Primary objectives: The first aim is to examine the role of microtubule network in electrical conduction, protein localization and function in induced cardiomyocytes from pediatric BrS patients, life threatening ventricular arrhythmia patients and…
ID
Source
Brief title
Condition
- Cardiac arrhythmias
- Cardiac and vascular disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Spontaneous cellular contractions, electrical conduction and calcium
oscillations in induced cardiomyocytes will be measured. Using
fluorescence-based microscopy experiments, the effect of altered microtubule
dynamics on electrical conduction will be studied as well as on the
localization of important proteins and protein-protein interactions in the
intercalated disk. We will test the efficacy of novel drugs by performing the
same measurements. We will perform T2C measurements, RNA-Sequencing, and a
modified form of RNA-Sequencing called Ribo-Seq, in order to study the
transcription factor-based regulation of SCN5A expression, general molecular
mechanism underlying the function of SCN5A, and molecular consequences of its
dysfunction in arrhythmia patients. The induced cardiomyocytes data will be
correlated to the clinical phenotype of the patients investigated by ECG,
24-hours 12-lead Holter monitoring, ECG during exercise testing, ECG during
fever or ECG during Ajmaline testing, Signal Averaged ECG and echocardiography.
Due to the explorative nature of laboratory molecular research (statistical
consultation provided by Prof. dr. ir. H. Boersma, professor in clinical
epidemiology of cardiovascular disease), endpoints of change in certain
parameters cannot be given yet.
Secondary outcome
Not applicable
Background summary
Sudden Cardiac Death (SCD) contributes 10% to Dutch pediatric mortality. At
least 30% of SCD in children is caused by inheritable arrhythmia syndromes,
mainly channelopathies like Brugada Syndrome (BrS), Long QT syndrome (LQTS) and
catecholaminergic polymorphic ventricular tachycardia (CPVT). Timely
prophylactic treatment of disease carriers will result in reduction of
mortality and post-resuscitation morbidity. Phenotypic expression of BrS
differs with respect to age of onset and severity of arrhythmia, even between
patients with identical (SCN5A) mutations. However, for the majority of BrS
patients (70-80%) no mutation has currently been identified. Knowledge of
additional contributing factors responsible for a specific phenotypic
expression is lacking, as is the identification of ultimate effective medical
therapy to prevent potential life-threatening arrhythmia. Ventricular
arrhythmia in BrS patients usually present between the 3rd and 4th decade.
However currently also pediatric BrS patients are increasingly described in
literature and seen in daily practice of pediatric cardiology. Underlying
factors responsible for phenotypic expression or non-expression of BrS in the
pediatric age group are unknown. Medical treatment to prevent life-threatening
arrhythmia in these children is yet unavailable.
Recently, the microtubule cytoskeleton has been shown to fine-tune the
function, transport, localization and turnover of proteins that are mutated in
BrS and to be essential for electrical conduction in the heart.
We hypothesize that increasing microtubule stability ameliorates stability of
electrical conduction and cardiac rhythm in pediatric BrS patients. This will
provide new targets for arrhythmia treatment. A cell based platform, allowing
to test efficacy of (novel) medication, will provide opportunities to develop
and test tailor-made treatments for specific phenotypes of inheritable
arrhythmia. In this project, pediatric BrS serves as a model for inheritable
arrhythmia in pediatric patients that can be extended to other types of
inheritable arrhythmia in children.
Study objective
Primary objectives: The first aim is to examine the role of microtubule network
in electrical conduction, protein localization and function in induced
cardiomyocytes from pediatric BrS patients, life threatening ventricular
arrhythmia patients and controls.
The second aim is to test the efficacy of novel drugs -potentially effective in
the (prophylactic) treatment of arrhythmia in BrS- on the electrical and
molecular properties of cultured induced cardiomyocytes derived from pediatric
BrS patients and pediatric survivors of an out of hospital cardiac arrest due
to ventricular arrhythmia. The third aim is to develop a model that allows
prediction which children at risk for Brugada syndrome will develop a Brugada
phenotype at what time in the future.
Study design
Observational, non-interventional, non-therapeutic patient-based study
Study burden and risks
The risk and burden associated with the one-time collection of 10ml blood by
venepuncture is that it will be painful for the child and can cause a
localized, temporary hematoma. We aim to combine all the investigations on a
regularly planned outpatient clinic visit. Drawing blood is usually not
performed during regular outpatient clinic examinations and is therefore
mentioned as study related (invasive) procedure. The other described
investigations, except the non-invasive Signal Averaged ECG, are standardly
used investigations during regular follow up of the described patient
population. Of course for the healthy controls, the burden of participation is
extended to an outpatient clinic visit with all the investigations described
above because they do not need regular follow up in a cardiology outpatient
clinic. We will ask patients planned for ear - nose - throat (ENT) surgery as
control patients. Blood will then be drawn during general anaesthesia used for
the surgery to minimize the burden of pain related to the venipuncture. The
other investigations in control patients will be combined during other
outpatient clinic visits that are obligatory in order to prepare the patient
for the planned ENT surgery. There are no direct benefits to the patients
associated with participation. Group relatedness: The study can only be done in
the pediatric age group because we aim to search for specific factors that
particularly predispose to a pediatric phenotype of BrS or life threatening
arrhythmia. We expect to determine molecular changes either responsible for a
BrS phenotype or protective against a BrS phenotype in childhood. Conversely,
the phenotype of adult BrS patients is also influenced by myocardial changes
related to aging of the heart and coronaries resulting in cardiac conduction
and functional changes. These age-related changes might interfere with our
phenotype analysis if we would study adult BrS patients. Since we aim to
develop a cell based platform to test novel medication that eventually will be
used to medically treat the pediatric phenotypes of BrS/life threatening
arrhythmia, we need pediatric derived induced cardiomyocytes. These will
optimally approximate the clinical and cellular phenotype and are therefore the
best model in order to predict medication effectiveness for the prevention of
life threatening arrhythmia in pediatric patients.
Wytemaweg 80
Rotterdam 3055 CN
NL
Wytemaweg 80
Rotterdam 3055 CN
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all
of the following criteria:
- Age >= 0.5 and < 18 years and
Patient population/ cases
- Proven SCN5A mutation with phenotypic BrS,
- or a SCN5A mutation without phenotypic BrS,
- or phenotypic BrS, proven without specific genetically recognized mutation,
- or aborted SCD due to ventricular arrhythmia proven without recognized
genetic mutations in currently known arrhythmia genes.
Control population:
- Phenotypic cardiac healthy persons with a negative family history of (non
coronary related) SCD < 45 years of age, inheritable arrhythmia syndromes,
pacemaker or ICD implantation and heart failure.
- Same age range as the patient cases
- Same gender proportion as the cases
- Planned Ear Nose Throat surgery without cardiac involvement in surgery or
underlying disease
- Control patients will not be subjected to DNA testing because of the ethical
inappropriateness to perform DNA diagnostics in healthy children under 18 years
and the psychological burden and societal implications of eventual unexpected
accidental genetic abnormalities found. The risk however to include a
phenotypic cardiac healthy control patient accidently carrying a mutation in
one of the known cardiac arrhythmia genes will be minimized by exclusion of
controls with a family history of a potential inheritable arrhythmia
syndrome.E,v#Î
- Non SCN5A mutation carrier without phenotypic BrS, sibling of a SCN5A
mutation carrier with phenotypic BrS
Exclusion criteria
A potential subject patient population or control who meets any of the
following criteria will be excluded from participation in this study:
- Non-consent for the collection of blood
- Presence of any other (anatomic) cardiac disease or cardiac conduction
disturbance other than the ones described for the inclusion criteria.
- Additional known genetic mutations other than the ones described for the
inclusion criteriaIn addition to the above exclusion criteria, healthy controls
will be excluded if
- they have a positive family history for a potential inheritable arrhythmia
syndrome defined as a positive family history for SCD < 45 years of age
(exception: proven coronary disease), inheritable arrhythmia syndromes (e.g.
BrS, LQTS, CPVT, idiopathic ventricular fibrillation or short QT syndrome),
pacemaker or ICD implantation, or heart failure in first or second degree
family members.
Design
Recruitment
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 | NL62724.078.18 |