Children's Cardiomyopathy Foundation
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RESEARCH

PROGRESS TO DATE

Pediatric cardiomyopathy is a chronic disease with no known cure or treatment to prevent or eliminate the existing disease. Unlike other congenital heart conditions, the heart cannot be "repaired" by surgery or drug therapy. In spite of its severity, there have been few medical advances in understanding the disease since it was first formally recognized in the late fifties. Up to 87% of current pediatric cardiomyopathy cases are still of unknown origin. For some diagnosed children, the cause may remain unknown even after exhaustive testing.

The slow rate of progress in understanding pediatric cardiomyopathy is primarily due to the lack of public awareness and research support. Because it is a rare heart condition, it often does not receive enough focus and funding from Federal agencies, pharmaceutical companies and medical institutions. As a result, only a handful of physicians and research scientists have the incentive to study pediatric cardiomyopathy in depth.

Most of the research done to date has been in the preliminary stages of genetic investigation, and focused on the more common form of the disease diagnosed in adults. Studies conducted primarily in Canada, Europe, Japan and the U.S. have concentrated on identifying and characterizing the genetic mutations and other abnormalities responsible for the disease. The National Heart, Lung and Blood Institute (NHLBI) has also initiated some research on the early detection of persons carrying the gene associated with cardiomyopathy.

There have been very little national investigations completed on children. Frequently and erroneously, findings from studies done on adults with cardiomyopathy are applied to children even though there are distinct differences between the two groups. Some researchers have started to explore the reasons the disease manifests and progresses so differently in children. Unfortunately, most of the recent findings have been non-conclusive on a national scale due to small sample sizes, issues with methodology or insufficient follow up. At this point, researchers who study the genes for dominant cardiomyopathies cannot find any genetic abnormalities in infants with cardiomyopathy. It is therefore unclear whether the genetic mutations found in adults with cardiomyopathy are also responsible for pediatric cardiomyopathy or whether there is a different, unidentified gene that causes the pediatric form. Because the causes of the disease remain unknown, developments in targeted and effective therapies continue to lag behind other childhood disease.

Perhaps the greatest medical advances will come from uncovering the genetic defect responsible for different forms of pediatric cardiomyopathy. This breakthrough will be a major step towards earlier, more definitive intervention and possibly even preventative measures. By understanding the underlying cause of this rare condition, the occurrence rate and mortality rate can be reduced. The ultimate goal is to create a reliable, cost effective laboratory test to diagnosis and screen children as early as possible. These assessments would be particularly useful in identifying babies and children where the disease may not be fully expressed yet. If the exact defective gene could be pinpointed, a patient could then check to see whether he/she is a carrier. Knowledge of the basic genetic defect could also help physicians to determine the prognosis of the disease and select earlier and more targeted treatments. Additionally, families with a strong history of cardiomyopathy who wish to have children could screen the fetus or consider pre-implantation genetic diagnosis with in-vitro fertilization to ensure that their offspring would be unaffected.

Clinical research conducted in the past has focused primarily on the definition of the diagnostic features and disease progression, as well as the development and application of better forms of treatments. Due to the lack of data on children with cardiomyopathy, there has been very little clinical research done on therapies for pediatric cardiomyopathy. Until the exact genetic cause can be determined, clinical research will continue to progress slowly.

Research continues to be done on identifying new genes that cause cardiomyopathy and understanding how these genetic mutations lead to heart abnormalities. Highlights of some research done to date are listed below. A more comprehensive listing of medical publications on past and current research can be found at Pub Med, a service of the National Library of Medicine. In addition, Federally funded scientific projects on pediatric cardiomyopathy are listed on the CRISP database of biomedical research funding (search terms "pediatric cardiomyopathy" with global logic "and"). Some information on clinical research done on children with cardiomyopathy can also be found on the National Institutes of Health site ClinicalTrials.gov.

Genetic Research
  • The lack of a specific protein responsible for the proper contraction of the heart muscle, called Alp, has been found to cause cardiomyopathy in mice. While this discovery is only the tip of the iceberg in genetic research, this information may be used to develop therapies that prevent cardiomyopathy from leading to congestive heart failure. (Nature Medicine, May 2001)
  • Scientists suggest that defects in specific genes could play a role in cardiomyopathy. However, each gene can have up to 200 individual mutations, making the identification of a genetic marker extremely difficulty.
    1. Actin: A type of sarcomere protein gene which is a group of genes that form the basic structure of muscle functions. Actin is believed to affect the contractions of the heart, and defects in this gene have been found to lead to HCM.
    2. Desmin: An intermediate filament between cardiac and skeletal muscle. A mutation of this gene had been linked to cases of inherited cardiomyopathy.
    3. Dystrophin: A gene that plays a role in muscle function. Defects in this gene can lead to an inability for muscle to regenerate, and have been linked to X-linked DCM, muscular dystropy and other disorders.
    4. Tafazzin: A gene involved in musculoskeletal function that causes Barth Syndrome in boys.
    5. Beta-myosin: One of a family of genes responsible for the contraction of the heart muscle cells.
    6. Troponin T: A gene responsible for creating Troponin T, a protein involved in the contraction of the heart muscle cells.
  • Some basic research has begun on the underlying genetic mechanism responsible for cardiac hypertrophy. To date, abnormalities in at least 9 related genes have been identified to cause hypertrophic cardiomyopathy. These genes are responsible for the development and contraction of heart muscle cells in units called sarcomere. The scientific terms for these genes that encode proteins of cardiac sarcomere are 1) beta-myosin heavy chain, 2) myosin-binding protein C, 3) cardiac troponin T, 4) troponin I 5) alpha-tropomyosin, 6) essential myosin light chains, 7) regulatory myosin light chains, 8) cardiac actin and 9) titin. The first three genes are the most predominate in familial hypertrophic cardiomyopathy. Other investigators are working on discovering the specific genes responsible for the clinical manifestation and outcome of the disease's varied condition among family members. (Current Cardiology Report, Mar 2000)
  • Specific gene products related to the myocyte cytoskeleton and contratile proteins have been identified to cause familial dilated cardiomyopathy. Mutations in cardiac cytoskeletal proteins, act as the cell's scaffolding and serve as transmitters allowing the force that enables the heart to pump to be sent through the cell. Mutations in the cardiac beta-myosin heavy chain and the cardiac protein troponin T genes contribute to approximately 10-15 % of inherited dilated cardiomyopathies, and are more frequently associated with sudden death. These defects in the genes that form the basic structure of muscle functions can lead to diseased muscle fibers, enlarged heart chambers and failure of the heart to pump properly. Mutations in these genes were particularly common in young patients with DCM but were not prevalent in affected infants. (New England Journal of Medicine, Dec 2000)
  • Recent research on mice suggests that the patient's immune system may be connected to the development of dilated cardiomyopathy. A specific immune system substance called PD-1 that, when lacking in the mice, led to an auto-immune response. However a second group of mice without PD-1 showed no signs of heart disease suggesting that PD-1 is only part of the puzzle, along with other genetic factors. An auto-immune response occurs when the body's immune system mistakes ones own cells as foreign and attacks them. This onslaught on the body's own cells can cause severe damage to attacked tissue. Further research into the immune responses of humans with cardiomyopathy may lead to new treatment options. (Science, Jan 2001)
  • Researchers are exploring the link between heart disease and infectious agents such as bacteria and viruses. Researchers have discovered the presence of Coxsackie B virus in heart tissue samples taken from children with DCM. Further research may result in the use of antiviral agents to combat the Coxsackie B virus as part of the treatment of acquired DCM. (American College of Cardiology, Nov 2000)
  • A new X-linked maternal gene, termed G4.5 found in cardiac and skeletal muscles, has been identified to be responsible for Barth syndrome. (National Genetics, April 1996)
  • A genetic mutation in PTPN11, a gene that encodes the protein tyrosine phosphatase (SHP-2) has been identified to account for approximately 50% of Noonan syndrome cases. The disease is believed to arise from excessive SHP-2 activity in the body. (National Genetics, Dec 2001)
Clinical Research
  • A nationwide Pediatric Cardiomyopathy Registry was started in September 1995 to describe the features and clinical course of selected cardiomyopathies in patients aged 18 years or younger. It provides a large database of socio-demographic and clinical information on children with pediatric cardiomyopathy for the medical and scientific community.
  • Some clinical study has been done on identifying factors that increase or decrease the risk of death for cardiomyopathy patients (i.e. episodes of passing out, diagnosis at young age, family history of sudden death, marked heart thickening on echocardiogram, fast heart rhythms). Discoveries in this area will help to determine the best evaluation and treatment methods.
  • Recent studies shows that there is a slight possibility that some drugs may decrease the degree of muscle thickening and more studies are being performed on the use of pacemakers to reduce the effects of "obstruction". These studies are still preliminary and further research needs to be done to determine its feasibility and effectiveness for children. Researchers continue to investigate whether drugs used to treat other conditions can be used to help treat cardiomyopathy.
  • Implantable defibrillators have been proven to be effective in preventing sudden cardiac death in patients with hypertrophic cardiomyopathy, especially those patients susceptible to arrhythmias. (New England Journal of Medicine, Feb 2000)
  • Initial clinical trials of enzyme therapy show promise for Pompe disease (glycogen storage disease type II) if started early. The treatment known as recombinant human acid alpha-glucosidase enzyme therapy (rhGAA) was found to improve cardiac and skeletal muscle functions in infants. However, further study is needed to assess the overall potential of the therapy. (Genetic Medicine, March 2001)
  • Fatty Acid oxidation disorders are increasingly being recognized as a cause for cardiomyopathy. The associated clinical issues (diagnosis, spectrum of disorder, prognosis, treatments) are also being better defined. (Current Opinion Pediatrics, Oct 2000)
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