Download Objectives Cardiovascular disease, congestive heart failure (CHF

Objectives
Cardiovascular disease, congestive heart failure (CHF) and disturbances in heart rhythm (arrhythmias)
are still dominant causes of mortality and morbidity in the Western World. Treatment of these diseases
and their consequences (especially stroke as a consequence of atrial fibrillation (AF)) consumes an
important part of the health care budget. Therefore, prevention and early treatment of heart failure and
arrhythmias is of utmost importance for good health care and can reduce costs of health care.
Cardiac Resynchronization Therapy (CRT) is a novel pacemaker therapy that increases the pump
function of the heart and offers the opportunity to reverse some of the adverse ventricular adaptations.
Implantable Cardioverter Defibrillators (ICDs) are the most effective therapy against life-threatening
arrhythmias. Not all patients benefit from CRT, and ICDs are not always needed to deliver therapy. Other
patients may need therapy, but are currently not recognized.
For these reasons there is a strong need for:
- identification of patients at risk for CHF or arrhythmias.
- optimization of response to implantable cardiac devices.
Biomarkers to predict cardiac failure, arrhythmias and success of treatment (COHFAR) –
University Medical Center Utrecht, Utrecht
Principal Investigator: Prof. Dr. M. A. Vos
CTMM Program manager: Erna Erdtsieck-Ernste
CHF and arrhythmias are tightly linked to each other, among others because both are caused by gradual
adverse 'remodeling' processes in the heart muscle. Also, arrhythmias disturb pump function of the heart,
thereby worsening CHF in the long run. CHF is hard to treat and treatment mainly consists of preventing
worsening.
An important part of the 'remodeling' of the heart is deposition of collagen, a protein that causes stiffening
of the heart muscle and interrupts the electrical connections between heart muscle cells. Therefore,
reduction of collagen in the heart or prevention of its deposition, using pharmacological therapy, appears
an important target for treatment and prevention of CHF.
Cardiac Resynchronization Therapy (CRT) is a novel pacemaker therapy and is one of the few therapies
that actually increases pump function of the heart and thereby offers the opportunity to reverse some of
the adverse adaptations, including the susceptibility to arrhythmias. Implantable Cardioverter Defibrillators
(ICDs) are the most effective therapy against life threatening arrhythmias. Both ICD and CRT are
relatively expensive. Not all patients benefit from CRT and ICDs do not always need to deliver the
therapy. Other patients may need the therapies, but are currently not recognized.
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For these reasons there is a strong urge for:
1. earlier recognition of patients at risk for CHF and/or arrhythmias, allowing prevention of these
derangements
2. better identification and stratification of patients who require device and/or pharmacological therapy
3. treatment which can be tailored to the individual patient.
4. Objectives: It is the purpose of this proposal to develop strategies for early, justified treatment using
biomarkers that allow:
5. identification of patients that will respond to CRT
6. identification of patients that are at high risk for cardiac arrhythmias
7. prediction of success of therapy.
Those biomarkers include a) genes and gene products, b) substances in the blood, c) electrical signals
derived from the body surface or from implanted pacemaker/ICD electrodes, d) relevant proteins, imaged
with molecular probes, and e) indicators of mechanical abnormalities, derived from novel
echocardiographic techniques.
Overall approach: To this purpose genetic (DNA, microRNA) data from well-defined clinical populations
(infarction, CRT, heart transplant) will be assessed (Workpackage 1 (WP1)). Partly in parallel, several
apparently relevant biomarkers are investigated (plasma procollagen, neurohumoral factors; imaging of
collagen, type of fibrosis and cardiac sympathetic denervation) in hearts with infarction and/or a
conduction abnormality (left bundle branch block; known to be corrected by CRT) (WP 2). Similarly,
structural substrate for AF in relation to CHF is investigated in isolated cells and pre-clinical experiments
(WP 3), also involving the markers used in WP2. In this workpackage also predictors of the reversal of AF
upon CRT are investigated. In WP 4 improvements in application of CRT and related device therapies are
studied, with emphasis on the use of biosensors to modulate pacemaker operation, allowing individual
treatment.
Proof of concept: The approach will be translational, starting with genetic exploration in patients, using
this information in pre-clinical experiments and finally pilot studies in small groups of patients using the
insights achieved in the pre-clinical studies.
Plan of investigation: In total the application consists of 7 WPs of which 4 have an experimental design.
Industrial partners are Medtronic and Astra Zeneca. A third party, Nanosens, will be hired to produce
nanosensors for relevant biomarkers, ultimately allowing biofeedback for pacemakers and ICDs.
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Budget, organization and partners
Total project budget 15.5 M€
Start date: 01-01-2010
2 Industrial partners
4 Academic partners
Medtronic Bakken Research Center
Merck Sharp & Dohme
Academic Medical Center Amsterdam
Interuniversity Cardiology Institute
Maastricht University Medical Center
University Medical Center Groningen
University Medical Center Utrecht
VU University Medical Center Amsterdam
End date: 31-12-2014
Allocated at year-end 2011:
51 researchers (21.7 FTEs)
General
In response to the first call for project proposals in 2007, the Center for Translational Molecular Medicine (CTMM)
announced on April 1, 2008, that nine first-call projects would receive research funding amounting to a total of 150
million Euro. On March 10, 2009, it announced that eight new project proposals, submitted in the fall of 2008 in
response to the second call for proposals, will receive funding amounting to a total of almost another 100 million
Euro.
All Dutch university medical centers, plus several universities, a broad spectrum of small and medium-sized
enterprises, major industry leaders including Philips and DSM, and the Dutch Government are involved.
The funding is provided by the Dutch government, industry and academia. The research is focused firmly on the
‘translational’ aspects of molecular medicine so that results can be applied as quickly as possible to actual patient
care.
Cohfar is one of the projects from the first call.
Update: 13-03-2012
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