Primary - to determine factors that predict outcome in children with symptomatic heart failure secondary to cardiomyopathy, in order to choose an optimal management strategy for these children. Secondary - to identify predictive factors that can be…
ID
Source
Brief title
Condition
- Heart failures
- Cardiac and vascular disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
o death, heart transplantation or institution of mechanical support of the
circulation
Secondary outcome
o listing for heart transplantation, hospitalization for worsening heart
failure, hospitalization for all causes
Background summary
Cardiomyopathy is an important cause of heart failure in children. The
incidence of cardiomyopathy in infancy is high (8/100.000) as compared to older
age groups (0.7/100.000). Dilated cardiomyopathy is the most common form and
carries a high mortality and morbidity. After presentation,
transplantation-free survival at 1 and 5 years is only 70% and 50%,
respectively. Beyond infancy, cardiomyopathy is the most important indication
for heart transplantation. A subset of children, however, will do clinically
well for years or recover completely. Prognostic factors that reliably predict
outcome at presentation or during follow-up are lacking]. The majority of
children (*) with dilated cardiomyopathy have idiopathic disease, in the
remainder neuromuscular disorders and myocarditis are most prevalent]. It has
been suggested that prior myocarditis [8] and familial disease [9] each may
account for * of idiopathic cases.
The pathogenic mechanisms underlying dilated cardiomyopathy share common
features. In most genetic forms proteins are affected that somehow link the
contractile apparatus to the sarcolemma and extracellular structures. In
enteroviral myocarditis proteases disrupt dystrophin, a crucial protein linking
the cytoskeleton to the sarcolemma. Similarly, in Duchenne (DMD) and Becker
(BMD) muscular dystrophy, two common neuromuscular disorders, dystrophin is
disrupted, causing skeletal muscle weakness and dilated cardiomyopathy in a
very high percentage of affected individuals. Irrespective of the underlying
initial insult causing cardiomyocyte dysfunction, compensatory neurohumoral
mechanisms are activated that, initially, maintain myocardial function, but
ultimately are responsible for adverse myocardial remodelling and the
development of overt heart failure]. Based on these concepts asymptomatic
stages (A & B) of heart failure are recognized in subjects either having risk
factors or asymptomatic myocardial dysfunction with a high risk to develop
symptomatic heart failure (stages C & D). In the majority of children, the
first presentation is with an episode of symptomatic heart failure. However,
subjects with neuromuscular disorders generally can be recognized in the
asymptomatic stage of heart failure. This may allow studying early markers of
myocardial disease and subsequently designing strategies to modify the course
of the disease by early intervention. DMD patients generally are diagnosed
before the age of 6 years and develop dilated cardiomyopathy between the age of
10-16 yrs in the majority of cases]. Prognostic markers in asymptomatic DMD
patients may be applicable to other forms of cardiomyopathy and thus may be
relevant to a much broader group of children.
The treatment strategies for children with symptomatic heart failure and
cardiomyopathy are, in general, similar to those recommended for adults with
heart failure. They include ACE inhibitors (ACEI) and β-blockers, in addition
to diuretics and digoxin. However, the efficacy of medical therapy in
paediatric heart failure is poorly defined. The beneficial effects in children
are based on small non-randomized and often non-controlled studies. These have
suggested favourable effects of ACEI and of β-blockers in children with
symptomatic heart failure and of ACEI in presymptomatic boys with DMD. However,
in a recent randomized placebo-controlled trial the beneficial effect of
carvedilol in children with heart failure could not, statistically, be
demonstrated. The somewhat disappointing result of this study reflects the
difficulties to overcome in such studies in children. These include, amongst
others, the ability to attain sufficient statistical power, the heterogeneity
of underlying heart disease in children included in such studies, the lack of
meaningful endpoints and the uncertainty of adequate drug dosing in children.
A number of studies have analyzed outcome parameters in children with heart
failure. Collectively, these studies have demonstrated that signs of congestive
heart failure at presentation, poor ventricular function and older age are
related to an unfavourable outcome. Furthermore, the outcome in children with
idiopathic disease and neuromuscular disorders is uniformly poor. However,
these factors lack sufficient predictive power in individual patients.
What might be useful predictors to assess the outcome in children with heart
failure, based on what we know from adult and paediatric studies?
In many instances subtle changes in clinical condition herald the onset of
deterioration in these children, but these are often difficult to quantify.
Furthermore, longitudinal assessment of parameters within children may contain
important prognostic information. We are not aware of studies that have
systematically and prospectively analyzed a broad range of such parameters.
Scoring systems to objectify the clinical condition of children may be useful
in the longitudinal follow-up. Functional class scoring systems, the paediatric
equivalents of the NYHA classification, have mainly been used in patients with
congenital heart disease. Similarly, health related quality of life, may reveal
information about the clinical condition, but has hardly been measured in
children with heart failure and cardiomyopathy.
Growth failure in children with chronic illnesses is a common problem and, in
general, a marker of poor outcome. In children with heart failure secondary to
congenital heart disease growth failure has been well documented, but in heart
failure secondary to cardiomyopathy almost no data are available on the
incidence, the prognostic significance and the outcome. Recently, a
single-centre retrospective review revealed that * of the patients on the
waiting list for heart transplantation were wasted. Despite the lack of
information, growth failure in children attributable to heart failure (stage C)
has been accepted as a class I indication for heart transplantation.
Echocardiography has been one of the cornerstones for the diagnosis and
follow-up of children with heart failure. Severely depressed LV function at
presentation and during follow-up carries a poor prognosis. Only few studies
have evaluated newer echocardiographic techniques in children. One study
revealed that a decreased diastolic and systolic function of the RV, measured
by pulse wave TDI, was related to an unfavorable outcome. In another study,
using 3D echocardiography, dyssynchrony was found to be common but unrelated to
outcome. In asymptomatic boys with DMD diastolic dysfunction has been found and
its severity correlates with the onset of systolic dysfunction.
MRI has been used to a limited extent in adults with cardiomyopathy. In adults
with non-ischemic cardiomyopathy positive late enhancement was found to convey
a higher risk of adverse events and to predict a diminished response to β-
blocker therapy. In patients with DMD progressive abnormalities in strain and
fibrosis have been demonstrated as the disease progresses from the asymptomatic
to the symptomatic stage. MRI has hardly been systematically employed in
paediatric heart failure, but it conveys potentially important anatomical and
functional information.
In adults, the determination of oxygen uptake at peak exercise level (VO2max)
has been a very important prognostic marker and a cornerstone in selecting
candidates for heart transplantation. Recent studies, however, have suggested
that the addition of β-blockers might favour medical therapy over
transplantation in subgroups of patients. Notably, for the translation of these
results to younger subjects, it has been demonstrated that a cut-off level of
VO2max < 50% of predicted would yield similar results in adults. Although
formal data in children are lacking a VO2max < 50% of predicted has been
accepted as a class I indication for transplantation in children with stage C
heart failure. Exercise testing in (young) children may be challenging,
especially obtaining VO2max. In younger children, as of 6-7 years of age,
performing a 6-minute walk test is generally possible. Reference data in
children have recently be obtained. Furthermore, the 6-minute walk test has
been used as a follow-up tool in various cardiovascular disease states in both
children and adults, including pulmonary hypertension and congenital heart
disease. In general, follow-up measurements were found to correlate with
clinical condition as well as with VO2max. Thus, the 6-minute walk test may be
a useful follow-up tool in children with heart failure and cardiomyopathy.
Neurohumoral axis activation is a prominent feature in heart failure. In recent
years, numerous studies in adults with heart failure have demonstrated the
diagnostic and predictive value of natriuretic peptides. BNP and NT-proBNP
levels have been found to correlate closely. In adults increased BNP levels
predict a higher risk of adverse cardiovascular events and longitudinal
alterations in BNP levels have been related to outcome. Interventional
strategies aiming at a decrease in BNP have also resulted in improved outcome.
In children, BNP is increased immediately after birth and rapidly drops of to
levels at or slightly above those in older children and adults]. BNP levels are
increased in children with heart disease and are higher in LV systolic
dysfunction than in congenital heart disease. In children with LV dysfunction
elevated BNP levels were found to predict adverse cardiovascular events. These
results suggest that longitudinal assessment of (NT-pro)BNP may be a sensitive
predictor of outcome in children.
Central sleep apnoea/hypoventilation has been well documented in adults with
systolic heart failure, but not in children. Recently, we found this phenomenon
in children with severe heart failure (see pilot results), but the incidence
and the prognostic significance is unclear.
In summary, heart failure in children secondary to cardiomyopathy carries a
poor prognosis. The paradigms used to treat these children have been obtained
from insights obtained in adults, but to a large extent have not been tested in
children. We propose to study systematically and prospectively a set of
potential prognostic markers that will allow better selection of patients for
various treatment strategies and that may serve as surrogate markers in future
therapeutical trials.
We hypothesize that longitudinal, in-depth, follow of children after
presentation with symptomatic heart failure will reveal markers that predict
(adverse) outcome. We speculate that alterations within patients during
follow-up may provide sensitive prognostic markers. In this part of the study
we will address questions arising in children that have developed signs of
heart failure.
Study objective
Primary - to determine factors that predict outcome in children with
symptomatic heart failure secondary to cardiomyopathy, in order to choose an
optimal management strategy for these children.
Secondary - to identify predictive factors that can be used as surrogate
markers in future outcome research.
Study design
multi-center, prospective, longitudinal, observational study in children with
symptoms of heart failure secondary to cardiomyopathy
Study burden and risks
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.
Dr Molewaterplein 60
Rotterdam 3000 CB
NL
Dr Molewaterplein 60
Rotterdam 3000 CB
NL
Listed location countries
Age
Inclusion criteria
Children with dilated cardiomyopathy
Exclusion criteria
inabilty to cooperate with the study protocol (i.e mental retardation)
For specific procedures within the protocol general accepted contra-indications may apply. Specifiically, for MRI the presence of MRI incompatible materials in the body and for the application of contrast because of renal impairment.
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 |
---|---|
Other | NL30649.078.10 |
CCMO | NL32651.078.10 |