Cardiac Biomarkers in Pediatric Cardiomyopathy (PCM Biomarkers)

Pediatric cardiomyopathy is a heterogeneous disease with high morbidity and mortality in
which children often present with fulminant disease leading to death or transplant. Highly
sensitive and specific cardiac biomarkers or panels of biomarkers, representing different
pathologic mechanisms or pathways, are the least invasive (a particularly important
consideration in children) and most-cost-effective approach to the early detection of cardiac
dysfunction. The long-term goal of this project is to identify such biomarkers in children
with cardiomyopathy. These findings could represent a major advance in determining the most
appropriate evidence-based clinical care for these children, including when to consider heart
transplantation.

The specific aims of this study are:

1. To determine the ability of established and novel cardiac biomarkers to predict short-
and long-term outcomes in children with newly diagnosed (incident) dilated
cardiomyopathy (DCM)

2. To assess the clinical utility of cardiac biomarkers of collagen metabolism in
determining the presence of myocardial fibrosis, as established by cardiac MRI (cMRI),
and left ventricular (LV) diastolic dysfunction, as established by echocardiography in
both newly diagnosed and existing cases of idiopathic and familial hypertrophic
cardiomyopathy (HCM) in children.

3. To determine whether longitudinal changes in cardiac biomarkers are associated with
worsening heart failure (HF) class in clinically stable children with dilated or
hypertrophic cardiomyopathy. This study will determine the importance of serological
biomarkers, in conjunction with cardiac imaging, in the early identification of heart
disease before cardiac remodeling and functional impairment have become irreversible in
a pediatric population.

This is a 5-year prospective study of up to 480 children with either primary dilated or
hypertrophic cardiomyopathy. The study will have three components: 1) clinical data
collection by chart review, 2) biospecimen collection and testing, and 3) centralized review
and measurement of echocardiograms and cMRIs.

Inclusion Criteria:

- Patient is alive and has not received a transplant prior to enrollment in the study.

- Under age 21 years at age of enrollment

- For Group 1 (incident DCM), a case of DCM presenting to a study site within 2 years of
the original cardiomyopathy diagnosis

- Group 2 (incident/recent HCM), a new or existing diagnosis of idiopathic or familial
HCM with a cMRI within 12 months of diagnosis

- Group 3 (prevalent HCM or DCM), any child with a diagnosis of DCM or idiopathic,
familial, or HCM due to a known disease-causing mutation who has survived
transplant-free at least 12 months from the date of original cardiomyopathy diagnosis

- For all 3 groups, diagnosis of cardiomyopathy must be confirmed by Echocardiographic
or cMRI criteria

Exclusion Criteria:

A patient is not eligible for enrollment if one or more of the following conditions are met
at the time of presentation with cardiomyopathy:

- Any cardiomyopathy diagnosis other than DCM or idiopathic HCM, familial HCM or HCM due
to a known disease-causing gene

- Endocrine disease known to cause heart muscle disease (including infants of diabetic
mothers)

- History of rheumatic fever

- Toxic exposures known to cause heart muscle disease (anthracyclines, mediastinal
radiation, iron overload or heavy metal exposure)

- HIV infection or born to an HIV positive mother

- Kawasaki disease

- Congenital heart defects unassociated with malformation syndromes (e.g., valvular
heart disease or congenital coronary artery malformations)

- Immunologic disease

- Invasive cardiothoracic procedures or major surgery during the preceding month, except
those specifically related to cardiomyopathy including left ventricular assist device
(LVAD), extracorporeal membrane oxygenator (ECMO), and automatic implantable
cardioverter defibrillator (AICD) placement

- Uremia, active or chronic

- Abnormal ventricular size or function that can be attributed to intense physical
training or chronic anemia

- Chronic arrhythmia, unless there are studies documenting inclusion criteria prior to
the onset of arrhythmia (except a patient with chronic arrhythmia, subsequently
ablated, whose cardiomyopathy persists after two months is not to be excluded)

- Malignancy

- Systemic Hypertension

- Pulmonary parenchymal or vascular disease (e.g., cystic fibrosis, cor pulmonale, or
pulmonary hypertension)

- Ischemic coronary vascular disease

- Association with drugs (e.g., growth hormone, corticosteroids, cocaine) or other
diseases known to cause hypertrophy