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NHLBI Working Group

Cardiomyopathies in Children with Rare Diseases

Executive Summary

The National Heart, Lung, and Blood Institute convened a Working Group of investigators on March 14, 2005, in Bethesda, Maryland, to advise the NHLBI and the NIH Office of Rare Diseases on new research directions needed to understand the etiology of cardiomyopathies in children with rare diseases and to improve the care of children with cardiomyopathies, particularly those resulting from rare diseases.

Discussion:

The Working Group reviewed data on the etiology and underlying mechanisms of various pediatric cardiomyopathies, the epidemiology of cardiomyopathies, and current and potential treatments for these cardiomyopathies. The results of the treatment of cardiomyopathies in children stand in stark contrast to the successes seen with the treatment of adult cardiomyopathies. Moreover, the diseases and associated consequences impose personal, medical, economic, psychological, and social burdens on the children and their families.

Data indicate that survival of childhood cardiomyopathy patients in the U.S. is bleak and does not substantially differ from that in other regions of the world. Almost 40 percent of children with symptoms of cardiomyopathy die or require cardiac transplantation, and this percentage has remained substantially unaffected by medical research. Even though the search to identify the genetic causes of structural heart disease began only ten years ago, estimates to date indicate that perhaps more than 30 percent of dilated cardiomyopathy is of genetic origin. Hypertrophic cardiomyopathy, characterized by left ventricular hypertrophy, is an autosomal dominant genetic disorder, the main pathological hallmarks of which are myocyte hypertrophy and disarray, and interstitial fibrosis. It is a disease of the cardiac sarcomere, and can result from mutations in cardiac ß-myosin heavy chain, cardiac troponin T, cardiac troponin I, and myosin binding protein C genes. Dilated cardiomyopathy, on the other hand, can result from mutations in either sarcomeric or filamentous proteins. X-linked forms of skeletal myopathy that affect young boys, such as Duchenne and Becker muscular dystrophies, Barth's syndrome, and Danon's disease, exhibit cardiac involvement in addition to other serious disease manifestations. In a few instances, such as those involving deficiencies in metabolic enzymes, specific treatments can reverse the cardiomyopathies, but this is generally not the case for most cardiomyopathies associated with these rare childhood diseases.

Although not all pediatric cardiomyopathies can be treated equally, commonalities do exist. Developing technologies for detection and diagnosis that delineate underlying genetic contributions could result in signatures for recognizing specific diseases. Phenotypic characterization may make it possible to begin clustering various cardiomyopathies for unified treatment approaches, even though some types of these diseases will require individual approaches. Understanding the molecular underpinnings of these diseases may make it possible for targeted therapies to be developed.

Recommendations:

The gaps in our knowledge, inability to screen and diagnose cardiomyopathies in children, and inadequate treatments for children with cardiomyopathies led to the following recommendations:

Convene a group to define standards of care for managing pediatric cardiomyopathies.
Establish a Task Force to identify the research priorities and scientific opportunities and barriers to address the public health problems associated with pediatric cardiomyopathies.
Develop new technologies and screening methods to delineate cardiac gene mutations that result in pediatric cardiomyopathies.
Develop new animal models for studying human genetic cardiomyopathies.
Elucidate the mechanisms involved in viral myocardial disease.
Establish an on-line health information system that could be accessed by families and health professionals to obtain current peer-reviewed information on pediatric cardiomyopathies, including screening/detection, treatment, prevention, supportive care, and clinical trials.
Initiate a clinical treatment trial of ACE inhibitors in Duchenne muscular dystrophy patients asymptomatic for cardiac dysfunction.
Stimulate research on enzyme replacement therapy in metabolic diseases affecting the heart.

Publication Plans:

The Working Group is planning to publish a formal report, which will include an overview of the field and review of the literature, as well as the Group's recommendations. The report will be posted on the NHLBI public web site with a link to the journal or journals where the report is published. Anticipated publication date is 2006.

NHLBI Contact:

John Fakunding, Ph.D., NHLBI, NIH
FakundiJ@nhlbi.nih.gov