The main objective of the study is to dissect the genetic and stress-based mechanisms on the development of pediatric heart failure in congenital heart disease (ConHD) with the use of induced pluripotent stem cell-derived cardiomycoytes (iPSC-CMs).…
ID
Source
Brief title
Condition
- Congenital cardiac disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To dissect genetic contribution to development of heart failure, i.e.
dysfunction of cardiomyocytes, we intend to study induced pluripotent stem-cell
derived cardiomyocytes (iPSC-CM) from patients with a known genetic mutation.
The control group consists of iPSC-CMs from the same patients in which the
mutation has been corrected in the stem cells using Crispr-cas9 technology,
before the cardiomyocytes will be differentiated. Alternatively, we will use
commercially available and other normal iPSC lines as controls. The main
endpoints for the induced pluripotent stem-cell derived cardiomyocytes
(iPSC-CM) are functional parameters: electrical conduction, calcium
oscillations and force production. Corrected and uncorrected cardiomyocytes
will be compared. We will perform RNA-sequencing and a modified form of
RNA-sequencing (Ribo-Seq) to study the molecular consequences of the genetic
mutation and stress-based effects. The iPSC-CM data will be correlated to the
clinical phenotype of the patients. Due to the explorative nature of laboratory
molecular research, endpoint of change of certain parameters cannot be given
yet.
In the patients in which also cultured residual tissue obtained at surgery is
available, the endpoints of these LTS are force production and force-frequency
relationships.
Secondary outcome
Not applicable.
Background summary
Heart failure in congenital heart disease (ConHD) is the result of longstanding
abnormal stress - or workload - for the heart even after surgery, in
combination with a genetic mutation that leads to the ConHD itself. The most
prevalent form of ConHD leading to heart failure is Tetralogy of Fallot
(pulmonary atresia with ventricular septal defect). At present, no therapy
exists to support the failing heart in ConHD. Hence, there is an urgent need to
study mechanisms of pediatric heart failure in ConHD and test new therapeutic
strategies. Recent studies suggest that genetic variations associated with the
malformed heart in ConHD may also affect cardiomyocyte development and function
and thereby contribute to heart failure. The research question of this study is
to dissect the contribution of the genetic mutation to the development of
pediatric heart failure in Tetralogy of Fallot (pulmonary atresia with
ventricular septal defect) and to develop a platform to test therapeutic
strategies. For that purpose, we aim to study cardiomyocytes derived from
induced pluripotent stem cells (iPSCs), which in turn are generated from
patients* blood. In patients in whom residual tissue will be available from
surgery, we will compare the studies in cardiomyocytes with cardiac function
studies obtained from cultures of residual tissues.
Study objective
The main objective of the study is to dissect the genetic and stress-based
mechanisms on the development of pediatric heart failure in congenital heart
disease (ConHD) with the use of induced pluripotent stem cell-derived
cardiomycoytes (iPSC-CMs). The second objective is to develop a platform to
test the efficacy of novel drugs / therapies on cardiomycyte function in
iPSC-CMs from patients at risk to develop heart failure in ConHD. The third
objective is to verify the results from iPS-CMs in cultured residual tisses
obtained at surgery (LTS).
Study design
Observational, non-interventional, non-therapeutic patient-based study.
Study burden and risks
Burden: Single collection of 8 ml of blood will occur in combination with
planned blood sampling or from cord blood. If the mutation is known before
birth (in the case of antenatal diagnosis), blood will be collected from cord
blood if possible, this will carry no burden. Alternatively, blood will be
withdrawn before surgery or heart catheterization (if necessary), when the
patient is under anaesthesia, which will not be painful, or during preparation
before surgery in combination with routine blood sampling. Blood volume of
patients during surgery is for children ~ 85 ml/kg, average weight at surgery 5
kg , hence 8 ml constitutes < 3% of total blood volume and can be withdrawn
safely. Residual tissue obtained during surgery will be mounted in the 3D-LTS
culture system. The other described investigations are all routine procedures
during work up for surgery and follow up visits.
Benefits: there are no direct benefits for the patients associated with
participation.
Group relatedness: This study can only be done in children with a ConHD since
these patients are at risk or have developed heart failure. The children need
surgery and hence residual tissue may become available. In addition, the
genetic variation must be known, since routine genetic screening has become
available for patients born last decade, this study can only be performed in
children.
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Listed location countries
Age
Inclusion criteria
- Diagnosis as stated above
- Age between 0-18 years
- Known genetic mutation
- Written informed consent.
Exclusion criteria
- Non-consent to collect blood or residual tissue obtained at surgery or
transplantation.
- Presence of multiple mutations or deletion of chromosome.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL81863.078.22 |