
heterogeneity of microcirculatory flow.
We also exposed endothelial cell cultures to plasma from patients
subjected to cardiopulmonary bypass and assessed the barrier function
of these cells by Electrical Cell-substrate Impedance Sensing (ECIS).
The figure C shows a typical example of the overall resistance as a
measure of barrier function of endothelial cells exposed to plasma
obtained prior to CPB (Pre-CPB), following CPB (Post-CPB) and upon
admission to the ICU. The addition of plasma induced a transient rise in
resistance, followed by a steady state. The steady-state values were
further used to define the effect of cardiopulmonary bypass on endothelial barrier function. Exposure to cardiopulmonary bypass reduced the
overall resistance of endothelial cells as measured by ECIS. Furthermore,
we could not attribute this loss of resistance to the hemodilution
component that is associated with extracorporeal circulation.
1600
1400
Pre-CPB
Post-CPB
ICU
1200
1000
800
0
A
1
B
2
Time (hours)
3
4
Figure A: Example of the sublingual microcirculation in a patient undergoing surgery.
Figure B: Microcirculatory perfusion
disturbances in a rat CPB model can only
partially be explained by hemodilution. Data
represent mean ± SD. Circles: hemodilution
group. Squares: CPB group.
Figure C: Plasma obtained following CPB
(post-CPB; ICU) decreases endothelial barrier
function when compared to pre-CPB values.
Biere SS, van Berge Henegouwen MI,
Maas KW, Bonavina L, Rosman C,
Garcia JR, Gisbertz SS, Klinkenbijl JH,
Hollmann MW, de Lange ES, Bonjer HJ,
van der Peet DL, Cuesta MA.
Minimally invasive versus open
oesophagectomy for patients with
oesophageal cancer: a multicentre,
open-label, randomised controlled
trial.
The Lancet 2012; 379:1887-92.
Bulte CSE, Slikkerveer J, Meijer RI,
Gort D, Kamp O, Loer SA, de Marchi SF,
Vogel R, Boer C, Bouwman RA.
Contrast-enhanced ultrasound for
myocardial perfusion imaging.
Anesthesia Analgesia 2012; 114:938-45.
Trof RJ, Beishuizen A, Cornet AD,
de Wit RJ, Girbes AR, Groeneveld AB.
Volume-limited versus pressure-limited
hemodynamic management in septic
and nonseptic shock.
Critical Care Medicine 2012; 40:1177-85.
Franschman G, Boer C, Andriessen TM,
van der Naalt J, Horn J, Haitsma I,
Jacobs B, Vos PE.
Multicenter evaluation of the course
of coagulopathy in patients with
isolated traumatic brain injury:
relation to CT characteristics and
outcome.
Journal of Neurotrauma 2012;
29:128-36.
Viersen VA, Greuters S, Korfage AR,
van der Rijst C, Van Bochove V,
Nanayakkara PWB, Vandewalle E, Boer C.
Hyperfibrinolysis in out of hospital
cardiac arrest is associated with
markers of hypoperfusion.
Resuscitation 2012; 83:1451-55.
Koning NJ, Vonk AB, van Barneveld LJ,
Beishuizen A, Atasever B, van den
Brom CE, Boer C.
Pulsatile flow during cardiopulmonary
bypass preserves postoperative
microcirculatory perfusion irrespective
of systemic hemodynamics.
Journal of Applied Physiology 2012;
112:1727-34.
Krishnan R, Klumpers DD, Park CY,
Rajendran K, Trepat X, van Bezu J,
van Hinsbergh VWM, Carman CV,
Brain JD, Fredberg JJ, Butler JP,
van Nieuw-Amerongen GP.
Substrate stiffening promotes
endothelial monolayer disruption
through enhanced physical forces.
American Journal of Physiology-Cell
Physiology 2011; 300: C146-54.
Welvaart WN, Paul MA, Stienen GJM,
van Hees HW, Loer SA, Bouwman RA,
Niessen HWM, de Man FS, Witt CC,
Granzier H, Vonk-Noordegraaf A,
Ottenheijm CAC.
Selective diaphragm muscle weakness
after contractile inactivity during
thoracic surgery.
Annals of Surgery 2011; 254:1044-49.
115
P r o gr e s s R ep o r t 2010 / 2011
117
Those who matter
It is the people of the Institute
who are at the heart of the
research accomplishments.
We are proud to introduce them
and to present their recent
achievements and plans for
the future.
I C A R -V U m c
117
I C A R -V U m c
119
VU University Medical Center
ICaR-VU

Circulating Matters Progress Report 2010>2012

Transcription

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