Cardiomyopathy Registry Study-II (CARS-II):
Dilated cardiomyopathy in children. Improving diagnosis by state-of-the-art
genotyping and outcome by risk stratification and by optimizing
pharmacotherapy

Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy in
children with an annual incidence of 0.57/100.000 and is characterized by a
(severe) systolic dysfunction. It is the most important indication for heart
transplantation in children. Overall 1-year reported survival is 87% and 1- and
5-year transplantation-free survival is only 70% and 50%, respectively.
Pediatric DCM is a heterogeneous group of conditions that can be caused by
multiple factors, i.e. genetic, metabolic, neuromuscular, immunological and
inflammatory. However, in the majority (*) of patients the cause remains
unknown (idiopathic DCM (iDCM)). A large proportion of iDCM cases may have a
genetic origin, but large-scale studies are lacking and so far only limited
numbers of genes were investigated.
The natural history of DCM is very variable and hard to predict, ranging from
patients with little to no symptoms to patients with an overt heart failure and
a rapidly deteriorating clinical condition. As DCM is a heterogeneous disease,
clinical treatment is challenging and centres around the questions which
children are most at risk to die, and therefore should be listed for
transplant, and how we can optimally treat DCM children to prevent or slow
disease progression. Although in the previous years much research has been
done, the following specific questions remain to be answered.

A. Are there susceptibility gene(s) underlying iDCM and is there a link between
genotype and phenotype?
In half of iDCM cases a familial disease is being found suggesting an
underlying genetic cause [3-5]. Mutations in genes encoding cytoskeletal
proteins, calcium-metabolizing proteins, cell-signalling molecules, and
mitochondrial enzymes for myocardial energy production have all been shown to
cause DCM, but only explain a fraction of all cases with paediatric DCM. The
identification of pathogenic mutations is of course important for genetic
counselling and it will give us essential insights in the underlying mechanisms
of DCM. This may be important for risk-stratification strategies and may
provide us with the opportunity to develop novel treatment modalities. The
novel next generation sequencing techniques including whole exome sequencing
offer an unprecedented state-of-the-art opportunity to fully genetically
characterize these patients.

B. What are clinical risk factors for progression DCM?
In many instances subtle changes in clinical condition herald the onset of
deterioration in DCM children, but these are often difficult to quantify.
Previous studies have demonstrated that idiopathic disease, age at presentation
> 6 years, congestive heart failure, inotropic support on admission and lower
LV fractional shortening are predictors for progression of the disease,
requiring maximum pharmacotherapy, mechanical support of the heart and/or heart
transplantation [1-2, 6-10]. However, the hazard ratios of these risk factors
at presentation are relatively low to be clinically useful for risk
stratification. Additional risk factors during follow-up need to be further
explored in-depth, to identify the children at highest risk. The scaffold of
the current CARS study offers a unique opportunity for such in-depth phenotypic
characterization.

C. What is the optimal dosing of adult heart failure medication in pediatric
DCM?
An additional problem in DCM children is the lack of evidence-based dosing
guidelines. Current therapy and dosing is based on adult data. However, due to
developmental changes in drug disposition and probably also effect, this simple
extrapolation leaves the pediatric population with suboptimal drug therapy. To
address this clinical problem we propose the following strategies.
C1. Determination of PK data in DCM children. At first in the grade 4 heart
failure patients who are admitted in the ICU and are treated with Milrinone.
This drug is a phosphodiesterase type III inhibitor, with both positive
inotropic and vasodilatory activities, but for the application in children with
ADHF it is not known whether the used dosage range of 0.25-0.75 ug/kg/min leads
to adequate plasma levels. The few available studies do suggest that impaired
renal function, common in children with ADHF, should be taken into account as
it might lead to high plasma levels Secondly in outpatients, treated with
diuretics, β-blockers, ACE inhibitors and digoxin, most commonly carvedilol and
enelapril. A few paediatric studies suggest comparable beneficial effects as in
adults, but they lack methodological or statistical power. Furthermore, the
dosages recommended for children may be too low to achieve adequate plasma
concentrations. Pharmacokinetic (PK) data are scarce in children, while
optimisation of dosing might improve outcome as it does in adults. C2 Recent
studies in adults show that novel biomarker levels (MMP-9, TIMP-1 and B+ Tn-C),
in addition to (NTpro)BNP, are associated with disease progression. Such data
in children are lacking. These data may not only identify patients at risk of
poor outcome, but also may aid to more precisely monitoring the effect of heart
failure drugs and enable age-appropriate dosing guidelines to be developed

Due to the limited numbers of patients per year, (inter-) national
collaboration is essential to increase power to perform proper scientific
research. In our ongoing nationwide pediatric DCM cohort study (CARS-1) we have
thus far included 97 children aiming to obtain a solid database from which risk
factors for progression of disease are to be identified. We speculate that
alterations within patients during follow-up may provide sensitive prognostic
markers.The motive for CARS-2 not only lies in continuation of CARS -1 and to
acquire more patients needed for statistical robust analysis. We believe, due
to progressive insight, that expansion of this study with thorough genetic
analysis and pharmacological studies would significantly contribute to
improving treatment of DCM children.

The Cardiomyopathy Registry Study (CARS)-II aims to

1) Create a national cohort with biorepository of patients with paediatric DCM

2) To elucidate (epi) genetic causes of iDCM in a uniform and state of the art
way.

3) Identify clinical risk factors for progression of DCM at presentation and
during follow up, both genotypic and phenotypic, to guide therapy.

4) To obtain farmacokinetic data which will help te determine age appropriate
dosing of heartfailure drugs and to support future research on optimisation of
farmacotherapy.

multi-center, prospective, longitudinal, observational study in children with
symptoms of heart failure secondary to cardiomyopathy

The risk of participating in this study is nil, especially in relation to the
"natural history" of the disease with an transplantation-free survival of 70
and 50% respectively afer 1 and 5 years after presentation. The burden of
participating is low as all data will be collected at time points that coincide
with normal follow-up in the vast majority of participating patients.
Furthermore most data that are collected belong to the routine follow-up for
these patients. There is no short-term benefit for participating patients, the
long-term benefit may include the potential for improvement of clinical care.